Gastric cancer

Question 1

What is the estimated incidence of gastric cancer in the United States and
worldwide?

Answer 1

United States: 28,000 cases/yr with 10,960 deaths (2017)

Worldwide: ∼952,000 new cases/yr; 3rd-leading cause of death

Question 2

Where are the high-incidence areas in the world?

Answer 2

The highest incidences are found in East Asia (Japan and China) > Eastern Europe > South America.

Question 3

What are some acquired and genetic risk factors for developing gastric
cancer?

Answer 3

Acquired factors: Helicobacter pylori infection, high intake of smoked and salted foods, nitrates, diet low in fruits/vegetables, smoking, RT exposure, obesity, Barrett esophagus/gastroesophageal reflux disease (GERD), prior
subtotal gastrectomy

Genetic factors: E-cadherin (CDH-1 gene) mutation, type A blood group, pernicious anemia, HNPCC, Li-Fraumeni syndrome

Question 4

What are the molecular subtypes of gastric adenocarcinoma proposed by
The Cancer Genome Atlas (TCGA Nature 2013)?

Answer 4

EBV Positive: Epstein–Barr virus positive, PIK3CA mutation, PD-L1/2
overexpression, extreme deoxyribonucleic acid (DNA) hypermethylation,
amplification of JAK2

Microsatellite Instability: hypermutated, MLH1 silencing, mitotic pathways

Genomically Stable: diffuse histology, RHOA mutations or fusions

Chromosomal Instability: intestinal histology, TP53 mutation, amplification
of receptor tyrosine kinases

Question 5

How does tumor location relate to the underlying etiology of gastric adenocarcinoma?

Answer 5

Body and antral lesions are associated with H. pylori infection and chronic
atrophic gastritis, whereas proximal gastric lesions (gastroesophageal [GE]
junction, gastric cardia) are associated with obesity, GERD, and smoking.

Question 6

Which has poorer prognosis: proximal or distal gastric cancer?

Answer 6

Stage for stage, proximal gastric cancer has a poorer prognosis

Question 7

What are the 2 histologic types of gastric adenocarcinoma? How do these 2 types differ in terms of etiology of the gastric cancer?

Answer 7

Intestinal and diffuse are the 2 histologic types of adenocarcinomas described in the Lauren Classification.

Intestinal type: differentiated cancers with a tendency to form glands, occur in the distal stomach, and arise from precursor lesions seen mostly in endemic areas and in older people, more commonly men, suggesting an environmental etiology. Associated with chromosomal instability.

Diffuse type: less differentiated (signet ring cells, mucin producing), have extensive submucosal/distant spread, and tend to be proximal. They do not arise from precancerous lesions, are more common in low-incidence areas, and are more common in women and younger people, suggesting a genetic
etiology. Associated with the genomically stable molecular subtype.

Question 8

What is the Japanese Research Society (JRS) classification of nodal
spread?

Answer 8

1st echelon: N1 (stations 1–6)—perigastric nodes (lesser and greater curvature) and periesophageal nodes (proximal gastric)

2nd echelon: N2 (stations 7–11)—celiac axis, common hepatic, splenic

More distant: N3 (stations 12–14)—hepatoduodenal, peripancreatic, mesenteric root; N4 (stations 15, 16)—portocaval, P-A nodes, middle colic

JRS N1–N4 are not the same as AJCC nodal staging, but do correspond to LND (D) classification (see below)

Question 9

What are the patterns of spread for gastric cancer?

Answer 9

Local extension to adjacent organs, lymphatic mets, peritoneal spread, or
hematogenous (liver, lung, and bone). Liver/lung mets are more common for
proximal/GE junction tumors.

Question 10

What is the most important prognostic factor for gastric cancer?

Answer 10

TNM stage is the most important factor. Histologic grade has not been shown to be independently prognostic apart from tumor stage. The prognostic value of molecular subtype remains unclear.

Question 11

How do pts with gastric cancer generally present?

Answer 11

Anorexia, abdominal discomfort, weight loss, fatigue, n/v, melena, weakness from anemia

Question 12

What aspects of the physical exam are relevant for evaluating a pt for a possible gastric malignancy?

Answer 12

General physical exam with focus on abdominal mass (local extension), liver mets, ovarian mets (Krukenberg tumor), distant LN mets (Virchow: left SCV; Irish: left axillary; Sister Mary Joseph: periumbilical), ascites, Blumer shelf (palpable peritoneal involvement on rectal exam)

Question 13

What is important in the workup for gastric cancer?

Answer 13

Gastric cancer workup 2018 NCCN Guidelines: H&P (onset, duration, Hx of risk factors), CBC, CMP, esophagogastroduodenoscopy + Bx, CT C/A/P with oral and IV contrast, PET/CT and EUS +/– FNA of regional LN mets if no
evidence of M1 Dz, diagnostic laparoscopy to r/o peritoneal seeding, if M1 testing for MSI-H/dMMR including HER2 and PD-L1 if adeno.

Question 14

How many layers are seen on EUS when imaging the GI tract?

Answer 14

5 layers are seen on EUS: layers 1, 3, and 5 are hyperechoic (bright), and layers 2 and 4 are hypoechoic (dark). Layer 1 is superficial mucosa, layer 2 is
deep mucosa, layer 3 is submucosa, layer 4 is muscularis propria, and layer 5 is subserosa fat and serosa.

Question 15

What is the rate of upstaging to stage IV using diagnostic laparoscopy?

Answer 15

35%–40% of pts are found to have mets using diagnostic laparoscopy.

Question 16

What is the AJCC 8th edition (2017) T-staging classification for gastric cancer?

Answer 16

T-staging classification is unchanged from the AJCC 8th edition (2017).
Tis: confined to mucosa without invasion to lamina propria
T1a: invades lamina propria or muscularis mucosae
T1b: invades submucosa
T2: invades muscularis propria
T3: penetrates subserosa without invasion of visceral peritoneum (serosa) or
adjacent organs
T4a: invades serosa
T4b: invades adjacent structures/organs

*Tumor is classified as T3 if it penetrates through the muscularis propria with
extension into the gastrocolic or gastrohepatic ligaments or into the greater or lesser omentum without perforation of the visceral peritoneum covering these
structures. Tumor is classified as T4 if it penetrates the visceral peritoneum covering the gastric ligaments or the omentum

Question 17

What is the AJCC 8th edition (2017) N-staging classification for gastric
cancer?

Answer 17

N1: 1–2 LNs
N2: 3–6 LNs
N3: ≥7 LNs
N3a: 7–15 LNs
N3b: >15 LNs

Question 18

What are the AJCC 8th edition (2017) stage groupings for gastric cancer?

Answer 18

Clinical (cTNM) Stage Groupings:
Stage I: T1–2N0
Stage IIA: T1–2N1–3
Stage IIB: T3–4aN0
Stage III: T3–4aN1–3
Stage IVA: T4b
Stage IVB: M1

Pathologic (pTNM) Stage Groupings:
Stage IA: T1N0 (adds to 1)
Stage IB: T1N1, T2N0 (adds to 2)
Stage IIA: T1N2, T2N1, T3N0 (adds to 3)
Stage IIB: T1N3a, T2N2, T3N1, T4aN0 (adds to 4)
Stage IIIA: T2N3a, T3N2, T4aN1, T4aN2, T4bN0 (adds to 5 mostly)
Stage IIIB: T1–2N3b, T3–4aN3a, T4bN1–2 (adds to 6 mostly)
Stage IIIC: T3–4bN3b, T4bN3a (adds to 7 mostly)
Stage IV: M1

Post-Neoadj Therapy (ypTNM) Stage Groupings:
Stage I: T1–2N0, T1N1
Stage II: T3–4aN0, T2–3N1, T1–2N2, T1N3
Stage III: T4bN0, T4a–bN1, T3–4bN2, T2–4bN3
Stage IV: M1

Question 19

What surgical margin is generally considered adequate in gastric cancer?

Answer 19

En bloc resection with ≥4-cm margin from gross tumor

Question 20

For what tumor location is subtotal vs. total gastrectomy indicated? Is there a benefit with total gastrectomy?

Answer 20

Subtotal gastrectomy for distal tumors (antrum/body); total gastrectomy for
proximal tumors (cardia, greater curvature)

No. According to the following 2 trials, there is no benefit of advocating total
gastrectomy:

Gouzi JL et al. randomized distal tumors to total gastrectomy vs. subtotal
gastrectomy. There were no differences in morbidity/ mortality (1.3% vs. 3.2%) or survival outcomes (5-yr OS 48%). (Ann Surg 1989)

Italian data from a 2nd randomized trial (Bozzetti F et al., Ann Surg 1999)
showed no difference in 5-yr survival b/t subtotal gastrectomy (65%) and
total gastrectomy (62%).

Question 21

Should splenectomy be performed for proximal gastric tumors to get
splenic LN clearance?

Answer 21

No. There was no value of splenectomy in a randomized trial. (Csendes A et al., Surgery 2002) Splenectomy and pancreatectomy had an adverse impact on survival in the Dutch and MRC D1 vs. D2 RCTs (see below).

Question 22

How are GE junction cancers classified, and how is the classification important therapeutically?

Answer 22

GE junction cancers are classified by the Siewert classification as 3 entities:
Type I has lymphatic drainage reminiscent of esophageal primaries
(mediastinal and celiac), whereas types II–III drain to celiac, splenic, and P-A nodes. Esophagectomy is typically recommended for type I tumors, & gastrectomy is recommended for types II–III.

Type I: adenocarcinoma of distal esophagus, arising from Barrett metaplasia,
epicenter b/t 1 cm and 5 cm proximal to anatomical cardia, treat as esophageal primary

Type II: adenocarcinoma of cardia portion, arising from cardia and short segment of intestinal metaplasia at GE junction, epicenter b/t 1 cm
proximal and 2 cm distal to anatomical cardia, treat as esophageal primary

Type III: adenocarcinoma of subcardial stomach, which may infiltrate GE junction or distal esophagus from below, epicenter b/t >2 cm and 5 cm distal to anatomical cardia, treat as gastric primary

Question 23

What are the types of nodal dissection for gastric cancer?

Answer 23

D0: no nodal dissection
D1: perigastric nodes removed (stations 1–6)
D2: D1 + celiac axis nodes (left gastric [7], common hepatic [8], celiac trunk
[9], splenic hilum [10], splenic artery [11])
D3: D2 + hepatoduodenal (12), peripancreatic (13), mesenteric root (14)
D4: D3 + middle colic (15), portocaval/P-A nodes (16)

Question 24

Is extended lymphadenectomy necessary for surgical cure of gastric
cancer?

Answer 24

No. Although results from numerous randomized trials have not shown an
OS advantage of extended lymphadenectomy, CSS and LRR may be improved with extended dissection in the most recent update of the Dutch trial (see below).

Question 25

What 4 major trials investigated the extent of lymphadenectomy on
outcomes in gastric cancer?

Answer 25

Dutch trial (Bonenkamp JJ et al., NEJM 1999): 711 pts randomized to D1 vs. D2 dissection. There was greater mortality in the D2 group (10% vs. 4%, SS), and 5-yr OS was 45% vs. 47% (NSS). In the most recent 15-yr update (Songun I et al., Lancet Oncol 2010), the 15-yr OS was 21% in the
D1 group and 29% in the D2 group (p = 0.34). However, the gastric cancer–related death rate was significantly higher in the D1 group (48%)
vs. the D2 group (37%), while deaths from other Dz were similar in the 2 groups. LR was lower in the D2 group (12% vs. 22%) as well as regional recurrence (13% vs. 19%) (all SS).

MRC trial (Cushieri A et al., Br J Cancer 1999): 400 pts randomized to D1 vs. D2. There was greater mortality in the D2 group (13% vs. 6.5%), and 5-yr OS was the same (35% vs. 33%).

Japanese trial JCOG9501 (D2 vs. D2 + PAND) (Sasako M et al., NEJM 2008) demonstrated that although extended LND does not increase morbidity or mortality, there is also no difference in 5-yr OS (69.2% for D2 vs. 70.3% for D2 + PAND) or for LRR.

An Italian trial (D1 vs. D2) (Degiuli M et al., Br J Surg 2014) showed no difference in 5-yr OS and no increased morbidity or mortality with
extended lymphadenectomy.

Question 26

What is the min number of LNs that should be pathologically assessed in a
gastrectomy specimen?

Answer 26

In the United States, at least 15 LNs should be assessed by the pathologist, since survival improves if ≥15 LNs are examined (Hundahl S et al., Cancer 2000).

Question 27

What are the selection criteria for endoscopic mucosal resection,
endoscopic submucosal dissection, or limited surgical resection (without
nodal evaluation) of gastric cancer?

Answer 27

Favorable early-stage gastric cancer: Tis–T1 (but not involving more than
superficial submucosa), small (≤2 cm), nonulcerated, well differentiated, N0. In general, these types of tumors have <5% LN mets rate.

Question 28

When is Sg alone potentially adequate for gastric cancer?

Answer 28

T1N0 or T2N0 (but not beyond the muscularis propria). 5-yr OS for
favorable early-stage gastric cancer is 80%–90%. For all others without metastatic Dz, adj Tx is recommended.

Question 29

What is the relapse pattern after “curative” resection of gastric cancer?

Answer 29

Distant Dz (50%) and LRR. LRR is common in the gastric bed, nearby LNs,
anastomotic site, gastric remnant, and duodenal stump. In the classic paper of the University of Minnesota reoperative analysis (Gunderson L et al.,
IJROBP 1982), local-only recurrence was seen in 29%, LR and/or regional
LN mets in 54%, and LF as any component of failure in 88% of pts.

Question 30

What is the randomized evidence that demonstrated a benefit of adj CRT after surgical resection for gastric cancer?

Answer 30

INT-0116 (Macdonald JS et al., NEJM 2001): 556 pts, stages IB–IV (nonmets) adenocarcinoma of stomach and GE junction (∼20%), randomized after en bloc resection with −margin to (a) observation or (b) CRT (1 cycle bolus 5-FU/leucovorin [LV]) before RT, 2 cycles during 45 Gy RT, and 2
cycles after RT. Median f/u was 5 yrs. CRT was beneficial for all outcomes
except for DM. 3-yr RFS 31% vs. 48%; 3-yr OS 41% vs. 50%; median OS 27 mos vs. 36 mos. Toxic deaths in 1%. Only 2/3 of pts completed full Tx with 41% grade 3 toxicity and 32% grade 4 toxicity. Over 2/3 of pts had T3 or T4 Dz and 85% had nodal involvement.

Question 31

What is the major criticism for the benefit of CRT seen in INT-0116?

Answer 31

Suboptimal LND (54% D0, 10% D2) is the major criticism of INT-0116.

Question 32

How was RT delivered in INT-0116?

Answer 32

Most pts were treated AP:PA to 45 Gy in 25 fx.

Question 33

What does the 10-yr f/u data from INT-0116 show?

Answer 33

persistent strong benefit with adj CRT; HRs were 1.32 (p = 0.0046) for OS and 1.51 (p <0.001) for RFS favoring CRT; more 2nd malignancies observed in CRT group (21 vs. 8, NSS). Regarding crudes failure rates for the
observation vs. CRT groups, LF was 8% vs. 2%, regional relapse was 39% vs. 22%, and distant relapse was 18% vs. 16%, respectively. (Smalley SR et al., JCO 2012)

Question 34

Is there a survival benefit to postop CRT vs. chemo alone in pts with more extensive lymphadenectomy?

Answer 34

No. The Korean ARTIST trial (Lee J et al., JCO 2011; update Park S et al.,
JCO 2014) randomized 458 pts after D2, R0 resection to (a) chemo alone with capecitabine and cisplatin chemotherapy (XP) × 6 cycles (capecitabine
2,000 mg/m2 d1–14 + cisplatin 60 mg/m2 d1 q3wks) or (b) CRT with XP × 2 cycles → 45 Gy with capecitabine 825 mg/m2 bid → XP × 2 cycles. At 7 yrs, there was no difference in OS. However, a trend for improved DFS was observed for CRT (p = 0.09). Tx completion rate was much higher than in
INT-0116 (82% CRT, 75% chemo alone). Also in contrast to INT-0116, appx
60% of pts had early-stage IB–II Dz, which could contribute to the negative
result for CRT.

Question 35

What was the result from the ARTIST trial subgroup analysis?

Answer 35

CRT significantly improved DFS compared to chemo alone for pts with
node+ Dz and intestinal type histology. (Park S et al., JCO 2014)

Question 36

Is there a role for preop CRT for gastric cancer?

Answer 36

Possibly, although no phase III studies have been published to date. A phase
II study of neoadj CRT (RTOG 9904: Ajani JA et al., JCO 2006) using induction chemo × 2 (5-FU/LV/cisplatin) → CRT (continuous infusion [CI] 5-FU/weekly taxol) showed pCR of 26% and R0 resection of 77%.

Question 37

What is the approach to resectable gastric cancer in Europe and what major RCT is it based on? What is the major weakness of this trial?

Answer 37

Periop chemo (without RT) with ECF regimen (epirubicin/cisplatin/5-FU
[ECF]); MRC Adj Gastric Cancer Infusional Chemo (MAGIC) trial (Cunningham D et al., NEJM 2006): 503 pts with gastric, GE junction, and
distal esophageal adenocarcinoma (26%) randomized to (a) preop ECF × 3 and postop ECF × 3 or (b) Sg alone showed a survival benefit for chemo. 5-yr OS was 36% vs. 23%, respectively (p = 0.009). Only 42% completed all chemo. A major weakness of the MAGIC trial is that the pCR rate was 0%.

Question 38

What major question did the CRITICS trial try to answer, and what were
the results?

Answer 38

The CRITICS trial compared periop chemo with preop chemo and postop CRT in the context of a D1+ (≥15 nodes removed) resection. The trial randomized 788 pts to (a) preop epirubicin/cisplatin/oxaliplatin,
and capecitabine (ECC and EOC) chemo × 3 cycles (epirubicin,
cisplatin/oxaliplatin, and capecitabine q3wks) → Sg → postop ECC or EOC × 3 cycles or (b) preop ECC or EOC × 3 cycles → Sg → postop CRT to 45 Gy/25 fx with concurrent cisplatin and capecitabine. 5-year OS and
EFS were equivalent between the 2 arms, and toxicity similar with only clinically irrelevant grade ≥3 non-febrile neutropenia more frequent in the chemo group. Preop chemo compliance was high with >90% dose intensity delivered for all drugs, but only 46% of chemo & 50% of CRT patients completed all treatment as planned. Therefore, in the successor CRITICSII
trial all chemo & RT (docetaxel-based chemo vs. CRT vs. both) will be given preop. (Cats A and Jansen EPM et al., Lancet Oncology 2018)

Question 39

What is the survival of pts with locally advanced unresectable gastric
cancer? How are these pts managed?

Answer 39

5-yr OS is generally 5%–20%. In most randomized studies of these pts, CRT has benefit over chemo alone (5-yr OS 12%–18% vs. 0%–7%). GITSG
G274 (Schein PS et al., Cancer 1982) used CRT (50 Gy) vs. chemo alone (5-
FU/1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea [methyl-
CCNU]). There was better survival with CRT (18% vs. 7%).

Question 40

For metastatic gastric cancer pts, what are some palliative Tx options?

Answer 40

Surgical resection for carefully selected pts with good PS with Sx of obstruction or hemorrhage is better for palliation than stents or bypass. RT
alone or CRT can be considered for the nonsurgical candidates (30 Gy/10 fx is most common). A large retrospective series showed response rates to
palliative RT were 81% for bleeding, 46% for pain, and 53% for obstruction with no dose response for BED10 > 39 Gy (Tey et al., Medicine 2014). Endoluminal laser ablation can be used for proximal lesions with
esophageal obstruction → chemo. Palliative chemo c/w best supportive care had an overall HR of 0.39, and MS increased from 4.3 to 11 mos based on Cochrane meta-analysis. (Wagner A et al., Cochrane Database Sys Rev 2006)

Question 41

What novel targeted therapy may be considered for select pts with metastatic or recurrent gastric cancer?

Answer 41

Trastuzumab (Herceptin); based on the trastuzumab for gastric cancer (name of randomized trial) (ToGA) randomized trial, which showed improved median OS (13.5 vs. 11.1 mos, p = 0.0048) with addition of
trastuzumab to chemo (cisplatin/5-FU) vs. chemo alone (Bang YJ et al., Lancet 2010). The HER2 positive rate was 22.1%.

Question 42

What is the irradiation volume and dose of postop CRT after gastric tumor
resection?

Answer 42

Tumor bed and nodal volumes constructed with preop/postop imaging and surgical clip placement. In general, node+ Dz requires wide coverage of the tumor bed, remaining stomach, all resection/anastomotic sites, and nodal drainage areas (which is dependent on tumor location). Use 45 Gy to the initial volume as per RTOG 0116. CD to 50.4 Gy to the surgical bed or at-risk areas if margin+ or gross Dz. Pre-Tx J-tube placement (at time of
staging laparoscopy) is helpful for nutritional support (See contouring atlas Wu J. et al., PRO 2013).

Question 43

When would it be optional to treat the nodal beds in a resected gastric cancer?

Answer 43

Tx would be optional for pts with negative nodes, pts having had adequate Sg
and pathologic evaluation for nodes (>10–15 nodes), and wide surgical margins (at least 5 cm).

Question 44

In general, what are the at-risk regional nodal sites based on anatomic
location of the gastric tumor?

Answer 44

GE junction: mediastinal, periesophageal, celiac, perigastric

Proximal stomach: perigastric, periesophageal, celiac, pancreaticoduodenal,
porta hepatis

Body: perigastric, splenic, celiac, peripancreatic, porta hepatis

Distal stomach: perigastric, periduodenal, peripancreatic, porta hepatis,
celiac

Question 45

How does the target volume differ for proximal vs. distal gastric lesions?

Answer 45

For proximal and distal lesions and negative nodes with adequate dissection,
the remnant of the stomach does not need to be covered. For body lesions,
however, the gastric remnant needs to be covered in all cases.

Proximal lesions: include splenic hilum and left medial diaphragm in the target volume, but inf extent does not need to go to L3 (may just go to L1–2 coverage of the sup mesenteric artery/P-A nodes)

Distal lesions: include 1st portion of the duodenal C-loop but not the splenic
hilum

Question 46

What is the preferred postop RT planning technique?

Answer 46

3D-CRT (e.g., 4 field) or IMRT can spare normal tissues and reduce toxicity better than traditional AP/PA fields, but greater conformality requires a more careful target delineation.

Question 47

What are some long-term complications of gastrectomy?

Answer 47

Dumping syndrome (diarrhea, cramping, palpitations, reactive hypoglycemia) and malabsorption (B12, iron, calcium; supplement if necessary)

Question 48

Dumping syndrome (diarrhea, cramping, palpitations, reactive hypoglycemia) and malabsorption (B12, iron, calcium; supplement if necessary)

Answer 48

H&P q3–6mos × 1–2 yrs, then 6–12 mos × 3–5 yrs, then annually; CBC/CMP & endoscopy as clinically indicated; CT chest/abd/pelvis q6-12
mos × 2 years, then annually up to 5, and/or PET/CT as indicated; and monitor for B12 and iron deficiency. (NCCN 2018)