Gastrointestinal Cancers in focus

Gastrointestinal Cancers in focus

Introduction to GI cancer

This page provides an overview of gastrointestinal (GI) cancers, the associated disease burden and clinical considerations relating to the most common GI tumor types.

GI tract 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 cancers (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 (NETs) and stromal tumors (GISTs), which are characterized by their cell type of origin.4,5

Watch Dr Victoria Zazulina (Corporate VP and Global Head of Oncology Medicine) discuss Boehringer Ingelheim’s research focus on GI cancers in the video below.

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Dr Victoria Zazulina explains why treating GI cancers represents an area of focus for Boehringer Ingelheim. Video filmed in 2019.

Disease burden

GI cancers are responsible for more cancer-related deaths than any other type of cancer.6 In 2020, they accounted for an estimated 3.5 million deaths worldwide, with a further 5.0 million new cases diagnosed in the same year.6

Common GI cancers: global incidence and mortality6

Global GI cancer incidence and mortality

*Global data, both sexes, all ages; **CRC, gastric cancer, esophageal cancer, pancreatic cancer and liver cancer.

CRC, colorectal cancer; GI, gastrointestinal.

Common types of GI cancer

CRC is the most common type of GI cancer, with 1.9 million new cases diagnosed worldwide in 2020, making it the third most common of all organ cancers, after lung and breast.6

In the same year, gastric (or stomach), liver, esophageal and pancreatic cancers were ranked the fifth, sixth, eighth and twelfth most commonly diagnosed cancers, with 1.1, 0.9, 0.6 and 0.5 million new cases worldwide, respectively.6

Incidence of common GI cancers in 20206

Incidence of common GI cancers

CRC, colorectal cancer; GI, gastrointestinal.

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 25% of patients with CRC present with metastases at the time of initial diagnosis, and almost a half go on to develop metastases at some point, contributing to its high mortality rate.7

Location of the colon and rectum within the digestive system

Location of the colon and rectum within the digestive system

Common symptoms include: changes in bowel habits, general or localized abdominal pain, weight loss without other specific causes, weakness, iron deficiency and anemia.8

 

Risk factors include: age, inflammatory bowel disease, family history, elevated body mass index, reduced physical activity, alcohol consumption and cigarette smoking, as well as a number of dietary factors. High consumption of processed and red meat is thought to contribute to increased risk, while high fruit and vegetable intake is thought to confer protection9

 

Staging: staging of metastatic CRC should include clinical examination, blood counts, liver and renal function tests, carcinoembryonic antigen evaluation, and a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the abdomen and chest.7 Additionally, a colonoscopy is often performed as part of initial diagnostic procedures.8 The optimum therapeutic strategy is further determined by an evaluation of the patient’s general condition, organ function and presence of any relevant comorbid (non-malignant) diseases.7

 

Management (first-line standard of care):

  • Early-stage disease:
    • Colon cancer: surgery is the standard of care, followed by adjuvant chemotherapy according to the patient’s overall risk profile8
    • Rectal cancer: a curative treatment approach is possible based on surgery, often with chemoradiation10
  • Metastatic disease: the heterogenous nature of CRC means that effective treatment 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.11,12 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 goals7

Gastric cancer

The prevalence of gastric (or stomach) cancer varies significantly around the world.6,13 The highest rates are seen in Eastern Asia, Eastern Europe and South America, and the lowest in North America and Western Europe.13 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.13

Location of the stomach within the digestive system

Location of the stomach within the digestive system

Common symptoms include: weight loss, dysphagia, dyspepsia, vomiting, early satiety and/or iron deficiency anemia.13

 

Risk factors include:13

  • General: male gender (incidence is twice as high as in females), Helicobacter pylori infection, tobacco use, atrophic gastritis, partial gastrectomy and Ménétrier’s disease
  • Anatomical subsite-specific:
    • H. pylori and dietary factors are associated with antral or distal cancers
    • Obesity is associated with cancers of the cardia or proximal stomach
    • Reflux is associated with cancers occurring at the gastroesophageal junction

 

Staging:13

  • Initial staging and risk assessment should include physical examination, blood count and differential, liver and renal function tests, endoscopy and contrast-enhanced CT scan of the thorax, abdomen and pelvis
  • Laparoscopy is recommended for patients with resectable disease
  • Multidisciplinary planning is strongly recommended before any treatment is administered

 

Management (first-line standard of care):13

  • For very early tumors: endoscopic resection is appropriate
  • For Stage IB–III gastric cancer: radical gastrectomy is indicated and perioperative therapy is recommended
  • For metastatic disease:
    • Doublet or triplet platinum/fluoropyrimidine combinations are recommended for fit patients with advanced gastric cancer
    • Trastuzumab is recommended, in conjunction with platinum- and fluoropyrimidine-based chemotherapy, for patients with HER2-positive advanced gastric cancer

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

Location of the liver within the digestive system

Location of the liver within the digestive system

Common symptoms include: pain, fatigue, weight loss and obstructive syndromes, such as ascites and jaundice15

 

Risk factors include: chronic liver disease, liver cirrhosis and hepatitis infection.14

 

Staging and management: several staging systems have been developed, including the Barcelona Clinic Liver Cancer (BCLC) system. BCLC staging links tumor stage, liver function, cancer-related symptoms and performance status (PS) to an evidence-based treatment algorithm:14

  • BCLC A: patients with early HCC who may benefit from ablative treatment
  • BCLC B: patients with intermediate disease, for whom transarterial chemoembolization (TACE) may be indicated
  • BCLC C: patients with advanced disease, for whom the kinase inhibitor sorafenib may be suitable
  • BCLC D: for patients with end-stage disease, best supportive care (BSC) is recommended (end-stage liver function; Eastern Cooperative Oncology Group [ECOG] PS 3 or 4)

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.16,17

Location of the esophagus within the digestive system

Location of the esophagus within the digestive system

Common symptoms include: difficult or painful swallowing, progressive weight loss, nausea, vomiting, loss of appetite, chest pain and hoarseness16

 

Risk factors include:17

  • Smoking and alcohol consumption for SCC
  • Chronic gastroesophageal reflux and obesity for adenocarcinoma

 

Staging should include:17

  • A complete clinical examination and a CT scan of the neck, chest and abdomen. In candidates for surgical resection, endoscopic ultrasonography should be carried out to evaluate T and N tumor categories; in candidates for esophagectomy, 18F-fluorodeoxyglucose Positron Emission Tomography (18F-FDG-PET) should be performed
  • Multidisciplinary planning is strongly recommended before any treatment is administered

 

Management (first-line standard of care):17

  • Early-stage disease:
    • Surgery is the treatment of choice in limited disease, with disease histology and stage guiding the choice of technique: endoscopic submucosal dissection, radical and transthoracic esophagectomy, endoscopic therapy, endoscopic resection or endoscopic en bloc resection
    • For patients unable or unwilling to undergo surgery, combined chemoradiotherapy is superior to radiotherapy alone
  • Metastatic disease:
    • Management focuses on palliative treatment, with options (e.g. brachytherapy, chemotherapy or BSC) governed by clinical situation

Uncommon tumors at a glance

Anal cancer

Anal cancer represents only 1.5% of GI cancers, but there has been an increase in the global incidence in recent decades.18 SCC of the anus is strongly associated with human papillomavirus (HPV) infection, which represents the causative agent in 80–85% of cases.19

Location of the anus within the digestive system

Location of the anus within the digestive system

Common symptoms include: a perianal mass, non-healing ulcers, pain, bleeding, itching, discharge, fecal incontinence and fistulae.19

Risk factors include: HPV infection, anal intercourse, a high lifetime number of sexual partners, human immunodeficiency virus infection, immune suppression in transplant recipients, use of immunosuppressants, a history of other HPV-related cancers, autoimmune disorders, social deprivation and cigarette smoking.19

Staging should include: MRI of the pelvis or, if not available, endo-anal ultrasound. MRI has good spatial resolution and contrast, providing information on tumor size, local extent and spread. Distant metastases can be assessed with CT of the thorax and abdomen. 18F-FDG-PET/CT has a high sensitivity for identifying involved lymph nodes. Needle aspiration biopsy is usually only carried out for clinically palpable inguinal nodes or those enlarged >10 mm on CT or MRI. Sentinel lymph node biopsy can reveal micrometastatic spread of the disease.19

Management:

  • For initial management of local and locoregional disease, combinations of 5-fluorouracil-based chemoradiotherapy and other cytotoxic agents (mainly mitomycin C) have been established as the standard of care. A multidisciplinary approach is essential, involving radiation therapists, medical oncologists, surgeons, radiologists and pathologists. Although surgery is no longer considered the primary therapeutic option, the role of surgery as a salvage treatment is generally accepted. Small lesions (<2 cm in diameter) involving the anal margin and not poorly differentiated are candidates for surgery, provided that adequate margins (>5 mm) can be obtained without compromising sphincter function19
  • For management of advanced/metastatic disease, there is no consensus on the standard chemotherapy treatment. The choice of chemotherapy is often influenced by previously used agents in the initial chemoradiotherapy regimen. Patients who are otherwise fit but are unsuitable for surgery often receive chemotherapy (usually with a combination of cisplatin and 5-fluorouracil). Other agents with reported activity in anal cancers include carboplatin, doxorubicin, taxanes and irinotecan ± cetuximab, or combinations of these agents19

GI NETs

Neuroendocrine neoplasms (NENs) are relatively rare, comprising ~2% of all malignancies; however, 62–67% of NENs occur in the GI tract.20

GI NETs arise from the diffuse neuroendocrine system and comprise a heterogeneous group of tumors that can present with a variety of clinical symptoms.21,22 The risk factors are not well characterized, but multiple endocrine neoplasia type 1 syndrome is implicated, and genetic and familial associations have been observed.20

NENs are broadly divided into two groups on the basis of clinical behavior, histology and proliferation rate:20,22

  • Well-differentiated (low to intermediate grade) NETs
  • Poorly differentiated (high grade) neuroendocrine carcinoma

Therapeutic decision-making is based on tumor grade, somatostatin receptor expression, proliferative activity and tumor growth; 12–22% of patients present with metastatic disease.20-22 Potential treatment options include surgery, somatostatin analogues, chemotherapy, sunitinib, peptide receptor radionuclide therapy and interferon alpha.22

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.5,23

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.5,23

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.23 A family history of GISTs is generally associated with more symptomatic disease and multiple (rather than single, ‘sporadic’) tumors.23

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).23

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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References

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Ferlay J, et al. Int J Cancer 2015;136(5):E359–86.

2

Pourhoseingholi MA, et al. Gastro Hepat Bed to Bench 2015;8(1):19.

3

GI Cancer Alliance. GI Cancers. http://www.gicancersalliance.org/gi-cancers (Accessed: January 2021).

4

Hirabayashi K, et al. Front Oncol 2013;3:2.

5

National Cancer Institute. Gastrointestinal Stromal Tumors Treatment (PDQ®)–Health Professional Version. https://www.cancer.gov/types/soft-tissue-sarcoma/hp/gist-treatment-pdq (Accessed: January 2021).

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International Agency for Research on Cancer (IARC). Estimated number of new cases and deaths of cancer in 2020. https://gco.iarc.fr/today/home (Accessed: January 2021).

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Van Cutsem E, et al. Ann Oncol 2016;27:1386–422.

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Argilés G, et al. Ann Oncol 2020;31(10):1291–305.

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Johnson CM, et al. Cancer Causes Control 2013;24(6):1207–22.

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Glynne-Jones R, et al. Ann Oncol 2017;28(Suppl. 4):iv22–iv40.

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Fearon ER. Annu Rev Pathol Mech Dis 2011;6:479–507.

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Zarkavelis G, et al. Ann Gastroenterol 2017;30(6):613.

13

Smyth EC, et al. Ann Oncol 2016;27(Suppl. 5):v38–49.

14

Vogel A, et al. Ann Onol 2018;29(Suppl. 4): iv238–iv255.

15

Sun VC, Sarna L. Clin J Oncol Nurs 2008;12(5):759–66.

16

Harris C, et al. Ann Cardiothorac Surg 2017;6(2):190.

17

Lordick F, et al. Ann Oncol 2016;27(suppl_5):v50–7.

18

Salati SA, et al. Int J Health Sci (Qassim) 2012;6(2):206–30.

19

Glynne-Jones R, et al. Ann Oncol 2014;25(Suppl. 3):iii10─iii20.

20

Oronsky B, et al. Neoplasia 2017;19:991–1002.

21

Yang Z, et al. Cell Physiol Biochem 2018;45:389–96.

22

Pavel M, et al. Ann Oncol 2020;31(7):844–60.

23

U.S. National Library of Medicine. Genetics Home Reference: Gastrointestinal stromal tumor. https://ghr.nlm.nih.gov/condition/gastrointestinal-stromal-tumor#resources (Accessed: January 2021).

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Page last updated: January 2021