review of management of gastric cancer

Review of management of gastric cancer

Odei-Ansong Francis.

Overview

• Introduction• Aetiological factors• Pathology• Clinical features• Investigations• Treatment modalities• Conclusion

Introduction

• Common since the 80s, now surpassed by lung cancers worldwide.

• Worldwide incidence contributed mostly by Japan/ Parts of south America.

• 10th most common in US with ised incidence in the black pop.• Risk increases with increasing age.• Risk decreases amongst migrant pop from endemic areas

(Japan--US).• Site of tumor now showing a shift from distal to proximal and

also an increase in incidence in whites(smoking, alc, ? H pylori eradic.)

Aetiological factors Nutritional• Low fat or protein consumption• Salted meat or fish• High nitrate consumption• High complex-carbohydrate

consumption Environmental• Poor food preparation (smoked,

salted)• Lack of refrigeration• Poor drinking water (well water)• Smoking

Social• Low social class Medical• Prior gastric surgery• Helicobacter pylori infection• Gastric atrophy and gastritis• Adenomatous polyps• Male gender Medical• Prior gastric surgery• Helicobacter pylori infection• Gastric atrophy and gastritis• Adenomatous polyps• Male gender

Pathology

Intestinal Diffuse Environmental Gastric atrophy, , intestinal metaplasia Men > womenIncreasing incidence with ageGland formationHematogenous spreadMicrosatellite instabilityAPC gene mutationsp53, p16 inactivation

FamilialBlood type AWomen > menYounger age groupPoorly differentiated, signet ring cellsTransmural/lymphatic spreadDecreased E-cadherin

p53, p16 inactivation p53,

Mostly adenocarcinoma (95%)Others; squamous cell ca, adenoacanthoma , carcinoid tumors,GISTs, and lymphoma.Adenocarcinoma can be diffuse or intestinal

Pathology

• WHO of classification ;

• Borders in 1942 classified gastric carcinomas according to the degree of cellular differentiation, from 1 (well differentiated) to 4 (anaplastic)

gastric cancer is divided into five main categories: adenocarcinoma, adenosquamous cell carcinoma, squamous cell carcinoma ,undifferentiated carcinoma, and unclassified carcinoma

Adenocarcinomas further subdivided into four types according to their growth pattern:papillary, tubular, mucinous, and signet ring

Pathology

The Borrmann classification system developed in 1926

Clinical features

• Early stages are asymptomatic• Most Px are seem in advanced stage and

symptomatic . • Symptoms related to the location of the tumor.• Symptoms include:-abdominal discomfort/pain; -anorexia +/- nausea; -weight loss; -vomiting (pyloric lesions); -dysphagia (lesions of cardia); -hematemesis/ melaena

Clinical features

• Physical signs develop late and associated with locally advanced or metastatic disease.

• Palpable abdominal mass, supraclavicular (Virchow’s) or periumbilical (Sister Mary Joseph’s) lymph node,

• Rectal examination (Blumer’s shelf), or ovarian mass (Krukenberg’s tumor).

• Hepatomegaly , jaundice, ascites, and cachexia.

Investigations Diagnostic investigations

• Double contrast barium meal

• Endoscopy + biopsy• Endoscopy + biopsy +

Brush cytologyGeneral investigations

• FBC• BUE& Cr, FBS• ECG etc.

Staging investigations

• LFT, • EUS,• CT scan(abdomen⁺/₋

pelvic)• CXR• Laparoscopy, peritoneal

cytology• Abdominal ultrasound

Staging anatomy

Treatment modalities

• Surgery• Chemotherapy• Radiation • Endoscopic dilatation and stent placement.• Laser recanalization.

Surgery -review

• Traditionally been the main standard of treatment.

• Associated with a high level of recurence• Aimed at resection margin of 5-6cm from

macroscopic site

• Goal ; removal of the primary tumor with any direct extension removal of the nodal basins at risk for metastasis

Surgery –review(proximal tumors)

Total vrs Proximal gastrectomy.• Many studies advocates total gastrectomy• Reasons; most proximal tumours present advanced LN dissection difficult (around pylorus) ↑ dumping, heartburn, and reduced appetite* anastomatic stricture, local recurrence** hypergastrinoma


• Yoo et al. Analysis of local recurrence following proximal gastrectomy in patients with upper third gastric cancer. Cancer Res Treat 2002;34:247-251

• revealed that the risk factors for local recurrence following proximal gastrectomy were diffuse type tumor, greater than 5cm in tumor size, and serosal invasion

• Advocated for a comprehensive research on the importance of proximal gastrectomy for advanced ca.


• although we can save distal stomach by performing proximal gastrectomy for the upper third gastric cancer, it should be considered only in early gastric cancer because of the insufficient regional lymph node dissection, relatively high postoperative complication rate.

• Editorial review by Han-Kwang Yang,Issues in the Management of the Upper Third Gastric Cancer,Cancer Research and Treatment 2004


• Ji Yeong An et al, The American Journal of SurgeryVol 196, Issue 4 , Pg 587-591, Oct 2008

- 423 patients who underwent total or proximal gastrectomy for early gastric cancer in the upper third of the stomach.

• Post operative complication rate -total gastrectomy 12.6% -proximal gastrectomy 61.8%, was significant (P < .001)

• Anastomotic stenosis and reflux esophagitis -total gastrectomy 6.9% and 1.8% -proximal gastrectomy 38.2% and 29.2%

• Conclusion; that proximal gastrectomy is not a better option for upper-third early gastric cancer

than total gastrectomy

Surgery –review(LN dissection)

• Reviewed by Dr Nsoh(International Society of Gastrointestinal Oncology annual meeting. Abstract 0945. Presented October 3, 2009.)

• East favours a more extensive node dissection• West favours a limited node dissection• The east has more gastric surgical experience as

the dx is prevalent there• best approach is determined by tumor, patient,

and treatment factors, • Pxs in the east are more likely to be healthier as

they are seen earlier.

D2 vs D1 Lymph Node Dissection• Dutch trial, from 1989 to 1993(N Engl J Med. 1999;340:908-

914) 331 patients underwent D2 lymph node dissection ;43% complication rate

and a 10% postoperative mortality rate

• A study at Yonsei University in South Korea in 2002

646 patients who underwent a D2 dissection ;17.6% complication rate and a 0.6% postoperative mortality rate

Conclusion;D2 lymph node dissection favored by surgeons in the East is supported by a number of factors; surgery performed safely, better local control and thus accurate pathologic staging,the West favors D1 lymph node dissection; They lack evidence to support the superiority of D2 over D1 surgery.D2 has high postoperative morbidity and mortality in Western trials.

Chemotherapy

Adjuvant therapy(varied results) • 603 patients randomized to either observation or combined modality therapy after

surgery.• median follow-up of 5 years,• 3 year relapse-free survival rates (48 vs. 31%, P<0.001)

• OS rates (50 vs. 41%,P¼0.005), median OS (36 vs. 27, P¼0.0005)

• A total of 1059 patients with advanced ca.• Were randomized to either observation or 1-year oral S-1 adjuvant therapy. S-1• The 3-year OS was improved in the S-1 group (80.1% in S-1 group vs. 70.1% in the

observation group, P¼0.003).• Disappointing results showed when same research was

changed b/n the west/ east.

INT-01165fu/LV, 45Gy radiotherapy

Sakuramoto S et al. N Engl J Med 2007

• More than 30 trials comparing adjuvant chemotherapy to surgery alone showed varied results

• Reasons being different tumor biology.• 5-FU/LV remains the standard care in the

United States

• CALGB 80101

Perioperative chemotherapyPhase III UK MAGIC trial Cunningham D,N Engl J Med 2006

• 503 patients with resectable gastric cancer• randomized to receive surgery with neoadjuvant ECF or surgery

alone. • The neoadjuvant group demonstrated a significantly better OS

(hazard ratio¼• 0.75, 95% CI 0.60–0.93, P¼0.009, 5-year survival rate of 36 vs. 23%)

and progression free survival (hazard ratio¼ 0.66, 95% CI 0.53–0.81, P<0.001).

Shortfalls;• nonstandardized surgery,inaccurate preoperative staging

because of the absence of laparoscopy,

Preoperative chemoradiationmost of the studies have number of patients.

• Advantages• May downstage the tumor and potentially

increase the rate of resectability• may sterilize the operative field and thereby

reduce the risk of tumor seeding. • may eliminate micrometastasis without delay. • also allows better radiation field design.More research needed to validate its importance.

Preoperative chemoradiation

Ajani et al.J Clin Oncol 2005• treated 40 patients 5-FU, paclitaxel and cisplatin, radiotherapy • Followed by surgery in 40 patients.• The study showed a pathologic complete response rate (RR) of 20%, R0

resection rate of 78%, and median survival beyond 36 months

• A meta-analysis of 4 randomized trials also indicated a survival benefit with preoperative radiotherapy, compared with surgery alone

Fiorica F et al Cancer Treat Rev 2007

Therapy for metastatic disease

• Single active agents have included 5-FU, cisplatin, mitomycin C, doxorubicin, epirubicin, and etoposide

RRs(response rate) vary from 10 to 20% [38–43]. Cullinan SA, et al. JAMA 1985 Barone C, et al.two parallel randomized phase II studies. Cancer 1998;

• 4 trials showing improved survival of 4-8 months with combined chemotherapy

Small studies QOL reported to be better

Scheithauer et al. 1995 ELF vs. BSC Pyrhonen et al. 1995 FEMTX vs. BSC

Glimelius et al. 1997 ELF vs. BSCMurad et al. 1999 FAMTX vs. BSC

Outcomes From Phase III Trials

Response Rate Median Survival

FAM 25-40% 6.9 months

FAMTX 20-30% 7.7 months

EAP 20% 6.1 months

ELF 21% 7.0 months

ECF 45% 8.9 months

Mayer ASCO 2005

Therapy for metastatic disease

• Conclusion; trials have showed that chemotherapy is better than best supportive , combination chemotherapy with doublet is superior than single agent, and the best survival is achieved with three agents at the cost of more toxicities

Newer Drugs.

• bevacizumab, cetuximab and trastuzumab• Phase III Trastuzumab( for Gastric Cancer trial at the 2009 American Society of

Clinical Ontology (ASCO))

• A total of 594 patients with Her2/Neu positive• randomized to receive either chemotherapy (cisplatin

and capecitabine or 5FU) with trastuzumab or chemotherapy alone

• The median OS was significantly improved with the addition of trastuzumab(13.5 vs. 11.1 months, respectively)

J Clin Oncol 2009; 27:18s

Newer drugs. 2nd agent

• Kang et al, At the 2010 ASCO annual meeting,• Presented the Study of Bevacizumabin With Capecitabine and Cisplatin as

First-line Therapy in Patients With Advanced Gastric Cancer (AVAGAST); • a total of 774 patients received chemotherapy with placebo or with

bevacizumab• progression-free survival is significantly longer in the bevacizumab arm(6.7

months in bevacizumab arm vs. 5.3 months in the placebo arm• The overall RR was increased from 29.5 to 38% (P¼0.012) with the

addition of bevacizumab.

J Clin Oncol 2010; 28:18s

Conclusion

• The challenges associated with the management of gastric cancer has been evolving.

• A multidisciplinary approach is required for the management.

• Recent introduction of newer agent has been promising yet the prognosis still remains poor.

review of management of gastric cancer

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