COLORECTAL CANCER

ARIF ZUHAN
Sub Bag BEDAH Digestif FK UNRAM /RSUDP NTB
 CRC: Overview
Symptoms: blood in
Characteristics:
stools, rectal bleeding, 
uncontrolled cell growth
anemia, weight loss,
in the colon, rectum or
fatigue, abdominal pain,
appendix
bowel obstruction

Etiology: diet, Diagnosis: typically

environmental factors, through sigmoidoscopy
underlying genetic or colonoscopy
disorders (some cases) (preferably)

Screening: effective at
Outcomes: associated preventing cancer,
with high mortality rates reducing mortality,
improving prognosis

http://www.hopkinscoloncancercenter.org; http://www.gponline.com/Clinical/article/1137481/Clinical-Review---Colorectal-cancer/
 Etiology
5–10% of cases Genetic risk factors:11
Hereditary
Hereditary non-polyposis
non-polyposis CRC
CRC (HNPCC)
(HNPCC)
inherited1 Familial
Familial adenomatous
adenomatous polyposis
polyposis (FAP)
(FAP)

Non-dietary risk factors:1,2

1,2

Smoking tobacco, inflammatory bowel disease,

previous malignant disease, metabolic syndrome
90–95% of cases Chronic NSAID use
sporadic1
Dietary risk factors:33
Red meat, processed meat, alcohol
Possibly high iron diet, cheese, animal fats, sugars
Fish and milk may be protective

NSAID, non-steroidal antinflammatory drug

1. Labianca R, et al. Ann Oncol 2010; 21 (Suppl. 5): v70–v77

2. Esposito K, et al. Diabetes Care 2012; 35: 2402–2411
3. World Cancer Research Fund / American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a
Global Perspective. Washington DC: AICR, 2007
 Many patients present with already metastatised
CRC (mCRC) at time of diagnosis
~25% of patients present
with mCRC
(Synchronous metastases) 1,3
1,3*

~50% of patients will

develop metastases
(Metachronous metastases)1,3
1,3

The liver is the most common organ site for CRC metastases22

*There is no consensus about the precise definition of synchronous metastases. In studies they are often defined as metastases detected by preoperative screening, or
during resection of the primary tumor, and occurring within 3, 6, or even 12 months of the initial diagnosis of CRC3

1. Van Cutsem E, et al. Ann Oncol 2014; 25 (Suppl. 3): iii1–iii9

2. DiSibio G, French SW. Arch Pathol Lab Med 2008; 132: 931–939
3. Mekenkamp LJ, et al. Br J Cancer 2010;103:159–164
 CRC is associated with high mortality rates
Account for 8.5% of all
cancer-related deaths

Fourth highest mortality among cancers

~700,000 deaths from CRC ~ 11% of patients diagnosed

worldwide with CRC survive for ≥5 years

GLOBOCAN 2012. Ferlay J, et al. Int. J. Cancer: 136, E359–E386 (2015)

 Survival rates depend on disease spread

5-year relative survival† of patients with CRC (2002–2011)1

% patients
Median overall survival
100 of patients with
89.8
90 mCRC: ~2 years22
80
70.5
70
60 After resection of liver
50 metastases, 5-year survival
40 rates of
30 30–>50% reported22
20 12.9
10
0 Recent studies reported
Localized* Regional** Metastatic median OS of more than 30
*Confined to primary site;**spread to regional lymph nodes; †survival relative
months after start of 1st line
to similar individuals who do not have cancer therapy3-5
3-5

1. Howlader N, et al. (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute, Bethesda, MD. Available at
http://seer.cancer.gov/csr/1975_2011/ Last accessed November 2014
2. Van Cutsem E, et al. Ann Oncol 2010; 21 (Suppl. 5): v93–v97;
3.Van Cutsem E, et al. J Clin Oncol 2015;33:692–700;
4. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075; 5. Lenz HJ, et al. ESMO 2014 (Abstract No. 501O)
 Patient pathway in CRC
Person with suspected Emergency
CRC presentation

Patient information

Investigating and
diagnosing CRC

Staging CRC

Managing local tumors or advanced or

metastatic CRC

Ongoing care/support and

follow up

Adapted from http://pathways.nice.org.uk/pathways/colorectal-cancer#content=view-node%3Anodes-information

Diagnosis And Staging
DIAGNOSIS
 Anamnesis
 Physical Examination
 Lab Study :
 Colonoscopy
 Foto Barium enema double contras
 CT Scan Abdomen / CT pneomocolonography
 X Photo Thorax
Anamnesis
 Perdarahan per anum diserta i peningkatan frekuensi defekasi
dan/atau diare selama minimal 6 minggu (semua umur);
 Perdarahan per anum tanpa gejala anal (di atas 60 tahun);
 Peningkatan frekuensi defekasi atau diare selama minimal 6
minggu (di at as 60 tahun);
 Massa teraba pada fossa iliaka dekstra (semua umur);
 Massa intraluminal di dalam rektum;
 Tanda-tanda obstruksi mekanik usus;
 Setiap pasien dengan anemia defisiensi Fe (Hb <11 g% untuk
laki·laki atau <10 g% untuk perempuan pascamenopause);
 SIGN AND SYMPTOM
2009
2010 Signs and Symptoms

96
 Most frequent :
100
90  Lower GI Bleeding :
80 26%
70 63  Change bowel habit :
60 53
17%
50 42
40
37
31
 Pain : 14,2%
29
30 21
20
10
0

B. P. Budono ,I. Riwanto , A. Maleachi, K. Sety adi : Incidence of Colorectal Cancer in

Dr. Kariadi General Hospital Semarang 2009 - 2010 :
Pemeriksaan Fisik:
 3 Hal penting Colok Dubur:
 Keadaan tumor
 Mobilitas tumor:
 Ekstensi dan ukuran tumor
 Dilakukan pada setiap pasien dengan gejala anorektal;
 Menetapkan keutuhan sfingter ani;
 Menetapkan ukuran dan derajat fiksasi t umor pada rektum 1/3
tengah dan distal.
 Pemeriksaan penunjang
Kolonoskopi
- Biopsi, derajat histopatologis pra bedah
- Polip kolon
- Synchronous tumor
Foto Barium
Enema
double
Contras
Keunggulan
 Memiliki sensitivitas tinggi di
dalam mendiagnosis KKR;
 Toleransi pasien baik;
 Dapat memberikan informasi
keadaan di luar kolon,
termasuk untuk :
 menentukan stadium melalui
penilaian invasi lokal,
 metastasis hepar,
 kelenjar getah bening.
CT colonography (pneumocolon
CT)
Kelemahan
 Tidak dapat mendiagnosis polip berukuran
<10 mm;
 Memerlukan radiasi yang lebih tinggi;
 Tidak dapat menentukan adanya metastasis
pada kelenjar getah bening apabila kelenjar
getah bening tidak membesar;
 Jumlah spesialis radiologi yang
berkompeten masih terbatas;
 CT scan yang mumpuni masih terbatas;
 Bila belum terarah ke keganasan kolorektal
 CT scan abdomen bukan CT
colonagraphy;
 Persiapan kurang baik,  sulit
diinterpretasi
 Tidak dapat dilakukan biopsi atau
polipektomi
Penetapan stadium pra-operatif

 Deteksi perluasan tumor primer dan infiltrasinya

 Deteksi kelenjar getah bening regional dan para-aorta
 Deteksi metastasis ke hepar dan paru-paru;
 Deteksi metastasis ke cairan intraperitoneal.
Penetapan stadium pra-operatif pada karsinoma
kolan
 Rekomendasi Tingkat A
 Seluruh pasien karsinoma kolon yang akan menjalani pembedahan
elektif, harus menjalani pemeriksaan pencitraan hepar dan paru
pre-operatif dengan CT scan atau MRI, dan foto toraks.
 Pada pasien yang harus menjalani bedah darurat, dilakukan
pemeriksaan ultrasonografi intra-operatif dan pemeriksaan CT
scan atau MRI pascaoperatif.
 Rekomendasi Tingkat C
 Apabila fasilitas CT scan atau MRI tidak: tersedia, maka
ultrasonografi trans-abdominal dapat digunakan untuk mendeteksi
metastasis kehepar.
 Rekomendasi Tingkat A
 Seluruh pasien karsinoma rektum harus menjalani pemeriksaan
ultrasonografi endoluminal trans-rektal.
 Seluruh pasien karsinoma rektum yang akan menjalani pembedahan elektif,
harus CT scan atau MRI hepar dan paru-paru preoperatif , dan foto thoraks.
 Bila bedah emergensi, pemeriksaan ultrasonografi intra-operatif dan
pemeriksaan pencitraan CT scan atau MRI post-operatif.
 Rekomendasi Tingkat C
 Bila ERUS tidak tersedia, pemeriksaan colok dubur untuk menentukan
kurabilitas tumor.
 CT scan atau MRI tidak tersedia, maka ultrasonografi trans-abdominal 
untuk metastasis ke hepar.

Penetapan stadium pra-operatif pada

karsinoma rekti
Sistem Pentahapan (Staging}

 Sistem TMN ini dibuat oleh American Joint Committee on

Cancer (AJCC) dan International Union Against Cancer
(UICC).
 mulai digunakan pada 1 Januari 2010
TNM
  Evaluasl makroskopi meliputi:
 1. Jenis reseksi: hemikolektomi, low anterior resection (LAR atau rektosigmoidektomi),
total mesorectal excision (TME);
 2. Panjang usus yang direseksi;
 3. Lokasi tumor: sekum, kolon transversum, kolon asendens, kolon desendens, sigmoid, relt
um;
 4. Bentuk atau pertumbuhan massa tumor: sirkuler, polipoid, sesll, bertangkal, ulseratif;
 5. Ukuran tumor: ukuran diameter terbesarnya;
 6. Kondisi mukosa non-tumor: adakah radang atau polip
 7. Perluasan tumor: submukosa, lapisan muskularis, serosa;
 8. Keadaan di sekitar tumor: adakah perforasi, perlekatan, radang;
 9. Batas sayatan proksimal distal: be bas atau tidak bebas tumor, bila sangat dekat dengan
tumor berapa jaraknya;
 10. Batas sayatan lateral (lateral clearance): batas sayatan mesenterium atau mesorektal:
bebas atau tidak bebas dari tumor
 11. Khusus pada operasi TME penilalan mesorektum ada 3 kategori yaitu:
 a. Komplit: mesorektum utuh, permukaan licin, bila ada defek kedalamannya kurang dari 5 mm;
 b. Kurang komplit: permukaan mesorektal kasar, ada defek dengan ked ala man lebih dari 5 mm
tetapi tidak mencapai lapisan muskularis propria;

EVALUASI PATOLOGI ANATOMI

 12. Evaluasi makroskopik KGB: berapa jumlah KGB yang
mengandung sel tumor.
 Yang dimaksud dengan KGB regional adalah KGB
perikolika/mesenterial, perirektal. dan yang mengikuti arteri ileocoliea,
colica dextro, media dan sinistra, cabang-cabang arteri mesenteriea
inferior, cabang cabang arteri iliaca interna
 13. Metastasis kelenjar getah bening dinyatakan tidak ada apabila 12-
15 KGB dinyatakan negatif. Apabila ditemukan ada metastasis KGB
disebutkan jumlahnya dan letaknya.
Evaluasi mikroskopik
 Grading histologik, diferensiasi tumor, grading tumor;
 Stadium histopatologik, mengikuti sistem TNM;
 lnvasi angiolimfatik ada atau tidak ada ;
 Laporan bebas tidaknya balas sayatan t erhadap masa tumor, apabila
jarak tumor dengan batas say a tan <1 em, diukur dalam satuan mm;
 Bat as mesenterium atau batas keliling mesorektum pada operasi
TME dan LAR apabila ditemukan sel tumor dengan ja rak <1 mm
dari batas sayatan
 sirkumferensial dinyatakan tidak bebas tumor;
 Kondisi mukosa usus non tumor: adakah radang, polip, dan lain-lain;
 KGB:
 jumlah KGB.
 letak KGB
 ada tidaknya anak sebar pad a KGB tersebut.
 Apabila ditemukan nodul tumor >3 mm di jaringan lemak
perikolorektal dan tidak mengandung sisa jaringan limfoid
dianggap sebagai penyebaran pada KGB regional.
 Apabila batas nodul tersebut irregular secara mikroskopik maka
diklasifikasikan sebagai V1 (mikroskopik invasi vena), apabila
secara makroskopik sudah terlihat ireguler termasuk dalam
klasifikasi V2.
 Lain-lain: Perilaku pertumbuhan tumor infiltratif atau invasif,
ada atau tidak ada invasi perineural.
Pentahapan patologik (sistem TNM)
 Parameter-parameter berikut harus dilaporkan:10
 Derajat diferensiasi tumor;
 Kedalaman penetrasi (T);
 Jumlah KGB yang dievaluasi dan berapa yang positif (N);
 Status margin proksimal, distal, dan radial.
 lnvasi limfovaskular
 lnvasi perineural
 Deposit tumor ekstranodal
 Uji mutasi KRAS
 Mutasi pada kodon 12 dan 13 di ekson 2 regio penyandi dalam gen KRAS
merupakan faktor prediksi tidak adanya respons terapi terhadap antibodi anti
EGFR.
 Uji mutasi BRAF
 Mutasi BRAF V600E tampaknya memiliki prognosis yang lebih buruk.
 Tidak cukup data untuk menganjurkan terapi anti-EGFR pada kemoterapi aktif
linipertama berdasarkan status mutasi BRAF V600E.
 Data terbatas memberi kesan bahwa adanya mutasi V600E berkaitan dengan
kurangnya aktivitas antitumor terapi antibodi monoklonal anti-EGFR jika
diberikan pada pasien yang memburuk pada terapi lini pertama
 Uji microsatellite instability (MSI)
 Panel NCCN  pemeriksaan protein mismatch repair (MMR) pada KKR <50
tahun sindrom Lynch pada populasi tersebut.
 Uji M MR juga harus dipertimbangkan pada semua pasien stadium II, karena
pasien stadium II dengan high-grade MSI (MSI-H) mungkin memiliki prognosis
lebih baik dan tidak mendapatkan manfaat dari terapi ajuvan 5-FU.

Evaluasi patologi molekular

 Treatment options for primary and metastatic CRC
 Surgical techniques:
 Polypectomy (removal of polyps)
 Colon resection
 Partial colectomy, colectomy, diverting colostomy

 Metastasectomy (e.g. R0, R1, R2)

 Ablation/embolization
 Medical
 Chemotherapy
 Targeted therapies/biological agents
 Radiotherapy (mainly associated with treatment of rectal and anal cancer)

A multidisciplinary team approach is crucial to optimize patient outcomes due

to the multimodality treatment options

American Cancer Society.

Available at www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-treating-by-stage-colon
 Treatment by stage
Stage Typical treatment

Polypectomy or local excision through a colonoscope

0
Colectomy may be needed for larger tumors
I Partial colectomy
II Partial colectomy possibly with adjuvant chemotherapy
Partial colectomy with adjuvant chemotherapy
III
Radiotherapy may be required

IV Surgery, chemotherapy and/or targeted therapies

American Cancer Society. Available at www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-treating-by-stage-

colon
 Assessment of resectability determines
treatment strategies (ESMO guidelines 2014)
Clinical presentation ESMO Group

Primarily technically R0-resectable liver

or lung metastases Group 0

Potentially R0 resectable metastatic

disease with curative intention Group 1

Disseminated disease, technically

‘never’/ unlikely resectable – Group 2
intermediate intensive treatment

Never-resectable metastatic disease –

non-intensive/sequential treatment Group 3

R0, Resection for cure or complete remission

Van Cutsem E, et al. Ann Oncol 2014;25 (suppl 3): iii1–iii9
 Treatment for mCRC: Surgical options
Multidisciplinary team evaluation
Liver metastases:1
• 25–33% resectable at diagnosis
• 66–75% initially non-resectable
• 10–40% initially non-resectable
might become resectable
Surgical resection of liver metastases
if feasible and appropriate, based on
technical and oncological factors, either
at diagnosis or after conversion to
resectability by therapy1,2
*May be combined with surgery to achieve complete resection,
e.g. CARe (combined ablation and resection)
If surgical resection of liver metastases is not
technically feasible due to tumor location,
oligometastatic disease or comorbidities, other
therapies may be used3
Liver-directed therapies3
• Ablative techniques* (e.g. radiofrequency
ablation, microwave ablation)
• Hepatic artery infusion*
• Chemoembolization
• Radioembolization (e.g. radioactive yttrium90
microspheres)
• Stereotactic body radiation therapy
1. Haraldsdottir S, et al. Ther Adv Med Oncol. 2013;5:221–234
2. Adams RB, et al. HPB (Oxford) 2013;15:91–103
3. Clark ME, et al. J Gastrointest Oncol 2014;5:374–387
 Treatment of mCRC: Surgical resection
 Classification of residual tumor after surgery is1:
 R0, cure or complete remission
 R1, microscopic residual tumor
 R2, macroscopic residual tumor
 ESMO guidelines2 recommend that:
 Hepatic R0 resection provides the best chance of long-term survival (5-year survival
rates of up to 20%–45%) for patients with mCRC (liver metastases)
 However, 75% of these patients will suffer a relapse following resection of hepatic
metastases
 There is no role for palliative resection of metastases
 Resection of lung metastases in parallel with resection of liver metastases offers long-
term survival in carefully selected patients
 5-year survival rates of 25%–35%

MDT, multidisciplinary team 1. Wittekind C, et al. Cancer 2009; 115:3483-3488.

2. Van Cutsem E, et al. Ann Oncol 2014; 25 (Suppl. 3): iii1–iii9
 Treatment of CRC: Chemotherapy options
Agents1 Class Mechanism of action

5-fluorouracil (5-FU) Fluoropyrimidine Antimetabolite activity; administered intravenously

Capecitabine Oral fluoropyrimidine Converted to 5-FU after oral administration

Prodrug leading to DNA adduct formation and induction of

Oxaliplatin Platinum-based compound
apoptosis
Irinotecan Topoisomerase inhibitor Cytotoxic to cells in S-phase
Other2 Class Mechanism of action
Enhances the effect of 5-FU by inhibiting thymidylate
Folinic acid (FA)/leucovorin Adjuvant
synthase3

1. Burn J, et al. Dig Dis 2012; 30 (Suppl 2): 39-47

2. No authors listed. J Clin Oncol 1992;10:896–903
3. Chu E, et al. Oncologist 1996;1:255–260
 Treatment of mCRC: Chemotherapy regimens recommended in
1st and 2nd line by the NCCN guidelines5 (1)

Regimen* IRI OXALI LVa Fluoropyrimidine Schedule

400 mg/m2 over

Fluorouracil 400 mg/m2 bolus then
85 mg/m2 two hours days 1 Every 2
FOLFOX41 - 600 mg/m2 over 22 hours days 1 and
day 1 and 2 before weeks
2
fluorouracilb

Fluorouracil 400 mg/m2 bolus day 1, Every 2

100 mg/m2 400 mg/m2 over
FOLFOX6 2
- followed by 2400 to 3000 mg/m2c weeks
day 1 two hours day 1
over 46 hours, continuous infusion

Fluorouracil 400 mg/m2 bolus day 1,

Modified 85 mg/m2 350 mg/m2 over Every 2
- followed by 2400 mg/m2 over 46
FOLFOX3,4 day 1 two hours day 1 weeks
hours

*All doses shown are for intravenous (IV) administration, except capecitabine; aLeucovorin doses given for the d,l racemic mixture;
b
Note: The original trial report indicated a leucovorin dose of 200 mg/m 2 daily, but this was an error, and the correct dose used in
the protocol was 400 mg/m2; c2400 mg/m2 dose is commonly used
IRI, irinotecan; OXALI, oxaliplatin; LV, leucovorin; 5-FU/CAPE, fluorouracil/capecitabine

1. Goldberg R, et al. J Clin Oncol 2004;22:231–30; 2. Tournigand C, et al. J Clin Oncol 2004;22:229–237;
3. Cheeseman SL, et al. Br J Cancer 2002; 87:393–399; 4. Hochster HS, et al. J Clin Oncol 2008; 26:3523 –3529 ;
5. NCCN Guidelines Version 2.2015 Colon Cancer
Treatment of mCRC: Chemotherapy regimens recommended in 1st and 2nd line
by the NCCN guidelines5 (2)
Regimen* IRI OXALI LVa Fluoropyrimidine Schedule
180 Fluorouracil 400 mg/m2 bolus day 1,
400 mg/m2 over
FOLFIRI 1
mg/m2 followed by 2400 to 3000 mg/m2b Every 2 weeks
two hours day 1
day 1 over 46 hours, continuous infusion
Fluorouracil 400 mg/m2 bolus day 1,
180
Modified 20 mg/m2 on followed by 600mg/m2 over 22 Every 2
mg/m2
FOLFIRI2 both day 1 and 2 hours, continuous infusion on day 1 weeks
day 1
and day 2
165 200 mg/m2
85 mg/m2 Fluorouracil 3200 mg/m2 over 48 Every 2
FOLFOXIRI 3
mg/m2 leucovorin over
day 1 hours weeks
day 1 two hours day 1
180 400 mg/m2 Fluorouracil 400 mg/m2 bolus day 1,
85 mg/m2 Every 2
FOLFIRINOX4 mg/m2 leucovorin over followed by 2400 mg/m2 continuous
day 1 weeks
day 1 two hours day 1 infusion over 46 hours

*All doses shown are for intravenous (IV) administration, except capecitabine; aLeucovorin doses given for the d,l racemic mixture;
b
2400 mg/m2 dose is commonly used; IRI, irinotecan; OXALI, oxaliplatin; LV, leucovorin; 5-FU/CAPE, fluorouracil/capecitabine

1. Tournigand C, et al. J Clin Oncol 2004;22:229–237; 2. Lee MA, et al. Korean J Intern Med 2005;20:205–209;
3. Falcone A. J Clin Oncol 2007; 25:1670–1676; 4. Ychou M, et al. Cancer Chemother Pharmacol 2008;62:195–201 ;
5. NCCN Guidelines Version 2.2015 Colon Cancer
 Treatment of mCRC: Chemotherapy regimens recommended in 1st
and 2nd line by the NCCN guidelines3 (3)

Regimen* IRI OXALI LV• Fluoropyrimidine Schedule

130 Capecitabine† 1000 mg/m2
Every 3
XELOX1 mg/m2 orally twice per day on days 1 to
wks
day 1 15
250 Capecitabine† 1000 mg/m2
Every 3
XELIRI2 mg/m2 orally twice per day on days 1 to
wks
day 1 14

†
Capecitabine (XELODA); *All doses shown are for intravenous (IV) administration, except capecitabine; IRI, irinotecan; OXALI, oxaliplatin; 5-FU/CAPE,
fluorouracil/capecitabine

1. Hochster HS, et al. J Clin Oncol 2008; 26:3523–3529

2. Fuchs CS, et al. J Clin Oncol 2007;25:4779–4786
3. NCCN Guidelines Version 2.2015 Colon Cancer
 Other chemotherapy regimens
Regimen* IRI OXALI LV• Fluoropyrimidine Schedule
Every wks for 4
125 Fluorouracil 500 mg/m²
IFL1** - 20 mg/m² wk; repeated
mg/m² bolus
every 6 wk
85 mg/m2 500
Fluorouracil 500 mg/m2
FLOX 2***
- on weeks mg/m2 cycle x 3
bolus weekly x 6
1,3 and 5 weekly x 6

IRI: irinotecan, OXALI: oxaliplatin, LV: leucovorin

• IFL regimen is more toxic than infusional 5-FU regimens and is no longer considered appropriate for
use in combination with oxaliplatin or irinotecan 2
• FLOX is being used mainly in northern Europe

1. Hurwitz H, et al. New Engl J Med 2004;350:2335–2342;

2. NCCN Guidelines Version 2.2015 Colon Cancer.
The ‘Hallmarks of Cancer’ described in 2000
Sustaining proliferative signalling

Evading

Ɨ
Resisting cell
growth
death
suppressors

Activating
Inducing
invasion and
angiogenesis
metastasis

∾
Enabling replicative immortality

Adapted from: Hanahan D, Weinberg RA. Cell 2000; 100: 57–70

 Therapeutic targeting underway for all the hallmarks
of cancer EGFR inhibitors

Proapoptotic Cyclin-dependent
BH3 mimetics kinase inhibitors

Ɨ
Aerobic glycolysis
inhibitors Immune-activating
anti-CTLA4 mAb

Inhibitors of
VEGF signaling
∾ Telomerase inhibitors

PARP inhibitors Selective anti-

inflammatory drugs
CTLA-4, cytotoxic T-lymphocyte antigen-4;
EGFR, epidermal growth factor receptor;
HGF, hepatocyte growth factor;
PARP, poly ADP ribose polymerase; Inhibitors of HGF/c-Met
VEGF, vascular endothelial growth factor
Adapted from: Hanahan D, Weinberg RA. Cell 2011; 144: 646–674
 Growth factors contribute to all phases of tumor
progression
3. Carcinoma in situ or
1. Driver mutation
intraepithelial neoplasia

2. Clonal 4. Invasion
expansion • TGF-β
• IGF1 • HGF
• EGFFibroblast • FGF
9.
Metastasis
• EGF
Macrophage

Lymphatic vessel
8.
Angiogenesis
• VEGF Arterial capillary
5.
• FGF Dissemination
• HB-EGF
7. Resistant
clones 6. Micrometastases
• TGF-α Chemotharapy
• NRG &
• CSF-1 Radiotherapy

CSF-1, colony stimulating factor 1; FGF, fibroblast growth factor; HB-EGF, heparin-binding EGF; NRG, neuregulin;
TGF, transforming growth factor
Witsch E, et al. Physiology (Bethesda) 2010; 25: 85‒101
 Therapeutic targeting of EGFR:
One hallmark of cancer
EGFR inhibitors

Proapoptotic Cyclin-dependent
BH3 mimetics kinase inhibitors

Ɨ
Aerobic glycolysis
inhibitors Immune-activating
anti-CTLA4 mAb

Inhibitors of
VEGF signaling
∾ Telomerase inhibitors

Selective anti-
PARP inhibitors inflammatory drugs

Inhibitors of HGF/c-Met
Hanahan D, Weinberg RA. Cell 2011; 144: 646–674
 EGFR activation drives tumor growth

Akt, protein kinase B; DAG, diacylglycerol; ERK, extracellular signal-related kinase; JAK, Janus kinase;
MEK, mitogen-activated protein kinase kinase; MKP1, MAPK phosphatase-1; PI3K, phosphoinositide 3-kinase;
PKC, protein kinase C; PLC, phospholipase C; PTEN, phosphatase and tensin homolog;
STAT, signal transducers and activators of transcription Lee J, Moon C. Exp Biol Med 2011; 236: 375–389
High EGFR expression in mCRC
Type of tumor Tumors with
EGFR expression
Colorectal
Colon1 Up to 77%
Advanced CRC2 Up to 90%
SCCHN1 95%
Pancreas1 Up to 50%
SCCHN
Esophageal1 Up to 88%
Breast1 Up to 91%
NSCLC1 Up to 80%
NSCLC Ovary1 Up to 70%
Prostate1 Up to 100%
Glioblastoma1 Up to 60%
NSCLC, non-small-cell lung carcinoma; SCCHN, squamous cell carcinoma of the head and neck

1. Arteaga C. Semin Oncol 2003;30(suppl 7):3–14; 2. Saif MW. Expert Opin Investig Drugs 2010;19:357–369
 Anti-EGFR therapy and colorectal cancer
Anti-EGFR therapy

Agents that target EGFR signaling, such as anti-EGFR antibodies, inhibit several
mechanisms associated with the development of cancer, including survival,
proliferation, metastasis and angiogenesis

HER, human EGFR; MAPK, mitogen-activated protein kinase; SOS, son-of-sevenless

Adapted from Ciardiello F, Tortora G. N Engl J Med 2008; 358: 1160–1174

NEOADJUVAN CHEMOTX RESECTABLE
STAGE IV
CONVERSION CHEMOTX IN UNRESECTABLE
STAGE IV
PSEUDO ADJUVANT CHEMOTX FOR LIVER
METASTATES
PERIOPERATIVE CHEMOTHERAPY
 Summary
● CRC is associated with high mortality, but survival rates can be increased
with interventional treatment
● Liver metastases are the most common metastases in patients with CRC
and account for the majority of deaths
● Treatment is multimodal and dependent on stage of disease and assessment
of resectability
● Growth factors contribute to many of the hallmarks of cancer, including
clonal expansion, invasion, cell survival, angiogenesis and metastasis
● EGFR signaling is a central pathway in many of above processes.
Thank You