Bevacizumab is one of the chemotherapy for metastatic colorectal cancer. It is effective with Irinotecan, fluorouracil,, and Leucovorin for metastatic colorectal cancer.

1. presenter: Mandukhai G
00 Title:
Bevacizumab plus
Irinotecan,
Fluorouracil,
and Leucovorin
for Metastatic
Colorectal Cancer

2. What are Bevacizumab plus Irinotecan,
Fluorouracil, and Leucovorin?
Bevacizumab is a biologic agent.
Irinotecan, Fluorouracil, and Leucovorin are chemotherapy drug
s. These are commonly used for metastatic colorectal cancer.

3. Agenda Style
01
02
03
04
05
Author Affiliations
Conclusion
Background
PICO (Methods)
Results

4. Agenda Style
06
07
08
09
10
Discussion
Value
Correspondence
Impact on the community
Thank you !

5. 01 Author affiliation
In America
California
Pennsylvania,
San Francisco
Local research
• Herbert Hurwitz, M.D., Louis Fehrenbacher, M.D.,
William Novotny, M.D., etc
• Duke University, Vanderbilt University, the Univer
sity of California
• Kaiser Permanente: Health care company
• Genentech: biotechnology company
• Ocala Oncology: cancer treatment center, resear
ch institute
• Sarah Cannon Cancer Center
• Hematology and Oncology Associates of North
eastern Pennsylvania
• California Pacific Medical Center

6. 02 Conclusion
Bevacizumab + fluorouracil-based
combination chemotherapy =
statistically significant and clinically
meaningful
improvement in survival
among patients with
metastatic colorectal cancer.

7. 03 Background
Original contribution
Bevacizumab has shown promising
preclinical and clinical activity against
metastatic colorectal cancer
particularly in combination
with chemotherapy.
Bevacizumab is a monoclonal antibody
against vascular endothelial growth factor

8. 04 Methods (PICO)
Randomized controlled trial
• Overall survival
Outcome:
Primary
end point
• Progression-free survival
• The response rate
• The duration of the response
• Safety
• The quality of life
Secondary
end point
• Irinotecan, bolus
fluorouracil, and
leucovorin (IFL)
• bevacizumab (5 mg
per kilogram of body
weight every two
weeks)
Intervention,
treatment
• IFL
• placebo
Control
Patient: 813 patients with previously untreated metastatic colorectal cancer

9. Well-Built clinical question
For 813 patients with previously untreated metastatic colo
rectal cancer,
is receiving (IFL) plus bevacizumab
better than
receiving IFL plus placebo
for overall survival, progression-free survival, the respons
e rate, the duration of the response, safety, and the quality
of life?

10. 05 Results
• Overall survival
IFL+bevacizumab= 20.3
month
IFL+placebo= 15,6
month
hazard ratio, 0,66
(P<0.001).
Outcome:
Primary
end point

11. 05 Results
Secondary end point
• Progression-free survival:
IFL+bevacizumab= 10.6 months
IFL+placebo= 6.2 months
(hazard ratio for disease progression, 0.54; P<0.001)
• The response rate: 44.8 percent and 34.8 percent (P=0.004)
• The duration of the response
IFL+bevacizumab= 10.4 months
IFL+placebo= 7.1 months
(hazard ratio for progression, 0.62; P=0.001)
• Safety
Grade 3 hypertension was more common during treatment with IFL plus bevacizumab
than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed

12. 06 Discussion

13. Interpretation
Complication
An increased incidence of th
rombosis, bleeding, protein
uria, and hypertension.
With the exception of hypert
ension, we did not find an e
xcess of these side effects a
s compared with their incidenc
e in the group given IFL plus p
lacebo.
Complication
Increase of approximately 10 % in t
he overall incidence of grade 3 and
4 adverse effects, hypertension requ
iring treatment, diarrhea, and leukop
enia.
VEGF is associated with wound hea
ling,15,16 and VEGF inhibitors can i
nhibit dermal-wound angiogenesis i
n patients with cancer

14. Generalizability
Generalizability
Although there are not yet
sufficient long-term data on the
efficacy of bevacizumab in
combination with oxaliplatin
based regimens, studies
addressing the role of these
combinations are ongoing.
Generalizability
Bevacizumab to IFL or to
fluorouracil alone 6,19
suggests that blocking
VEGF may be a broadly
applicable approach to
the treatment of
colorectal cancer

15. Editorial article
ROBERT J. MAYER, MD
Dana-Farber Cancer Institute
EDUCATIONAL TITLES
Stephen B. Kay Family Professor of Medicine, Medicine, Harvard Medical School
Attending Physician, MGH Cancer Center, Massachusetts General Hospital
Consulting Staff, Medicine, Beth Israel Deaconess Medical Center
DF/HCC PROGRAM AFFILIATION
Gastrointestinal Malignancies, Member

16. 07 Value
Editorial article
FDA (Food and drug administration) to approve the use of bevacizumab in
patients with metastatic colorectal cancer.
Since the FDA granted a surprisingly broad indication for the use of beva
cizumab.
With approximately 30,000 to 40,000 such patients identified annually in the
United States, the fiscal impact of the FDA's approval could exceed $1.5 bil
lion each year.
Bevacizumab is an additional and welcome tool that can be incorporated
into at least one combination of chemotherapy — IFL — resulting in a def
inite and encouraging extension of median survival by 4.7 months.

17. 08 Correspondence
article

18. Correspondence 1
• this result was not known when our study was initiated.
• promising in early pilot or phase 2 studies often fail in phase 3 trials.2
• Even useful treatments may have value only in limited settings.3,4
• By providing high-quality evidence to guide medical practice, well-conducted phase 3 trials serve
the individual study patients and society by minimizing the number of both study subjects and
general patients who are exposed to treatments that may involve additional cost,
inconvenience, and toxicity without providing a benefit.
• Our study required informed consent, complied with all local and federal ethical and legal
requirements, and was monitored by an independent data safety monitoring board, with
stopping rules for both efficacy and toxicity.
• Once the data demonstrating a survival benefit were known, the study centers
were notified of the results, and the treating physicians
were given the option of offering patients randomly
assigned to the control group access to bevacizumab.
• The value of bevacizumab in the second- or third-line setting for colorectal cancer is not
known.
The randomized
study did not allow
the crossover of
patients with disease
progression in the
group that received
placebo to treatment
with bevacizumab.
(Ethical problem)
Guru Sonpavde, M.D.
Baylor College of Medicine
Herbert Hurwitz, M.D.

19. Correspondence 2
• The percentage of patients receiving any second-line therapy
was reported in our article (approximately 50 percent), as was
the percentage of patients receiving second-line oxaliplatin
(approximately 25 percent).
• Formal quality-of-life data and pharmacoeconomic analyses for
our study could not be reported in our initial manuscript because
of space limitations.
• Given the improvement in all measures of clinical benefit, which
was also seen across all clinical subgroups, the addition of
bevacizumab to first-line chemotherapy would probably be
acceptable for most patients in whom this therapy is indicated.
1. The patients with signs of disease
progression were given a second line of
treatment. However, the authors did not
report how many in each group required it
and also did not adjust for it statistically.
2. The authors report more adverse
events in the bevacizumab-plus-IFL
group, without reporting how patients
perceived them — for example, in terms
of quality-adjusted life-years,1 though the
quality of life was a secondary outcome
measure.
3. It appears to be worthwhile to conduct
a cost–utility analysis nested within a
double-blind, randomized, controlled trial.
Waseem Sharieff, M.D.
University of Toronto
Herbert Hurwitz, M.D.

20. 09 Impact on community
• FDA (Food and drug administration) approved.
• NICE National Institute for Health and Care Exc
ellence (UK) approved.
(Clinical Guideline Colorectal cancer: the diagn
osis and management of colorectal cancer)

21. Reference
1. Herbert Hurwitz, M.D., Louis Fehrenbacher, M.D., William Novotny, M.
D., etc (2004)
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastat
ic Colorectal Cancer Online source: https://www.nejm.org/doi/pdf/10.10
56/NEJMoa032691?articleTools=true
2. Robert J. Mayer, M.D. (2004) Two Steps Forward in the Treatment of C
olorectal Cancer,
Online source: https://www.nejm.org/doi/full/10.1056/NEJMe048098?q
uery=recirc_curatedRelated_article
3. CORRESPONDENCE: Bevacizumab in Colorectal Cancer (2004)
Online source: https://www.nejm.org/doi/full/10.1056/NEJM200410143
511622?query=recirc_curatedRelated_article
4. https://www.nice.org.uk/guidance/cg131/documents/colorectal-cancer-f
ull-guideline2

22. Thank you!