© Springer International Publishing AG 2017
Theodore Hong and Prajnan Das (eds.)Radiation Therapy for Gastrointestinal Cancers10.1007/978-3-319-43115-4_55. Gastric Cancer: Background and Clinical Evidence
(1)
Mayo Clinic, Rochester, MN 55905, USA
5.1 Epidemiology and Risk Factors
The United States in 2016, 26,370 new cases and 10,730 deaths [1]
Worldwide in 2012, 951,600 new cases and 723,100 deaths [2]
Large variation in incidence worldwide, highest Asia
Risk factors: age, male gender, atrophic gastritis, Helicobacter pylori infection, smoking, alcohol use, dietary factors (high salt, nitrates, red and processed meats), obesity, hereditary factors (<5 %; hereditary diffuse gastric cancer, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Lynch syndrome), and prior abdominal radiation
5.2 Staging
EGD with biopsies and EUS
CT of chest, abdomen, and pelvis
PET/CT
Laparoscopy with peritoneal cytology
AJCC staging [3]
5.3 Prognostic Factors
Gender/age
Subtype (intestinal more favorable than diffuse)
Stage
Extent of resection (R0 vs. R1 vs. R2)
5.4 Molecular Biology
>90 % adenocarcinoma
Two distinct morphologic and molecular subtypes: intestinal and diffuse
Intestinal type:
Associated with H. pylori infection, dietary factors
More commonly well differentiated
Progressive accumulation of genetic alterations in oncogenes (K-ras) and tumor suppressor genes (p53, APC, TTF, CDKN1B)
More favorable prognosis
Diffuse type:
Clinically can present with “linitis plastica”
More commonly poorly differentiated
Most cases have loss of E-cadherin (CDH1 gene) expression
Worse prognosis
HER2 overexpression in ~20 %. More common in intestinal subtype and moderately/well-differentiated tumors
The Cancer Genome Atlas (TCGA) identified four molecular subtypes: [4]
Epstein-Barr virus positive (9 %) – PIK3CA mutations, DNA hypermethylation, amplification of JAK2, PD-L1, and PD-L2
Microsatellite unstable (22 %) – hypermutation, MLH1 silencing
Genomically stable (20 %) – mutations in RHOA, fusions involving RHO-family GTPase, CDH-1. Enriched for diffuse histology
Chromosomal instability (50 %) – marked aneuploidy and focal amplification of receptor tyrosine kinases, RAS pathway activation, p53 mutations. Enriched for intestinal histology
5.5 Patterns of Failure
5.6 Multidisciplinary Treatment
Early stage (Tis-T1, N0, M0)
Endoscopic resection (Tis or T1a and favorable features)
Gastrectomy + lymphadenectomy
Locally advanced (T2-T4 or N+, M0)
Neoadjuvant therapy* → gastrectomy + lymphadenectomy → adjuvant therapy*
Gastrectomy + lymphadenectomy → adjuvant therapy*
Chemotherapy ± chemoradiation (if not a surgical candidate)
*Chemotherapy ± radiotherapy
Metastatic (M1)
Palliative systemic therapy ± local therapy
5.7 Key Clinical Trials
5.7.1 Surgery
Italian trial of total vs. subtotal gastrectomy for distal tumors [9, 10]
Phase 3 RCT, resectable gastric cancer of distal 50 % of stomach (n = 624)
Total vs. subtotal gastrectomy (proximal clearance ≥ 6 cm) + D2 lymphadenectomy
No difference in survival, lower morbidity with subtotal gastrectomy
Dutch trial of D1 vs. D2 lymphadenectomy [11, 12]
Phase 3 RCT, resectable gastric cancer (n = 711)
Gastrectomy + D1 (perigastric LN) vs. D2 (perigastric + extended regional LN) lymphadenectomy
No difference in survival at 15 years median follow-up
D2 lymphadenectomy: ↑ perioperative morbidity/mortality, ↓ local-regional recurrence, ↓ cancer-specific mortality
Authors recommend spleen-preserving D2 resection at high-volume center
MRC trial of D1 vs. D2 lymphadenectomy
Phase 3 RCT, resectable gastric cancer (n = 400)
Gastrectomy + D1 lymphadenectomy vs. D2 lymphadenectomy
No difference in survival
D2 lymphadenectomy: ↑ perioperative morbidity/mortality
5.7.2 Postoperative Adjuvant Therapy
Intergroup 0116 (US) [6, 13]
Phase 3 RCT, resected gastric cancer (n = 556).
Observation vs. 5FU/leucovorin × 1c → RT (45 Gy) + 5FU/leucovorin → 5FU/leucovorin × 2c.
Increased risk of death with observation (HR 1.32, p = 0.005).
No prospective surgical quality control and lymphadenectomy was reported as D2 (10 %), D1 (36 %), or D0 (54 %).
Adjuvant therapy reduced local and regional (but not distant) recurrence.
Grade 4 adverse events: 32%.
Statistically significant benefit in OS in all subgroups, although trend (p = 0.08) toward greater benefit in intestinal (vs. diffuse) histology.
Establishes postoperative adjuvant chemoradiotherapy as a standard of care for patients with locally advanced, resected gastric cancer who have not received neoadjuvant therapy.
Intergroup CALGB 80101 (US) [14]
Phase 3 RCT, resected gastric cancer (n = 546)
ECF × 1c → RT (45 Gy) + 5FU → ECF × 2c vs. 5FU/leucovorin × 1c → RT (45 Gy) + 5FU → 5FU/leucovorin × 2c
ECF did not improve survival (HR 1.03, p = 0.8)
ECF associated with lower rate of grade 4 adverse events: 26 % vs. 40 % (p < 0.001)
CLASSIC (Korea) [7, 15]
Phase 3 RCT, resected gastric cancer with D2 lymphadenectomy (n = 1035)
Observation vs. capecitabine/oxaliplatin × 8c
Adjuvant chemotherapy reduced risk of death (HR 0.66, p = 0.0015)Related posts:
Basics of Chemotherapy
Primary Liver Cancer: Background and Clinical Evidence
Stereotactic Body Radiation Therapy for Liver Metastases: Radiation Therapy Planning
Pancreatic Cancer: Background and Clinical Evidence
Rectal and Colon Cancer: Radiation Therapy Planning
Gastric Cancer: Radiation Therapy Planning
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