Vinorelbine : Effective Therapeutic

Strategies for each Stage of The

Disease
 Proposed treatment algorithm for advanced NSCLC

Advanced-Stage NSCLC and PS 0-1

EGFR mutation ELM4‐ALK positive EFGR mutation and ALK negative and EFGR mutation and ALK
positive non squamous histology negative and squamous
histology

Bevacizumab Bevacizumab
appropriate inappropriate

Erlotinib or Consider Consider cisplatin or Consider cisplatin or

Consider crizotinib first
gefitinib first line carboplatin/paclitaxel + carboplatin carboplatin combined
or second line bevacizumab combined with pemetrexed, with docetaxel
Or cisplatin/pemetrexed docetaxel or gemcitabine or or gemcitabine or
± Bevacizumab paclitaxel paclitaxel
or or
cisplatin/vinorelbine cisplatin/vinorelbine
± cetuximab ± cetuximab

“Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective”

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
 3
“Company Confidential – Internal Use Only" 3
 4
“Company Confidential – Internal Use Only" 4
 5
“Company Confidential – Internal Use Only" 5
Kemoterapi Lini Pertama
 Vinorelbin + sisplatin atau
karboplatin, siklus 3 mingguan
 Vinorelbin 30 mg/BSA (hari 1,8) +
sisplatin 60 – 80 mg/BSA (hari 1)
 Vinorelbin 30 mg/BSA (hari 1,8) +
karboplatin AUC-5 (hari 1)
 Treatment of patients candidates for adjuvant
chemotherapy

Early stage of disease – Stages IB to IIIA

• Surgical resection in functionally fit patients

• Cisplatin‐based adjuvant combination CT is recommended in
• Stage II and IIIA
• Stage IB for selected patients (T> 4 cm)
• Postoperative RT may be considered in patients not radically resected
• PORT not recommended for radically resected Stage I and II
• PORT recommended for resected Stage IIIA
• Curative conformal RT as a single modality is to be considered in patients
unfit for standard surgery.

Clinical practice guidelines metastatic nsclc, Peters, Annals of Oncology 2012 ;

Azzoli, ASCO Guidelines, JCO 2010; NCCN Practice Guidelines in Oncology NSCLC V3 2012
 VINORELBINE in stage II-IIIA NSCLC
ALPI n=1209 MVP - No survival benefit of CT at 5 years
JNCI 2003 Stage I - IIIA vs Obs
IALT n=1867 Plat. based - Survival benefit at 5 y. Not maintained > 5 y.
NEJM 2004 Stage I - IIIA vs Obs - increase in noncancer deaths in the CT arm.
BLT n=381 Plat-based - No survival benefit with adjuvant CT
Eur J. Card. Surg. Stage I - IIIA vs Obs
2004

CALGB 9633 n=344 P + Cb - No Survival benefit with paclitaxel +

JCO 2008 Stage IB vs Obs carboplatin for patients with stage IB.

ANITA n=840 VNB + - Survival benefit of CT at 5 and 7 y.

Lancet Onco. 2006 Stage I - IIIA CDDP - For stage II and IIIA
vs Obs

JBR 10 n=482 VNB + - Significant survival benefit at 5 years.

NEJM 2005 / JCO Stage IB - II CDDP - For stage II
2010 vs Obs
- Benefit maintained after 9 years.

Vinorelbine + CDDP is the gold standard in the adjuvant

setting for patients aged < 75 y with PS 0 or 1
 VINORELBINE in stage II-IIIA NSCLC
LACE LACE VINORELBINE
Chemotherapy VINORELBINE +CDDP
100 1.0
Control
Control

80 80 +8.9%
+5.3%
61.0 55
Survival (%)

Survival (%)
60 60
48.8
57.1

40 40 46.1
43.5

20 20

p=0.004 p=0.0007
0 0

0 1 2 3 4 5 ≥6 0 1 2 3 4 5 ≥6
Time (years) Time (years)
• 5 trials • 4 trials
• Absolute survival benefit of 5.3% at 5-years • Absolute survival benefit of 8.9% at 5-years

Pignon, JCO 2008 Douillard, JTO 2010

VINORELBINE + CDDP is the gold standard in the adjuvant setting

 ANITA study VINORELBINE+CDDP as adjuvant CT

Phase III study

n=840 VNB+CDDP Observation
Stage IB, II, IIIA (n= 407) (n= 433)

Median survival 65.7 m p=0.017

43.7 m
2-year survival 62.8% +4.7% 67.9%
5-year survival 51.2% +8.6% 42.6%
7-year survival 45.2% +8.4% 36.8%

Benefit in survival increases with time

VINORELBINE 30 mg/m² weekly

CDDP, 100 mg/m² D1
every 4 weeks, x 4 cycles Douillard, The Lancet 2006
* ANITA : Adjuvant NVB International Trialist Association
 Optimizing survival in advanced NSCLC
Treatment recommendations for patients with good PS (0-1)
– Platinum-based 2-drug combination with a 3rd generation agent
– New agent/platinum combinations have generated a plateau in OR (25-25%),
in TTP (4-6m) and in MS (8-10m)
– Histology of NSCLC is important in the selection of systemic therapy
– 4 cycles of an initial chemotherapy (6 cycles maximum)
– Switch or continuous maintenance as an option to prolong PFS and survival

CT regimen choice based on several factors

– Efficacy
– Drug schedule / preference
– Adverse events

Clinical practice guidelines metastatic nsclc, Peters, Annals of Oncology 2012 ;

Azzoli, ASCO Guidelines, JCO 2010; NCCN Practice Guidelines in Oncology NSCLC V3 2012
Vinorelbine + CDDP vs gemcitabine + CDDP in
advanced NSCLC

Phase III study Vinorelbine + CDDP gemcitabine + CDDP

n= 272 n=137 n= 135

Squamous / Adenocarcinoma 29% / 52% 28% / 54%

Median age 62 63

OR 32.1% 26.7%
OR adenocarcinoma 32.3% 26%
OR squamous 45% 36.8%

MS 11 m 11 m

VINORELBINE+CDDP offers high response rate in

adenocarcinoma and squamous histologies

Martoni, EJC 2005

 Phase III carbo-vino vs carbo-gem
CV vs CG in advanced NSCLC shows similar efficacy

Carbo-iv vino: 210 pts

Carbo-gem: 219 pts Hellbekmo N et al., Br J Cancer 97: 283-9, 2007
 VINORELBINE + CBDCA versus gemcitabine +
CBDCA in advanced NSCLC

Phase III study n= 432 VINORELBINE + CBDCA Gem + CBDCA

n= 218 n= 214

MS 7.3 m 6.4 m

MS PS 0-1 9m 8.9 m

1-YS PS 0-1 35% 38%

Tolerability, Gr 3-4, % pts

Leucopenia 45% p<0.01 30%

Thrombocytopenia 2.5% p<0.01 44%

Anaemia 6% p<0.01 19%

Nb blood transfusions 136 p<0.01 283

Nb platelet transfusions 5 p=0.02 30

VINORELBINE + CBDCA is an optimal option in 1st line effective and safe

VNB I.V. 25 mg/m² D1, D8 + CBDCA AUC 5 D1 every 3 weeks Helbekkmo, BJC 2007
Gem 1,000 mg/m² D1, D8 + CBDCA AUC 5 D1 every 3 weeks
 Patients candidates for a single agent CT

“When the use of a platinum agent plus a new agent is considered

standard, the use of a single agent may be considered for some
patients, including patients aged 70 years or older, patients who
have a performance status of two, or patients for whom platinum
therapy might be contraindicated.”

Goffin et al, JTO 2010; 5 (2):260-274

Gridelli, JCO 2005
Single agent VINORELBINE for elderly patients

Phase III ELVIS study

n= 154
median age= 74 VNB 30 mg/m2 BSC
73% stage IV

OR 20% -
Disease control 50% -
Median survival 6.5 m p = 0.03 4.8 m
1-YS 32% 14%

Gridelli, JNCI 1999

VINORELBIN shown to improve survival

Single agent VINORELBINE for elderly patients

Phase III ELVIS study

WHO G3/4, % pts VNB 30 mg/m2

Neutropenia 4% (Gr 4)
Infection none
Vomiting 1 pt
Cardiac toxicity 1 pt (Gr 2)
Constipation 5.6%
Alopecia 4% (Gr 3)
Gridelli, JNCI 1999
VINORELBINE: the standard chemotherapy for elderly patients

Randomised VNB 25 mg/m² Gem 800 mg/m² DCT 30 mg/m²

phase III study D1, D8, D15 q4w D1, D8, D15 q4w D1, D8 q4w

n (med. Age) 45 (73y) 43 (72y) 46 (72y)

PS 0-1/2-3 33% / 66% 33% / 66% 33% / 66%
OR 20% 16% 22%
Disease control 51% 37% 48%
MS 6.8 m 5.1 m 5.0 m

 Disease Control for half of the patients

 with a longer survival

Leong, JTO 2007

VINORELBINE: the standard chemotherapy for elderly patients

Phase II studies VNB 25 mg/m² Gem 800 mg/m² DCT 30 mg/m²

G3/4, % pts D1, D8, D15 q4w D1, D8, D15 q4w D1, D8 q4w

Neutropenia 36% 7% 7%
Anaemia 11% 14% 2%

Nausea / Vomiting 2/2% 0 9/0%

Asthenia 22% 12% 20%

 A tolerance profile as single agent

 that fits with elderly patients

Leong, JTO 2007

 Optimizing survival in stage III NSCLC
Locally advanced or stage III disease accounts for around 30% of patients
with NSCLC.

Treatment recommendations:
• CT + RT prolongs survival compared to RT alone.
• Platinum-based CT, preferably concurrent with RT, is the standard
treatment for selected patients with locally advanced, unresectable Stage
III and adequate pulmonary function.
• Cisplatin-vinorelbine or vinblastine or etoposide and carboplatin-
paclitaxel at systemic doses are the reference regimens
Radiotherapy dose:
• No less than the biological equivalent of 60 Gray

D’Addario, Annals of Oncology 2010.

Auperin et al. 2010 ESMO Clinical Recommendations (Guidelines), Annals of
Oncology 2010
Pfister, JCO 2004
 Randomized phase II study of cisplatin with gemcitabine or paclitaxel
or vinorelbine as induction chemotherapy followed by concomitant
chemoradiotherapy for stage IIIB NSCLC: CALGB study 9431

Cycle 1 Cycle 2 Cycle 3 Cycle 4

D1 D8 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78

Arm I
Arm II
Arm
III

Cisplatin 80 mg/m2
Radiotherapy 66Gy
Gemcitabine 1250 mg/m2 600 mg/m2 2 Gy/day - 6.5 weeks
Paclitaxel 225 mg/m2 135 mg/m2 Vokes EE et al, J Clin Oncol 2002;20:4191-8

Vinorelbine 25 mg/m2 15 mg/m2

Randomized phase II study of cisplatin with gemcitabine or paclitaxel
or vinorelbine as induction chemotherapy followed by concomitant
chemoradiotherapy for stage IIIB NSCLC: CALGB study 9431

Vokes EE et al, J Clin Oncol 2002;20:4191-8

Randomized phase II study of cisplatin with gemcitabine or paclitaxel
or vinorelbine as induction chemotherapy followed by concomitant
chemoradiotherapy for stage IIIB NSCLC: CALGB study 9431

Vokes EE et al, J Clin Oncol 2002;20:4191-8

 VINORELBINE + CDDP: Sequential or concurrent CT+RT?

Randomised study
VNB +CDDP VNB+CDDP + RT (60 Gy)
n=102
then RT (60 Gy) then NVB+CDDP
IIIA 15% - IIIB 85%
OR 47% 80%
CR 17% 21%
Median Survival 12.9 m 16.6 m
1-YS 53% 69%
2-YS 14% 34%

Concurrent NVB+CDDP and radiotherapy appears

more efficacious than sequential use of the same
therapeutics…

Zatloukal, Lung Cancer 2004

 VINORELBINE + CDDP: Sequential or concurrent CT+RT?

Tolerance, Gr 3-4 % pts

Sequential Concurrent
70

60

50

40

30

20

10

0
ia . a itis g y x.
en ut
ro eni g itin xi cit to
p e p ha m to ry
tro N bo op /Vo ro na
u ile m s ea
u o
Ne br ro e Ne lm
Fe Th O
a us Pu
N

But concurrent approach requires

Zatloukal, Lung Cancer 2004 patient’s selection to limit toxicity burdens
 Induction followed by concomitant CT+RT with
VINORELBINE+CDDP

Tolerance WHO G3-4, % pts

VNB-CDDP PCT-CDDP GEM-CDDP

60

50

40

30

20

10

0
Granulocytopenia Thrombocytopenia Oesophagitis Early RT stop

VINORELBINE I.V.+CDDP+RT offers the

best efficacy/tolerability ratio
Vokes, JCO 2002
BAGAIMANA dengan di RSDM?
Tinjauan Kepustakaan II

KOMPLIKASI EKSTRAVASASI PADA KEMOTERAPI

Oleh
Levana Kasumadewi, dr
NIM. S601602005
Pembimbing
Dr. Ana Rima Setijadi, Sp.P(K), FISR

PROGRAM PENDIDIKAN DOKTER SPESIALIS

PULMONOLOGI DAN KEDOKTERAN RESPIRASI
FK UNS / RSUD DR. MOEWARDI
SURAKARTA
38

2018
 MEKANISME KERJA OBAT
ANTIKANKER
Berdasarkan siklus sel, Obat
antikanker terbagi menjadi:

Cell cycle specific Cell cycle nonspecific

(CCS) (CCNS)

Antimetabolit
Epipodophyllotoxin Alkylating
Taxanes Camptothecins
Vinca alkaloids Platinum analogs
Antimicrotubule inhibitor Anthracyclines
Antitumor antibiotik 39
Gambar 2. Mekanisme obat antikanker berdasarkan cara kerjanya
40
pada siklus sel. Sumber : Antineoplastic drugs part 1,2017
Jenis obat antikanker

Jenis obat antikanker

Potensi yang
dapat
Mekanisme menimbulkan
kerja kerusakan
jaringan

41
 Tabel 1. Golongan obat antikanker berdasarkan mekanisme kerja
Golongan Sub golongan Obat
1. Alkilating Mustar nitrogen Mechlorethamine,
Cyclophosphamide, Iphosphamide,
Melphalan, Chlorambucil
Etilrnamin dan Metilmelamin Trietilen melamin, Thiotepa
Metilhidrazin Prokarbazin
Alkil sulfonat Busulfan
Platinum Cisplatin, Carboplatin, Oxaliplatin
2. Antimetabolit Analog pirimidin 5-Fluorouracil, Cytarabine, 6-
Azauridine, Floxuridine, Gemcitabine
Analog purin 6-Mercaptopurine, 6-Thioguanine,
Fludarabine, Penthostatine
Antagonis folat Methotrexate, Phemetrexate
3. Produk Alkaloid vinka Vinblastine, Vincristine, Vinorelbime
alamiah
Taxanes Paclitaxel, Docetaxel
Epipodophyllotoxin Etoposide, Teniposide
Kamptotesin Irenotecan, Topotecan
Antitumor antibiotik Dactinomycin, Daunorubicin,
Doxorubicin, Mitramicin,
Mitoxantrone, Bleomycin
Enzim 42
L-Asparginase
Sumber: Farmakologi dan terapi. Edisi 5, 2007
Tabel 1. Golongan obat antikanker berdasarkan mekanisme kerja.
4. Hormon Progestin Hidroksiprogesteron, kaproat
Estrogen Dietilstilbestrol, Etinil
estradiol
Anti estrogen Tamoksifen
Androgen Testoteron propionate,
Fluoksimesteron

5. Lain - lain Substitusi urea Hidoksiurea

Derivat metilhidrazin Prokarbazine
Penghambat tirosin Imatinib, Gefitinib, Erlotinib
kinase
Modulator respon Interferon alfa
biologik
Antibodi monoklonal Rituksimab, Transtuzumab,
Cetuksimab, Bevasizumad
43

Sumber: Farmakologi dan terapi. Edisi 5, 2007

 Jenis obat antikanker

Berdasakan potensi menimbulkan kerusakan

jaringan:

Vesikan Iritan Non Iritan

44
Tabel 2. Daftar obat vesikan kuat, vesikan lemah, iritan, non
vesikan
Vesikan kuat Vesikan lemah Iritan Non vesikan

Actinomycin D Aclacinomycin Bleomycin Asparaginase

Amsacrine Cisplatin Carboplatin Bevacizumab
Bisantrene Dacarbazine Cyclophosphamide Cetuximab
Daunorubicin Docetaxel Carmustine Cytarabine
Doxorubicin Etoposide Gemcitabine Estramustin
Epirubicin Esorubicin Ifosfamide Interferon
Idarubicin Fluorouracil Irinotecan Interleukin
Mechlorethamin Liposomal Melphalan Methotrexat
e Menogaril Pentostatine e
Mitomycin C Mitoxantron Plicamycin Panitumuma
Vinblastine Oxaliplatin Streptozocin b
Vincristine Paclitaxel Topotecan Rituximab
Vindesine Trastuzumab
Vinorelbine 45

Sumber: Fakultas Kedokteran Universitas Udayana. 2013

 Take home message

 Vinorelbine is endorsed by ESMO – NCCN guidelines

– PDPI guideline in 1st Line as single agent, and
combination
 Manageable tolerance profile. Minimal Alopecia

46
 Thank You

TERIMAKASIH