XELOX and bevacizumab followed by single-agent bevacizumab as maintenance therapy as first-line treatment in elderly patients with advanced colorectal cancer: the boxe study

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Cancer Chemotherapy andPharmacology ISSN 0344-5704 Cancer Chemother PharmacolDOI 10.1007/s00280-012-2004-x

XELOX and bevacizumab followed bysingle-agent bevacizumab as maintenancetherapy as first-line treatment in elderlypatients with advanced colorectal cancer:the boxe studyGerardo Rosati, Antonio Avallone,Giuseppe Aprile, Alfredo Butera,Giorgio Reggiardo & Domenico Bilancia

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ORIGINAL ARTICLE

XELOX and bevacizumab followed by single-agent bevacizumabas maintenance therapy as first-line treatment in elderly patientswith advanced colorectal cancer: the boxe study

Gerardo Rosati • Antonio Avallone •

Giuseppe Aprile • Alfredo Butera •

Giorgio Reggiardo • Domenico Bilancia

Received: 28 July 2012 / Accepted: 10 October 2012

� Springer-Verlag Berlin Heidelberg 2012

Abstract

Purpose The addition of bevacizumab to oxaliplatin-

based chemotherapy significantly improved progression-

free survival (PFS) in patients with metastatic colorectal

cancer (CRC). An increased risk of arterial thromboem-

bolic events has been observed in some trials in older

patients, and the potential benefit of a maintenance therapy

with bevacizumab alone has not been clearly demonstrated.

This phase II study was designed to evaluate the efficacy

and safety of XELOX (capecitabine plus oxaliplatin) plus

bevacizumab followed by bevacizumab alone in elderly

patients with advanced CRC.

Methods Treatment consisted of bevacizumab 7.5 mg/kg

and oxaliplatin 130 mg/m2 on day 1, plus capecitabine

1,000 mg/m2 twice daily on days 1–14, every 3 weeks up to

a maximum of 8 cycles. Patients then received maintenance

therapy consisting of bevacizumab alone (7.5 mg/kg) once

every 3 weeks up to disease progression. The primary study

end-points were safety and response rate.

Results A total of 44 patients were recruited. In an

intention-to-treat analysis, the overall response rate was

52 % [95 % confidence interval (CI) 37 to 68 %], with

86 % of patients achieving disease control. Median PFS and

overall survival were 11.5 months (95 % CI 10.0–12.9

months) and 19.3 months (95 % CI 16.5–22.1 months),

respectively. In all, 10 patients (23 %) had grade 3/4

adverse events (AEs), the most common being diarrhea

(9 %), neutropenia (7 %), peripheral neuropathy (7 %), and

stomatitis (7 %). No patients died because of treatment-

related AEs. The rate of bevacizumab-related AEs (hyper-

tension, thromboembolic events, and gastrointestinal

perforation) was consistent with that reported earlier in the

general CRC population.

Conclusion The combination of XELOX and bev-

acizumab is effective and has a manageable tolerability

profile when administered to elderly patients with advanced

CRC. Maintenance therapy with single-agent bevacizu-

mab may be considered to extend PFS in this setting of

patients.

Keywords Bevacizumab � Colorectal cancer � Elderly

patients � Maintenance therapy � XELOX

Introduction

The annual incidence rates of colorectal cancer (CRC)

increase considerably with age, and over 70 % of the newly

diagnosed patients are older than 65 years, with a median

age of 71 years. Nevertheless, the number of elderly

patients included in clinical trials remains limited [1, 2].

The restriction in the functional reserve of various organ

G. Rosati (&) � D. Bilancia

Medical Oncology Unit, S. Carlo Hospital,

Via Potito Petrone, 1, 85100 Potenza, Italy

e-mail: [email protected]

A. Avallone

Department of Gastrointestinal Medical Oncology,

National Cancer Institute, Naples, Italy

G. Aprile

Department of Medical Oncology,

University Hospital, Udine, Italy

A. Butera

Medical Oncology Unit, S. Giovanni di Dio Hospital,

Agrigento, Italy

G. Reggiardo

Biostatistic Unit Medi Service, Genoa, Italy

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Cancer Chemother Pharmacol

DOI 10.1007/s00280-012-2004-x

Author's personal copy

systems, the increasing prevalence of comorbid conditions,

and the fear of greater susceptibility to side effects may be

the factors that account for the reluctance to use chemo-

therapy in this setting of patients [3, 4].

A number of studies showed that elderly patients con-

stitute a very heterogeneous population and those deemed

‘‘fit’’ could receive the same treatment as that for the

youngest [5–9]. Thus, given the current evidence in the

metastatic setting, both the oxaliplatin-based and the iri-

notecan-based doublets seem to be reasonable regimens to

use at least in fit, older patients. At any rate, the results of a

previous study by our group suggested that capecitabine

plus oxaliplatin (CAPOX) is preferable to capecitabine

plus irinotecan (CAPIRI) because of the more favorable

toxicity profile [10].

The management of metastatic CRC has evolved sub-

stantially over the past decade with the introduction of

biologic agents. Bevacizumab, a recombinant humanized

monoclonal antibody against vascular endothelial growth

factor (VEGF), when added to first-line chemotherapy for

metastatic CRC, produces clinically meaningful improve-

ments in efficacy [11–18]. In addition, a recent Spanish

phase III study (the MACRO trial) suggested that a main-

tenance strategy with single-agent bevacizumab after

induction with XELOX plus bevacizumab may be a suitable

option in this setting [19]. However, the main adverse events

associated with bevacizumab are thrombosis, hypertension,

proteinuria, and epistaxis. Concerns surround the use of

bevacizumab and the risk of arterial thromboembolism

(ATE) in elderly patients, specifically regarding those with

preexisting cardiovascular risk factors or known cardio-

vascular disease. A pooled data analysis of five randomized

controlled trials of bevacizumab with chemotherapy versus

chemotherapy alone in patients affected by metastatic CRC,

breast, or lung cancer revealed that the addition of bev-

acizumab increased the risk of ATE [hazard ratio 2.0; 95 %

confidence interval (CI) 1.05–3.75; p = 0.031]. In this

study, ATE development was associated with prior ATEs

(p \ 0.001) or age C65 years (p = 0.01) [20]. Two other

pooled subset analyses of elderly patients with metastatic

CRC showed similar efficacy data for bevacizumab

in patients C65 years compared with patients \65 years

[21, 22]. However, in the Cassidy et al. study, in patients

aged C65 years, the ATE rate was 5.7 % for bevacizumab

versus 2.5 % for controls; in patients aged C70 years, it was

6.7 versus 3.2 %, respectively. Finally, two observational,

community-based trials revealed a higher rate of ATEs only

in patients treated with bevacizumab and aged C75 years,

although this might have been related to preexisting vascular

disease [15, 17].

Since the unclear impact of adding bevacizumab to

doublet chemotherapy in older patients (it has not been

assessed prospectively), the results of the MACRO trial,

and the lack of available data regarding the role of main-

tenance with antiangiogenics in the older population, we

designed and conducted this phase II trial. Aims of the study

were to analyze the efficacy and safety of bevacizumab plus

a combination of capecitabine and oxaliplatin (XELOX)

followed by single-agent bevacizumab as maintenance

therapy in older patients with advanced CRC.

Patients and methods

Patient selection

Patients with histologically confirmed metastatic or locally

advanced CRC were eligible for the study. Patients were

required to have unresectable disease and at least one

measurable lesion according to the response evaluation

criteria in solid tumors (RECIST) by computed tomography

scan [23], age C70, Eastern Cooperative Oncology Group

(ECOG) performance status (PS) B2, life expectancy of at

least 3 months, adequate bone marrow reserve (absolute

neutrophil count C1.5 9 109/L, hemoglobin Cg/dL, plate-

lets C100 9 109/L), and total bilirubin \1.25 times the

upper limit of normal, absence of other malignancies, with

the exception of basal skin/squamous cancer or in situ

cervical carcinoma. If prior adjuvant 5-FU-based chemo-

therapy had been given, it should have been completed at

least 6 months before study entry. Similarly, palliative

radiotherapy was allowed, provided that a target lesion was

present outside the irradiation fields. Exclusion criteria

included inadequate renal function (creatinine clearance

B50 mL/min), previous chemotherapy for advanced dis-

ease, severe cardiac dysfunctions, chronic diarrhea, unre-

solved or partial bowel obstruction, central nervous system

or isolated bone metastases, major surgical procedures or

open biopsy within 28 days before study entry, clinical use

of full-dose anticoagulants or thrombolytics, significant

bleeding diathesis or coagulopathy, and other serious illness

or medical condition. The study was performed in accor-

dance with the Helsinki declaration and its amendments,

and ICH-GCP guidelines [24]. The protocol was approved

by local ethics review boards, and all patients provided

written, informed consent before enrollment.

Treatment

Initially, patients received a 2-hour intravenous infusion of

oxaliplatin 130 mg/m2 on day 1 plus oral capecitabine

1,000 mg/m2 twice daily for 2 weeks of a 3-week cycle.

Bevacizumab was administered at a dose of 7.5 mg/kg as a

30- to 90-min intravenous infusion before oxaliplatin on

day 1. Treatment was repeated up to a maximum of 8

cycles. Patients then received maintenance therapy


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consisting of bevacizumab (7.5 mg/kg) once every

3 weeks until disease progression, unacceptable toxicity, or

patient refusal. During each treatment cycle, therapy was

withheld in case of grades 3 or 4 hematological toxicity

(i.e., absolute neutrophil count \1.0 9 109/L or platelet

count \50 9 109/L) or grades 2–4 nonhematological tox-

icity. The days when therapy was withheld because of

toxicity were counted as treatment days. Capecitabine

intake was resumed if the toxicities resolved during the

patient’s treatment window; however, the remaining days

of the treatment course were completed at a decreased

fluoropyrimidine dose level. The capecitabine dose was

decreased by 20 % for all grade 3 or 4 hematological and

nonhematological toxicities. For subsequent cycles, treat-

ment was withheld until hematological recovery (neutro-

phil count[1.5 9 109/L and platelet count[100 9 109/L)

and complete resolution of all nonhematological toxicities

to baseline or grade 1. Patients were taken off study for

toxicity, with treatment delays greater than 2 weeks.

Throughout the study, the doses of bevacizumab remained

unchanged regardless of the toxicity grade observed. Ox-

aliplatin was decreased by 20 % in case of significant

gastrointestinal (grade 3–4 vomiting or diarrhea), hemato-

logical (grade 3–4 thrombocytopenia, grade 4 neutropenia),

or neurological toxicity (paresthesia with pain or functional

impairment [7 days, or paresthesia with pain persistent

between cycles). If paresthesia with functional impairment

was persistent between cycles, oxaliplatin was dropped out

of the regimen. In case of allergic reactions or occurrence

of laryngeal spasm syndrome, duration of oxaliplatin

infusion was increased from 3 to 6 h.

Evaluation procedures

Before initiating chemotherapy, all patients were assessed

by physical examination, PS assessment, routine hemato-

logical and biochemical blood analyses, and ECG. Radio-

logical examinations (chest radiography and CT scan of

abdominal and/or thoracic measurable lesions) were per-

formed within 1 month before the onset of treatment to

serve as a baseline for serial evaluation of the patients’

disease. Serum chemistries were repeated at least once

every course. All adverse reactions were recorded before

each chemotherapy course. Physical examination and

radiological tumor parameter assessment were obtained

every four cycles of treatment. Toxicities were scored

according to the standard National Cancer Institute com-

mon toxicity criteria version 3. Duration of response was

calculated from the first documentation of response to

disease progression or last examination. Progression-free

survival (PFS) was defined as the interval from the

beginning of therapy to the date when disease progression

was first documented. Survival was measured from the date

of registration to the date of death. All analyses were made

on an intention-to-treat basis. The European Organization

for Research and Treatment of Cancer (EORTC) ques-

tionnaire (QLQ-C30) was used to assess quality of life

(QoL). Designed to be completed by the patient enrolled in

clinical trials, the EORTC QLQ-C30 consists of multi-item

functioning scales, and multi- and single-item scales that

evaluate general cancer-related symptoms [25]. For the

QoL analysis, the multi-item scales were computed by

calculating the mean raw scores of single items and then

transforming them linearly, so that all scales ranged from 0

to 100. The questionnaire was filled in by the enrolled

patients at baseline and after every four cycles.

Sample size and statistical considerations

To define the sample size, Simon’s minimax two-stage

design for phase II clinical trials was used [26], setting the

alpha and beta errors as 0.05 and 0.20, respectively, and

defining the minimum activity of interest (p0) for the

experimental treatment as a response rate of 35 % (at least

5 objective responses among the first 14 patients). To test

the alternative (p1) hypothesis of a 50 % activity, at least

22 responses had to be reported among the final sample of

44 patients. Overall survival (OS) and PFS were calculated

using the Kaplan–Meier method [27]. The 95 % confidence

intervals (95 % CI) were also calculated. For the QoL

analysis, differences between the QLQ-C30 scores regis-

tered after every four chemotherapy cycles and baseline

scores were compared by the Wilcoxon rank-sum test.

Results

Patient demographics

The study population consisted of 44 patients enrolled from

February 2010 to June 2011. Their characteristics are

shown in Table 1. The patients’ median age was 74 years,

range 70–83, and 19 patients (43 %) were 75 years old or

older. Patients generally had widespread disease, with the

most frequent distant sites including liver, lung, lymph

nodes, and peritoneum. In 10 patients (23 %), the primary

tumor was not resected. Among 16 patients (36 %) who

had received prior adjuvant chemotherapy, 6 had received

an oxaliplatin-based therapy and 10 had received fluoro-

pyrimidines. Eight patients (18 %) had received prior

radiotherapy. Baseline assessment for evaluation of QoL

was missing for 14 patients. An investigation concerning

the missing values was performed with the result that the

number and the distribution of the missing values proved

not to be substantial for the analysis. Details of comor-

bidities are reported in Table 2. We found that 23 % of


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patients had no comorbid disease at entry in the study. The

most frequent comorbidity was cardiovascular (hyperten-

sion, ischemic cardiopathy, peripheral, or cerebral vascu-

lopathy), which was reported in approximately 40 % of

patients. Respiratory diseases were reported in more than

one-tenth of patients, with most of these patients having

chronic obstructive pulmonary disease. Gastrointestinal/

hepatobiliary comorbidities (gastritis, peptic ulcer, gall-

bladder lithiasis, or chronic hepatitis) were reported in less

than one-tenth of all patients. Genitourinary comorbidity

(benign prostatic hypertrophy, lithiasis, and urinary

incontinence) and osteoarticular comorbidities (arthrosis or

osteoporosis) were both reported in 20 % of patients.

Diabetes was reported in 25 % of patients.

Treatment

On the cutoff date (January 31, 2012), the median follow-

up time for the entire group was 17 months. The median

duration of treatment was 6 months (1–8) and a median of

8 cycles of combination therapy (range, one to 8 cycles)

was administered. Twenty-seven out of 38 patients

reporting clinical response or stable disease after the

combination therapy completion continued with only bev-

acizumab as maintenance therapy. A median number of 6

cycles were administered in these cases. A total of 14

patients (32 %) completed 8 cycles of therapy without any

dose reductions. Twenty-two (50 %) received further che-

motherapy after disease progression. The most common

agents used were: irinotecan (45 %); cetuximab or pani-

tumumab (16 %).

Efficacy

All efficacy analyses were conducted on the intent-to-treat

population, which included all patients enrolled. Early

discontinuation of therapy (after three cycles) was due in

one case by patient refusal and withdrawal of consent. One

death occurred within 21 days from the beginning of study

treatment because of intestinal obstruction caused by per-

itoneal carcinomatosis. A third patient committed suicide

after two cycles for severe depression. These cases were

considered as treatment failures in the overall response rate

(ORR) evaluation. Table 3 shows the results. An objective

response was observed in 23 patients (52 %; 95 % CI

37–68 %) with 2 (4 %) complete responses (CR) and 21

(48 %) partial responses (PR). In addition, 15 patients

(34 %) reported a stable disease (SD). Thus, the overall

rate of disease control (CR ? PR ? SD) was 86 %,

Table 1 Baseline characteristics of the study patients

Characteristics All patients (%)

Enrolled 44 (100)

Gender

Male 23 (52)

Female 21 (48)

Age (years)

Median 74

Range 70–83

\75 25 (57)

C75 19 (43)

Primary site

Colon 34 (77)

Rectum 10 (23)

Site of metastases

Liver 31 (70)

Local (recurrent) 3 (7)

Lung 20 (45)

Peritoneum 9 (20)

Lymph nodes 9 (20)

Other 1 (2)

Involved sites

1 22 (50)

2 15 (34)

[2 7 (16)

ECOG performance status

0 32 (73)

1 12 (27)

Previous therapy

Surgery 34 (77)

Adjuvant chemotherapy 16 (36)

Radiotherapy 8 (18)

K-ras mutational status

Wild type 12 (27)

Mutant 22 (50)

Unknown 10 (23)

Table 2 Baseline comorbidities at study entry

Type N (%)

0 10 (23)

1 15 (34)

2 14 (32)

3 5 (11)

Cardiovascular 18 (41)

Respiratory 5 (11)

Gastrointestinal or hepatobiliary 4 (9)

Genitourinary 9 (20)

Osteoarticular 9 (20)

Neurological or psychiatric 5 (11)

Diabetes 11 (25)

Hematological –

Cutaneous –

Endocrinological 3 (7)


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whereas a progressive disease (PD) was documented in 3

cases. The first CR was achieved in a patient with multiple

lymph node metastases, while the second CR was reported

in a case of lung metastases from rectal cancer. Our regi-

men achieved consistently high response rates (at least

50 %) both in patients aged less than 75 and in those even

more older than 75 (data not shown).

Four patients (9 %) underwent an attempt at curative

liver metastasectomy. These patients achieved a complete

R0 resection of all disease, with a relapse-free interval of

16 months at the time of analysis. Postoperative morbidity

was overall limited, with a median hospital stay of 13 days.

Two patients received palliative radiotherapy. At the time

of the last analysis, 25 patients (50 %) were still alive. The

median PFS in the intent-to-treat population was

11.5 months (95 % CI 10.0–12.9 months) (Fig. 1), and

median OS 19.3 months (95 % CI 16.5–22.1 months)

(Fig. 2). PS (0 vs 1), number and type of comorbidities,

and k-ras mutational status were not predictive of ORR,

PFS, and survival (data not shown).

Safety

Safety was evaluated in all patients who received treat-

ment. The all-grade incidence of main toxic effects is

summarized in Table 4 as the maximum grade seen per

patient. A total of 298 chemotherapy cycles plus bev-

acizumab were evaluated. The majority of treatment-rela-

ted adverse events were mild to moderate in intensity. In

all, 10 patients (23 %) had grade 3/4 adverse events (AEs)

the most common being diarrhea (9 %), neutropenia (7 %),

peripheral neuropathy (7 %), and stomatitis (7 %). Only

two patients experienced grade 4 treatment-related adverse

event. Fourteen patients (32 %) received a cumulative

oxaliplatin dosage of 1,040 mg/m2 without dose reduction.

Cold-induced dysesthesia was reported in 7 cases (16 %)

and could be prevented in the following treatment cycles

by prolonging the oxaliplatin infusion duration. In no case,

oxaliplatin was prematurely discontinued because of severe

neurotoxicity. Severe stomatitis was observed in 3 cases

with this treatment combination, while grade 3 hand-foot

syndrome was reported in only 2 patients. Grade 1 or 2

hyperbilirubinemia was observed in 3 cases and was not

accompanied by elevations in alkaline phosphatase or liver

transaminases. Nausea and/or vomiting and myelotoxicity

were mild (grade 1–2) in the majority of the patients.

The combination demonstrated a similar favorable

safety profile among the subgroups of patients aged\75 or

older than 75 (data not shown). Dose reductions were

required in 16 patients (36 %); the main reasons were

peripheral neuropathy (n = 3) and thrombocytopenia

(n = 2) due to oxaliplatin. Capecitabine doses were

reduced to 80 % of starting dose in 4 patients; the reasons

were hand-foot syndrome (n = 2) and nausea and vomiting

(n = 2). Dose reductions were required for both drugs in 7

patients (16 %), and capecitabine and oxaliplatin doses

were reduced to 40 % of starting dose in only 3 cases

(7 %).

Table 3 Best response to treatment according to RECIST criteria

Response No. of patients %

Complete response 2 4

Partial response 21 48

Stable disease 15 34

Progressive disease 3 7

Not evaluablea 3 7

a Patients included as treatment failures in the intention-to-treat

analysis

Fig. 1 Progression-free survival (PFS)

Fig. 2 Overall survival (OS)


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Bevacizumab-related severe adverse events occurred

in 5 out of 44 patients (11 %). Although 39 % of patients

experienced bleeding events, mostly epistaxis, none of them

were grade 3 or 4. Hypertension of any grade occurred in 14

patients, of whom only 2 had grade 3 hypertension; how-

ever, this event was manageable with standard oral anti-

hypertensive agents and, there were no discontinuations of

bevacizumab therapy, hypertensive crises, or deaths due to

it. A total of 10 patients (23 %) experienced proteinuria,

but none of them having a grade 3 or 4. One patient (2 %)

experienced grade 3 bowel perforation. This event

involved a patient with unresected primary tumor and

resolved without sequelae after stopping treatment. Serious

venous thromboembolic events (VTEs) were observed in

2 patients (5 %), while no arterial thrombotic event was

reported.

QoL data

Thirty patients (68 %) participated in QoL assessment.

At cycle 4, global health status improved in 47 % of

patients. Some specific variations were observed. Three

dimensions—emotional, social, and role—improved with

treatment from baseline, and nausea and vomiting and

fatigue decreased evenly. At cycle 8, the global health

status improvement percentage was unchanged. Role

functioning and general condition improved. Several items

such appetite, insomnia, and diarrhea tended to improve,

whereas fatigue tended to increase. Differences in QoL

scores for each item at the various time intervals were not

statistically significant, likely because of sample-size lim-

itations. Neither response to treatment nor occurrence of

side effects significantly influenced changes in patients’

QoL.

Discussion

In the last decade, the use of bevacizumab in first-line

therapy has contributed to extend the median OS of

advanced CRC patients up to 24 months [28]. However,

the decision to treat the elderly population with bev-

acizumab and chemotherapy necessitates careful consid-

erations of the potential benefits in the context of the

functional status of the patient, life expectancy, costs,

comorbidities, and the reported increases in ATEs. This

multicentre, prospective phase II trial is the first study

aimed to investigate the safety and efficacy of bevacizumab

in combination with capecitabine and oxaliplatin (XELOX)

in elderly patients with advanced CRC. It also assessed the

potential clinical benefit of a maintenance therapy with

bevacizumab alone in those patients who did not progress

following induction chemotherapy with XELOX plus

bevacizumab.

Consistent with other previous reports, the ORR of

52 %, the disease control achievement in 86 % of the

patients, and the median of PFS of 11.5 months parallel the

results obtained earlier in nonelderly patients [11–18]. In

our study, the median PFS appears longer than that

reported in the MACRO study (11.5 vs. 9.7 months) [19].

This may reflect appropriate patient selection, although

caution should be exercised when comparing phase II to

randomized phase III trial results.

The possibility to offer elderly patients an initial inten-

sive treatment followed by a maintenance therapy is a

strength of the trial. During the initial months of most

treatments, many if not most side effects are acceptable,

particularly in the setting of gratifying tumor responses.

However, by some months of treatment, particularly when

tumor responses have plateaued, the accumulated burden of

toxicities can become intolerable. When patients take

prolonged breaks from scheduled treatments, there can be

concerns about compliance, particularly in the elderly.

Thus, to offer a sustainable therapy can limit repeated visits

to the clinic, admissions to the hospital, and copayments

for many supportive care medications.

A retrospective exploratory pooled analysis of four

randomized trials suggested that when bevacizumab is

combined to chemotherapy both tolerance and survival

outcome are not influenced by age, at least in medically fit

older patients [22]. Accordingly, subgroup analysis of our

study showed that the response rate remained high (at least

50 %) irrespectively of patient age. This has been partially

Table 4 All-grade treatment-induced toxicities (N = 44)

Toxicity Grade 1–2

N (%)

Grade 3

N (%)

Grade 4

N (%)

Related to capecitabine and oxaliplatin

Anaemia 4 (9) 1 (2) 0

Neutropenia 8 (18) 2 (5) 1 (2)

Thrombocytopenia 4 (9) 2 (5) 0

Nausea and vomiting 7 (16) 2 (5) 0

Diarrhea 7 (16) 3 (7) 1 (2)

Hand-foot syndrome 5 (11) 2 (5) 0

Peripheral neuropathy 4 (9) 3 (7) 0

Stomatitis 5 (11) 3 (7) 0

Related to bevacizumab

Gastrointestinal perforation 0 1 (2) 0

Hemorrhage 17 (39) 0 0

Hypertension 12 (27) 2 (5) 0

Proteinuria 10 (23) 0 0

Arterial thromboembolism 0 0 0

Venous thromboembolism 0 2 (5) 0

Wound dehiscence 0 0 0


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confirmed by a large, recent, community-based German

observational cohort study demonstrating an effective role

for bevacizumab even in patients C75 years with meta-

static CRC [29]. Number and type of comorbidities, PS (0

vs 1), and k-ras mutational status were not predictive of

ORR, PFS, and survival, confirming the use of XELOX

and bevacizumab even in selected elderly patients.

Although neither response to treatment nor occurrence of

side effects substantially influenced the QoL changes,

global health status was improved in 47 % of patients. This

is similar to the 45 % improvement reported with oxa-

liplatin and capecitabine in our previous study [10].

Toxicity was generally manageable with no toxic death

reported. This was particularly significant, with 43 % of

patients exceeding the age of 75 years. Nevertheless, the

combination of XELOX plus bevacizumab was well tol-

erated and we found no evidence for a higher rate of severe

AEs (only 23 %) in this population. This is probably due to

the low rate of grade 3/4 diarrhea (9 %) and peripheral

neuropathy (7 %) observed in our study. Although large

previous phase III trials with XELOX plus bevacizumab

have reported a significant incidence of grade 3/4 diarrhea

(19–21 %) [12, 18, 30], our results were similar to those of

the MACRO study [19]. While considering the limitations

of a phase II study, a reason for this difference remains

unclear, but it should be speculated that our older patients

were generally fit, able to tolerate treatment, and evidently

derive similar clinical benefits to younger patients. The low

rate of severe oxaliplatin-associated neurotoxicity (7 %)

seems noteworthy and is likely to be related to the per

protocol predetermined interruption of chemotherapy, to

the dose reductions required in 36 % of patients, and to the

fact that only 14 patients (32 %) received a cumulative

oxaliplatin dosage of 1,040 mg/m2.

Although baseline minor cardiovascular comorbidities

were reported in approximately 40 % of patients, bev-

acizumab was generally well tolerated both when com-

bined with XELOX and when used as single-agent as

maintenance therapy. Adverse events were mostly mild to

moderate in intensity and manageable using the standard

procedures. The incidences of all-grade hypertension,

venous thromboembolism, and bowel perforation were

consistent with earlier studies of bevacizumab in first-line

therapy in the older population [22]. Even if it was noted,

an overall increase in arterial thromboembolic events

among elderly patients, particularly in those of 75 years or

older, this type of event was not reported in our study.

Thus, age alone should not preclude patients with advanced

CRC from receiving bevacizumab-containing therapy, and

the risk–benefit balance must be weighted carefully for

each patient individually.

Limitations and points of weakness related to this study

should be noted. First of all, the sample size is limited to 44

patients, and the conclusion regarding maintenance with

bevacizumab are based on 27 patients only. However,

sample size is similar to that reported in recent phase II

study evaluating capecitabine and bevacizumab in elderly

patients [31, 32], while this is the first prospective study

that investigates on the potential role for maintenance with

antiangiogenics in this setting of patients. Secondly, the

trial lacks for an extended geriatric baseline evaluation, and

the comprehensive geriatric assessment (CGA) was not

performed. At baseline, all enrolled patients were scored

with ECOG PS and 68 % of them participated in QoL

assessment with repeated evaluation by means of the EO-

RTC QLQ-C30 questionnaire. As a result, some of the

reported analyses (particularly those dealing with specific

items differences) failed to reach statistical significance

because of sample-size limitations. Moreover, the patients

were not provided with other available tests, such as the

Mini-Mental State Questionnaire, the Mini Nutritional

Assessment, the Timed Get up and Go or the Geriatric

Depression, and the QoL analysis was not continued within

the maintenance phase. Thirdly, patient’s selection may be

a potential bias. Median age of our patients was 74 years,

but most of them were fit and with optimal PS, and they

may not be representative of the average older population.

This intrinsic limit, that has every phase II trial, may be

potentially higher when selecting older people.

In conclusion, our results suggest that elderly patients

may benefit from bevacizumab in combination with

XELOX with an acceptable toxicity profile and without

compromising the QoL. The use of bevacizumab as

maintenance therapy should be considered as an option,

particularly in this setting of patients. Nevertheless, this

therapeutic strategy is still pending, and large, prospec-

tively-designed clinical studies are needed.

Conflict of interest None.

References

1. World Health Organization (2004) GBD 2001: deaths by age, sex

and cause for the year. http://www.who.int/healthinfo/global_

burden_disease/GBD_report_2004update_part2.pdf. Accessed 29

Nov 2010

2. Ries LAG, Harkins D, Krapcho M, et al. (2003) Contents of the

SEER cancer statistics review, 1975–2003. National Cancer Insti-

tute, Bethesda. http://seer.cancer.gov/csr/1975_2003/. Accessed 3

Aug 2010

3. Simmonds PD, Best LY (1999) Should chemotherapy be used as

a treatment of advanced colorectal carcinoma (ACC) in patients

over 70 years age? Contra. Eur J Cancer 35:1640–1649

4. Balducci L, Extermann M (2000) Management of cancer in the

older person: a practical approach. Oncologist 5:224–237

5. Kohne CH, Folprecht G, Goldberg RM, Mitry E, Rougier P

(2008) Chemotherapy in elderly patients with colorectal cancer.

Oncologist 13:390–402


123


http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_part2.pdf

http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_part2.pdf

http://seer.cancer.gov/csr/1975_2003/

6. Folprecht G, Cunningham D, Ross P et al (2004) Efficacy of

5-fluorouracil-based chemotherapy in elderly patients with met-

astatic colorectal cancer: a pooled analysis of clinical trials. Ann

Oncol 15:1330–1338

7. Goldberg RM, Tabah-Fisch I, Bleiberg H et al (2006) Pooled

analysis of safety and efficacy of oxaliplatin plus fluorouracil/

leucovorin administered bimonthly in elderly patients with

colorectal cancer. J Clin Oncol 24:4085–4091

8. Folprecht G, Seymour MT, Saltz L et al (2008) Irinotecan/fluo-

rouracil combination in first-line therapy of older and younger

patients with metastatic colorectal cancer: combined analysis of

2,691 patients in randomized controlled trials. J Clin Oncol

26:1443–1451

9. Sanoff HK, Bleiberg H, Goldberg RM (2007) Managing older

patients with colorectal cancer. J Clin Oncol 25:1891–1897

10. Rosati G, Cordio S, Bordonaro R et al (2010) Capecitabine in

combination with oxaliplatin or irinotecan in elderly patients with

advanced colorectal cancer: results of a randomized phase II

study. Ann Oncol 21:781–786

11. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bev-

acizumab plus irinotecan, fluorouracil, and leucovorin for meta-

static colorectal cancer. N Engl J Med 350:2335–2342

12. Saltz L, Clarke S, Dıaz-Rubio E et al (2008) Bevacizumab in

combination with oxaliplatin-based chemotherapy as first-line

therapy in metastatic colorectal cancer: a randomized phase III

study. J Clin Oncol 26:2013–2019

13. Kabbinavar F, Hurwitz H, Fehrenbacher L et al (2003) Phase II,

randomized trial comparing bevacizumab plus fluorouracil (FU)/

leucovorin (LV) with FU/LV alone in patients with metastatic

colorectal cancer. J Clin Oncol 21:60–65

14. Kabbinavar F, Schulz J, McCleod M et al (2005) Addition of

bevacizumab to bolus fluorouracil and leucovorin in first-line

metastatic colorectal cancer: results of a randomized phase II

trial. J Clin Oncol 23:3697–3705

15. Van Cutsem E, Rivera F, Berry S et al (2009) Safety and efficacy

of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and

fluoropyrimidines in metastatic colorectal cancer: the BEAT

study. Ann Oncol 20:1842–1847

16. Cohn AL, Bekaii-Saab T, Bendell JC et al (2010) Clinical out-

comes in bevacizumab (BV)-treated patients (pts) with metastatic

colorectal cancer (mCRC): results from ARIES observational

cohort study (OCS) and confirmation of BriTE data on BV

beyond progression (BBP). J Clin Oncol 28:15s Abstr 3596

17. Grothey A, Sugrue MM, Purdie DM et al (2008) Bevacizumab

beyond first progression is associated with prolonged overall

survival in metastatic colorectal cancer: results from a large

observational cohort study (BriTE). J Clin Oncol 26:5326–5334

18. Hochster HS, Hart LL, Ramanathan RK et al (2008) Safety and

efficacy of oxaliplatin and fluoropyrimidine regimens with or

without bevacizumab as first-line treatment of metastatic colo-

rectal cancer: results of the TREE study. J Clin Oncol

26:3523–3529

19. Dıaz-Rubio E, Gomez-Espana A, Massutı B et al (2012) First-line

XELOX plus bevacizumab followed by XELOX plus bev-

acizumab or single-agent bevacizumab as maintenance therapy in

patients with metastatic colorectal cancer: the phase III MACRO

TTD study. Oncologist 17:15–25

20. Scappaticci FA, Skillings JR, Scott N et al (2007) Arterial

thromboembolic events in patients with metastatic carcinoma

treated with chemotherapy and bevacizumab. J Natl Cancer Inst

99:1232–1239

21. Kabbinavar FF, Hurwitz HI, Yi J et al (2009) Addition of bev-

acizumab to fluorouracil-based first-line treatment of metastatic

colorectal cancer: pooled analysis of cohorts of older patients

from two randomized clinical trials. J Clin Oncol 27:199–205

22. Cassidy J, Saltz LB, Giantonio BJ et al (2010) Effect of bev-

acizumab in older patients with metastatic colorectal cancer:

pooled analysis of four randomized studies. J Cancer Res Clin

Oncol 136:737–743

23. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New

guidelines to evaluate the response to treatment in solid tumors.

European Organization for Research and Treatment of Cancer,

National Cancer Institute of the United States, National Cancer

Institute of Canada. J Natl Cancer Inst 92:205–216

24. ICH website: http://www.ich.org

25. Aaronson NK, Ahmedzai S, Bergman B et al (1993) The Euro-

pean Organization for Research and Treatment of Cancer QLQ-

C30: a quality-of-life instrument for use in international clinical

trials in oncology. J Natl Cancer Inst 85:365–376

26. Simon R (1989) Optimal two stage design for phase II clinical

trials. Control Clin Trial 10:1–10

27. Kaplan EL, Meier P (1958) Non-parametric estimation from

incomplete observations. J Am Stat Assoc 53:457–458

28. Kozloff M, Yood MU, Berlin J et al (2009) Clinical outcomes

associated with bevacizumab-containing treatment of metastatic

colorectal cancer: the BRiTE observational cohort study.

Oncologist 14:862–870

29. Hofheinz R, Grothe W, Tummes D et al. (2012) Bevacizumab in

the first-line treatment of elderly patients with metastatic colo-

rectal cancer: mature results from a large community-based

observational study. ASCO GI, Abstr 566

30. Tol J, Koopman M, Cats A et al (2009) Chemotherapy, bev-

acizumab, and cetuximab in metastatic colorectal cancer. N Engl

J Med 360:563–572

31. Vrdoljak E, Omrcen T, Boban M, Hrabar A (2011) Phase II study

of bevacizumab in combination with capecitabine as first-line

treatment in elderly patients with metastatic colorectal cancer.

Anticancer Drugs 22:191–197

32. Feliu J, Safont MJ, Salud A et al (2010) Capecitabine and bev-

acizumab as first-line treatment in elderly patients with metastatic

colorectal cancer. Br J Cancer 102:1468–1473


123


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XELOX and bevacizumab followed by single-agent bevacizumab as maintenance therapy as first-line treatment in elderly patients with advanced colorectal cancer: the boxe study