Cancer &

Chemotherapy
Andhika Rachman
Division of Hematology & Medical
Oncology
Dept Of Internal Medicine Medical School
University of Indonesia

DR. dr. Andhika Rachman, Sp.PDKHOM

PERSONAL DATA:
Birth: Jakarta, December 29th, 1974

EDUCATION:

1999 : M.D., University of Indonesia, Jakarta, Indonesia

2005 : Internist, Internal Medicine, University of Indonesia, Jakarta
2009 : PhD, Sandwich Giessen Universitat &Biomedical Dept UI
2013 : Consultant in Hematology & Medical-Oncology, Internal
Medicine, University of Indonesia, Jakarta

HOSPITAL POSITION :
Staff of Division of Hematology Medical-Oncology, Department of
Internal Medicine, University of Indonesia / Cipto Mangunkusumo
Hospital, Jakarta

Volume I

Aims of session
Understand Cell Cycle
Chemotherapy and the
cancer cell
Side effects

Definition:
Chemotherapy
The treatment of cancer using specific
chemical agents or drugs that are
destructive to malignant cells and tissues.
The term comes from two words that
mean "chemical" and "treatment."
Cytotoxic
literally translated means toxic to cells.

The Cell Cycle

The Cell Cycle

Mitosis

Cell Biology: Mitosis

A cell in mitosis

Normal Cell Characteristics:

Metabolism. Strictly controlled &
predictable
Maturation & Specialisation.
Occurrs before dividing. Strictly
controlled.
Reproduction = Cell death
Contact Inhibition. Mechanism for
switching off division when in contact
with different cells
Recognition. Like cells stay together.

Cancer Cell Characteristics:

Unchecked & Uncontrolled Growth

Loss of contact inhibition
Loss of capacity to differentiate
Increased growth fraction
Chromosomal Instability
Capacity to metastasise
Altered biochemical properties

Chemotherapy and Cancer

Cells
Cell Cycle specific :
Most active against cells in a specific
phase therefore need prolonged
exposure
or repeated doses.
Cell Cycle Non-specific:
Most effective against actively dividing
cells but also effective in G0.

Chemotherapy
Chemotherapy may be used
conventionally to:
Cure patients
Prolong survival
Palliative care symptom control

Chemotherapy
Combination Therapy.
Prevents resistance.
Adjuvant Therapy.
Administered after primary therapy
e.g.Surgery
Neo adjuvant Therapy:
Given before surgery to reduce
tumour size.

Chemotherapy
Over 50 different chemotherapy drugs
Administered as an outpatient or inpatient
depending on toxicity
Modes of administration include:

Oral e.g. Methotrexate, Hydroxyurea

IV: Canula/Indwelling Central Venous Catheter
Sub cut
Intracavity e.g pelvic cavity, bladder
Intrathecal. Can be fatal if wrong drug
administered!

Intrathecal Chemotherapy

Chemotherapy Side Effects

Chemotherapy targets cells which are
dividing rapidly.
Chemotherapy cannot distinguish
between normal cells and cancer cells
Healthy Cells which have a high rate
of growth and multiplication include
cells of the bone marrow, hair, GI
mucosa and skin.

Chemotherapy Side effects

contd
Side effects may be drug specific e.g.
anthracyclines and cardiotoxicity,
vinca alkaloids and
neuropathy/constipation, bleomycin
and pulmonary fibrosis
Severity of side effects varies between
drugs.
Side effects often occur 7-14 days post
treatment.

Side Effects: Acute

Tumour Lysis Syndrome.
A Metabolic Emergency.
Occurrs due to rapid cell lysis
(death) & large amounts of cell
metabolites in blood.
If untreated can lead to acute renal
failure, cardiac arrest and death.

Side Effects: Acute

Neutropenic Sepsis:
Occurs due to Bone Marrow Failure and
poor immune response to infection.
Predisposing factors include:
Neutropenia
Underlying disease
Chemotherapy
Venous access devices

Neutropenic Sepsis
Severe overwhelming infection where
inadequate blood flow to the tissues
results in cellular dysfunction and, if
not reversed, eventual organ failure.
Most common micro organism is
gram negative
Mortality rate 40-90%

Side Effects: Acute

Haemorrhage
Invading tumours e.g MALT
lymphomas
Haemorrhagic Cystitis related to high
dose Cyclophosphomide
Anaphylactic Reaction

Side Effects:Bone Marrow

Neutropenia:
Increased risk of infection.
Anaemia:
Tiredness, lethargy & breathlessness
Thrombocytopenia:
Increased risk of bleeding

Side Effects: GastroIntestinal

Nausea & Vomiting

Diarrhoea & constipation
Loss of appetite
Taste Changes
Mucositis

Side Effects
Example of Grade 4 Mucositis

Side Effects: Body Image

Hair Loss
Weight Loss/ Weight Gain
Long term central venous catheters
Skin changes (colour, rashes,
sensitivity to sunshine/chlorine, dry)

Side Effects: Other

Fatigue: Often multi-factorial

Peripheral neuropathy
Altered Kidney Function
Changes in hearing (high dose Cisplatin)
Cardiac Toxicity (Doxorubicin/ Idarubicin)
Late Effects: Infertility, secondary
malignancy, growth retardation.

Key Points:
Chemotherapy is a major treatment in
curing or prolonging survival in cancer
patients
It has a wide range of side effects
depending on the drugs given.
Nurses have a key role to play in caring
for a patient receiving chemotherapy
Safety issues are paramount in
administration.

Summary:

The potential benefit to the

patient of treatment as an
option must always outweigh
the toxic effects.

Volume II

Cancer and Age

Breast

ALL

Colon

Testicular

CNS

NCCC 1988 - 2004

Nomenclature
Benign
Polyp

Malignant
Epithelial
Carcinoma

Mesenchyme
Sarcoma

Hematopoietic
Leukemia, lymphoma, myeloma

Etiology
Nature
Inherited cancer syndromes
p53, BRCA1 and 2, MMR

Immune deficiency syndromes

Inherited/Congenital or acquired

Nurture
Radiation (cosmic, fallout, radon)
Chemotherapy (MDS)
Viruses and bacteria
EBV, HTLV-I/II, H. pylori

Repeated injury (Acid reflux, hepatitis)

Cancer pathogenesis
Oncogenes
myc, ras, src, abl, bcl2

Tumor suppressor genes

p53, Rb, APC, MEN1, NF1

MicroRNA
Transcriptome control

The path to cancer

Clonal proliferation
Starts from a single cell
Expansion in steps
Pre-malignant states
Polyp, MDS, MGUS

Serial accumulation of mutations

Clonal evolution
Resistance

Hallmarks of cancer

Self-sufficiency in growth signals

Insensitivity to anti-growth signals
Evading apoptosis
Limitless reproductive potential
Sustained angiogenesis
Tissue invasion and metastases
Genomic instability
Hanahan & Weinberg, 2000

I always thought that record would

stand until it was broken.
Yogi Berra

Tissue and tumor architecture

Dingli & Pacheco, 2008

Cancer stem cells

Present in most (all) tumors

Small fraction of population
No universal marker
Often resistant to therapy
May be important target of therapy
Cancer initiating cells in mice

Genomic instability
Is it necessary?
Normal vs abnormal mutation rate
2 current views

Chromosomal instability
Gross translocations, loss and gain of chromosome
parts

Mutator phenotype
Repair genes
Xeroderma pigmentosum
MMR etc

Cytogenetic abnormalities
Translocations
Balanced
Reciprocal

Aneuploidy

Pseudodiploid
Hyperdiploid
Complex
Random loss or gain

Limitless reproductive potential

Hayflick hypothesis
Limited number of doublings
Telomere maintenance
Telomerase

Not all tumor cells have this potential

Tumor stem cells

Self-sufficiency in growth signals

Autocrine loops
Over-expression of
receptor
Receptor is always
on
Downstream signals

Scaltriti et al, 2006

Insensitivity to antigrowth signals

Hanahan & Weinberg, 2000

Evading apoptosis

External triggers
Intracellular triggers
Death receptors
Caspases
Sensors (8, 9)
Executioners (3)

Sustained angiogenesis
VEGF
FGF1/2
Thrombospondin
Thalidomide
Avastin

Tissue invasion and metastases

Tumor burden - Staging

Tumor
Size, capsule invasion

Nodes
Involved, how many?

Metastases
Present/absent
Unknown primary

Imaging

CT scan
PET/CT
SPECT/CT
MRI

Staging
Response

Prognostic scoring systems

Host vs Disease

Disease burden
Disease biology
Co-morbid conditions
Performance status

Therapy

Surgery
Radiation
Chemotherapy
Antibodies
Small molecules
Adjunctive

Surgery
Diagnosis
Therapy
Curative
Palliative
Debulking
Symptoms control
Prevent complications

Radiation
External beam radiation
Gamma photons
Neutron beams

Radioimmunoconjugates
Antibody targeted radiation

Radioconjugates
Isotope tagged to bone seeking material

Free isotopes
131I, Gallium

Radiation targets
DNA
Water
Free radical generation
Oxygen is required
Anti-oxidants are not helpful

Direct and indirect effects

Not all cells are created equal
Geometry important

Radiation
Consolidation
Mantle radiation
Axillary radiation

Palliation
Spinal cord compression
Pain relief

Radio(immuno)conjugates
or -emitters

Free isotopes

Chemotherapy
Antimetabolites
Antifolates, Purine nucleosides, nucleoside
synthesis inhibitors

Alkylators
Direct DNA damage (Many), platinum

Spindle poisons
Vinca alkaloids, taxanes

Topoisomerase inhibitors
Anthracyclines, Etoposide

Chemotherapy
Often used in combinations
CHOP, ABVD, AC, Taxol/Carbo

Minimizes resistance
Reduces toxicity
Different side effects

Can be curative in specific cases

AML, ALL, HD, NHL, Testicular cancer

Antibodies
Target specific antigen
Specificity is relative
Various mechanisms of action
Complement activation
ADCC
Calcium entry
May synergize with chemotherapy
R-CHOP and CHOP

Expected or unexpected toxicities

Antibodies

Small molecules
Target oncogene product
Bcr-Abl, PML-RARA,

Inhibit signaling at key steps

Safer than chemotherapy
Specific side effects
Specificity is often relative

Small molecules

Adjuncts
Glucocorticosteroids
Estrogens/anti-androgens/SERMs
Bisphosphonates

The target
Tumor cells do not live in isolation
Stroma
Adhesion resistance

Blood vessels
Angiogenesis inhibitors
Antibodies (Avastin)
Small molecules (Thalidomide, other IMiDs)

Immune system
Transplantation
Vaccines

Antimetabolites
interfere with the synthesis of DNA & RNA
Most antimetabolites act during S phase
of cell cycle, when cell proliferation is
more prominent

1. Antifolates

Pemetrexed
Methotrexate (MTX)

2. Pyrimidine Analogues

5-Fluorouracil
Capecitabine
Cytarabine (ara-C)
Gemcitabine

1. Purine Analogues

Thiopurines
Fludarabine
Cladribine
Clofarabine

Pemetrexed
Pemetrexed is a pyrrolopyrimidine analog
with activity in the S phase

Gemcitabine

JMDB: Largest ever clinical trial conducted in 1st line NSCLC

(N=1,725)
Pemetrexed/Cisplatin (P 500 mg/m2 d1; C 75
mg/m2 d1) every three weeks, up to 6 cycles,

Previously Untreated
Stage IIIB or IV
ECOG PS 0-1
n=1,725

n=862

Up to 6 Cycles
Gemcitabine/Cisplatin (G 1250 mg/m2 d1,8;
C 75 mg/m2 d1) every three weeks, up to 6
cycles
n=863

The primary endpoint: non-inferiority, overall survival.

The Largest trial ever reported in this setting with 1,725 patients
from 177 sites in 26 countries*

Pemetrexed/cisplatin is similar to Gemcite/cisplatin:

Overall survival (overall population)

Median OS
(95% CI)
Adjusted HR
(95% CI)

ALIMTA + Cisplatin
(N=862)

Gemcite + Cisplatin
(N=863)

10.3 mos
(9.8, 11.2)

10.3 mos
(9.6, 10.9)

0.94 (0.84, 1.05)

Pem/Cis vs. Gem/Cis

Significant treatment-related differences

observed by histology type

Favors PC

Favors GC

Gender, Smoking, PS, ethnics are prognostic factors

Is the toxicity profile different among the histology groups

examined in this study?
Grade 3 or 4 Toxicity: Pemetrexed + Cisplatin
Adenocarcinoma
(n=425)

Large Cell
Carcinoma
(n=76)

Other
Histology
(n=103)

Squamous
Carcinoma
(n=235)

Neutropenia
Anemia
Thrombocytopenia
Leukopenia

15.5%
4.0%
3.1%
4.0%

14.5%
3.9%
2.6%
3.9%

12.6%
9.7%
6.8%
4.9%

15.7%
7.2%
5.1%
6.4%

Febrile neutropenia
Alopecia (all grades)
Nausea
Vomiting
Dehydration (all grades)
Fatigue

1.4%
14.1%
7.3%
5.4%
4.0%
6.4%

0.0%
11.8%
11.8%
6.6%
3.9%
7.9%

1.9%
4.9%
7.8%
9.7%
4.9%
6.8%

1.3%
11.1%
5.1%
5.5%
2.1%
6.8%

G 3/4 Toxicity

No clinically relevant differences were observed for the safety profile

of pemetrexed + cisplatin within the histology subgroups2
1. Data on file. Eli Lilly and Company
2. ALIMTA [Summary of Product Characteristics]. Eli Lilly and Co; Approved 08 April 2008.

Efficacy of Pemetrexed-Cisplatin (PC) in East Asian

Patients: Subgroup Analysis of a Phase III Study
Comparing PC vs Gemcitabine-Cisplatin (GC) in Firstline Treatment of Advanced Non-small Cell Lung
Cancer (NSCLC)
M. Orlando1, J. S. Lee2, C. Yang3, L. Simms4, K. Park5
Eli Lilly Interamerica, Buenos Aires, Argentina; 2National Cancer Center
Hospital, Goyang Gyeonggi, Republic of Korea; 3National Taiwan University
Hospital, Taipei, Taiwan; 4Eli Lilly Canada, Toronto, ON, Canada; 5Samsung
Medical Center, Seoul, Republic of Korea
1

Pem-Cis vs. Gem-Cis in E. Asian pts

Randomization Factors

Stage (IIIB vs IV)

Performance status

Cisplatin 75 mg/m2 day 1 +

Pemetrexed 500 mg/m2 day 1

(0 vs 1)

Gender (M vs F)

Histologic vs
cytologic diagnosis

History of brain
metastases (Y vs N)

Cisplatin 75 mg/m2 day 1 +

Gemcitabine 1250 mg/m2 days 1 & 8
Vitamin B12, folate, and dexamethasone given in both arms

PC=pemetrexed/cisplatin; GC=gemcitabine/cisplatin

Number of Patients Enrolled by Country

Enrolled
Country

Sites

Entered

Argentina

32

Australia

Austria

Enrolled
Country

Sites

Entered

28

Italy

11

129

123

63

62

Korea

55

54

39

37

Mexico

31

28

Belgium

44

44

Netherlands

113

110

Brazil

70

62

Poland

85

80

Canada

60

56

Portugal

32

31

Denmark

35

33

Spain

13

94

92

Finland

15

15

Sweden

37

35

France

62

58

Taiwan

80

72

Germany

20

205

205

Turkey

63

62

Greece

47

42

UK

46

46

Hungary

41

38

US

22

132

115

India

180

154

Total

177

1833

1725

country
entered

country
entered

Pem-Cis vs. Gem-Cis in E. Asian pts

Design
Aims: to describe the characteristics of the East
Asian patients enrolled in this study and assess
efficacy according to histology and smoking history
Objectives: survival, PFS, RR
Subjects: 126 chemonaive pts from Korea and
Taiwan
Arm A

Cis 75 mg/m2 day 1 + Pem 500

mg/m2 day 1

Arm B

Cis 75 mg/m2 day 1 + Gem 1250

mg/m2 day 1, 8

Each cycle was repeated every 3 weeks for up to 6

cycles. Vitamin B12, dexamethasone, folate were also
given in both arms

Baseline
Characteristic

All Patients (N=1725)

East Asian (n=126)

Korea and Taiwan Only

61.0

61.0

Male/Female

70%/30%

62%38%

Stage IIIB/IV

24%/76%

19%/81%

PS 0/1

36%/64%

38%/62%

Histology Sq/Nonsq

27%/73%

26%/74%

Ever/Never-smoker

73%/14%

49%/50%

Median OS (PC vs GC)

All pts, months
HR (95% CI)

10.3 vs 10.3
0.94 (0.84, 1.05)

17.1 vs 16.5
0.84 (0.51, 1.36)

Nonsq pts only, months

HR (95% CI)

11.0 vs 10.1
0.84 (0.74, 0.96)

21.2 vs 17.7
0.70 (0.39, 1.24)

25%/23%
28%/27%

58%/66%
64%/78%

Median age (years)

PDT TKI (PC vs GC)

All pts
Nonsq pts only
* updated

Baseline
Characteristic

All Patients (N=1725)

East Asian (n=126)

Korea and Taiwan Only

61.0

61.0

Male/Female

70%/30%

62%38%

Stage IIIB/IV

24%/76%

19%/81%

PS 0/1

36%/64%

38%/62%

Histology Sq/Nonsq

27%/73%

26%/74%

Ever/Never-smoker

73%/14%

49%/50%

Median OS (PC vs GC)

All pts, months
HR (95% CI)

10.3 vs 10.3
0.94 (0.84, 1.05)

17.1 vs 16.5
0.84 (0.51, 1.36)

Nonsq pts only,

months
HR (95% CI)

11.0 vs 10.1
0.84 (0.74, 0.96)

Median age (years)

PDT TKI (PC vs GC)

All pts
Nonsq pts only

* updated

25%/23%
28%/27%

21.2 vs 17.7
0.70 (0.39, 1.24)

58%/66%
64%/78%

JMDB Taiwan & Korea subgroup: PFS in Non-squamous

Yang et al, JTO 2009 submitted

JMDB Taiwan & Korea subgroup: PFS in Non-squamous

never-smokers

Yang et al, JTO 2009 submitted

Overall Survival East Asian

1.0
OS Median (95% CI)

Overall Survival Probability

0.9

PC (N=67) 17.1 mos (13.7, 26.8)

0.8

GC (N=59) 16.5 mos (10.8, 22.0)

0.7

OS Adjusted HR (95% CI)

0.6

PC vs GC 0.84 (0.51, 1.36)

0.5
0.4
0.3
0.2
0.1
0.0
0

18
12
Overall Survival Time (months)

24

30

Overall Survival East Asian Nonsquamous Patients

OS Median (95% CI)

Overall Survival Probability

1.0

PC (N=47) 21.2 mos (17.1, 28.2)

0.9

GC (N=46) 17.7 mos (11.7, 22.0)

0.8

OS Adjusted HR (95% CI)

0.7

PC vs GC 0.70 (0.39, 1.24)

0.6
0.5
0.4
0.3
0.2
0.1
0.0
0

18
12
Overall Survival Time (months)

24

30

Survival by Histology and Smoking Status

Histology and Smoking Group
All smokers
Median overall survival, mos

Overall Study Population

PC

GC

PC

GC

n=629

n=637

n=35

n=27

10.02

10.25

15.24

13.63

HR (95% CI)
Nonsquamous smokers
Median overall survival, mos

0.93 (0.81, 1.05)

Median overall survival, mos

0.74 (0.37, 1.48)

n=430

n=449

n=18

n=18

10.55

9.79

NE*

13.63

HR (95% CI)
Squamous smokers

East Asian (Korea & Taiwan Only)

0.81 (0.69, 0.94)

0.69 (0.25, 1.95)

n=199

n=188

n=17

n=9

9.43

10.94

13.67

10.81

HR (95% CI)

1.26 (1.01, 1.59)

0.78 (0.23, 2.68)

All never-smokers

n=128

n=122

n=31

n=32

Median overall survival, mos

15.90

15.28

20.34

17.74

HR (95% CI)

1.00 (0.71, 1.41)

0.73 (0.35, 1.50)

Nonsquamous never-smokers

n=112

n=105

n=28

n=28

Median overall survival, mos

17.12

16.49

21.19

17.74

HR (95% CI)
Squamous never-smokers
Median overall survival, mos
HR (95% CI)

0.96 (0.66, 1.39)

0.63 (0.29, 1.37)

n=16

n=17

n=3

n=4

12.85

15.28

3.19

NE*

2.51 (0.64, 9.31)

*NE= Not estimable due to too few deaths.

NE*

Post-discontinuation Therapy with EGFR TKIs

Histology Group
Receiving PDT
EGFR TKIs*

Overall Study
Population

East Asian (Korea &

Taiwan Only)

PC
n=862

GC
n=863

PC
n=67

GC
n=59

All histology

25%

23%

58%

66%

Nonsquamous

28%

27%

64%

78%

Squamous

19%

11%

45%

23%

EGFR TKIs=epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib.
*Decisions regarding post-discontinuation therapy were made by individual investigators.

In the overall study population, in the all histology and nonsquamous groups, the use of postdiscontinuation EGFR TKIs was similar between treatment arms. In the squamous group,
TKI use was slightly higher on the PC arm.
For the East Asian (Korea and Taiwan only) population, particularly in nonsquamous patients,
survival trended in favor of PC over GC despite a higher use of post-discontinuation TKIs on
the GC arm.
In East Asian (Korea and Taiwan only) squamous patients, the higher use of postdiscontinuation TKIs observed on the PC arm may help explain the OS results for PC
compared to GC in this population.

Pem-Cis vs. Gem-Cis in E. Asian pts

Conclusions
Pt and disease characteristics between the East Asian
subgroup and the overall population were similar
In the East Asian group, more patients were neversmokers compared with the overall population; however,
smoking status was balanced between arms
This analysis shows the improved efficacy outcomes for
East Asian nonsquamous pts treated with Pem-Cis is
consistent with the previously observed treatment effect of
Pem-Cis on nonsquamous NSCLC
In the East Asian group, survival for both the neversmokers and smokers with nonsquamous NSCLC trended
in favour of Pem-Cis treatment compared with Gem-Cis
For the East Asian population, particularly in
nonsquamous patients, survival trended in favour of PemCis over Gem-Cis despite higher use of postdiscontinuation TKIs on the Gem-Cis arm

Summary
There have been some significant
advances in the treatment options
for advanced NSCLC
We need to increasingly adopt a
personalized treatment approach in
lung cancer
Histology is a biomarker which is
helping guide our treatment options
First line matters most and it is
important to use best drugs first!

X Factors about GEMZAR 14 years

Over

30,000 patients had been treated with

Gemzar.*
At least

71 multi center Phase III studies that was

conducted with Gemzar worldwide.*

5 major cancer types are Gemzar indicated for*
Lung Cancer
Breast Cancer
Ovarian Cancer
Pancreatic Cancer
Bladder Cancer
*Data on file
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Current approved indications and dosages

Therapeutic Indications

Dosages

Non-Small Cell Lung Cancer

Single agent: Gemcitabine 1000mg/m2 repeated once weekly

for 3 weeks, followed by a 1 week rest period

Gemcitabine , alone or in combination with cisplatin, is indicated for the first line
treatment of patients with locally advanced or metastatic non- small cell lung cancer.

Pancreatic Cancer
Gemcitabine is indicated as 1st line treatment of patients with locally advanced or
metastatic adenocarcinoma of the pancreas. Gemcitabine is indicated for patients with
5-FU refractory pancreatic cancer.

Bladder Cancer
Gemcitabine in combination with cisplatin is indicated for treatment of patients with
advanced bladder cancer

Breast cancer

Combination with Cisplatin: Gemcitabine 1250mg/m2 D1,

D8, out of every 21 days OR Gemcitabine 1000mg/m 2 D1,
D8, D15 out of every 28 days
With Cisplatin 75-100 mg/m2 D1 after administration of
Gemcitabine of each 21 day or 28 day cycle

Single agent: Gemcitabine 1000mg/m2 weekly for 7 weeks +

1 week off;
Then 3 weeks out of every 4 weeks
Combination with Cisplatin: Gemcitabine 1000mg/m2 D1, D8,
D15 out of every 28 days, with Cisplatin 70mg/m 2 D1 or D2

Gemcitabine in combination with Paclitaxel is indicated for the treatment of patients

with unresectable, locally recurrent or metastatic breast cancer following
adjuvant/neoadjuvant chemotherapy. Prior chemotherapy should have included an
anthracycline unless clinically contraindicated

Combination with paclitaxel: Paclitaxel 175mg/m 2 D1,

followed by Gemcitabine 1250mg/m 2 D1, D8, out of every 21
days

Ovarian Cancer

Single agent: Gemcitabine 800-1250mg/m2 D1, D8, D15 out

of every 28 days

Gemcitabine, alone or in combination with Carboplatin, is indicated for the treatment

of patients with recurrent epithelial ovarian carcinoma who have relapsed following
platinum-based therapy

Combination with Carboplatin: Gemcitabine 1000mg/m 2 D1,

D8 out of every 21 days, with Carboplatin AUC 4 mg/ml.min
on D1

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Consistent, proven evidence across the largest

body of Phase III trials

All studies presented made use of Q21 day therapy schedule*

*Gemzar dosage: 1200-1250mg/m2; Cisplatin dosage: 75-80mg/m2, with the except of Alberola and Cardenal where 100mg/m2 were administered

GZ-13-10-24

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Gemzar platinum offers longer survival time after

2nd line treatment

Weiss et al. Annals of Oncology 2007; 18:453-460

GZ-13-10-24

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Increased survival, allowing more meaningful

time

Le Chevalier T et al: Lung cancer 47:69-80, 2005

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Copyright 2006 Eli Lilly and Company

Meta-analysis shows Gemcitabine-containing regimen

reduce the immediate risk of progression
Odds Ratio for Response (CR+PR)

Odds Ratio for Progression

G vs non-G

G vs non-G

P vs non-P

D vs non-D

D vs non-D

V vs non-V

V vs non-V

P vs non-P

0.6

0.8
G,P,D,V-free
better

1.0

1.2

1.4

G,P,D,V-containing
better

0.6

0.8

1.0

G,P,D,V-containing
better

Gross F et al. Oncologist. 2009 May;14(5):497-510.

GZ-13-10-24

1.2

G,P,D,V-free
better

1.4

Better tolerability allows patient maintain active

during treatment

GZ-13-10-24

102

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Copyright 2006 Eli Lilly and Company