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Gastrointestinal Cancers

Introduction to GI cancer

GI cancer is a collective term used to describe cancers that affect the digestive system. Worldwide, the most commonly diagnosed GI cancers include: colorectal cancer (CRC), gastric cancer, liver cancer (e.g. hepatocellular carcinoma [HCC]), esophageal cancer and pancreatic cancer.1 Less common GI cancers include those affecting the anus, appendix, bile duct, gallbladder and small intestine,2,3 as well as GI neuroendocrine tumors (GI NETs) and stromal tumors (GISTs).4,5

Common GI cancers at a glance

CRC

CRC occurs when a growth in the lining of the large intestine (colon), or at its end (rectum), becomes cancerous. It is one of the leading causes of cancer-related deaths in men and women, worldwide.6 Approximately 15%-30% of patients with CRC present with metastases at the time of initial diagnosis, and 20%-50% go on to develop metastases at some point, contributing to its high mortality rate.7

Management of CRC is dependent on the stage of the disease. For early-stage colon cancer, surgery (partial colectomy, with or without lymph node excision) is the standard of care, followed by adjuvant chemotherapy according to the patient’s overall risk profile.8 For early-stage rectal cancer, a curative treatment approach is usually possible with surgery, often with chemoradiation.9

The heterogenous nature of CRC means that effective treatment for metastatic disease remains a complex and individualized challenge. Numerous genes (tumor protein p53 [TP53], KRAS and BRAF) and pathways (Wnt, RAS−MAPK, PI3K, TGF-β, p53 and DNA mismatch-repair) are implicated in disease initiation and progression.10,11 Targeted agents are indicated in the majority of patients; the choice of treatment pathway is informed by the molecular profile of the tumor, prior therapy, treatment tolerability and treatment goals.7

Gastric cancer

The prevalence of gastric (or stomach) cancer varies significantly around the world.6,12 The highest rates are seen in Eastern Asia, Eastern Europe and South America. Over the last 60 years, there has been a gradual decline in new cases across North America and Western Europe and, more recently, in higher-prevalence regions.12

Treatment of gastric cancer is dependent on the stage of the disease. For very early gastric tumors, endoscopic resection may be appropriate. For Stage IB–III gastric cancer, radical gastrectomy is indicated and perioperative therapy is recommended. For metastatic disease treatment selection, all patients with metastatic gastric cancer should be tested (NGS performed on either solid or circulating tumor DNA) for tumor microsatellite instability/ mismatch-repair deficient (MSI/dMMR) and HER2 status (i.e., ERBB2 amplification), programmed death-ligand 1 (PD-L1) expression level, the presence of NTRK or RET gene fusions and BRAF V600 mutations, and tumor mutational burden (TMB). Chemotherapy doublet or triplet platinum/fluoropyrimidine combinations (with or without taxane) are recommended for fit patients with advanced gastric cancer without actionable biomarkers. Immune checkpoint inhibitors (nivolumab or pembrolizumab) in combination with 5-fluorouracil and platinum is an approved for initial therapy if the tumor is HER2-negative and combined PDL1 score (CPS) is ≥5 or ≥1, respectively, or MSI-H/dMMR. Trastuzumab is recommended, in conjunction with platinum- and fluoropyrimidine-based chemotherapy or in combination with chemotherapy plus a PD-1 inhibitor, for patients with HER2-positive advanced gastric cancer.12,13

Preferred second line and subsequent therapy for advanced or metastatic GC are Ramucirumab + paclitaxel, Trastuzumab deruxtecan (HER2-positive adenocarcinoma), taxane or irinotecan monotherapy, 5-FU + irinotecan Trifluridine/tipiracil (third line and beyond). The following targeted treatment options are useful in certain circumstances: Pembrolizumab (MSI-H/dMMR tumors), Pembrolizumab (TMB-H tumors ≥10 mut/megabase), nivolumab + ipilimumab (MSI-H/dMMR tumors), dostarlimab (MSI-H/dMMR tumors), entrectinib or larotrectinib (NTRK gene fusion–positive disease), Dabrafenib + trametinib (BRAF V600E mutated tumors), selpercatinib (RET gene fusion–positive disease).13

Liver cancer

Liver cancer is the third most common form of GI cancer.6 There are two major subtypes: HCC and intrahepatic bile duct cancer. HCC is the more common of the two, with rates increasing globally for the last 20 years and predicted to continue to increase until 2030.14

Liver function is often used to inform the choice of systemic therapy in liver cancer. Atezolizumab with bevacizumab, sorafenib monotherapy, or lenvatinib monotherapy is used for patients with adequate liver function (Child-Pugh class A).15

Esophageal cancer

There are two main subtypes of esophageal cancer – squamous cell carcinoma (SCC) and adenocarcinoma. SCC occurs more frequently in the upper and middle parts of the esophageal tract, while adenocarcinoma usually occurs in the lower part of the esophagus, near the junction with the stomach.16 Although SCC accounts for approximately 90% of cases of esophageal cancer, adenocarcinoma is associated with a higher mortality rate. Indeed, adenocarcinoma mortality rates have now surpassed those of SCC in some countries.17,18

Surgery is the treatment of choice in limited disease esophageal cancer, with disease histology and stage guiding the choice of technique. For patients unable or unwilling to undergo surgery, combined chemoradiotherapy is superior to radiotherapy alone.17 

Management of metastatic esophageal cancer focuses on palliative treatment, with options (e.g. brachytherapy, chemotherapy or best supportive care) governed by clinical situation.17

Uncommon GI tumors at a glance

Biliary Tract Cancer (BTC)

BTCs are a rare and heterogeneous group of cancers arising from the biliary tract.18 Although relatively uncommon overall (3% of all adult cancers), BTC accounts for approximately 15% of all primary liver cancers.18,19 Worldwide, gallbladder cancer is the most common cancer of the biliary tract.20 Global incidence of BTC and deaths from the disease are rising, mainly driven by the increase in bile duct cancer (cholangiocarcinoma or CCA). The rise in CCA may be linked to increasing rates of metabolic-associated conditions including obesity and type 2 diabetes.20,21

The majority of patients with BTC have unresectable disease.18 For patients with unresectable/metastatic disease who are fit enough to tolerate the known side-effect profile of intravenous systemic chemotherapy, the mPFS is 7.2–8.0 months.18,22

The identification of distinct patient subgroups harboring unique molecular alterations enabling treatment with corresponding targeted therapies is beginning to change the treatment paradigm.23 However, second-line targeted therapies associated with better survival outcomes are currently applicable to only a small and very specific sub-population of BTC patients.24,25

GI NETs 

Neuroendocrine neoplasms (NENs) are relatively rare, comprising ~2% of all malignancies; however, 62–67% of NENs occur in the GI tract.26

GI NETs arise from the diffuse neuroendocrine system and comprise a heterogeneous group of tumors that can present with a variety of clinical symptoms.27,28 The risk factors are not well characterized, but multiple endocrine neoplasia type 1 syndrome is implicated, and genetic and familial associations have been observed.26

NENs are broadly divided into two groups on the basis of clinical behavior, histology and proliferation rate: [1] Well-differentiated (low to intermediate grade) NETs and [2] poorly differentiated (high grade) neuroendocrine carcinoma.25,27

Therapeutic decision-making is based on tumor grade, somatostatin receptor expression, proliferative activity and tumor growth; 12–22% of patients present with metastatic disease.26-28 Potential treatment options include surgery, somatostatin analogues, chemotherapy, sunitinib, peptide receptor radionuclide therapy and interferon alpha.28

GISTs

GISTs account for approximately 1% of all GI tumors, but they are the most common mesenchymal tumors of the GI tract.5 They are thought to grow from specialized interstitial cells of Cajal that function as pacemaker-like intermediates between the GI autonomic nervous system and smooth muscle cells, regulating GI motility and autonomic nerve function.6,29

GISTs may be either malignant or benign and can occur anywhere in or near the GI tract; they appear most often in the stomach (60%) or small intestine (30%). They are typically diagnosed in adults aged 40–70 years.6,29

Some people with GISTs may experience pain or swelling in the abdomen, nausea, vomiting, loss of appetite or weight loss. Anemia, black and tarry stools and vomiting of blood can also occur in cases where GISTs cause GI bleeding. A family history of GISTs is generally associated with more symptomatic disease and multiple (rather than single, ‘sporadic’) tumors.29

The formation of GISTs is most commonly associated with mutations in the tyrosine-protein kinase KIT gene (approximately 80% of cases) and the platelet-derived growth factor receptor alpha gene (PDGFRA; approximately 10% of cases).29

Treatment may involve surgery and/or use of tyrosine kinase inhibitors (TKIs), depending on the extent of disease and TKI sensitivity.5

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