Clinical Case: Gastric Cancer

Ajay Tejwani MD, MPHMarch 2011

Objectives• Present a case I saw• Review select gastric

cancer points• Review the evidence

behind our treatment decision

• Review our treatment decision and actual plan

• More to come in 2011-2012 symposia season

H & P• 75 year old female with longstanding 2-3 year history of

dyspepsia and chronic gastritis. The patient has been evaluated by several doctors in this time period who gave her proton pump inhibitors with some relief. The patient chose not to follow-up because of her symptom relief.

• 2/2010 the patient had an EGD which appreciated an ulcer in the body of the stomach, we do not have records of a biopsy at that time but the patient was told to follow-up. She did not followup because her symptoms improved. Since then, her symptoms have gotten worse, including abdominal discomfort, no pain, and no appetite.

• Recently over the last year has developed decreasing appetite and a 30-50 pound weight loss.

• PMHx: HTN, gastritis• PSurgHx: None• Medications: Protonix• SHx: No Tob, No EtOH, lives at home with

family, 6 children• FamHx: negative

ExamKPS 80, VSS, AfebrileGeneral: Alert&Oriented x3, No Acute Distress HEENT: NCAT, Oral cavity clear, no palpable masses Lymph Nodes: No palpale Lymphadenopathy Cardiovascular: Regular rate and rhythm Respiratory: Clear to Auscultation Bilaterally Abdomen: Soft, nontender, nindistended no organomegaly 8

cm healing vertical incision with staples in place, no evidence of bleeding.

Neurologic: CNs II-XII intact, nonfocal motor/sensory exam Musculoskeletal: No bone tenderness to palpation Rectal: Hemoccult negative

Work-up

• Blood work• EGD• CT abd/pelvis

Upper Endoscopy

• The patient was evaluated by EGD on and an ulcer was found in the lesser curvature of the stomach in the body.

BiopsyDuodenum, biopsy:Small intestinal mucosa with normal villous architecture.Intraepithelial lymphocytes are not increased.Negative for celiac disease or parasites.

B. Lesion, body, stomach, biopsy:Adenocarcinoma, moderately differentiated.Chronic gastritis, severe.

No H. pylori identified by immunohistochemistry.

CT Abdomen/Pelvis w oral/IV contrast

There is an area of low density along the anterior margin of the liver adjacent to the falciform ligament compatible with focal fatty infiltration. There is no intrahepatic biliary ductal dilatation. The gallbladder, spleen, pancreas, adrenal glands, and right kidney are unremarkable. There are a few subcentimeter low-density lesions in the left kidney, too small to characterize but statistically likely

representing tiny cysts. There is no hydronephrosis. There is no evidence of large or small bowel obstruction. No bowel wall thickening is identified. There is no free intraperitoneal air. There is an umbilical hernia containing a short segment of nonobstructed small bowel. Although the provided history is of gastric carcinoma, please note evaluation of the stomach is limited by CT evaluation.

No enlarged abdominal or pelvic lymph nodes are identified. There is no abdominal or pelvic ascites. The abdominal aorta is normal in diameter without evidence of dissection. Evaluation of the osseous structures demonstrates degenerative changes of the spine.

Surgery Specimen labeled" distal stomach", subtotal gastrectomy

Specimen Type- stomachProcedure- subtotal gastrectomyTumor Site- lesser curvatureTumor Size- 3.5 CMHistologic Tumor Type (WHO)-

adenocarcinoma, intestinal typeHistologic Grade- moderately differentiatedLocal Invasion (microscopic extent)-

subserosa (T3)Lympho-Vascular Invasion- presentPerineurial Invasion- presentSurgical Margins- negativeProximal margin- 4 cmDistal margin- 5 cmOmental margin-3.5 cm

Distance of invasive carcinoma from nearest margin- omental margin, 3.5 cm

In Situ Carcinoma (for cases also having an invasive component)- present

Polyps (away from the carcinoma)- not presentNon-neoplastic Stomach- Intestinal metaplasia.Chronic gastritis.Helicobacter Organisms- not presentLymph Nodes- Metastatic carcinoma in five out of 24 lymph

nodes ( 5/24).

Specimen labeled" proximal stomach for margin" :

Chronic gastritis with reactive lymphoid aggregate, no tumor seen.

Specimen labeled" lesser omentum" :Unremarkable fibroadipose tissue, no tumor

seen.Two benign lymph nodes (0/2).

Assessment

• 75 yo F with stage IIIA (T3N2M0) gastric CA s/p subtotal gastrectomy now referred for adjuvant therapy

Plan

• Patient given 1 cycle of 5FU/leucovorin and scheduled for concurrent chemo-RT, with chemo given on week 1 and 5, followed by 2 additional cycles of 5FU/leucovorin

• RT to be given via IMRT: 5040 (4500) cGy/180 cGy fractions

Select Gastric Cancer Pearls

Anatomy• Stomach: The alimentary reservoir for mixing and enzymatic digestion of food

– Cardia: Surrounds the esophageal orifice into stomach; lesser and greater curvature meet here– Fundus: Most cephalic part of stomach; touches left hemidiaphragm– Body: Main portion; principal site of acid production– Antrum: Vestibule; pre-pyloric part of stomach– Pylorus: Sphincter opening into duodenum; formed by thickened middle layer of smooth muscle and a thin fibrous

septum• Mural anatomy Wall consists of 3 layers of smooth muscle (outermost = longitudinal; middle = circular;

inner = oblique); circular is thickest• Gastric folds (rugae): Redundant folds of the gastric mucosal surface• Layers (inside out): mucosa, submucosa, muscularis externa, serosa• Mucosa is columnar epithelium• Gastric glands: Vary in prevalence in different parts of the stomach; produce mucous (which lines and

protects gastric surface), pepsinogen (precursor to pepsin), and hydrochloric acid (activates digestive enzymes, assists with breakdown of food)

Anatomy• Location: Most commonly

antrum/distal stomach (40%), followed by proximal stomach or GE junction (35%), then body (25%). The incidence of proximal lesions has increased (used to be the least common site).

• Patterns of spread– Lymph node drainage is to nodes along the

greater and lesser curvatures (gastroepiploic and gastric nodes respectively), to the celiac axis (includes porta hepatis, splenic, suprapancreatic, pancreaticoduodenal LN), paraaortics, distal paraesophageal.

– left gastric LNs (largest drainage) - from lesser curvature

– gastro-epiploic LNs - from greater curvature

– right gastric LNs - from pyloris

Epidemiology• In 2010: 21,000 cases and 10,570 deaths in US (NCI).• Incidence in men is 8.4 per 100,000 in North America. Sharp decrease in incidence

in Western countries over the past 60 years (by a factor of about 5). (However, incidence of GE junction and proximal gastric tumors is increasing.)

• More common in men by 1.5 to 1.• Third most common cancer in the world and 2nd leading cause of cancer deaths.

Common in Japan (78 per 100,000 men), China, other East Asian countries, Eastern Europe and South America.

• Risk factors: – smoked and salted food, low fruit/vegetable intake, low socioeconomic status, pernicious

anemia (5-10% patients develop gastric ca.).– H.pylori infection (3-6X risk), confined to distal cancers and intestinal type malignancy)– No increased risk found with gastric ulcers.– 2nd generation Japanese have similar risk factor to general U.S. population and not Japanese

population

Intergroup INT-0116 (1991-1998) -- Observation vs. Concurrent Chemo-RT + Adjuvant Chemo

• Randomized. 556 patients. Completely resected (R0) adenocarcinoma of the stomach or GE junction (20%). Stage IB to IV(M0) [1988 staging; IB=T1N1 or T2N0]. – Arm 1) Observation – Arm 2) Bolus 5-FU (425 mg/m2/d) + LV (20 mg/m2/d) x 1 cycle, followed by

concurent chemo-RT one month later. Chemotherapy given on first 4 and last 3 days of RT (5-FU 400 mg/m2 + LV 20 mg/m2). Adjuvant chemo one month following RT with two 5-day cycles of 5-FU/LV given one month apart. A D2 lymph node dissection was recommended, but most (54%) had a less than D1 dissection or had a D1 dissection (31%). 64% completed protocol

• RT technique: 45 Gy to tumor bed, regional nodes, 2 cm beyond proximal and distal margins of resection. Defined tumor bed by pre-op CT. Lymph nodes included were: perigastric, celiac, local para-aortic, splenic, hepatoduodenal or hepatic-portal, and pancreaticoduodenal. Exclusion of the splenic nodes was allowed in patients with antral lesions if it was necessary to spare the left kidney. For tumors of GE junction, included paracardial and paraesophageal lymph nodes.

INT 0116• 2001— "Chemoradiotherapy after surgery compared with surgery alone for

adenocarcinoma of the stomach or gastroesophageal junction." (MacDonald JS, N Engl J Med. 2001 Sep 6;345(10):725-30.) – Median F/U 5 years

• Outcome: – Median survival observation 2.2 years vs chemo-RT 3.0 year (SS, HR for death 1.35). – 3-year OS 41% vs 50%. 3-year RFS 31% vs 48%, median 19 months vs 30 months (SS, HR for

relapse 1.52). LR 29% vs 19%, regional relapse 72% vs 65% (largely abdominal carcinomatosis), DM higher 18% vs 33%.

– Regional failure included peritoneal spread or liver mets.• Toxicity: Grade 3+ hematologic 54%, GI 33%. 17% stopped treatment due to toxic

effects. 32% of pts in chemo/RT group experienced grade 4 toxic effects; 1% had treatment-related deaths.

• Conclusion: Postop chemo-RT should be considered for patients at high risk for recurrence after curative resection• After R0 resection, patients with Tis or T1, N0 or T2, N0 tumors may be observed w/ low risk

features (well diff, no PNI, no LVI, age >50)

RTOG 0114; 2006 (2001-2004) • Phase II, randomized. 73/78 patients.

• Arm 1) "PCF" - Induction 5-FU, cisplatin, paclitaxel then concurrent 5-FU, taxol

• Arm 2) "PC" - Induction cisplatin, paclitaxel then concurrent cisplatin, paclitaxel.

• RT 45/25 in both arms. • Induction: 2 cycles. PCF - 5-FU(by continuous infusion,

24/hr x days 1-5,29-33), cisplatin(days 1-5,29-33), taxol(24-hr infusion, days 1,29). PC - cisplatin(days 1,29), taxol(days 1,29)

• Concurrent: PCF - 5-FU(continuous infusion x 5 days,weekly), taxol(weekly). PC - cisplatin(weekly), taxol(continuous infusion x 5 days,weekly).

• 2009-- "Randomized Phase II Trial Evaluating Two Paclitaxel and Cisplatin–Containing Chemoradiation Regimens As Adjuvant Therapy in Resected Gastric Cancer (RTOG-0114)" (Schwartz GK, J Clin Oncol. 2009 Apr 20;27(12):1956-62.)

• Closed at interim analysis (with 22 pts entered on PCF arm) due to increased toxicity. Accrual continued on PC arm.

• Grade 3+ GI toxicity 59% in PCF arm (significantly worse than in INT0116). Median DFS 14.6 mo (PCF), Median DFS not reached in PC arm; 2-yr DFS 52% (PC).

• Conclusion: Although PC appears safe, the DFS failed to exceed the target goal (set by INT0116) and cannot be recommended.

CALGB 80101 - accruing

• Arm 1: surgery + fluorouracil/leucovorin + RT• Arm 2: surgery + epirubicin, cisplatin, and

infusional fluorouracil (ECF) + RT• Goal of 536 pt accrual.• After 138 pts, grade 4-5 events greater in

5FU/LV arm (37% vs 25%)

RT Technique

Simulation and Treatment Planning• Patient should be instructed to avoid intake of

heavy meal for 3 hours before sim and tx• Oral and/or IV contrast may be helpful• Supine position with immobilization device• Target Volume (General)– Preoperative: Pre tx diagnostic studies. Must weight

relative risk of nodal mets in relation to site of origin, size, depth

– Postoperative: Pre tx diagnostic studies + clip placement. Must weigh risk of txt to remaining stomach, and above factors

Conventional Treatment

Our Technique

• External Beam RT given via IMRT technique• PTV encompassed: Gastric remnant,

perigastric, suprapancreatic, celiac, splenic hilar, porta hepatic, and pancreaticoduodenal lymph nodes