Cancers of the gastrointestinal system

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11 Cancers of the gastrointestinal system

TV. Ajithkumar, E. de Winton

Oesophageal cancer

Epidemiology

Oesophageal cancer is an aggressive cancer with an overall survival rate of less than 10%. There are over 7000 new patients per year in the UK and 16,000 per year in USA. The median age at diagnosis is 69 years. The male to female ratio is 2.5 : 1; but cervical oesophageal cancer is more common in women.

Aetiology

Oesophageal reflux and Barrett’s oesophagus are thought to increase the risk of adenocarcinoma. Oesophageal reflux may account for the increased incidence of adenocarcinoma (10% per year) in the Western world.

Box 11.1 shows risk factors for oesophageal cancer. A diet rich in fruit and vegetables has been shown to reduce the relative risk.

Box 11.1
Risk factors for oesophageal cancer

• Gastro-oesophageal reflux (achalasia – SCC, hiatus hernia and obesity – adenocarcinoma)
• Barrett’s oesophagus (adenocarcinoma)
• Nutritional deficiency (vitamins A, C and riboflavin – SCC)
• Oesophageal injury (SCC)
• Alcohol (SCC)
• Smoking (SCC)
• Fungal toxins (infected cereals)
• Plummer–Vinson syndrome (upper third SCC)
• Tylosis palmaris (50% lifetime risk of SCC)
• History of head and neck cancer (SCC)
• Diet – high fat, low-protein and low calorie (SCC)
• Nitrosamines (both adenocarcinoma and SCC)

Anatomy

The oesophagus extends from the cricopharyngeal sphincter to the gastro-oesophageal junction (GOJ) and is 25 cm in length. Figure 11.1 shows the anatomic sections of the oesophagus. The majority of tumours (85%) arise in the middle and lower third of oesophagus and 15% arise in the upper third.

image

Figure 11.1 Anatomic section of oesophagus.

Pathogenesis and pathology

Oesophageal cancer is thought to be the end result of a multi-step process of carcinogenesis. Adenocarcinoma arising from Barrett’s oesophagus is thought to undergo a stepwise progression with associated genetic changes.

The common malignant tumours are adenocarcinoma, squamous cell carcinoma (SCC) or undifferentiated carcinoma. Most adenocarcinomas occur at or immediately above the GOJ which are classified (Siewert Classification) as follows:

• Type I – distal oesophageal cancer which may infiltrate GOJ.
• Type II – straddles the GOJ (cancer of the cardia; also called junctional cancer).
• Type III – subcardial cancer which may infiltrate OGJ and distal oesophagus.

Adenocarcinoma – accounts for 65% of oesophageal cancers in the UK and the major aetiological factor is Barrett’s oesophagus. The incidence of carcinoma arising in Barrett’s oesophagus is 1 per 100 patient-years.

Squamous cell carcinoma (SCC) accounts for 25% of oesophageal cancer. Alcohol and smoking are the major etiological factors. SCC is common in upper and mid third cancers.

Most common sites of metastatic spread are lymph nodes (70%), lung (20%), liver (35%), bone (9%) and adrenal glands (2%).

Clinical features

Most patients present with progressive dysphagia and difficulty in swallowing liquids indicate an advanced stage. 50% patients experience painful swallowing and other presentations include reflux, regurgitation and vomiting following eating, rapid weight loss. Local invasion of cancer leads to pain, and nerve compression leading to Horner’s syndrome, recurrent laryngeal nerve palsy and a raised hemi-diaphragm.

Metastatic disease can result in liver capsular pain, bony metastases, ascites or peritoneal deposits. Patients are usually cachectic at this stage.

Evaluation

History: details of symptoms including performance status, weight loss and degree of dysphagia.
Examination: cachexia, anaemia, jaundice, enlarged supraclavicular nodes, chest (for pleural effusion) and abdomen (hepatomegaly, ascites).

Investigations and staging

Investigations are aimed at establishing the extent of disease, obtaining histologic diagnosis and assessing fitness for appropriate treatment:

• Barium swallow is usually the initial investigation of choice which shows the level of obstruction. Malignant strictures appear as asymmetric narrowing with abrupt, shelf-like margins and irregular contours, and may show proximal dilatation (Figure 11.2A).
• Endoscopy allows visual assessment of the tumour and biopsy.
• Endoscopic ultrasound (EUS) helps to assess the depth of invasion through the various layers of oesophagus (>90% accuracy), adjacent structures and neighbouring lymph nodes (70–80% accuracy). The normal oesophagus has five alternating hyperechoic and hypoechoic layers with inner most hyperechoic superficial mucosa. Oesophageal cancers appear as hypoechoic masses that can disrupt this layered pattern (Figure 11.2B, arrow). Malignant lymph node is characterized by more than 1 cm, round, hypoechoic area with distinct margins (Figure 11.2B, arrowhead). EUS guided fine needle aspiration (FNA) of any suspicious lesions, particularly lymph nodes of >5 mm, helps to improve the diagnostic accuracy.
• CT scan of the thorax, abdomen and pelvis is routinely done to assess the local extent of the tumour and local and distant staging.
• Positron emission tomography (PET) is useful in detecting distant metastases (sensitivity of 90% and specificity of >90%) and has been increasingly used in oesophageal cancer.
• Laparoscopy is useful in lower third oesophageal and gastro-oesophageal junction tumours prior to major surgical procedure. This helps to visualize and biopsy small peritoneal metastases, which may not have been detected on CT or PET. Up to 20% patients are up-staged after this procedure and major surgery can be avoided.
• Bronchoscopy is useful as a preoperative procedure in upper and middle third oesophageal cancer to rule out bronchial invasion.
• Tissue diagnosis is obtained via endoscopic biopsy.
• Other investigations – include full blood count, biochemistry and coagulation profile. Patients considered for surgery need pulmonary function tests, arterial blood gases, ECG and an exercise test.
image

Figure 11.2 Barium swallow (A) and EUS (B) in oesophageal cancer. (Weinstein WM, Hawkey CJ, Bosch J. Clinical Gastroenterology and hepatology, 1st edition, Page 183, fig 32.7 (Mosby, 2005).)

Staging

Staging determines prognosis and guides treatment. TNM staging is given in Box 11.2.

Box 11.2
Staging of oesophageal cancer

Stage I

• T1 N0 M0 Invasion of lamina propria or submucosa

Stage IIa

• T2 N0 M0 Invasion of the muscularis mucosa
• T3 N0 M0 Invasion of the adventitia

Stage IIb

• T1–2 N1 M0 Regional nodal involvement

Stage III

• T3 N1 M0
• T4 N0–1 M0 Invasion of adjacent structures

Stage IVa

• Any T any N M1a

Stage IVb

• Any T any N M1b

Tumours of upper third cancer

• M1a: Metastasis in cervical lymph nodes
• M1b: Other distant metastasis

Tumours of middle third cancer

• M1a: Not applicable
• M1b: Non regional lymph node or other distant metastasis

Tumours of lower third cancer

• M1a: Metastasis in coeliac lymph nodes
• M1b: Other distant metastasis

Management of oesophageal cancer (Figure 11.3)

Localized disease

This group consists of patients with stages I–III oesophageal cancer as well as a subgroup of operable stage IVa (involving pleura, pericardium and diaphragm). However, only one-third of patients present with localized disease. The majority of these are stage II or III disease and less than half of these patients are curable. Assessment of fitness for suitable treatment is an essential component of the decision. A number of treatment options are available depending on the stage, location of tumour, and fitness to undergo treatment, which include:

• Endoscopic mucosal resection (EMR) – for superficial cancer limited to the mucosa.
• Radical surgery alone (T1N0M0 tumours located >5 cm from the cricopharyngeal junction and fit for surgery).
• Radical chemoradiotherapy (tumours within 5 cm from the cricopharyngeal junction, unresectable/medically unfit patients with T1–T3N0–1M0 tumours and selected T4N0–1M0).
• Preoperative chemotherapy followed by radical surgery (operable and medically fit patients with T1–T4N0–N1M0 cancer located >5 cm from the cricopharyngeal junction).
• Radical chemoradiotherapy followed by surgery (only in those with residual disease after radical chemoradiotherapy and fit for surgery).
• Radical radiotherapy (not suitable for surgery and chemotherapy).
• Palliative treatment or best supportive care (PS >2).
image

Figure 11.3 Management of oesophageal cancer.

Radical surgery

Surgery is the best single modality treatment compared with radiotherapy alone. The best outcome from specialist centres is 5-year survival of approximately 35% with a postoperative mortality of less than 5%.

Type of surgery depends on the site of tumour, histology and the extent of lymphadenectomy required. The surgery involves subtotal oesophagectomy with the upper part of the stomach and anastomosis of the cervical oesophagus and gastroplasty. 60–70% of patients have involved lymph nodes at the time of surgery and hence need dissection of abdominal and mediastinal nodes in middle and lower third cancers (a minimum of 15 nodes should be removed).

The common procedures are as follows:

• Upper third oesophageal cancer: three-phase approach with complete removal of the tumour and mediastinal and supraclavicular lymphadenectomy.
• Middle and lower third cancers: two stage Ivor–Lewis approach. The first stage consists of laparotomy and mobilization of the stomach, followed by right thoracotomy to remove the tumour and to form an oesophagogastric anastomosis.

Minimally invasive surgical approaches are evolving.

Radical radiotherapy (Box 11.3)

Radical radiotherapy is the treatment of choice in patients with localized disease who are medically unfit for surgery and in whom chemotherapy is contraindicated. The best results are an overall 5-year survival of less than 10%.

Box 11.3
Radiotherapy for oesophageal cancer

Position – supine (with arms above head for middle and lower third, and arms by side for upper third)
Localization – CT planning with information from EUS
Target volume

Radical chemoradiotherapy

• GTV – tumour with enlarged nodes
• CTV:

• Superio-inferior

– Tumours above carina (cervical and upper-third) – GTV + 2 cm and bilateral supraclavicular nodes
– Middle third – GTV + 2 cm margin
– Lower third – GTV + 2 cm margin and coeliac axis basin nodes and gastrohepatic ligament (lesser curve, paracardial and left gastric nodes)

• Lateral and anterior – GTV + 1 cm
• Posterior – GTV + 0.5–1 cm

• PTV – CTV + 1 cm
• 2 phase treatment – phase I CTV = GTV + 3–5 cm superio-inferior margin and 1.5–2 cm axial margin and phase II CTV as GTV with 2 cm margin superoinferiorly and 1.5–2 cm axially

Radical radiotherapy

PTV – 5 cm superior inferior margin for phase I and 2.5–3 cm for phase II and 2.5 cm axial margin

Palliative radiotherapy

PTV – tumour and node + 3 cm margin

Dose

Indication Single phase 2 phase
Radical chemoradiotherapy 50–50.4 Gy in 25–28 fractions
Phase I – 30 Gy in 15
Phase II – 20 Gy in 10

Radical radiotherapy
55 Gy in 20 or
66 Gy in 33 fractions

Phase I – 33 Gy in 12 and phase II – 22 Gy in 8
Phase I – 36 Gy in 18 and Phase II 30 Gy in 15

Preoperative chemoradiotherapy 45 Gy in 25 fractions   Palliative 30 Gy in 10 fractions or 20 Gy in 5 fractions  

Normal tissue tolerance

• Lung V20 (volume receiving 20 Gy) <25%
• Heart V30 <40%
• Spinal cord total dose below 45 Gy

Care during radiotherapy

• Weekly blood test
• Keep Hb >12 gm%
• Avoid significant weight loss (consider PEG/RIG feeding)

Radical chemoradiotherapy (CRT)

Radiotherapy is given in combination with chemotherapy which is proven to be superior to radical radiotherapy alone. Chemotherapy improves local control by radiation sensitization and helps to minimize distant metastatic relapses. This approach results in an overall 3-year survival of 30%. The commonly used combination is cisplatin with 5-fluorouracil with radiotherapy at a dose of 50 Gy in 2 Gy per fraction (Box 11.3). However, locoregional recurrence remains the major cause for overall failure with 50% of patients developing locoregional disease. Attempts to increase the radiotherapy dose to improve local control has resulted in increased treatment-related deaths without improvement in local control or survival. Studies comparing CRT with CRT followed by surgery showed similar overall survival, but with high treatment-related mortality with surgery.

Preoperative chemotherapy followed by surgery

A meta-analysis showed that preoperative chemotherapy followed by surgery improved 2-year survival by 7% compared with surgery alone (HR 0.90; CI 0.81–1.00). The largest study (MRC OE02) of 802 patients which compared surgery alone with two cycles of 3-weekly preoperative cisplatin (80 mg/m2 on day 1 as 4 hour infusion) and 5-fluorouracil (1 g/m2/day continuous infusion for 4 days) followed by surgery showed that chemotherapy improves overall survival from 34% to 43% at 2-years (p = 0.004). Hence, this is the standard treatment option in most UK centres.

Preoperative CRT followed by surgery

A meta-analysis showed that preoperative CRT followed by surgery improved 2-year survival by 13% compared with surgery alone (HR 0.81 95% CI 0.70–0.93; p = 0.002). However, this benefit was only seen with concurrent chemoradiotherapy rather than sequential and treatment-related mortality was increased with preoperative CRT (p = 0.053). Due to concerns about morbidity and mortality, it is not practised in the UK.

Advanced and recurrent disease (Figures 11.3 and 11.4)

Two-thirds of oesophageal cancer patients present with advanced disease and a significant number of patients who had initial radical treatment will relapse. The treatment is essentially palliative, aimed to improve symptoms, quality of life and possibly to extend life. Pre-treatment performance status is important in deciding potentially toxic treatment.

image

Figure 11.4 Management of recurrence.

Systemic treatment

Chemotherapy for advanced oesophageal cancer improves survival when compared to best supportive care alone. In the UK, the combination of epirubicin, cisplatin and 5FU (ECF) has been used as the standard regime (Box 11.4). A randomized study (REAL-2) to explore the role of oxaliplatin instead of cisplatin and capecitabine instead of 5-FU (EOX regime) showed that toxicity of 5FU and capecitabine were similar; oxaliplatin resulted in increased neuropathy and diarrhoea but reduced renal toxicity, thromboembolism, alopecia and neutropenia when compared with cisplatin. Patients receiving EOX survived longer than ECF (38% vs. 47% at 1-year; p = 0.02).

Box 11.4
Chemotherapy for oesophageal cancer

Preoperative chemotherapy

• Cisplatin 80 mg/m2 on day 1 and 5-FU 1 gm/m2/day continuous infusion for 96 hours. Cycles repeated every 3 weeks for 2 cycles.

Chemoradiotherapy

• Cisplatin 60–80 mg/m2 repeated 3 weekly for 4 cycles with 5-fluorouracil 250 mg/m2/day initially reducing to 200 mg/m2/day during radiotherapy.

Palliative

ECF regime

• Epirubicin 50 mg/m2 day1, cisplatin 60 mg/m2/day1 and 5-FU 200 mg/m2/day; cycle repeated 3-weekly

ECX regime

• Epirubicin 50 mg/m2 day1, cisplatin 60 mg/m2/day1 and capecitabine 625 mg/m2 orally twice daily ; cycle repeated 3-weekly

Palliative treatment of dysphagia

Dysphagia is the predominant symptom which needs palliation. The various methods to relieve dysphagia are:

• Endoscopic dilatation – results in immediate but short lived (2–4 weeks) improvement and hence useful only for those with limited life expectancy.
• Stent – immediate and prolonged improvement. There are two types of stents: uncovered and covered (has risk of migration).
• Local therapies – laser, ethanol injection and photodynamic therapy. Response is short lived.
• Radiotherapy – is delivered by external beam radiotherapy or brachytherapy. Radiotherapy will not result in immediate relief of dysphagia and may cause initial deterioration.
• Palliation of other symptoms follows the principles that of any other cancer (p. 66).

Prognosis and survival

Stage, particularly depth of invasion of the oesophageal wall, is an important prognostic factor. Other prognostic factors include age, performance status and weight loss (>10% in 3 months). Grade and histologic subtypes have no prognostic importance.

The overall 5-year survival of oesophageal cancer is <10%. Less than a third of patients are suitable for surgical resection. Around 80% of patients with stage I disease are alive at 5 years whereas only 15% of stage IIa/III patients are alive at 5 years. The median survival of patients treated with palliative intent is 4 months.

Follow-up

All patients are followed up after curative treatment. The follow-up involves history and clinical examination, 4-monthly for one year, 6-monthly for two years and yearly thereafter. Investigations are done as clinically indicated.

Ongoing studies and new agents

New chemotherapy regimes and drugs are being tested to improve the efficacy of CRT. UK SCOPE 1 trial is testing the addition of cetuximab (an EGFR inhibitor) to standard CRT.

MRC OE05 study is comparing ECF chemotherapy followed by resection versus ECX chemotherapy followed by resection in patients with resectable adenocarcinoma of the oesophagus.

Along with various attempts to improve the loco-regional control of oesophageal cancer, studies are ongoing to assess the benefit of various biological agents. Gefinitib (500 mg daily), a tyrosine kinase inhibitor which acts by blocking epithelial growth factor receptor (EGFR), has been shown to have some benefit in patients with advanced oesophageal cancer (50% 6-month survival). Bortezomib, a proteasome inhibitor, is also being studied along with chemotherapy. Another agent under investigation is a monoclonal antibody, panitumumab (REAL 3 study).

Screening and surveillance

The role of screening is not fully established. In the UK, high-risk patients (tylosis and Plummer–Vinson syndrome) are regularly screened with endoscopy. Routine surveillance of chronic reflux (absolute individual risk of less than 1 in 1000 per annum) is not justified. Patients with Barrett’s oesophagus with mild dysplasia are treated with acid suppression therapy followed by a repeat endoscopy and multiple biopsies at 8–12 weeks. If this remains stable, six-monthly repeat biopsy is recommended. Patients with high-grade dysplasia have a 30–40% risk of having invasive adenocarcinoma and hence full staging is undertaken with a view to oesophagectomy.

Small cell carcinoma of oesophagus

This accounts for 0.5–2.4% of oesophageal cancers. The usual presentation is dysphagia (86%) of 1–3 months’ duration and presents in patients in their late 50s. Treatment is similar to small cell lung cancer with chemoradiotherapy. There are some reports suggesting that addition of surgical resection may improve long-term survival. The reported median survival ranges from 12–18 months.

Gastric cancer

Epidemiology

Gastric cancer is the second commonest cause of cancer death in the world. There are approximately 8200 new patients per year in the UK and over 26,000 per year in USA. Although the overall incidence has decreased significantly, there has been an exponential rise in tumours of the proximal stomach and cardia. The median age at diagnosis in men is 70 years and in women 74 years. It is common in men (male to female ratio 2.3 : 1).

Only 20% of patients present with localized disease and the overall 5-year survival is 15–20%.

Aetiology

The aetiology of gastric cancer is multifactorial. The following factors increase the risk:

• Diet: low consumption of fruits and vegetables and high intake of salts, nitrates and smoked or pickled foods increases the risk.
• Smoking.
• Helicobacter pylori – associated with gastric lymphoma and adenocarcoma (2.8-fold increase).
• Blood group A (20% increased risk for infiltrative type).
• Gastric resection, chronic atrophic gastritis and pernicious anaemia.
• Family history of gastric cancer (2–3-fold increase).
• Genetic syndromes: hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, and Peutz–Jeghers syndrome.

High intake of fruits and vegetables (high in vitamin C and E, and antioxidants) and regular use of aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a reduced risk of gastric cancer.

Pathology

Gastric cancer arises through a multistage and multifactorial process. The intestinal type of gastric cancer evolves through the stages of metaplasia to dysplasia to carcinoma. However details of evolution of diffuse type of gastric cancer is not known.

• Adenocarcinoma accounts for 95% of gastric cancers. Histologically these are divided into intestinal or diffuse type. The intestinal subtype usually arises in distal stomach in older patients and the diffuse subtype is common in younger patients. The variant diffuse subtype which extensively infiltrates the stomach wall is known as linitis plastica.
• Primary lymphomas (MALT) are increasing.
• Gastrointestinal stromal tumours (GIST) (p. 261).
• Other tumours include small cell carcinoma, carcinoid and squamous cell carcinoma.

Clinical features

Most patients present with advanced disease. Presenting features are often nonspecific and typically include weight loss, persistent abdominal pain, nausea, anorexia, and early satiety. Dysphagia can occur with GOJ or proximal gastric tumours, whilst distal tumours can produce gastric outflow obstruction. 10–20% patients have haematemesis. Paraneoplastic features include dermatomyositis, acanthosis nigricans, diffuse seborrhoiec keratoses (sign of Leser–Trelat), circinate erythemas and microangiopathic haemolytic anaemia.

Evaluation

• History – detailed history including performance status, recent weight loss and family history.
• Clinical examination:

• General: anaemia, jaundice, cachexia, enlarged left supraclavicular lymph node (Virchow’s node).
• Abdomen: epigastric mass, hepatomegaly, periumbilical nodule (Sister Mary Joseph nodule), mass on anterior rectal wall on per rectal examination (Blumer’s shelf) and ovarian masses (Kruckenberg’s tumour).

Investigations and staging

Evaluation of patients helps to establish histological diagnosis, to assess the extent of disease (stage) and assess fitness to undergo appropriate treatment.

Initial assessment

Flexible oesophagogastroduodenoscopy (OGD) is the diagnostic procedure of choice which permits direct visualization of tumour and biopsy of any suspicious lesions. However, the diagnosis of the diffuse-type gastric cancer can be difficult endoscopically as the overlying mucosa may appear normal.

Double contrast barium studies (Figure 11.5) complement endoscopy.

image

Figure 11.5 Barium study shows a large circumferential lesion in the body of the stomach (with permission).

Further assessment

Once histological diagnosis is made, staging investigations are necessary to determine the treatment options.

• CT scan of chest, abdomen and pelvis should be undertaken to establish loco-regional (sensitivity of 65–80%) and metastatic staging. High resolution dynamic two-phase multi-slice CT with contrast and water (600–800 ml) to distend the stomach has improved the diagnostic accuracy. The drawbacks of CT scan are that it is not very accurate for staging early cancer and up to 30% of peritoneal metastases will not be detectable.
• Endoscopic ultrasound (EUS) is useful in predicting depth of tumour invasion and helps to guide FNA of suspicious perigastric lymph nodes. The stomach is seen as five layers of alternating bright (hyperechoic) and dark (hypoechoic) bands.
• Laparoscopy – laparoscopy allows direct visualization of the liver surface, peritoneum and local lymph nodes. Laproscopy alters CT staging by up to 40% (up or down-staging) and is recommended in all patients with gastric cancer and GOJ cancer with a gastric component. Biopsy should be taken from all suspicious lesions. Intraoperative ultrasound may further increase the yield of liver metastasis and is useful in assessing lymph nodes. Cytology of peritoneal washings may be undertaken, but its sensitivity is limited by contamination with mesothelial cells.
• PET scan may be useful for establishing metastatic disease and to predict response to neoadjuvant treatment, particularly for intestinal type cancer.

Preoperative evaluation

Includes full blood count, biochemistry, coagulation profile, arterial blood gas, pulmonary function tests and ECG. All patients should undergo nutritional screening prior to surgery. A body mass index of <18.5, body weight <90% predicted, >20% weight loss and a low albumin predict an increased risk of perioperative complications.

Staging

Box 11.5 shows the pathological staging of gastric cancer. Sixteen nodal stations defined by the Japanese Research Society for Gastric Cancer help to define the extent of lymph node dissection in gastric cancer (Figure 11.6 and see below).

Box 11.5
TNM staging of gastric cancer

Stage 0

TisN0M0 carcinoma-in-situ (intraepithelial tumour without invasion of the lamina propria)

Stage IA

T1N0M0 tumour invades lamina propria or submucosa

Stage IB

T1N1M0 metastasis in 1–6 regional lymph nodes
T2N0M0 tumour invades muscularis propria (a) or subserosa (b)

Stage II

T1N2M0 metastasis in 7–15 regional lymph nodes
T2N1M0
T3N0M0 tumour penetrates serosa (visceral peritoneum)

Stage IIIA

T2N2M0
T3N1M0
T4N0M0 tumour invades adjacent structures

Stage IIIB

T3N2M0

Stage IV

T1–3N3M0 metastasis in >15 regional lymph nodes
T4N1–3M0
Any T Any N M1

image

Figure 11.6 Upper abdominal nodal stations.

Management of gastric cancer (Figure 11.7)

All patients should be assessed in a multidisciplinary setting. Assessment of the performance status and co-morbidities should be done.

image

Figure 11.7 Management of gastric cancer.

Early gastric cancer (EGC)

By definition the tumour is limited to the gastric mucosa or submucosa (T1) irrespective of nodal involvement. There is a 10–20% risk of lymph node involvement, depending on the size of the tumour, histologic subtype and presence of submucosal invasion. With treatment the 5-year survival is >90%, whereas if untreated up to two-thirds progress to advanced cancer over 5 years. The treatment options include:

• Endoscopic mucosal resection (EMR) – is appropriate for small well-differentiated polypoidal or raised lesions.
• Gastric resection with lymphadenectomy.

Resectable gastric cancer

All patients should undergo laparoscopy with or without peritoneal washings for malignancy cells prior to open laparotomy to assess the extent of disease and resectability. Surgery is feasible only in less than half of the newly diagnosed patients and only 13–50% patients are cured with surgery.

Surgery

Surgery is aimed at complete removal of the tumour and lymph nodes. When performing gastric resection a 5 cm free margin is required for infiltrative tumours whereas 2 cm may be sufficient for expanding tumours. The pylorus seems to act as a barrier to extension of cancer and hence 2–3 cm surgical margin for pylorus may be necessary.

The extent of gastric resection depends on the size and location of the primary tumour (Figure 11.8).

• Subtotal gastrectomy – for an early or well circumscribed T2 cancer, >2 cm away from GOJ. A 5 cm margin is needed for more infiltrative lesions.
• Total gastrectomy – for tumour located <5 cm from GOJ or the tumour is diffuse with submucosal infiltration.
• Distal gastrectomy – is the option for distal gastric tumours which can be completely excised.
image

Figure 11.8 Gastric resections and reconstructions.

Lymphadenectomy with recovery of a minimum of 14, and an optimal of 25 lymph nodes is recommended. Based on the extent of lymphadenectomy, dissection is categorized as:

• D0 – gastric resection with incomplete dissection of level 1 nodes.
• D1 – gastric resection with complete dissection of level 1 nodes.
• D2 – gastric resection with complete dissection of level 1&2 nodes.
• D3 – gastric resection with complete dissection of levels1–3 nodes.
• D4 – gastric resection with complete dissection of level 1–4 nodes.

The current UK practice is to perform D2 lymphadenectomy without pancreatico-splenectomy. Laparoscopic gastrectomy and laparoscopy assisted D2 dissection are shown to be promising.

Adjuvant chemotherapy

Meta-analyses showed improved survival benefit with adjuvant chemotherapy (one study reported HR 0.85–95%; CI: 0.80–0.90); but there was no standard chemotherapy regime. Adjuvant chemotherapy is hence not offered except in a clinical trial.

Adjuvant chemoradiotherapy

A randomized trial showed better 3-year survival with post-operative chemoradiation (50% vs. 41%; p = 0.005) compared with surgery alone. However, it is not an accepted standard treatment in the UK and Europe because of the drawbacks of the study such as only 10% patients had D2 dissection, significant radiotherapy error in 30% patients and 30% patients did not complete chemoradiotherapy due to toxicity.

Perioperative treatment

A randomized study (UK MRC MAGIC) showed that three cycles of pre- and postoperative chemotherapy with epirubicin, cisplatin and continuous infusion 5 fluorouracil (ECF) significantly improved 5-year survival (36% vs. 23%; p = 0.009) compared with surgery alone in resectable gastric and lower oesophageal cancers (Box 11.6). This is the standard of care in most of the UK and parts of the Europe (Box 11.6).

Box 11.6
Treatment regimes in gastric cancer

Perioperative chemotherapy and surgery (UK MRC MAGIC trial)

• ECF chemotherapy: Epirubucin 50 mg/m2 IV day 1, cisplatin 60 mg/m2 IV day 1 and 5-fluorouracil 200 mg/m2/day continuous IV infusion for 21 days. Cycle repeated 3-weekly. Total 3 cycles preoperatively.
• Surgery 3–6 weeks after chemotherapy
• Postoperative chemotherapy – 3 cycles of ECF started 6–12 weeks after surgery

Metastatic or unresectable cancer

ECF regime (see above)

ECX regime

• Epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2/day 1 and capecitabine 625 mg/m2 orally twice daily; cycle repeated 3-weekly

Unresectable gastric cancer

The median survival of patients with unresectable non-metastatic cancer is 6 months without treatment. Treatment is aimed at improving the symptoms and quality of life and possible extension of life. The various palliative measures include:

• Bleeding – endoscopic laser photocoagulation or argon plasma coagulation is effective in controlling bleeding. If these measures fail, palliative resection may be considered.
• Obstruction – tumours of the proximal stomach may present with dysphagia whereas distal stomach tumours present with gastric outlet obstruction. Endoscopic stent placement offers effective palliative. However, 15–40% with develop recurrent symptoms. An alternative option is palliative bypass.
• Radiotherapy – is effective in controlling bleeding or obstruction in patients who are unsuitable candidates for other interventions. Radiotherapy is effective in controlling pain.

Systemic treatment of unresectable gastric cancer

Patients with unresectable and/or disseminated gastric cancer should be considered for a clinical trial, and those with good performance status (0–2) may be offered systemic therapy. Randomized trials suggest that chemotherapy may improve survival compared with best supportive care (9–11 months vs. 3–4 months HR 0.39) and quality of life. A meta-analysis showed that combination chemotherapy improves survival by 6 months and the best survivals are achieved by three-drug regimens containing 5-FU, anthracycline and cisplatin. The standard regime used in the UK is ECF (Box 11.6). A recent study (REAL 2) showed that ECF is comparable to EOX. This regimen has the advantage of avoiding the need for continuous infusion of 5-FU.

Other active agents include taxanes, and irinotecan.

Follow-up

There is no evidence that regular intensive follow-up improves outcome and hence symptom driven follow-up is recommended.

Management of recurrence

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