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 Social• Low fat or protein • Low social class consumption Medical• Salted meat or fish • Prior gastric surgery• High nitrate consumption • Helicobacter pylori infection• High complex-carbohydrate • Gastric atrophy and gastritis consumption • Adenomatous polyps Environmental • Male gender Medical• Poor food preparation (smoked, salted) • Prior gastric surgery• Lack of refrigeration • Helicobacter pylori infection • Gastric atrophy and gastritis• Poor drinking water (well water) • Adenomatous polyps • Male gender• Smoking
PathologyMostly adenocarcinoma (95%)Others; squamous cell ca, adenoacanthoma , carcinoid tumors,GISTs, and lymphoma.Adenocarcinoma can be diffuse or intestinalIntestinal DiffuseEnvironmental FamilialGastric atrophy, , intestinal metaplasia Blood type AMen > women Women > menIncreasing incidence with age Younger age groupGland formation Poorly differentiated, signet ring cellsHematogenous spread Transmural/lymphatic spreadMicrosatellite instability Decreased E-cadherinAPC gene mutationsp53, p16 inactivation p53, p16 inactivation p53,
Pathology• WHO of classification ; 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• Borders in 1942 classified gastric carcinomas according to the degree of cellular differentiation, from 1 (well differentiated) to 4 (anaplastic)
PathologyThe 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.
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
Surgery –review(proximal tumors)• 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.
Surgery –review(proximal tumors)• 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
Surgery –review(proximal tumors)• 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 D2 lymph node dissection favored by surgeons in the East isConclusion; 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.
INT-0116 Adjuvant therapy(varied results)5fu/LV, 45Gy radiotherapy • 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)Sakuramoto S et al. N Engl J Med 2007 • 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.
• 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 chemotherapy Phase 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 chemoradiation most 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 chemoradiationAjani 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. BSC Murad et al. 1999 FAMTX vs. BSC
Outcomes From Phase III Trials Response Rate Median SurvivalFAM 25-40% 6.9 monthsFAMTX 20-30% 7.7 monthsEAP 20% 6.1 monthsELF 21% 7.0 monthsECF 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.