Oesophageal-, and gastric tumor

SZTE Onkoterápiás Klinika

Epidemiology of oesophageal cancer

• Increasing incidence, 250-300 new tu/year in

Hungary

• Male:female = 10:1

• Mainly squamosus cell- and adenocc.

• unfavourable prognosis, after resection 1 year

survival 70%, 2 year 25-30%, 5 year 15-18%

• Frequently advanced disease at dg. (inop.T3-T4)

Localisation

• Neck part: fraom the cricoid cartillage to thorax

• Thoracic part:

upper third to the bifurcation(18-24 cm)

midle. third bifurcation (24-32 cm)

lower third up to 40 cm

abdominal part: cardio-oesophageal junction

cardia ca 2-3 cm.

• Squanosus cell cancer: intraluminar, extraluminar intramural frequent invasion into the neighbouring organs (aorta, trachea

• Adenocc: Barreth metapl.

• Lgl: to periesophageal, supraclavicular, mediastinal and truncus coeliaca region

Spread

• T1: lamina propria,

submucosa

• T2: muscularis propriae

• T3: adventitia

• T4: infiltr. of the

surrounding structures

• N1: Regional lgl. met.

• M1: distant met

TNM

Diagnostic workup• Anamnesis: more frequent in the case of

gastric resection, hypopharynx tumor,

gastro-esophageal reflux disease (GERD)

smoking, alcohol, sharp spicy meals

• Physical signs : weight loss, swalloving

problems

• Endoscopy: oesophagoscopy, ebdoscopic

USG, bronchoscopy

• Imaging: barium swallow, thorax CT

abdominal UH/CT, PETCT

• Biopsy, histology

• Laboratory values

Tracheo-oesophageal fistule

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

30mg/m2 CISPLATIN weekly1x

radiation

RADIO-CHEMOTHERAPY

Makr. tumor and safety margin, lat:2 cm, craniocaudal: 5-5 cm,

including potential intramuralis and lymphatic spread.

Dose: 45 Gy + boost 1,8 Gy fr. up to 66-70 Gy

3D

planning

RT procedures

Pat. Positioning

immobilisation

CT

MR-PET-CT

Dynamic PTV reduction

Plan evaluation

Irrad, regular

portal imaging

Palliative

brachyther.

3x5 Gy

Gastric cancer

Gastric Cancer - Epidemiology

• 2nd leading cause of cancer mortality worldwide

(7th in the US)

• > 60% of new cases are in developing countries

Sleisenger and Fordtran (9th Edition)

Gastric Cancer - Epidemiology

http://info.cancerresearchuk.org/

cancerstats

Sleisenger and Fordtran (9th Edition)

Gastric Cancer - Epidemiology

http://info.cancerresearchuk.org/cancerstats

�Diet appears to be a significant factor.

�A diet high in smoked foods and low in fruits

and vegetables may increase the risk of gastric

cancer.

�Other factors related to the incidence of gastric

cancer include chronic inflammation of the

stomach, anemia, gastric ulcers, H. pylori

infection, genetics, Smoking, a diet poor in

fiber, and Drink alcohol

Etiology

Gastric Cancer

http://www.rnpedia.com/home/notes/medical-surgical-nursing-notes/gastric-cancer

Carl-McGrath S, et

al. Cancer Therapy

(2007).

Gastric Cancer – “Correa Sequence”

“Vogelgram” of CRC

http://www.hopkinscoloncancercenter.org

Increasing risk

NormalChronic

gastritis

Mucosal

atrophy

Intestinal

metaplasia

Intestinal-type

carcinomaDysplasia

Potentially reversible

Not HGD

Hartgrink HH, et al. Lancet (2009).

Gastric Cancer - Pathogenesis

• H. pylori (HP) is main pathogenic factor in development of chronic AG and IM (AG risk: 1-3%/yr of infection)

• Classified as class I carcinogen by WHO in 1994– Plays role in ∼ 60% of gastric ca cases

• Atrophic gastritis and IM may regress after HP eradication – Healthy carriers don’t have ↓ gastric ca post-eradication– Those with premalignant lesions do � ? “point of no return”

• Only 1-2% of HP-infected pts develop gastric ca (2-3-fold increased risk)

Tan YK and Fielding JWL. Eur J Gastroenterol and Hepatol (2006).Vauhkonen M, et al. Best Prac & Res Clin Gastroenterol (2006).

Carl-McGrath S, et al. Cancer Therapy (2007).Sleisenger and Fordtran (9th Edition)

Gastric Cancer – Role of H. pylori

http://www.jpp.krakow.pl/journal/archive/12_05/articles/01_article.html

Gastric Cancer – Clinical Presentation

• Initial diagnosis usually delayed due to lack of early symptoms

– Only 50% have non-specific GI sxs (i.e. dyspepsia) �indistinguishable from benign disease

– Sxs may improve with PPI (“healing” of malignant ulcer � up to 37% have ca missed on EGD)

– Should withhold PPI for new dyspeptic sxs in pts > 45 y.o. until after EGD

• Up to 90% of Western gastric ca pts first present with advanced cancer

Carl-McGrath S, et al. Cancer Therapy (2007).Tan YK and Fielding JWL. Eur J Gastroenterol and Hepatol (2006).

Gastric Cancer – Staging Systems

• Defines 2 distinct histological entities �

different clinically and epidemiologically

• Clinical significance is limited

Carl-McGrath S, et al. Cancer Therapy (2007).

Vauhkonen M, et al. Best Prac & Res Clin Gastroenterol (2006).

Gastric Cancer – Staging Systems

• TNM: most important clinical prognostic factor

http://www.hopkins-gi.orghttp://www.medscape.com/viewarticle/543068_3

Spread

•Multicentricity characterizes up to 20% of gastric cancers.

•Direct extension (lesser and greater omentum, liver and

diaphragm, spleen, pancreas, transverse colon)

•regional and distant nodal metastases:perigastric, gastroepiploic,

and porta hepatis lymphnode regions

•hematogenous metastases (liver, lungs, bone, brain); and

peritoneal metastases.

Pathology

• Adenocarcinoma is the predominant form: 95%– Subtypes: intestinal or diffuse; mixed types (rare). Often preceded by

intestinal metaplasia.

– Diffuse-type cancers are composed of infiltrating gastric mucous cells that infrequently form masses or ulcers.

• Primary lymphoma of the stomach is increasing in frequency

• Stromal tumors GI stromal tumors (GISTs) are mesenchymal tumors of the GI tract, most commonly arising from the stomach. GISTs commonly express KIT (CD117)

• Other histologic types Infrequently, squamous cell carcinomas, small-cell carcinomas, and carcinoid tumors. Metastatic spread of disease from primaries in other organs(eg, breast cancer and malignant melanoma) is also seen occasionally.

Prognostic factors

• Stage, PFS

• Patients with cancers of the diffuse type fare worse than those with intestinal-type lesions.

• Aneuploidy may predict a poor prognosis in patients with adenocarcinoma of the distal stomach.

• High plasma levels of vascular endothelial growth factor (VEGF) and the presence of carcinoembryonic antigen (CEA) in peritoneal washings predict poor survival in surgically resected patients.

• As with colorectal cancer, intratumoral levels of dihydropyrimidine dehydrogenase (DPD) may be prognostic of gastric cancer. Low levels appear to predict better response to fluorouracil (5-FU)–base chemotherapy and longer survival.

Diagnose• Anamnesis: gastric diseases, GERD,

gastritis, ulcus, polyp, very salty, spicy dietmight dispose, helicobacter pylory?

• Physical examinations: loss of weight, hindered gastric discharge, pain

• Endoscopy: gastroscopy

• Imaging: gastric rtg?,

• abdominal UH/CT

chest rtg, chest CT

Biopsy, histology

• Labors

Screening and diagnosis

• Screening is effective in high-incidence areas. Mass screening, as has been practiced in Japan since the 1960s, has probably contributed to the 2.5-fold improvement in long-term survival compared with Western countries, though differences in biology may also play a role.

• Endoscopy.

• CT scan Once a diagnosis has been established and careful physical examination and routine blood tests have been performed, a CT scan of the chest, abdomen, and pelvis

• Endoscopic ultrasonography (EUS)

• Capsule video endoscopy A capsule containing a tiny camera is swallowed by the patient. 2 pictures per second are taken. The capsule can be especially helpful in imaging the small intestine.

• Laparoscopy Laparoscopy is particularly suited to detect small-volume visceral and peritoneal metastases missed on CT prior to curative intent locoregional - or preoperative CRT

• PET scan may be used to show metastatic disease and may also be helpful in assessing response to neoadjuvant therapy.

Gastric Cancer - Treatment

• For Tis, studies have shown > 95% 5- and 10-yr survival with endoscopic resection

• Lap gastrectomy recommended for T1N0/T2N0 � scarce long-term data

• Pre- and post-op XRT doesn’t change survival

• Adjuvant/neoadjuvant chemo has minimal survival benefit– May benefit pts with advanced gastric ca

• Post-op chemo/XRT might improve survival

Hartgrink HH, et al. Lancet (2009).

Gastric Cancer – The Japan Story

• In 1960, gastric ca accounted for 51.6% of deaths

in men and 38.4% in women

• Mass screening program started for > 40 y.o.

• Significant increase in diagnosis of early gastric ca

and improved survival

• Now 60% of gastric cancers are diagnosed as early

cancers (10-20% in Western countries)Tan YK, et al. Eur J Gastroenterol & Hepatol (2006).

Is Gastric Cancer Preventable?

• Preceded by very prolonged latency period

• Precancerous cascade exists (IGCA)

• H. pylori is responsible for majority of gastric ca.

• Serum markers show some relation with cancer risk

– Pepsinogen: ↓ levels associated with atrophic gastritis

– HP Abs: Screening tool for dyspeptic pts < 45 y.o. (sens

97%, spec 87%) � if Ab neg, pt doesn’t need EGD

Tan YK and Fielding JWL. Eur J Gastroenterol and Hepatol (2006).Correa P. Gut (2004).

Radical surgery

• Radical surgery

– Distal tumors: subtotal gastrectomy

– In all other localisation: total gastrectomy

• Lymphadenectomy (LA):

– limited (D1),

– extended (D2)

• min. 15 lgl.

Treatment and survival

Stage Therapy 5 years survival (%)

0 surgery >90

IA surgery 60-80

IB surgery, CRT 50-60

II surgery+CRT 30-50

IIIA surgery+CRT kb. 20

IIIB surgery+CRT, preop.CRT! kb. 10

IV pall. CT,RT,S <5

43

• Total gastrectomy may be performed for a resectable cancer.

The entire stomach, the duodenum, the lower portion of the

esophagus, supporting mesentry, and lymph nodes are

removed. Esophagojejunostomy is performed to reconstruct

the GI tract.

Neoadjuvant Chemotherapy

MAGIC Trial

• Evaluate the efficacy of preoperative and postoperative ECF vs. surgery alone

• 503 patients, stage II or greater

• Adenocarcinoma stomach/ge junction/distal esophagus

• ECF was chosen secondary to high RR in two prior randomized trials for locally advanced and metastatic gastric cancer

Schema

Arm A Surgery alone-(type of surgery and extent

of nodal dissection left to discretion of surgeon)

Arm B ECF x 3 -> surgery -> ECF x 3

Epirubicin (50mg/m2) D1

Cisplatin (60mg/m2) D1

Fluorouracil (200mg/m2) CIVI D1-21

Cycles q3weeks

Survival Results

ECF Surgery Benefit to

ECF

2 yr survival 50% 41% 9%

5 yr survival 36% 23% 13%

Median

Survival

24 mo. 20 mo. 4 months

Results unchanged on multivariate analysis adjusted for age, PS, site of

Disease and gender.

Conclusions for Magic Trial

• First trial with neoadjuvant chemotherapy to show PFS/OS benefit

• Pathologic staging showed improvement in downsizing of primary tumor

• Chemotherapy tolerated fairly well

• Value of post-operative chemotherapy unknown (only 42% completing tx)

• Follow-up study: Magic B planned comparing ECX perioperative with ECX +bevacizumab perioperative.

Adjuvant ChemoradiationMacDonald, NEJM 2001; 345: 725

556 resected adenocarcinoma

Stomach/GE junction

Surgery alone

N=275

Adjuvant radiation and 5FU/LV

N=281

Results-Median f/u 5 YearsMacDonald NEJM 2001; 345: 725

• Median OS:

Surgery alone - 27 months

Chemoradiation - 36 months (p<0.005)

• DFS:

Surgery alone – 19 months

Chemoradiation – 30 months (p<0.001)

• Pivotal trial establishing chemoradiation as standard of care in United States

7.4 years f/u ASCO 2005 Update

7.4 years F/U ASCO 2004 Update

• Subgroup analysis showed the benefit of

adjuvant chemoradiation did not differ with

regards to:

T stage

N stage

Tumor location-proximal vs. distal

Extent of LN dissection D0 vs. D1 vs. D2

Difficulties in irradiation planning

• Definiotion of target volume (GV):

– tumorbed

– anastomosis

– regional lymphnodes

• perigastrical, around the a. coeliaca, hepatoduodenal,

peripancreatic, periaortic, lien hylus, hepatic portal,

paraoesophageal

• Reduced ratiation tolerance of the surrounding

healthy tissues (liver, bowels, kidney, spinal

cord)

Method - KT

• Chemotherapy - 4 cycle – in each 4 weeks

5-FU 425 mg/m2, LV 20 mg/m2

1-5. day,

1-1 cycle before and after RT

5-FU 400 mg/m2, LV 20 mg/m2

1-4. and 1-3. days,

1. and 5. weeks of RT

Method - RT• Radiotherapy:

– CT- based 3D radiation planning

– CTV, PTV definition

– Dose-limits for organs at risk

– CT- based simulation

– Conformal 15 MV fotonfields

– Dose: 25x1,8 = 45 Gy

• No. of fields: 4,9±1,8 (3-8)

• Dose homogenity (-5,+7%): 90±3 (85-95%)

• Remark: camera-renography is performed at each patient because of theexpected late nephrotoxicity!

Target

volume

3D plan

Palliative therapy

• In the case of inoperability:– RT: 45-50,4 Gy, + 5-FU

– CTX

• Palliative CTX for metastatic tumor

– FAM (5FU-Adriamycin-Mitomycin) /gold standard in the

years of 1980/

– 5FU-Cisplatin

– Xeloda-Cisplatin

– ELF (Etopozid-LV-5FU)

– Mono-Xeloda

New CTX agents

• Campto (irinotecan):topoizomerase

inhibitor

• Taxánok: docetaxel, paclitaxel

• Oxaliplatin: 3. generation of platina

• Xeloda (capecitabine): oral 5FU-prodrug

• Biological response modifyers

The tumor induces VEGF expression

EGF

IGF-1 PDGF

IL-8

bFGF

Hypoxia ↑↑↑↑COX-2 ↑

NO ↑Oncogének ↑

VEGF elválasztásKöődés a VEGF receptorhoz,s annak aktivációja

H2O2

ProliferációTúlélés Migráció

ANGIOGENESISPermeábilitás

Megnövekedett expresszió(MMP, tPA, uPA, uPAr,

eNOS, etc.)

– P

– P

P–

P–

IGF = insulin-like growth factor; PDGF = platelet-derived growth factor

VEGF and other signals starts „angiogén

schwitch” in tumors

Adapted from Bergers G, et al. Nature 2002;3:401–10

Role of angiogenesis in the formation, growth and

metastasis of the tumor

Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207–25

Stages of tumor progression: role of angiogenesis

Premalignantstate

Malignanttumor

Tumorgrowth

Vascularinvasion

„Sleeping”micrometastasis

„Awakening”metastasis

(Avasculartumor)

(Angiogenswitch)

(Vascularisedtumour)

(Intravazationof tumor cells

)

Metastaseto distant organs)

(Secondaryangiogenesis)

Anti-VEGF

Reduces the interstitial liquid pressure

and vessel density

Increases the amount of

medicine getting into the tumor

The anti-VEGF antibody normalizes the

vasculature of the tumor

Jain R. Nature Med 2001;7:987–9; Willett CG, et al. Nat Med 2004;10:145–7;

Tong R, et al, Cancer Res 2004;64:3731–6

NormalNormal again

Abnormal