Gastric Cancer

Elshami Elamin, MDMedical Oncologist

Central Care Cancer Center

www.cccancer.com

Wichita, KS - USA

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INTRODUCTION

Gastric cancer is defined as any malignant tumor arising from the region extending between the gastroesophageal (GE) junction and the pylorus.

The incidence and mortality of gastric cancer have been declining in most developed countries.

The age-adjusted risk fell 5% from 1985-1990.

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Risk Factors Low vegetable, fruit Nitrates Coal mining, nickel, rubber Intestinal metaplasia Blood group A ?Gastrectomy Pernicious anemia

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Pathology Adenoca: 95%

Intestinal Diffuse Mixed

Lymphoma Squmous Leimyosarcoma Carcinoid

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Clinical Classification

Superficial Focal, fungating, polypoid Infiltrative, linitis plastica

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Physical exam Hepatomegaly Ascites Virchow’s node (Lt. SCV)

Irish node (Lt. Ant. Axilla.)

Sister Mary Joseph nodule/sign (palpable nodule bulging into the umblicus)

Krukenberg’s tumor Blumer’s shelf

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Staging

IA : T1 (invade lamina propria/submucosa) IB: T1, N1 (1-6 +ve)

T2 (invade muscularis/subserosa II: T1, N2 (7-15 +ve)

T2, N1 T3 (penetrate visceral peritoneum only)

IIIA: T2, N2 T3, N1 T4 (invade structures)

IIIB: T3, N2 IV: T1-3, N3 (>15 +ve)

T4, N1-3 OR M1

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Prognostic factors

Aneuploidy: poor prognosis in patients with adenocarcinoma of the distal

stomach. High plasma levels of vascular endo-thelial growth factor (VEGF) presence of CEA in peritoneal washings

predict poor survival in surgically resected patients. intratumoral levels of dihydropyrimidine dehydrogenase (DPD)

low levels appear to predict better response to 5-FU based chemotherapy and longer survival.

The prognostic implications of tumor-suppressor genes and oncogenes are an area of active investigation.

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

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•H&PH&P

•CBC/CMPCBC/CMP

•C-x-rayC-x-ray

•CTCT

•EGDEGD

•H. pyloriH. pylori

•BariumBarium

•EUSEUS

•PET/CT PET/CT

Locoregional

Locoregional

I - III

I - III

IVIV

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Multi-

Disciplinary

eval

Locore

gio

nal I-

III

Locore

gio

nal I-

III

Operable

/Med fi

t

Operable

/Med fi

t

Inop

erable

Inop

erable

Unresectab

le/Med

unfit

Unresectab

le/Med

unfit

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TREATMENT

Resection provides the only chance for cure. Radiotherapy and chemotherapy

potential roles as adjuncts to surgery patients with unresectable tumors.

Preoperative chemo and chemoradiation therapy are active areas of current investigation.

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Confirmation of resectability

CT scan +/- EUS Laparoscopy

assess the extent of disease and resectability. adds to the accuracy of preoperative imaging

peritoneal spread or small liver metastases. peritoneal washings

Laparoscopic ultrasonography identify lesions with a high risk of recurrence

(T2b or >, N+), for which a preoperative chemotherapy protocol

may be available.

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Extent of resection

Depends on: The site and extent of the primary cancer.

Subtotal gastrectomy is preferred over total gastrectomy comparable survival benefit but lower morbidity. A 5-cm proximal and distal resections margins.

If total gastrectomy is necessary: transection of the distal esophagus and proximal duodenum omentectomy

In Japan, there is a growing experience with more limited resections of early-stage gastric cancer.

Endoscopic Mucosal Resection (EMR) of non-ulcerated T1 N0 lesions

pylorus-preserving gastrectomy. Laparoscopic resections are also being performed more

frequently.

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Extent of surgery

Routine or prophylactic splenectomy is not required

Splenectomy is acceptable if: Spleen or hilum is involved

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Extent of lymphadenectomy

Regional lymphatics: Perigastric (paracardial, paragastric, parapyloric) (D1)

Retroperitoneal “second echelon” and LN along the named vessels:

celiac trunk, left gastric artery, hepatic artery, splenic artery, and splenic hilus (D2)

The goal is > 15 LN

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Improved long-term survival rates for Japanese patients had been attributed to the extended lymphadenectomies routinely performed in this country (D2 or more).

Retrospective data had shown that D2 lymphadenectomy is safe and does not increase morbidity.

Two European randomized trials showed no sig differences in OS between D1 and D2

higher postop morbidity and mortality in the D2 due to a higher rate of splenectomy and/or partial pancreatectomy. When a subset of patients with N2 disease were studied in

long-term follow-up in the Dutch randomized trial, a survival advantage was shown with D2 dissection.

Extended lymphadenectomy should primarily be performed in specialized centers by experienced surgeons:

splenectomy and pancreatectomy should be avoided

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Reconstruction

Billroth I BillrothII Roux-en-Y esophagojejunostomy

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Surgical Surgical

outcomesoutcomes

RoRo

R1R1

R2R2

M1M1

ObserveObserve

T2T2

palliativepalliative

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T3-4 or N+T3-4 or N+

Tis-T1Tis-T1

RT + chemoRT + 5FU/LV or RT + chemoRT + 5FU/LV or

ECF if given preopECF if given preop

Observe or chemoRT (high risk) or Observe or chemoRT (high risk) or ECF if given preopECF if given preop

RT + chemoRT + 5FU/LV RT + chemoRT + 5FU/LV

RT + chemoRT + 5FU/LV or RT + chemoRT + 5FU/LV or

Chemo or BSCChemo or BSC

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Any role for Chemo/RT

<30% of locally advanced Gastric/GEJ adeno could be cure with surgery alone

Previous adj chemo failed to show clinical benefit

ADJUVANT THERAPY

The 5Y survival rate after “curative resection” 30-40%

A North American Intergroup trial randomizing resected patients (stages IB–IV[M0]) to receive chemoRT or observation:

sig improvement in median DFS (median 19 vs 30 m) and OS (26 vs 35 m)

Adj chemoRT (usually C.I. 5-FU) is the standard of care in the United State

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INT-0116 (SWOG 9008)

Randomized lll Trial: Resectable adeno of stomach GEJ (lB-IVA)

5-FU/LVx5d--> RT+5-FU/LV during first 4d and last 3d of RT --> 2cycles of 5-FU/LVx5d

postop CT/RT improve DFS&OS in R0 (resected locally advanced) [standard of care]

•Adj Option

•Macdonald et al; N Engl J Med. 2001 Sep 6;345(10):725-30.

? Is D2 LND required ? D2 LND was performed in only 10% of the

patients in this trial.

Subgroup analysis revealed that outcome did not differ based upon the type of lymphadenectomy (P = .80).

Still, since only a small percentage of pts underwent the recommended D2 dissection, further research is necessary before firm conclusions can be made in this area.

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Radiotherapy

Radiotherapy can decrease the rate of locoregional failure but has not been shown to improve survival as a single postop modality

Postop RT may be appropriate in patients who are not candidates for chemo

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Chemotherapy

Randomized trials of surgery +/- chemo: No definite survival advantage, with the possible

exception of pts with widespread nodal involvement. One meta-analysis included both Western and Asian

studies: showed a sig survival benefit with the use of chemo in the Asian

trials, but there was no benefit in the Western studies, possibly due to differences in biology or drug metabolism.

No specific regimen could be recommended

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Clinical > T2 or N +

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European Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) by Cunningham and associates.

The 5Y survival rate for ECF + surgery was 36%, vs 23% for surgery

Chemo also enhanced resectability

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The MAGIC TrialThe Medical Research Council Adjuvant Gastric Infusional

Chemotherapy

Operable adeno of the stomach, the lower third of the esophagus, and the GEJ ( 74% of pts had tumors in the stomach)

ECFx3->surg->ECFx3 (250 pts) vs Surgery alone (253 pts): 5Y survival: 36% vs 23% Chemo sig. improves resectability,PFS and OS

•Periop. option

•D. Cunningham, et al ; N Engl J Med. 2006 Jul 6;355(1):11-20.

Other options of ChemoRT

Docetaxel or Taxol + 5-FU/Xeloda

Cisplatin + 5-FU/Xeloda

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Preoperative Chemotherapy vs Surgery Alone

FNLCC ACCORD 07-FFCD 9703, multicenter, randomized trial indicated benefit of preoperative chemotherapy vs surgery alone for resectable adenocarcinoma of stomach and lower esophagus[1]

Higher rate of R0 resection (87% vs 74%; P = .04) Higher 5-yr OS (38% vs 24%; P = .021) No increase in postoperative morbidity or mortality

Boige V, et al. ASCO 2007; Abstract 4510.

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•ECF (n = 249) •ECX (n = 241)

•EOF (n = 235) •EOX (n = 239)

•Epirubicin 50 mg/m2 IV 3 weekly•Cisplatin 60 mg/m2 IV 3 weekly

•5-FU 200 mg/m2/day IV givencontinuously

•Epirubicin 50 mg/m2 IV 3 weekly

•Cisplatin 60 mg/m2 IV 3 weekly

•Capecitabine 625 mg/m2 BID PO

continuously

•Epirubicin 50 mg/m2 IV 3 weekly•Oxaliplatin 130 mg/m2 IV 3 weekly•5-FU 200 mg/m2/day IV given

continuously

•Epirubicin 50 mg/m2 IV 3 weekly

•Oxaliplatin 130 mg/m2 IV 3 weekly

•Capecitabine 625 mg/m2 BID PO

continuously

REAL-2: Phase III Capecitabine vs 5-FU and Oxaliplatin vs

Cisplatin

•Cunningham D, et al. N Engl J Med. 2008;358:36-46.

TAX325: Phase III Docetaxel/Cisplatin/5-FU (DCF) vs

Cisplatin/5-FU (CF) Primary endpoint: TTP from 4 → 6 mos Secondary endpoints: OS, RR, safety, QoL, clinical benefit

•Patients with advanced gastric

cancer and no previous palliative

chemotherapy•

(N = 457)

•DCF•Docetaxel 75 mg/m2 IV over 1 hr on Day 1

+•Cisplatin 75 mg/m2 IV over 1-3 hrs on Day

1 +•5-FU 750 mg/m2/day by CIV over 5 days

•q3w•(n = 227)

•CF•Cisplatin 100 mg/m2 IV over 1-3 hrs on Day

1 +•5-FU 1000 mg/m2/day by CIV over 5 days

•q4w•(n = 230)

•R

•Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.

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•Trastuzumab + chemo associated with increased OS: • 11.1 months vs. 13.8 months (HR=0.74; 95% CI, 0.60-0.91)

•Trastuzumab + chemo associated with an improved overall response rate:

• 47.3% vs. 34.5% (P=.0017)

•The treatment was generally well tolerated with no unexpected adverse effects in the trastuzumab group

ToGa results

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THANKS

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