Evidence Based Case Report

Targeted Therapy Combined with Chemotherapy

Compared as Chemotherapy Alone for The Survival
of Patients with Advanced Colorectal Cancer

Fitrinilla Alresna
NPM. 1306399733

Supervisor:
dr. Anna Uyainah Z, SpPD, KP, MARS

Department of Internal Medicine Faculty of Medicine Universitas Indonesia

Cipto Mangunkusumo Hospital, Jakarta
2014
 APPROVAL SHEET

Evidence Based Case Report

“Targeted Therapy Combined with Chemotherapy Compared as Chemotherapy Alone for The
Survival of Patients with Advanced Colorectal Cancer”

Written by:

dr. Fitrinilla Alresna

Resident of Internal Medicine

NPM 1306399733

Has been approved for presentation at Cipto Mangunkusmo Hospital

Desember 2014

Supervisor, Chief of Ward,

dr. Anna Uyainah Z, SpPD, KP, MARS dr. Hari Sutanto

ii
 PLAGIARISM FREE STATEMENT

I hereby proclaimed that this scientific literature titled:

“Targeted Therapy Combined with Chemotherapy Compared as Chemotherapy Alone for The
Survival of Patients with Advanced Colorectal Cancer”

Was written by me without any act of plagiarism as stated by the accepted rules of Universitas
Indonesia.

Should the opposite was proven in the future, I shall take full responsibility and any further
sanctions from Universitas Indonesia.

Jakarta, Desember 2014

Fitrinilla Alresna
NPM. 1306399733

iii
 TABLE OF CONTENTS
APPROVAL SHEET.......................................................................................................................2
PLAGIARISM FREE STATEMENT............................................................................................. 3
CHAPTER 1 INTRODUCTION.....................................................................................................1
CHAPTER 2 CLINICAL SCENARIO.......................................Error: Reference source not found
2.1. Clinical Scenario..............................................................Error: Reference source not found
2.2. Clinical Question.................................................................................................................. 3
CHAPTER 3 METHODS................................................................................................................4
CHAPTER 4 RESULT..................................................................................................................10
CHAPTER 5 DISCUSSION..........................................................................................................18
CHAPTER 6 CONCLUSION....................................................................................................... 22
REFERRENCES………………………………………………………………………………...23

iv
 CHAPTER 1
INTRODUCTION

Until now, cancer is a major problem in the world, especially in countries with
lower socio-economic level.1 In Indonesia, colorectal cancer (CRC) is an emerging public health
problem and currently ranks among the three highest cancers.2
CRC is a leading cause of cancer morbidity and mortality. 3 Data from a private hospital
in Jakarta (unpublished) revealed that 34% of colorectal patients presented at a advanced stage.
Survival of colorectal cancer in Indonesia is thought to be shorter due to to several factors,
among these: ethnic, nutritional, and the low affordability factors. 4 About 20% of patients
present with distant metastasis, conferring a 11.9%, 5-year relative survival in some report.5,6
The combination of multiple agents with 5-FU, leucovorin (LV) and oxaloplatin
(FOLFOX) or irinotecan (FOLFIRI) has been standard regimen for first line chemotherapy for
advanced CRC (aCRC). This regimen has prolonged median survival to about 20 months from
12 months in patients with aCRC when all of the available chemotherapeutic agents are
administered.4,7 However, 40% of patients who undergo systemic chemotherapy for advanced
cancers still do not achieve shrinkage of their tumours.3
Therefore, new strategies are warranted in order to improve these results. The approach is
focused on dissection of molecular pathways resulting in tumour growth and progression with
new biological targeted therapies. Among all the biological agents, three different strategies are
in advanced development in cancer treatment, epidermal growth factor receptor (EGFR) pathway
inhibitors, vascular endothelial growth factor receptor (VEGFR) pathways inhibitors and
cyclooxygenase-2 (COX-2) inhibitors.3 Bevacizumab (BEV) is a recombinant humanized
monoclonal antibody to VEGF, acting as a targeted antiangiogenic therapeutic agent for cancer. 8
The introduction of BEV into the treatment of advanced colorectal cancer was a milestone in
clinical oncology. The magnitude of interest for this new therapeutic approach is reflected by the
immense number of secondary publications on this topic, which is in contrast to the limited
available primary data from randomised clinical trials comparing anti-angiogenic treatments, in
combination with chemotherapy, to chemotherapy alone or chemotherapy and placebo would
reduced the risk of progression of CRC and prolonged the survival.9,10

1
 CHAPTER 2
CLINICAL SCENARIO

2.1 Clinical Scenario

The patient was a 35 years old male, with a chief complaint abdominal pain which increase
since two days before admission. Since six months ago, patients had started complaining of
abdominal pain accompanied by vomiting, anorexia, and loss of body wieght. The patient
had performed esophagogastroduodenoscopy (EGD) and colonoscopy five months before
admission, and then was diagnosed with colon cancer. Three months before admission, the
patient felt his stomach became distended, abdominal CT scan had done and the patient was
prepared for operation, but until he hospitalized now, he never got schedule for it, and he
also never controlled again to the hospital. He had a history of smoking and consuming
alcohol. On physical examination, the patient abdominal seemed distended, with cirrhosis
stigmata which are spider naevi, palmar erythema, venectasion, and ascites with karnoffsky
score 60, ECOG 3. Colonoscopy of the patient yielded ascenden colon tumour near hepatica
flexure, abdominal CT scan expertised circular mass at caecum and ascenden colon, massive
ascites with multiple mass at hepatica flexure region, and from the result of biopsy
concluded muscinosum adenocarcinoma colon. Ascites fluid analysis showed serum ascites
albumin gradient is 0,8, and cytology examination concluded the ascites contains
adenocarcinoma cells.
During hospitalization, the patient got partial bowel obstruction, so the patient has
scheduled for laparotomy to release the obstruction but the tumour unresectable and durante
operation there was no sign of obstruction again, so colostomy did not done yet and the
patient planned for chemotherapy. We check KRAS and NRAS mutation, but this
examination could not be held because the cell count from the biopsy of this patient less
than 50 cell counts. Because the staging of the adenocarcinoma colon in this patient is
T4N2M1, MFOLFOX-6 was the regimen prepared for patient’s chemotherapy three weeks
after surgery.

2
2.2 Clinical Question
We questioned about the survival of patients with advanced colorectal cancer who receive
chemotherapy combine with targeted therapy compared as chemotherapy alone. To answer
this problem, we formulating questioned based on background (PICO)
P (patient or problem) : advanced colorectal cancer patient
I (intervention) : chemotherapy combine targeted therapy
C (comparison) : chemotherapy
O (outcome) : survival
The clinical question of this EBCR is “How is the [survival] of patients with [advanced
colorectal cancer] treating with [chemotherapy combine targeted therapy] compared
[chemotherapy] alone?”

3
 CHAPTER 3
METHODS

Article searching was conducted using PubMed and Cochrane databases on November 30th, 2014
using a search command containing the words “advanced stage colorectal cancer AND
chemotherapy AND targeted therapy AND survival” (table 1). Based on this search strategy, the
results are shown in a flowchart (figure 1).
The article selection was based on inclusion and exclusion criteria. We only included
studies conducted on humans that were written in English, published in past five years, and using
clinical trial and meta-analysis method. We screened the abstracts to see if any of these articles
compared the using of chemotherapy combine targeted therapy with chemotherapy alone as the
intervention and the patient’s survival as the outcome. We screened the full text to considered the
eligibility of the article. After we did screening for the articles based on the titles, abstract, and
the full text, we found that the article written by Chao LV, et al was focusing on survival rate of
patient with advanced colorectal cancer who receive chemotherapy and targeted therapy,
antiangioenic inhibitor Bevacizumab, compared as chemotherapy alone.
Appraisal was conducted using appraisal tool concerning in validity, importancy and
applicability for meta-analysis from the Center of Evidence Based Medicine site as shown in
table 2.
After appraising the article, we came to conclusion that the study conducted by Chao LV, et
al has a validity to furthermore discussed. The findings can be applied to our patient since the
study subjects represent the characteristic of our patient. The results of the studies will further be
discussed in the next chapter.

Table 1. Search strategy conducted on November 30th, 2014 on PubMed and Cochrane
Engine Search Terms Results
PubMed advanced stage colorectal cancer AND chemotherapy 202
Date of search: AND targeted
Inclusion therapy
Advanced AND survival
colorectal cancer AND
th
November
Cochrane
Criteria: 30 , 2014
advanced stage colorectal cancer AND chemotherapy
chemotherapy AND targeted 14
 English AND targetedtherapy
therapy AND survival
 Human study
 Study in adult
 Published in PubMed Cochrane
last 5 years 4
 Clinical trial , 202 14
RCT, and
FullScreening
Text
4 availability
15 Limit
title/
the and screening
1 abstract
search Titles
3
meta-analysis
 Figure 1: Flow chart of literature searching and article selection
Table 2. Critical appraisal of systematic review/meta-analysis
What question (PICO) did the Yes
systematic review address?
Is it unlikely that important,
relevant studies were missed?
10
Selection Criteria:
 Chemotherapy
combine targeted
therapy as
intervention
 Survival as outcome
The Title, Abstract, and final paragraph of Introduction clearly
stated the question of the systematic review address with
PICO,
P : colorectal cancer
I : bevacizumab and chemotherapy regimens
C : chemotherapy regimen
O : efficacy
Yes
The Method section describe the search strategy, including the
terms used.
The comprehensive search for all relevant studies are
from major bibliographic databases (PubMed and Cochrane)
and manual searching (electronic search) of related reference
5

Were the criteria used to select
articles for inclusion
appropriate?
lists of identified trials and bibliographies of relevant books
and review articles was also performed to identify any articles
missed by initial search or any unpublished data.
The keywords retrieved were ((#colon) OR #rect) OR
#colorect AND (((#carcinoma) OR #neoplasm) OR #tumor)
OR #cancer AND ((#bevacizumab) OR #avastin). All titles
and abstracts identified by search strategies were assesses for
relevance. Full papers were obtained if potential relevance
could be confirmed or uncertainty existed. No language or date
limitations were imposed.
The Results section also outline the number of titles and
abstracts reviewed, the number of full-text studies retrieved,
and the number of studies excluded together with the reasons
for exclusion.
Yes
The Method section describe in detail the inclusion and
exclusion criteria, include the study design. The eligibility
criteria that used were specify the patients, interventions or
exposure and outcome of interest. The type of study design
also a key component of the eligibility citeria.
Selection criteria for studies that potentially eligible for
inclusion in this meta-analysis if they invoved a randomize
comparison of CTX with/without additional targeted agent-
BEV in the treartment of CRC patients (age >18), and CTX in
both compared groups should not be confounded by additional
chemotherapeutic, adjuvant agents or interventions. Prior
surgical cancer therapy was permitted. Exclusion were
considered if abstract reports of RCTs presenting preliminary
or interim data only, results of RCT were reported in letter or
editorials, they also excluded studies that were reviews, case
reports, animal studies, gene level studies, cellular level
6

Were the included studies
sufficiently valid for the type of The Method section describe the criteria used and the
question asked?
Were the results similar from
study to study?
studies, meta-analyses or systematic review, not the studies of
BEV, not he comparison of BEV with or without cytotoxic
chemotherapy regimens, not similar cytotoxic chemotherapy
regimens between experimental and control groups, not RCTs,
and have no relevant data assessment.
Major selective criteria of patients, and details of CTX
regimens for each trials in this meta-analyses were shown in
Result section figure 2.
Yes
assessment of quality. Quality assessments for eligible trials
were evaluated when referring to the Cochrane
collaborations’s tool for assessing risk of bias within the
Cochrane handbook 5.1.0 (available on www.cochrane-
handbook.org/), and performed by extracting key
methodological characteristics from published trials, including
random sequence generation, allocation concealment, blinding
of participants and personnel, blinding of outcome
assessments, incomplete outcome data, selective reporting, and
pother bias.
The Result section also provide information on the
quality of the individual studies. The quality of each study was
assessed using predetermined quality criteria appropriate to the
type of clinical question.
Overall effect : no ; Subtotal effect : yes
The Result section state that the results of overall effect for OS
and PFS are heterogeneous, the results for both outcomes
remained much the same when the above analyses were
repeated with fixed-effects models. and discuss all possible
reason for the heterogeneity. The forest-plot also show the
results of the chi-square test for the heterogeneity is
significant, and discuss possible reasons for heterogeneity.
7

Were studies selected and data
extracted by 2 or more
individuals?
How are the results presented?
Subgroup analyses were done, the results for subtotal
effects in OS show no evidence of statistical heterogeneity,
except in IFL group, but statistical heterogeneity disappeared
after eliminating trial 4 when sensitivity analyses performed.
Percentage of prior surgery and CTX could explain 100% of
between-study variance.
Subgroup analyses for PFS show no significant
heterogeneity, except in FOLFOX group, but statistical
heterogeneity disappeared after eliminating trial 8 when
sensitivity analyses were performed. The sample size, the
percentage of prior surgery for CRC, both of these two
confounding factors could explain 100% of between-study
variance.
Ideally, the results of the different studies should be
similar or homogeneous.
Yes
There is three independent selectors/extractors. The literature
search, inclusion and exclusion criteria establishment,
identification of relevant articles were all performed and
verified by both of the two investigators (D.Z., Y.L.W.)
independently. Any uncertainty or discrepancies aabout the
eligibility of a trial or particular treatment groups within trials
were resolved by discussion with the involvement of a third
investigator (C.L.), and final consensus was made.
This meta-analyses provides a summary of the data from the
results of a number of individual trials which displayed in a
figure called forest plot that gives weighted values to each of
the individual studies according to their size, and the
individual results expressed in a standard way, hazard ratio.
Details of this meta-analyses results and exploring the
heterogeneity will discuss in the Results section below.
8
9
 CHAPTER 4
RESULTS

Our search resulted in one eligible meta-analysis to answer the clinical question. The
study focused on the question whether chemotherapy (CTX) combine with targeted therapy is
more effective in prolonged the survival compared to chemotherapy alone in patients with
advanced colorectal cancer (aCRC).
Selected characteristics of included randomized controlled trials in this meta-analysis
describe in figure 2. The selected characteristics of ten trials are described on treatment
allocation, prior therapy whether as an adjuvant therapy, radio-chemotherapy, or surgery,
inclusion criteria, schedule of chemotherapy regimens, and quality assessment which has seven
points to be valued; random sequence generation, allocation concealment, blinding of
participants, blinding of outcome assessment, incomplete outcome data, selective reporting, and
other bias. There is 7.127 people diagnosed CRC involved into final meta-analysis. Two trials
underwent 5-fluorouracil + leucovorin (FLU+LEU) based chemotherapy, with 349 patients
involved; 3 trials underwent bolus 5-flurouracil/folinic acid/irinotecan (IFL) based
chemotherapy, with 1,249 patients involved; 3 trials underwent 5-flurouracil/folinic
acid/oxaliplatin (FOLFOX) based chemotherapy, with 3,834 patients involved; 1 trial underwent
capecitabine (CAP) based chemotherapy, with 313 patients involved; 1 trial underwent both
capecitabine + oxaliplatin (CAP+OXA) based and FOLFOX based chemotherapy, with 700
patients involved, respectively.
In meta-analyses done for Overall Survival (OS) and Progression Free Survival (PFS)
when comparing targeted agent bevacizumab (BEV) added to CTX versus CTX alone in the
treatment of CRC, BEV is associated with evidently decreased hazard ratio (HR), showed in
figure 3 and figure 4, and heterogeneity between trials could be identified (I 2 = 43.5%, p = 0.060
for OS; I2 = 61.6%, p = 0.004 for PFS). The results for both outcomes remained much the same
when the above analyses were repeated with fixed-effects models.
There were evidence of funnel-plot asymmetry for both outcomes about OS (p = 0.020)
and PFS (p = 0.001). Subgroup analyses were done basing on different CTX, significantly
decreased HRs for subtotal effects in OS were identified in the regimens about FLU + LEU
based and FOLFOX based chemotherapies with/without BEV, with no evidence of statistical

10
heterogeneity; while no significant differences were identified between CAP based CTX with or
without BEV (with no heterogeneity was identified) and IFL based chemotherapy with/without
BEV, but with evidence of statistical heterogeneity (I2 = 80.1%, p = 0.007) in IFL group.
Sensitivity analyses were performed, and statistical heterogeneity disappeared after eliminating
trial 4 which led to funnel-plot asymmetry. Additionally, subgroup analyses for PFS were done
basing on similar CTX, with evident decreased HRs for all of the subgroups; but significant
heterogeneity was found in FOLFOX group (I2 = 81.9%, q = 0.001). Sensitivity analyses were
performed, and then statistical heterogeneity disappeared after eliminating trial 8 which led to
funnel-plot asymmetry.
Subgroup analyses were reconfirmed after eliminating trial 4 in OS and trial 8 in PFS
which were attributable to evident between-study heterogeneity. All subgroup analyses for both
OS and PFS identified significantly decreased HR, excepting for CAP based CTX for OS (Figure
5 and Figure 6).

11
Figure 2. Selected characteristic of randomized controlled trials

12
Figure 2. (Continued)

13
Figure 3. Overall effect for OS

Figure 4. Overall effect for PFS

14
 Figure 5. Subtotal effect for OS

In meta-regression analyses for OS, the associations between additional targeted

chemotherapeutic agent-BEV and HRs were not substantially altered by sample size of each
individual trial, dose of BEV, and CTX. However, they did depend on the percentage of prior
surgery for CRC (p = 0.012). In multivariate meta-regression analyses, after adjusted for these
variables, percentage of prior surgery and CTX could explain 100% of between-study variance
(p = 0.0184), but with a stronger association with percentage of prior surgery than CTX (p =
0.009).

15
 Figure 6. Subtotal effect for PFS

As for meta-regression analyses for PFS, the associations between BEV and HRs were
not substantially altered by dose of BEV, and CTX. However, they did depend on the sample
size of each individual trial ( p = 0.001) and the percentage of prior surgery for CRC (p = 0.001).
Both of these two confounding factors could explain 100% of between-study variance.
The OS and PFS endpoints were also described with Kaplan-Meier curves, with median
survival duration prolonged approximate 1.9 months in OS (18.2 vs. 16.3, p = 0.0003) and 2.4
months in PFS (8.9 vs. 6.5, p = 0.0000), which were described in Figure 7 and Figure 8.

16
Figure 7. Kaplan-Meier survival estimate for OS

Figure 8. Kaplan-Meier survival estimate for PFS

17
 CHAPTER 5
DISCUSSION

Colorectal cancer is currently the third most diagnoses cancer in men and one of leading causes
of cancer death worldwide.11,12 About 20-25% of patients with CRC present with advanced
disease at time of diagnosis, and for these patients, systemic therapy is the primary treatment
option.10,12 5-FU, usually administered with FA, is the backbone of treatment for CRC. 10 In the
mid 90’s, the integration of oxaliplatin and irinotecan into infusional 5-FU/FA regimens resulted
in a significant improvement of response rate (45-54%) and prolongation of progression-free
survival (from 4.5 to 8 months), furthermore, median overall survival was extended to 14-18
months.10 These are some of combinations currently being used: (1) FOLFOX – 5FU and
leucovorin with oxaliplatin, (2) FOLFIRI – 5FU and leucovorin with Irinotecan, (3) FOLFOXIRI
– 5FU and leucovorin with both oxaliplatin and irinotecan, (4) CAPOX or XELOX –
capecitabine with oxaliplatin, (5) CAPIRI or XELIRI – capecitabine with irinotecan. 13
In recent years, considerable attention has been paid to targeted therapies to improve on the
therapeutic ratio.8 Tumor angiogenesis is associated with angiogenesis invasiveness and the
advanced potential of various cancers.
Angiogenesis refers to the development of new blood vessels from the pre-existing
vascular bed. It is a highly complex, dynamic process, necessary for the supply of oxygen,
nutrients, growth factors, hormones, proteolytic enzymes and dissemination of tumour cells to
distant sites. Angiogenesis is regulated by a number of pro-angiogenic and anti-angiogenic
molecules. Physiological angiogenesis is only transiently observed during embryogenesis,
wound healing and reproductive functions in adults. In contrast, abnormal angiogenesis
contributes to certain chronic diseases, such as diabetes, psoriasis, rheumatoid arthritis and
malignant tumours. A tumour requires angiogenesis to grow beyond 1-2 mm in size and to
facilitate metastasis. During tumour progression, the pre-vascular and the vascular phase may be
distinguished. In the initial pre-vascular phase, tumour growth is sustained by nutrients and
oxygen through passive diffusion from the host vasculature. Cell proliferation and cell death are
balanced, and the size of the tumour does not exceed a few mm. Once neovascularization occurs,
the tumour acquires a rapid growth rate and increased advanced potential tumour
neovascularization exhibits fundamental morphological differences: in contrast to the normal

18
blood vessel architecture, tumour vessels are irregular, heterogeneous, and leaky. They do not
exhibit a clear distinction between arterioles and venules, and their endothelial cells are
disorganized, irregularly shaped, and sometimes overlap each other.10
Angiogenesis inhibitors have been developed to block tumour angiogenesis and target
vascular endothelial cells. Angiogenesis Inhibitors may be classified as direct, indirect or mixed
inhibitors: (1) Direct angiogenesis-inhibitors target the endothelial cells involved in the
malignant disease by inhibiting their ability to proliferate, migrate, or form new blood vessels,
(2) Indirect angiogenesis-inhibitors interfere with the production of angiogenic factors by
malignant, stromal or inflammatory cells or extracellular processes, (3) Mixed angiogenesis-
inhibitors, such as multi targeting kinase inhibitors, target both tumour endothelial and malignant
cells. Principally, angiogenesis can be targeted by several mechanisms: (1) binding of angiogenic
factors, such as vascular endothelial growth factor (VEGF), e.g. anti-VEGF antibodies, VEGF
trap, (2) blockade of angiogenic factor receptors, e.g. anti-VEGFreceptor (R) antibodies, (3)
interruption of intracellular signalling pathways, e.g. tyrosine kinase inhibitors, (4) mimetics of
endogenous angiogenesis inhibitors, e.g. angiostatin-1 and -2, endostatin, thrombospondin 1.10
Vascular endothelial growth factor (VEGF), the most potent and specific angiogenic
factor identified to date, regulates normal and pathological angiogenesis. 8 It is one of the key
regulators of angiogenesis. Activation of the VEGF-receptor pathway triggers a network of
signalling processes that promotes endothelial cell growth/proliferation, migration, survival from
pre-existing vasculature, vessel sprouting and the recruitment of endothelial progenitor cells. 10,14
In addition, VEGF mediates vessel permeability, has been associated with malignant effusions,
and is involved in the mobilization of endothelial progenitor cells from the bone marrow to
distant sites of neovascularization.10
Bevacizumab (BEV) is a recombinant humanized monoclonal antibody to VEGF. 8 Acting
as a targeted antiangiogenic therapeutic agent for cancer, BEV provides little clinical benefits as
a single agent, and its additional benefits to CTX varied among each individual trial in the
treatment of CRC. Bevacizumab (BV) disrupts angiogenesis by binding to VEGF-A, reducing
availability of this ligand to its receptors, thus preventing their activation. 14 This metaanalysis of
individual trials identified that the addition of BEV to CTX was more effective comparing with
CTX alone in improving the rate of survival in terms of OS and PFS, which may confirm the
feasibility of adding targeted agents to CTX when treating CRC. The median survival duration

19
approximately prolonged 1.9 months in OS, and 2.4 months in PFS. The pooled estimate for
ORR also identified improved response rate of BEV after adding CTX compared with CTX
alone. It has a major prognostic effect on the survival of patients. The duration of BEV therapy is
likely to be important, and treatment until disease progression may be necessary to maximize the
clinical benefit derived from BEV therapy.
The additional benefits of BEV were not consistent across trials. As for OS, no efficacy
of additional BEV to CTX could be identified in several trials, including FLU + LEU, 15,16 IFL,17
FOLFOX4,18 and CAP18,19 based chemotherapy regimens. However, after being stratified based
on the CTX, the addition of BEV to FLU +LEU and FOLFOX based chemotherapy showed
evident efficacy; its additional benefit was also evident in IFL-based chemotherapy after
ignoring the trial11 leading greatly heterogeneity, suggesting that prior surgery treatment for CRC
maybe a main confounding factor; as for CAP-based chemotherapy regimens, both trials 18,19
identified no additional benefits of BEV. As for PFS, the additional benefits of BEV to CTX
were identified in all trials except trial 1(b) and trial 8. The additional benefits were evident in all
subgroups, after stratified basing on the CTX. And no alteration was identified after eliminating
trial 8, which led to greatly heterogeneity mainly due to prior surgery treatment for CRC. Its
largest sample size maybe also a confounding factor. Though adding BEV to CAP significantly
improved PFS, but did not improve OS. It should be considered as a first line therapy option for
patients with mCRC, especially when considering the benefits of controlling cancer with limited
adverse events, especially for those who are unfit for, or also do not require initial IRI or OXA.
As for study about the incidence of adverse events, the addition of BEV to CTX tended to
be associated with significantly higher OR for any adverse events when compared with CTX
alone (OR, 2.14; 95% CI, 1.71–2.69). The addition of BEV may also increase the incidence rate
of grade 3 and 4 adverse events in hypertension, thrombosis, proteinuria, gastrointestinal
perforation, and fatigue, with evident differences in ORs. But no evident between-group
differences could be identified in the adverse events for bleeding, diarrhea, and leukopenia.
Moreover, Saltz et al. pointed out that neurotoxicity, gastrointestinal disorders, and hematologic
events are the most common reasons for treatment discontinuation, which were attributable to
CTX rather than BEV. Frequent monitoring of blood pressure is necessary, and it is manageable
with oral antihypertensive when hypertension occurs. The use of low-dose aspirin (325 mg/day)
can also reduce the incidence of arterial thromboembolic events in high-risk patients treated with

20
BEV, but no increased bleeding risk in patients receiving BEV and anticoagulation therapy.
Cautions should be exercised in IRI contained regimens, since advanced age, prior pelvic
radiation therapy, impaired performance status, and low serum albumin have all been reported to
increase IRI-associated toxicities40–43; cautions should also be exercised in FOLFOX regimens,
since the association of increasing age with excess toxicity, despite BEV was not associated with
major additional toxicity except for a modest increase in rates of arterial thrombosis events in the
older patient group.
Additionally, predictive markers in relation to the treatment effects with/without BEV
were also explored, and the survival benefit with the addition of BEV in the treatment of aCRC
is independent of the status of biomarkers, such as k-ras, b-raf, and p-53. D-dimer may represent
a useful biomarker for patients treated with antiangiogenic agents, though strongly correlated
with OS, but not PFS.
In the end our patient planned to receive MFOLFOX-6 for the chemotherapy. The
unresolved question back then was whether this patient has better survival if BEV was added to
the MFOLFOX-6 chemotherapy. According to the systematic review, adding BEV into
MFOLFOX-6 chemotherapy prolonged the survival of the patients. On the other hand, it was
consistent with the controversy that the achievement of OS and PFS benefit with addition of
BEV to chemotherapy is at the cost of a significant increase toxicity. Major toxicities of
bevacizumab are hypertension, gastrointestinal perforations, proteinuria and arterial
thromboembolic events. Importantly, arterial thromboembolic events are significantly associated
with a history of prior thromboembolic complications. Furthermore, age > 65 is a risk factor for
arterial thromboembolic complications.10 So that, BEV should not be administered to patients
with cerebral metastases, uncontrollable hypertension, severe proteinuria, advanced
atherosclerotic disease, bleeding diatheses, or to those with nonhealing wounds or recent surgery
or trauma (i.e. within the previous 28 days).

21
 CHAPTER 6
CONCLUSION

For patients with advanced colorectal cancer receiving chemotherapy, the addition of
bevacizumab improves the rate of survival in terms of OS and PFS, with level of evidence 1A.
Further exploration should be considered to find out more directed prognosis predictors on the
basis of additional efficacy of BEV to CTX, especially for each specific chemotherapy regimens,
since there is no predictive marker for BEV yet.

22
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