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A phase II study of first-line biweekly capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer
Critical Reviews in Oncology/Hematology 71 (2009) 242–248
A phase II study of first-line biweekly capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer Ajithkumar Puthillath a , Terry Mashtare Jr. b , Gregory Wilding b , Nikhil Khushalani a , Lynn Steinbrenner c , Mary Ellen Ross d , Karen Romano a , Michelle Wisniewski a , Marwan G. Fakih a,∗ a
Department of Medicine at Roswell Park Cancer Institute, United States Department of Biostatistics at Roswell Park Cancer Institute, United States Department of Medicine at the Veterans Administration Hospital in Buffalo, United States d Clinical Research Services at Roswell Park Cancer Institute, United States b
c
Accepted 14 October 2008
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Treatment administration and dose modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Response evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Statistical analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Patient characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Treatment administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Purpose: This phase II study was conducted to determine the efficacy and safety of capecitabine and bevacizumab in untreated elderly metastatic colorectal cancer patients. Methods: Patients received 1500 mg/m2 /dose of capecitabine twice daily × 7 days and bevacizumab at 5 mg/kg on day 1, in 2 week-cycles. Results: The study was closed early, due to poor accrual, after a total of 16 patients enrolled. Four patients had an objective response and 11 patients had stable disease. The median time to progression and overall survival were 9.5 and 21.2 months, respectively. The most common grade ≥ 3 toxicities included diarrhea (13%) and hand and foot syndrome (25%). Three patients had an arterial thrombotic event and one patient developed a bowel perforation. ∗ Corresponding author at: Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton, Buffalo, NY 14263, United States. Tel.: +1 716 845 3362; fax: +1 716 845 3305. E-mail addresses: [email protected] (A. Puthillath), [email protected] (T. Mashtare Jr.), [email protected] (G. Wilding), [email protected] (N. Khushalani), [email protected] (L. Steinbrenner), [email protected] (M.E. Ross), [email protected] (K. Romano), [email protected] (M. Wisniewski), [email protected] (M.G. Fakih).
1040-8428/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2008.10.012
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Conclusions: In this underpowered phase II study in elderly patients with metastatic colorectal cancer, capecitabine plus bevacizumab was associated with considerable clinical activity but at an increased risk of hand and foot syndrome and arterial thrombotic events. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Metastatic colorectal cancer; Elderly; Capecitabine; Bevacizumab; Phase II
1. Introduction Colorectal cancer (CRC) is the third most prevalent and the second leading cause of cancer death in the United States. An estimated 148,810 cases of CRC are expected to occur in 2008, resulting in 49,960 deaths and accounting for almost 10% of all cancer deaths [1]. With an increasing overall life span, the incidence of CRC has been rising among the elderly with an estimated 50% or more of patients being 70 years or older [2,3]. Despite this, most CRC studies have enrolled patients with a median age of 60–65 years [4–6]. Lewis et al. found that elderly patients above 65 comprise only 25% of participants in cancer clinical trials due to strict inclusion and exclusion criteria [7]. Elderly people are often excluded from clinical trials because of presumed increased risk of treatment-related toxicities and an underestimation of the potential benefits of chemotherapy [8]. The limited representation of elderly patients, particularly those ≥70 years, in large randomized clinical trials has resulted in a lack of clear identification of an optimal regimen in this subgroup of patients [4,6,9]. Several combination chemotherapy studies have suggested an increased rate of neutropenia and grades 3–4 gastrointestinal toxicity in this population, suggesting that modified regimens may be needed [10–12]. Thus the development of novel schedules for elderly patients ≥70 years is of interest. One potentially promising approach involves the integration of the anti-angiogenesis agent bevacizumab with fluoropyrimidines. This combination has been studied in several randomized studies and has resulted in increased response rates and in improvements in time to tumor progression in metastatic CRC [13–15]. Furthermore, a combined analysis from three randomized studies of 5-fluoruracil (5-FU)/leucovorin (LV) with and without bevacizumab showed a statistically significant survival advantage of 18 months favoring the bevacizumab arm compared to 15 months for 5FU/LV alone in the firstline treatment of metastatic colorectal cancer [16]. Given the efficacy of this combination and its moderate impact on gastrointestinal and bone marrow function, 5-FU and other fluoropyrimidines–bevacizumab combinations should be investigated in elderly patients with metastatic CRC. We have investigated the combination of capecitabine and bevacizumab in metastatic CRC patients over 70 years. Capecitabine was chosen due to its convenient oral route of administration and its favorable toxicity profile compared to bolus 5-FU/LV [17,18]. A 1-week-on/1-week-off (dose-dense) capecitabine regimen was extrapolated from a biweekly capecitabine plus oxaliplatin regimen investigated by Scheithauer et al. that showed a favorable toxicity profile
in favor of the dose dense capecitabine schedule without compromising efficacy [19]. An attenuated dose of capecitabine 3000 mg/(m2 day) × 7 days every 2 weeks was used, taking into account the likely compromised renal function of elderly patients. This was given in combination with a standard dose of biweekly bevacizumab. The efficacy, tolerability, time to progression (TTP) and overall survival (OS) results of the above regimen are reported herein.
2. Patients and methods 2.1. Inclusion criteria Inclusion criteria included a diagnosis of a histologically proven metastatic CRC at an age of ≥70 years. Patients should have had measurable disease (defined as at least one lesion >20 mm with conventional CT or >10 mm with spiral CT scan), an Eastern Cooperative Oncology Group performance status (PS) of 0–2, and a life expectancy ≥3 months. Other eligibility criteria included: absolute neutrophil count (ANC) ≥1.5 × 109 L−1 , platelet count of ≥100 × 109 L−1 , serum hemoglobin concentration ≥9 g/dL, normal bilirubin, aspartate amino transferase and alanine aminotransferase ≤3 × upper normal limit, serum creatinine <1.5 × upper limit of reference range (ULRR) [If serum creatinine is >1.2 × ULRR, creatinine clearance should be >60 mL/min/1.73 m2 ], and no known hypersensitivity to fluoropyrimidines or capecitabine. Patients with central nervous system (CNS) metastases or clinically significant cardiovascular disease (previous history of myocardial infarction, uncontrolled hypertension) were excluded. Patients were also excluded if they had a major surgical procedure, an open biopsy, or a significant traumatic injury within 28 days prior to study treatment initiation. All patients provided signed informed consent before study entry. No prior chemotherapy for metastatic disease was allowed. Only prior 5-FU/LV adjuvant chemotherapy was allowed, provided it was completed more then 6 months prior to the development of metastatic disease. The study was conducted in accordance with the Good Clinical Practice Guidelines as issued by the International Conference on Harmonization and the Declaration of Helsinki and received Institutional Review Board (IRB) approval prior to its activation. 2.2. Treatment administration and dose modifications Bevacizumab was administered as an intravenous infusion at 5 mg/kg every 2 weeks. The first infusion was administered
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Table 1 Capecitabine dose modification for grade ≥ 2 toxicity (hematological and non-hematological). Toxicity NCIC grades
Grade 2
Grade 3
Grades 3–4
1st appearance
Interrupt capecitabine until resolved to grades 0–1
Interrupt capecitabine until resolved to grades 0–1. Treatment may be resumed at 75% of the original dose
Discontinue treatment permanently – unless investigators thinks it is the in the best interest of the patient to continue at 50% dose reduction
2nd appearance of same toxicity
Interrupt treatment until resolved to grades 0–1. Treatment may be resumed at 75% of original capecitabine dose Interrupt capecitabine treatment until resolved to grades 0–1 when treatment may be resumed at 50% of the original capecitabine dose Discontinue treatment permanently – unless investigators thinks it is the in the best interest of the patient to continue at 50% dose reduction
Interrupt treatment until resolved to grades 0–1. Treatment may be resumed at 50% of original capecitabine dose Discontinue treatment permanently – unless investigators thinks it is the in the best interest of the patient to continue at 50% dose reduction
3rd appearance of same toxicity
4th appearance of same toxicity
over 90 min. The second infusion was administered over 60 min and the third and subsequent infusions were administered over 30 min, granted no hypersensitivity reactions were noted at the 90 or 60 min infusions. Capecitabine was administered orally twice daily at 1500 mg/(m2 dose) for 7 days every 2 weeks. Capecitabine dose was rounded to the nearest 50 mg using a combination of capecitabine 500 and 150 mg tablets. The first dose of each capecitabine cycle was given on the morning of the scheduled bevacizumab dose. Patients were evaluated for adverse events before each cycle and toxicities were graded according to the NCI Common Toxicity Criteria (version 2.0). Dose modifications for capecitabine were indicated for grade 2 or above toxicities as detailed in Table 1. No dose reductions were allowed for bevacizumab. Patients who developed arterial thrombotic events or grade ≥ 3 bleeding were taken off the study. In the event a patient developed grade ≥ 3 proteinuria, bevacizumab was held until proteinuria improved to <2 g of protein in a 24h urine collection. Patients with uncontrolled hypertension (HTN) were discontinued from the study.
2.4. Statistical analysis This phase II study was designed to test the hypothesis that the addition of bevacizumab to capecitabine improves the time to progression from a historic upper limit of 5 months to 8 months. Thirty-nine patients were required to test this hypothesis (power = 0.8, one-sided α = 0.05). Secondary endpoints included response rate and median OS. TTP and survival were calculated using the Kaplan–Meier method. Due to slow accrual, this study was closed after 16 patients were enrolled over 2.5 years. Efficacy and toxicity analysis were reported on the treated population. TTP and survival were calculated using the Kaplan–Meier method. A onesided likelihood ratio test was used to evaluate effectiveness of the bevacizumab–capecitabine combination.
3. Results 3.1. Patient characteristics
2.3. Response evaluation Physical examination and baseline blood work for hepatic, renal, and hematological indices were obtained within 2 weeks prior to study treatment and repeated with every cycle. Radiological tumor assessments by CT scans were performed within 4 weeks prior to the initiation of treatment and repeated every 4 cycles (8 weeks) Response assessment was per the Response Evaluation Criteria in Solid Tumors (RECIST) [20]. Patients were allowed to continue to receive study treatment until disease progression or the development of unacceptable toxicities. TTP was estimated from the date of the first course of treatment to the date of the first documentation of disease progression or death. Survival was calculated from the date of the first cycle of treatment until the date of death.
Sixteen patients were enrolled between December 2004 and April 2007. Patient characteristics are summarized in Table 2. The median age was 78 years (range 73–91). Three patients received prior 5-FU-based adjuvant chemotherapy, two of whom received chemo-radiation. The distribution of ECOG performance status included 4 patients with a performance status of 2, 8 patients with performance status of 1, and 4 patients with performance status of 0. 3.2. Treatment administration The median duration of follow up of patients enrolled in the study is 28 months. In total, 309 cycles of chemotherapy were administered at the time of this analysis, with a median of 12 cycles per patient (range 3–69). Two patients received only 3 cycles, one discontinuing chemotherapy secondary to
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Table 2 Patients characteristics. Characteristics
No. of patients
Number of patients Median age, range
16 78 (73–91)
Sex Male Female
5 (31%) 11 (69%)
Primary tumor site Colon Rectum Previous adjuvant chemotherapy
12 (75%) 4 (25%) 3 (19%)
ECOG PS 0 1 2
4 (25%) 8 (50%) 4 (25%)
Metastatic sites ≤2 >2
8 (50%) 8 (50%)
Fig. 1. Time to progression curve.
early progression of disease while the second patient discontinued due to bevacizumab toxicity (perforation). Treatment delays were infrequent and caused by hand foot syndrome and diarrhea. The median dose intensity of capecitabine was 1150 mg/m2 per cycle (range: 750–1500 mg/m2 ). All patients who progressed on study received second line chemotherapy, predominantly oxaliplatin-based. Eight patients received third-line chemotherapy. 3.3. Efficacy All 16 patients were evaluable for response. Four patients (25%) had an objective response and 11 (69%) had stable disease (Table 3). There was one complete response. At the time of this report, 13 (81%) patients had progressed and 10 (62%) died. The median TTP was 9.5 months with a 95% confidence interval of 6.1–18.0 months (Fig. 1). The TTP on bevacizumab plus capecitabine was superior to historic controls of capecitabine alone of 5 months (p = 0.0024). The median overall survival was estimated to be 21.2 months with a 95% confidence interval of 14.4 months to 30.9 months (Fig. 2). 3.4. Toxicity
Fig. 2. Overall survival curve.
capecitabine-related adverse events were diarrhea and hand and foot syndrome. One patient was taken off study due to recurrent grade 3 hand and foot syndrome despite a 50% dose reduction in capecitabine. There was no grade ≥ 2 neutropenia observed. Treatment-related anemia and thrombocytopenia were limited to grade 1. The most frequent adverse event encountered on bevacizumab was hypertension with 6 (38%) patients having grades 2–3 hypertension. Arterial thrombotic events (ATEs) Table 4 Toxicity data with the exception of ATEa and perforationa .
Toxicity data for the 16 patients enrolled on study are summarized in Table 4. No deaths secondary to treatment toxicity were observed. The predominant grade 2 or greater Table 3 Response evaluation. Response
No of patients
Complete response Partial response Stable disease Progressive disease
1 (6%) 3 (19%) 11 (69%) 1 (6%)
Toxicity
G2
G3
All cycle toxicities ≥grade 2, N = 16 Diarrhea Mucositis Nausea Vomiting H and F syndrome HTN
4 (25%) 2 (13%) 4 (25%) 3 (19%) 8 (50%) 4 (25%)
2 (13%) 1 (6%) 0 1 (6%) 4 (25%) 2 (13%)
a Three patients experiences arterial thrombotic events (ATE): 1 CVA, 1 ischemic bowel and 1 right iliac artery thrombus. One patient also had a perforated sigmoid diverticulum. No G2 or above neutropenia or thrombocytopenia was noted on study.
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attributed to bevacizumab occurred in three patients and resulted in treatment discontinuation. One patient was a 91year male with chronic atrial fibrillation who did not comply well with warfarin treatment while on study. He developed a thrombo-embolic ischemic bowel after four cycles of chemotherapy but recovered well with conservative management. The second patient was a 75-year-old female who had an ischemic cerebro-vascular event with left sided hemi paresis that completely resolved within 48 h. The third patient was a 75-year female who was diagnosed with an asymptomatic thrombus in the right common iliac artery on staging CT scans after 16 cycles of bevacizumab and capecitabine. Bowel perforation occurred in one patient on study. This patient was an 80-year-old female with prior neoadjuvant chemoradiation to a rectal tumor who had received three cycles of treatment on study. This perforation was associated with a sigmoid colonic diverticulum at the time of surgical exploration. She required an end-colostomy and recovered well-post-surgery.
4. Discussion The treatment of elderly patients with metastatic CRC requires a delicate balance between chemotherapy toxicity and efficacy. Most elderly patients are willing to receive chemotherapy if there is a reasonable hope of benefit, provided that they perceive the treatment to be tolerable [21–23]. The aim of this study was to assess if a combination regimen of first-line capecitabine and bevacizumab could be feasible and effective in elderly patients with metastatic CRC. We show that the combination of capecitabine given in a 1week-on, 1-week-off regimen with bevacizumab was well tolerated except for Hand and Foot syndrome and risk of arterial thrombosis. No unexpected adverse event or toxic deaths occurred. Gastrointestinal toxicity was manageable with grade 3 diarrhea seen in 2/16 (13%) patients and compared favorably with other single agent capecitabine studies [24,25]. However, this combination was associated with an increased rate of grade 3 Hand and Foot syndrome which was seen in 4/16 (25%) patients. This doubling of the incidence of grade 3 Hand and Foot syndrome in our study compared to historic controls could be explained by the demographics of our population and by capecitabine scheduling. Prior capecitabine studies have shown that systemic exposure to capecitabine was about 25% greater in patients with moderate and severe renal impairment [26,27]. It is likely that the creatinine clearance in our population was compromised despite the normal serum creatinine mandated for study inclusion. A post hoc measurement of our study patients’ creatinine clearance as calculated by the Cockcroft-Gault formula showed a median value of 61 mL/min (range 40–80). The four patients who developed grade 3 Hand and Foot syndrome on this study had a median creatinine clearance of 48 mL/min (range: 40–57 mL/min) despite having a normal measured serum creatinine. This compared to a median of 68 mL/min for patients with ≤grade 1 Hand and Foot syndrome. It is also possible
that the dose-dense schedule may have also contributed to the increased rate of Hand and Foot syndrome. Another possibility for the increased Hand and Foot syndrome may be related to the conduct of our study in a US population. The risk of capecitabine-induced toxicities in North America has clearly exceeded that of Europe. This has been partly linked to a higher dietary supplementation of folic acid in North America [28]. Lastly, it is possible that the increased risk of Hand and Foot syndrome in our study is due to the improvement in TTP. Since this toxicity is in part cumulative, it would be expected to be more common in capecitabine-containing regimens with a median TTP exceeding 9 months in comparison with historic monotherapy controls where the median TTP is around 4–5 months [17,24]. Hypertension was the most frequent adverse event with grade ≥ 2 hypertension being observed in 38% of patients. This was easily managed with dose modification/addition of anti-hypertensive medications. Arterial thrombotic events (ATEs) were seen in 3 (19%) patients, all of whom were taken off study. This higher incidence of ATE is likely an aberrant finding due to our small patient population. A recent analysis of the BRiTE registry revealed that the incidence of ATE among patients ≥75 and ≥80% was 3.9% and 3.7%, respectively [29]. Multivariate analysis identified poor ECOG performance status and prior history of ATE as risk factors predictive of thrombotic events. Age by itself was not a contradiction for the use of bevacizumab. One (6%) patient with diverticulosis and an unresected rectal primary developed a bowel perforation on our study. Bowel perforation is a known side effect of bevacizumab and is estimated at 1–2% in the bevacizumab-treated patients. Both diverticulosis and unresected colorectal primaries have been established as risk factors for this complication [30,31]. Due to our small sample size, it would be impossible to determine at this point if an elderly capecitabine–bevacizumab treated population would be at increased risk of perforation. This is unlikely given the recent data from the BRiTE registry that showed no difference in the rate of GI perforation in the elderly (≥65 years) when compared to the general treated population [29]. The efficacy results on our study are encouraging. Median TTP and OS were 9.5 and 21.2 months, respectively. This is in line with other frontline combination chemotherapy regimens considered as standard in the non-elderly population [4,9,32]. Our TTP and RR results are also inline with combination chemotherapy studies in metastatic CRC patients ≥70 years [33–37]. However, the OS in our study is superior than most other elderly studies and could be attributed to the low proportion of elderly patients receiving second line treatments on other studies [38]. In our study more than 90% of the patients went on to receive second line chemotherapy. We cannot rule out, however, that some of the favorable efficacy results seen in our study could be due to chance, especially with an underpowered sample size of 16 patients. Of interest, a recent study evaluated the combination of capecitabine (1250 mg/m2 bid, 14 days of every 3-week
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cycle) with bevacizumab (7.5 mg/kg iv every 3 weeks) in 40 patients ≥70 years. The TTP data appear to mirror our study although survival data are still not mature [37]. In conclusion, the efficacy and convenience of the dosedense capecitabine and bevacizumab make this regimen a good alternative in patients older than 70 and without significant risk factors for thrombo-embolism. The risk of Hand and Foot syndrome of this regimen could be reduced by considering a lower starting dose of capecitabine or by ensuring strict guidelines for patients with impaired creatinine clearance despite a normal serum creatinine. However, our study is limited by its small patient population and does require further validation, preferably in a multicenter or co-operative group setting.
Reviewers Gurkamal Chatta, M.D. Associate Professor, University of Pittsburgh, Division of Hematology/Oncology, 5150 Centre Avenue, Rm 564, UPMC Cancer Pavilion, Pittsburgh, PA 15232, United States. Basil F. El-Rayes, M.D. Karmanos Cancer Institute, Wayne State University, Division of Hematology and Oncology, Detroit, MI 48201, United States. Gunnar Folprecht, M.D., Carl Gustav Carus University Hospital of Dresden, Department of Hematology and Oncology, Fetscherstrasse 74, D-01307 Dresden, Germany. Nasfat J. Shehadeh, M.D., Utah Cancer Speclsts, Salt Lake Clinic, 333 S 900 East Salt Lake City, UT 84102, United States.
Conflict of interest statement There are no conflicts of interest pertinent to this study to be reported.
Acknowledgements This study was supported in part by a Grant Support from Genentech Pharmaceutical and by a Mentored Scholar Award Grant from the American Cancer Society to Marwan G. Fakih.
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[22] Extermann M, Balducci L. Optimizing cancer care in the elderly: progress in geriatric oncology. Cancer Control 2003;10(6):440–1. [23] Extermann M, Albrand G, Chen H, et al. Are older French patients as willing as older American patients to undertake chemotherapy? J Clin Oncol 2003;21(17):3214–9. [24] Van Cutsem E, Hoff PM, Harper P, et al. Oral capecitabine vs. intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Brit J Cancer 2004;90(6):1190–7. [25] Feliu J, Escudero P, Llosa F, et al. Capecitabine as first-line treatment for patients older than 70 years with metastatic colorectal cancer: an oncopaz cooperative group study. J Clin Oncol 2005;23(13):3104–11. [26] Poole C, Gardiner J, Twelves C, et al. Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients. Cancer Chemother Pharmacol 2002;49(3):225–34. [27] Bajetta E, Procopio G, Celio L, et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005;23(10):2155–61. [28] Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol 2008;26(13):2118–23. [29] Kozloff M, Berlin MSJ. Safety and effectiveness of bevacizumab (BV) and chemotherapy (CT) in elderly patients (pts) with metastatic colorectal cancer (mCRC): results from the BRiTE Prospective Cohort Study. In: Gastrointestinal Cancers Symposium 2008. 2008. [30] Saif MW, Mehra R. Incidence and management of bevacizumab-related toxicities in colorectal cancer. Expert Opin Drug Saf 2006;5(4):553–66. [31] Badgwell BD, Camp ER, Feig B, et al. Management of bevacizumabassociated bowel perforation: a case series and review of the literature. Ann Oncol 2008;19(3):577–82. [32] Ducreux M, Bennouna J, Hebbar M, et al. Efficacy and safety findings from a randomized phase III study of capecitabine (X) + oxaliplatin (O) (XELOX) vs. infusional 5- FU/LV + O (FOLFOX-6) for metastatic colorectal cancer (MCRC). J Clin Oncol 2007;25(18 suppl.):4029 (Meeting Abstracts). [33] Sastre J, Marcuello E, Masutti B, et al. Irinotecan in combination with fluorouracil in a 48-hour continuous infusion as first-line chemotherapy
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Biography Dr. Marwan Fakih is an Associate Professor of Oncology at Roswell Park Cancer Institute where he leads the Section of Gastrointestinal Medical Oncology. Dr. Fakih’s research interests include novel therapeutics in the first, second, and refractory treatment of metastatic colorectal cancer. His other research interests include the development of novel neoadjuvant therapies for rectal cancer, treatment of elderly colorectal cancer patients, and novel prevention strategies for colorectal cancer.
A phase II study of first-line biweekly capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer Ajithkumar Puthillath a , Terry Mashtare Jr. b , Gregory Wilding b , Nikhil Khushalani a , Lynn Steinbrenner c , Mary Ellen Ross d , Karen Romano a , Michelle Wisniewski a , Marwan G. Fakih a,∗ a
Department of Medicine at Roswell Park Cancer Institute, United States Department of Biostatistics at Roswell Park Cancer Institute, United States Department of Medicine at the Veterans Administration Hospital in Buffalo, United States d Clinical Research Services at Roswell Park Cancer Institute, United States b
c
Accepted 14 October 2008
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Treatment administration and dose modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Response evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Statistical analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Patient characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Treatment administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Purpose: This phase II study was conducted to determine the efficacy and safety of capecitabine and bevacizumab in untreated elderly metastatic colorectal cancer patients. Methods: Patients received 1500 mg/m2 /dose of capecitabine twice daily × 7 days and bevacizumab at 5 mg/kg on day 1, in 2 week-cycles. Results: The study was closed early, due to poor accrual, after a total of 16 patients enrolled. Four patients had an objective response and 11 patients had stable disease. The median time to progression and overall survival were 9.5 and 21.2 months, respectively. The most common grade ≥ 3 toxicities included diarrhea (13%) and hand and foot syndrome (25%). Three patients had an arterial thrombotic event and one patient developed a bowel perforation. ∗ Corresponding author at: Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton, Buffalo, NY 14263, United States. Tel.: +1 716 845 3362; fax: +1 716 845 3305. E-mail addresses: [email protected] (A. Puthillath), [email protected] (T. Mashtare Jr.), [email protected] (G. Wilding), [email protected] (N. Khushalani), [email protected] (L. Steinbrenner), [email protected] (M.E. Ross), [email protected] (K. Romano), [email protected] (M. Wisniewski), [email protected] (M.G. Fakih).
1040-8428/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2008.10.012
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Conclusions: In this underpowered phase II study in elderly patients with metastatic colorectal cancer, capecitabine plus bevacizumab was associated with considerable clinical activity but at an increased risk of hand and foot syndrome and arterial thrombotic events. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Metastatic colorectal cancer; Elderly; Capecitabine; Bevacizumab; Phase II
1. Introduction Colorectal cancer (CRC) is the third most prevalent and the second leading cause of cancer death in the United States. An estimated 148,810 cases of CRC are expected to occur in 2008, resulting in 49,960 deaths and accounting for almost 10% of all cancer deaths [1]. With an increasing overall life span, the incidence of CRC has been rising among the elderly with an estimated 50% or more of patients being 70 years or older [2,3]. Despite this, most CRC studies have enrolled patients with a median age of 60–65 years [4–6]. Lewis et al. found that elderly patients above 65 comprise only 25% of participants in cancer clinical trials due to strict inclusion and exclusion criteria [7]. Elderly people are often excluded from clinical trials because of presumed increased risk of treatment-related toxicities and an underestimation of the potential benefits of chemotherapy [8]. The limited representation of elderly patients, particularly those ≥70 years, in large randomized clinical trials has resulted in a lack of clear identification of an optimal regimen in this subgroup of patients [4,6,9]. Several combination chemotherapy studies have suggested an increased rate of neutropenia and grades 3–4 gastrointestinal toxicity in this population, suggesting that modified regimens may be needed [10–12]. Thus the development of novel schedules for elderly patients ≥70 years is of interest. One potentially promising approach involves the integration of the anti-angiogenesis agent bevacizumab with fluoropyrimidines. This combination has been studied in several randomized studies and has resulted in increased response rates and in improvements in time to tumor progression in metastatic CRC [13–15]. Furthermore, a combined analysis from three randomized studies of 5-fluoruracil (5-FU)/leucovorin (LV) with and without bevacizumab showed a statistically significant survival advantage of 18 months favoring the bevacizumab arm compared to 15 months for 5FU/LV alone in the firstline treatment of metastatic colorectal cancer [16]. Given the efficacy of this combination and its moderate impact on gastrointestinal and bone marrow function, 5-FU and other fluoropyrimidines–bevacizumab combinations should be investigated in elderly patients with metastatic CRC. We have investigated the combination of capecitabine and bevacizumab in metastatic CRC patients over 70 years. Capecitabine was chosen due to its convenient oral route of administration and its favorable toxicity profile compared to bolus 5-FU/LV [17,18]. A 1-week-on/1-week-off (dose-dense) capecitabine regimen was extrapolated from a biweekly capecitabine plus oxaliplatin regimen investigated by Scheithauer et al. that showed a favorable toxicity profile
in favor of the dose dense capecitabine schedule without compromising efficacy [19]. An attenuated dose of capecitabine 3000 mg/(m2 day) × 7 days every 2 weeks was used, taking into account the likely compromised renal function of elderly patients. This was given in combination with a standard dose of biweekly bevacizumab. The efficacy, tolerability, time to progression (TTP) and overall survival (OS) results of the above regimen are reported herein.
2. Patients and methods 2.1. Inclusion criteria Inclusion criteria included a diagnosis of a histologically proven metastatic CRC at an age of ≥70 years. Patients should have had measurable disease (defined as at least one lesion >20 mm with conventional CT or >10 mm with spiral CT scan), an Eastern Cooperative Oncology Group performance status (PS) of 0–2, and a life expectancy ≥3 months. Other eligibility criteria included: absolute neutrophil count (ANC) ≥1.5 × 109 L−1 , platelet count of ≥100 × 109 L−1 , serum hemoglobin concentration ≥9 g/dL, normal bilirubin, aspartate amino transferase and alanine aminotransferase ≤3 × upper normal limit, serum creatinine <1.5 × upper limit of reference range (ULRR) [If serum creatinine is >1.2 × ULRR, creatinine clearance should be >60 mL/min/1.73 m2 ], and no known hypersensitivity to fluoropyrimidines or capecitabine. Patients with central nervous system (CNS) metastases or clinically significant cardiovascular disease (previous history of myocardial infarction, uncontrolled hypertension) were excluded. Patients were also excluded if they had a major surgical procedure, an open biopsy, or a significant traumatic injury within 28 days prior to study treatment initiation. All patients provided signed informed consent before study entry. No prior chemotherapy for metastatic disease was allowed. Only prior 5-FU/LV adjuvant chemotherapy was allowed, provided it was completed more then 6 months prior to the development of metastatic disease. The study was conducted in accordance with the Good Clinical Practice Guidelines as issued by the International Conference on Harmonization and the Declaration of Helsinki and received Institutional Review Board (IRB) approval prior to its activation. 2.2. Treatment administration and dose modifications Bevacizumab was administered as an intravenous infusion at 5 mg/kg every 2 weeks. The first infusion was administered
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Table 1 Capecitabine dose modification for grade ≥ 2 toxicity (hematological and non-hematological). Toxicity NCIC grades
Grade 2
Grade 3
Grades 3–4
1st appearance
Interrupt capecitabine until resolved to grades 0–1
Interrupt capecitabine until resolved to grades 0–1. Treatment may be resumed at 75% of the original dose
Discontinue treatment permanently – unless investigators thinks it is the in the best interest of the patient to continue at 50% dose reduction
2nd appearance of same toxicity
Interrupt treatment until resolved to grades 0–1. Treatment may be resumed at 75% of original capecitabine dose Interrupt capecitabine treatment until resolved to grades 0–1 when treatment may be resumed at 50% of the original capecitabine dose Discontinue treatment permanently – unless investigators thinks it is the in the best interest of the patient to continue at 50% dose reduction
Interrupt treatment until resolved to grades 0–1. Treatment may be resumed at 50% of original capecitabine dose Discontinue treatment permanently – unless investigators thinks it is the in the best interest of the patient to continue at 50% dose reduction
3rd appearance of same toxicity
4th appearance of same toxicity
over 90 min. The second infusion was administered over 60 min and the third and subsequent infusions were administered over 30 min, granted no hypersensitivity reactions were noted at the 90 or 60 min infusions. Capecitabine was administered orally twice daily at 1500 mg/(m2 dose) for 7 days every 2 weeks. Capecitabine dose was rounded to the nearest 50 mg using a combination of capecitabine 500 and 150 mg tablets. The first dose of each capecitabine cycle was given on the morning of the scheduled bevacizumab dose. Patients were evaluated for adverse events before each cycle and toxicities were graded according to the NCI Common Toxicity Criteria (version 2.0). Dose modifications for capecitabine were indicated for grade 2 or above toxicities as detailed in Table 1. No dose reductions were allowed for bevacizumab. Patients who developed arterial thrombotic events or grade ≥ 3 bleeding were taken off the study. In the event a patient developed grade ≥ 3 proteinuria, bevacizumab was held until proteinuria improved to <2 g of protein in a 24h urine collection. Patients with uncontrolled hypertension (HTN) were discontinued from the study.
2.4. Statistical analysis This phase II study was designed to test the hypothesis that the addition of bevacizumab to capecitabine improves the time to progression from a historic upper limit of 5 months to 8 months. Thirty-nine patients were required to test this hypothesis (power = 0.8, one-sided α = 0.05). Secondary endpoints included response rate and median OS. TTP and survival were calculated using the Kaplan–Meier method. Due to slow accrual, this study was closed after 16 patients were enrolled over 2.5 years. Efficacy and toxicity analysis were reported on the treated population. TTP and survival were calculated using the Kaplan–Meier method. A onesided likelihood ratio test was used to evaluate effectiveness of the bevacizumab–capecitabine combination.
3. Results 3.1. Patient characteristics
2.3. Response evaluation Physical examination and baseline blood work for hepatic, renal, and hematological indices were obtained within 2 weeks prior to study treatment and repeated with every cycle. Radiological tumor assessments by CT scans were performed within 4 weeks prior to the initiation of treatment and repeated every 4 cycles (8 weeks) Response assessment was per the Response Evaluation Criteria in Solid Tumors (RECIST) [20]. Patients were allowed to continue to receive study treatment until disease progression or the development of unacceptable toxicities. TTP was estimated from the date of the first course of treatment to the date of the first documentation of disease progression or death. Survival was calculated from the date of the first cycle of treatment until the date of death.
Sixteen patients were enrolled between December 2004 and April 2007. Patient characteristics are summarized in Table 2. The median age was 78 years (range 73–91). Three patients received prior 5-FU-based adjuvant chemotherapy, two of whom received chemo-radiation. The distribution of ECOG performance status included 4 patients with a performance status of 2, 8 patients with performance status of 1, and 4 patients with performance status of 0. 3.2. Treatment administration The median duration of follow up of patients enrolled in the study is 28 months. In total, 309 cycles of chemotherapy were administered at the time of this analysis, with a median of 12 cycles per patient (range 3–69). Two patients received only 3 cycles, one discontinuing chemotherapy secondary to
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Table 2 Patients characteristics. Characteristics
No. of patients
Number of patients Median age, range
16 78 (73–91)
Sex Male Female
5 (31%) 11 (69%)
Primary tumor site Colon Rectum Previous adjuvant chemotherapy
12 (75%) 4 (25%) 3 (19%)
ECOG PS 0 1 2
4 (25%) 8 (50%) 4 (25%)
Metastatic sites ≤2 >2
8 (50%) 8 (50%)
Fig. 1. Time to progression curve.
early progression of disease while the second patient discontinued due to bevacizumab toxicity (perforation). Treatment delays were infrequent and caused by hand foot syndrome and diarrhea. The median dose intensity of capecitabine was 1150 mg/m2 per cycle (range: 750–1500 mg/m2 ). All patients who progressed on study received second line chemotherapy, predominantly oxaliplatin-based. Eight patients received third-line chemotherapy. 3.3. Efficacy All 16 patients were evaluable for response. Four patients (25%) had an objective response and 11 (69%) had stable disease (Table 3). There was one complete response. At the time of this report, 13 (81%) patients had progressed and 10 (62%) died. The median TTP was 9.5 months with a 95% confidence interval of 6.1–18.0 months (Fig. 1). The TTP on bevacizumab plus capecitabine was superior to historic controls of capecitabine alone of 5 months (p = 0.0024). The median overall survival was estimated to be 21.2 months with a 95% confidence interval of 14.4 months to 30.9 months (Fig. 2). 3.4. Toxicity
Fig. 2. Overall survival curve.
capecitabine-related adverse events were diarrhea and hand and foot syndrome. One patient was taken off study due to recurrent grade 3 hand and foot syndrome despite a 50% dose reduction in capecitabine. There was no grade ≥ 2 neutropenia observed. Treatment-related anemia and thrombocytopenia were limited to grade 1. The most frequent adverse event encountered on bevacizumab was hypertension with 6 (38%) patients having grades 2–3 hypertension. Arterial thrombotic events (ATEs) Table 4 Toxicity data with the exception of ATEa and perforationa .
Toxicity data for the 16 patients enrolled on study are summarized in Table 4. No deaths secondary to treatment toxicity were observed. The predominant grade 2 or greater Table 3 Response evaluation. Response
No of patients
Complete response Partial response Stable disease Progressive disease
1 (6%) 3 (19%) 11 (69%) 1 (6%)
Toxicity
G2
G3
All cycle toxicities ≥grade 2, N = 16 Diarrhea Mucositis Nausea Vomiting H and F syndrome HTN
4 (25%) 2 (13%) 4 (25%) 3 (19%) 8 (50%) 4 (25%)
2 (13%) 1 (6%) 0 1 (6%) 4 (25%) 2 (13%)
a Three patients experiences arterial thrombotic events (ATE): 1 CVA, 1 ischemic bowel and 1 right iliac artery thrombus. One patient also had a perforated sigmoid diverticulum. No G2 or above neutropenia or thrombocytopenia was noted on study.
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attributed to bevacizumab occurred in three patients and resulted in treatment discontinuation. One patient was a 91year male with chronic atrial fibrillation who did not comply well with warfarin treatment while on study. He developed a thrombo-embolic ischemic bowel after four cycles of chemotherapy but recovered well with conservative management. The second patient was a 75-year-old female who had an ischemic cerebro-vascular event with left sided hemi paresis that completely resolved within 48 h. The third patient was a 75-year female who was diagnosed with an asymptomatic thrombus in the right common iliac artery on staging CT scans after 16 cycles of bevacizumab and capecitabine. Bowel perforation occurred in one patient on study. This patient was an 80-year-old female with prior neoadjuvant chemoradiation to a rectal tumor who had received three cycles of treatment on study. This perforation was associated with a sigmoid colonic diverticulum at the time of surgical exploration. She required an end-colostomy and recovered well-post-surgery.
4. Discussion The treatment of elderly patients with metastatic CRC requires a delicate balance between chemotherapy toxicity and efficacy. Most elderly patients are willing to receive chemotherapy if there is a reasonable hope of benefit, provided that they perceive the treatment to be tolerable [21–23]. The aim of this study was to assess if a combination regimen of first-line capecitabine and bevacizumab could be feasible and effective in elderly patients with metastatic CRC. We show that the combination of capecitabine given in a 1week-on, 1-week-off regimen with bevacizumab was well tolerated except for Hand and Foot syndrome and risk of arterial thrombosis. No unexpected adverse event or toxic deaths occurred. Gastrointestinal toxicity was manageable with grade 3 diarrhea seen in 2/16 (13%) patients and compared favorably with other single agent capecitabine studies [24,25]. However, this combination was associated with an increased rate of grade 3 Hand and Foot syndrome which was seen in 4/16 (25%) patients. This doubling of the incidence of grade 3 Hand and Foot syndrome in our study compared to historic controls could be explained by the demographics of our population and by capecitabine scheduling. Prior capecitabine studies have shown that systemic exposure to capecitabine was about 25% greater in patients with moderate and severe renal impairment [26,27]. It is likely that the creatinine clearance in our population was compromised despite the normal serum creatinine mandated for study inclusion. A post hoc measurement of our study patients’ creatinine clearance as calculated by the Cockcroft-Gault formula showed a median value of 61 mL/min (range 40–80). The four patients who developed grade 3 Hand and Foot syndrome on this study had a median creatinine clearance of 48 mL/min (range: 40–57 mL/min) despite having a normal measured serum creatinine. This compared to a median of 68 mL/min for patients with ≤grade 1 Hand and Foot syndrome. It is also possible
that the dose-dense schedule may have also contributed to the increased rate of Hand and Foot syndrome. Another possibility for the increased Hand and Foot syndrome may be related to the conduct of our study in a US population. The risk of capecitabine-induced toxicities in North America has clearly exceeded that of Europe. This has been partly linked to a higher dietary supplementation of folic acid in North America [28]. Lastly, it is possible that the increased risk of Hand and Foot syndrome in our study is due to the improvement in TTP. Since this toxicity is in part cumulative, it would be expected to be more common in capecitabine-containing regimens with a median TTP exceeding 9 months in comparison with historic monotherapy controls where the median TTP is around 4–5 months [17,24]. Hypertension was the most frequent adverse event with grade ≥ 2 hypertension being observed in 38% of patients. This was easily managed with dose modification/addition of anti-hypertensive medications. Arterial thrombotic events (ATEs) were seen in 3 (19%) patients, all of whom were taken off study. This higher incidence of ATE is likely an aberrant finding due to our small patient population. A recent analysis of the BRiTE registry revealed that the incidence of ATE among patients ≥75 and ≥80% was 3.9% and 3.7%, respectively [29]. Multivariate analysis identified poor ECOG performance status and prior history of ATE as risk factors predictive of thrombotic events. Age by itself was not a contradiction for the use of bevacizumab. One (6%) patient with diverticulosis and an unresected rectal primary developed a bowel perforation on our study. Bowel perforation is a known side effect of bevacizumab and is estimated at 1–2% in the bevacizumab-treated patients. Both diverticulosis and unresected colorectal primaries have been established as risk factors for this complication [30,31]. Due to our small sample size, it would be impossible to determine at this point if an elderly capecitabine–bevacizumab treated population would be at increased risk of perforation. This is unlikely given the recent data from the BRiTE registry that showed no difference in the rate of GI perforation in the elderly (≥65 years) when compared to the general treated population [29]. The efficacy results on our study are encouraging. Median TTP and OS were 9.5 and 21.2 months, respectively. This is in line with other frontline combination chemotherapy regimens considered as standard in the non-elderly population [4,9,32]. Our TTP and RR results are also inline with combination chemotherapy studies in metastatic CRC patients ≥70 years [33–37]. However, the OS in our study is superior than most other elderly studies and could be attributed to the low proportion of elderly patients receiving second line treatments on other studies [38]. In our study more than 90% of the patients went on to receive second line chemotherapy. We cannot rule out, however, that some of the favorable efficacy results seen in our study could be due to chance, especially with an underpowered sample size of 16 patients. Of interest, a recent study evaluated the combination of capecitabine (1250 mg/m2 bid, 14 days of every 3-week
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cycle) with bevacizumab (7.5 mg/kg iv every 3 weeks) in 40 patients ≥70 years. The TTP data appear to mirror our study although survival data are still not mature [37]. In conclusion, the efficacy and convenience of the dosedense capecitabine and bevacizumab make this regimen a good alternative in patients older than 70 and without significant risk factors for thrombo-embolism. The risk of Hand and Foot syndrome of this regimen could be reduced by considering a lower starting dose of capecitabine or by ensuring strict guidelines for patients with impaired creatinine clearance despite a normal serum creatinine. However, our study is limited by its small patient population and does require further validation, preferably in a multicenter or co-operative group setting.
Reviewers Gurkamal Chatta, M.D. Associate Professor, University of Pittsburgh, Division of Hematology/Oncology, 5150 Centre Avenue, Rm 564, UPMC Cancer Pavilion, Pittsburgh, PA 15232, United States. Basil F. El-Rayes, M.D. Karmanos Cancer Institute, Wayne State University, Division of Hematology and Oncology, Detroit, MI 48201, United States. Gunnar Folprecht, M.D., Carl Gustav Carus University Hospital of Dresden, Department of Hematology and Oncology, Fetscherstrasse 74, D-01307 Dresden, Germany. Nasfat J. Shehadeh, M.D., Utah Cancer Speclsts, Salt Lake Clinic, 333 S 900 East Salt Lake City, UT 84102, United States.
Conflict of interest statement There are no conflicts of interest pertinent to this study to be reported.
Acknowledgements This study was supported in part by a Grant Support from Genentech Pharmaceutical and by a Mentored Scholar Award Grant from the American Cancer Society to Marwan G. Fakih.
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Biography Dr. Marwan Fakih is an Associate Professor of Oncology at Roswell Park Cancer Institute where he leads the Section of Gastrointestinal Medical Oncology. Dr. Fakih’s research interests include novel therapeutics in the first, second, and refractory treatment of metastatic colorectal cancer. His other research interests include the development of novel neoadjuvant therapies for rectal cancer, treatment of elderly colorectal cancer patients, and novel prevention strategies for colorectal cancer.