Gastrointestinal cancer

Chapter 24 Gastrointestinal cancer



Ramesh Bulusu



Chapter contents



Cancer of the oesophagus


Epidemiology 

Aetiology and pathology 

Risk factors for squamous cell carcinomas 

Risk factors for adenocarcinoma 

Gastrooesophageal reflux disease (GORD or GERD) 

Obesity 

Alcohol and tobacco 

Anatomy 

Clinical manifestations 

Diagnostic evaluation 

Therapy 

Surgery 

Radiotherapy 

Definitive chemoradiation 

Adjuvant radiation or chemoradiation 

Radiation therapy techniques 

External beam radiation 

Brachytherapy 

Chemotherapy 

Neoadjuvant chemotherapy 

Palliative chemotherapy 

Other treatments 

Esophagogastric junctional tumours 

Summary 

Stomach


Anatomy 

Epidemiology 

Aetiology 

Pathology 

Clinical features 

Staging 

Management 

Surgery 

Perioperative (neoadjuvant and adjuvant) chemotherapy 

Adjuvant chemoradiation 

Radiation techniques 

Palliative treatments in advanced/metastatic gastric cancer 

Palliative chemotherapy 

Palliative radiotherapy 

Summary 

Hepatocellular carcinoma


Cholangiocarcinoma and Gallbladder cancer 

Pancreas


Anatomy 

Incidence and epidemiology 

Pathology 

TNM staging 

Clinical features 

Diagnostic evaluation and imaging 

Therapy 

Surgery 

Chemoradiotherapy in locally advanced pancreatic cancer 

External beam radiation techniques 

Adjuvant therapy 

Palliative chemotherapy 

Supportive care for symptom palliation 

Colon and rectum


Epidemiology 

Aetiology 

Histopathology and clinical features 

Staging systems 

Colon cancer – treatment principles 

Surgery 

Adjuvant chemotherapy 

Chemotherapy for advanced disease 

Newer targeted therapies 

Radiotherapy and colon cancer 

Follow up 

Rectal cancer – treatment principles 

Radiotherapy technique 

Chemotherapy 

Follow up 

Anal cancer


Epidemiology and aetiology 

Anatomy 

Histopathology 

Clinical features 

Staging 

Diagnostic work up and staging 

Treatment 

Surgery 

Definitive chemoradiation 

Radiotherapy treatment principles 

Treatment-related toxicity 

Follow up 

Salvage treatment 

Palliative treatment 

Prognosis 

Gastrointestinal Stromal Tumours (GISTS) 

Further reading



Cancer of the oesophagus



Epidemiology


Oesophageal cancer is among the top ten commonly occurring cancers and has a distinctive epidemiologic pattern characterized by marked geographic variation. It is more common in China, Iran, Russia, South Africa, France and Switzerland. In the UK, in excess of 7000 new cases area diagnosed per year with an annual death rate of around 6900. Three to four decades ago, most esophageal cancers were squamous carcinomas. Over the last two decades, an increasing incidence of adenocarcinomas of the oesophagus and cardia has been observed. Within Europe there are significant differences in the incidence of esophageal cancer, the highest rates being in the UK with 4.2–8.9/100   000 cases and Holland with 4.2/100   000, the lowest being 0.7/100   000 in Poland and 0.5/100   000 in the Czech Republic.


Worldwide, males are more commonly affected than females. The male to female ratio in the USA ranges from 2.1:1 to 3.7:1. Both squamous and adenocarcinomas are rare before the age of 40 years and steadily increase with each decade of life. Racial and ethnic differences have been reported in high incidence areas and also in the USA. The black populations of North America and South Africa appear to be at increased risk of squamous cell carcinomas (rates in excess of 15 cases/100   000 person years).



Aetiology and pathology


The most common histological subtypes are squamous cell carcinoma and adenocarcinoma, accounting for more than 90% of tumours.



Risk factors for squamous cell carcinomas


Alcohol and tobacco make up the largest risk factors for oesophageal squamous cell carcinoma in the western world. The relative risk is reported as 6.2 for smokers who do not consume alcohol. Smokers who have significant intakes of alcohol have a 10–25 fold increased risk of squamous cell cancer. Equally, chewing tobacco and betel leaves as practised in southern Asia, contributes to the excess risk seen in these regions. Nitrosamines, N-nitroso compounds, aromatic amines, polycyclic hydrocarbons found in alcohol and tobacco, alone or in combination contribute to the carcinogenic effect.


Patients with iron deficiency anaemia and diet low in riboflavin – Plummer-Vinson/Paterson-Kelly Brown syndrome – are at a higher risk of upper digestive tract squamous cell carcinomas. Tylosis, a hereditary condition characterized by hyperkeratosis of the palms and soles and papilloma of the oesophagus, is associated with a one in three chance of developing oesophageal cancer below the age of 50 years. Long-standing achalasia cardia is associated with 5% risk of oesophageal squamous carcinoma. Patients with a history of previous cancer of the aerodigestive tract have a 2–4% incidence of esophageal cancer. A higher incidence of squamous cell carcinomas was observed in individuals exposed to ionizing radiation.



Risk factors for adenocarcinoma



Gastroesophageal reflux disease (GORD or GERD)


Acid and bile reflux result in intestinal metaplasia of the esophageal squamous epithelium. The area of metaplastic change looks red on endoscopy, whereas the normal oesophagus has a pearly appearance. This change is called Barrett’s oesophagus. Obesity and smoking contribute to these changes. The probable morphological sequence is metaplasia→dysplasia→carcinoma, accompanied by a series of genetic events resulting in invasive cancer. The incidence of adenocarcinoma developing in Barrett’s oesophagus is 0.5–1% per year.



Obesity


Risk of adenocarcinoma of the oesophagus increases with increasing body mass index with up to threefold increases reported in the very obese cohorts.



Alcohol and tobacco


The association between alcohol and tobacco and esophageal adenocarcinoma is less robust than for squamous cancer, but several large studies show that there is a moderate increased risk of adenocarcinoma of the oesophagus and the cardia of the stomach.



Anatomy (Figure 24.1)


The oesophagus is a flattened muscular tube of 18–26   cm in length with diameters varying from 1.6 to 2.5   cm. The oesophagus starts at the pharyngoesophageal junction at the level of C5–6 vertebral interspace and ends at the esophagogastric junction at the level of T1 vertebra. It is traditionally divided into three segments, cervical, thoracic and abdominal. The cervical segment is about 4–5    cm long and extends from the pharyngoesophageal junction to the thoracic inlet. The thoracic oesophagus extends from the thoracic inlet to the diaphragmatic opening. The abdominal segment is short varying from 1 to 2.5   cm, extending from the hiatus to the esophagogastric junction. The esophageal hiatus in the diaphragm is at the level of T10 vertebra. The oesophagus moves a few millimeters during quiet respiration and by as much as 3–4   cm during swallowing.


image

Figure 24.1 Relations of the oesophagus and lymph node drainage.


(Reproduced with permission of Arnold from Jane Dobbs, Ann Barrett, Daniel Ash, Practical Radiotherapy Planning, 3rd edn, Arnold, 1999)


The lymphatic drainage is of importance to the surgeon and the oncologist. A dense lymphatic network is found in the submucosa, which travels a variable distance longitudinally before penetrating the muscle layer and draining into the periesophageal lymph nodes. This may explain the extensive intramural spread of the cancer beneath an intact mucosa and tumour-free margins may not necessarily mean complete tumour resection. The lymphatic drainage of the proximal oesophagus is towards the deep cervical chain and thoracic duct. The distal oesophagus drains into the lower mediastinal, left gastric and coeliac axis nodes.


The esophageal wall is composed of four layers: the innermost non-keratinized squamous epithelium – the mucosa, submucosal connective tissue, muscularis propria with inner circular and outer longitudinal layers and, finally, the adventitial layer. The myenteric or Auerbach plexus of nerves responsible for coordinating swallowing is located between the inner circular and outer longitudinal layers. The oesophagus has no mesentery or serosal lining which may explain the relatively easy spread of esophageal cancer into the surrounding tissues.



Clinical manifestations


Dysphagia and weight loss are the most common initial symptoms in over 90% of patients. Odynophagia (pain during swallowing) is seen in about 50% of patients. Epigastric pains, haematemesis, regurgitation of undigested food, aspiration pneumonia are less common but recognized symptoms. Cough from a tracheobronchial fistula, hoarse voice, superior vena caval obstruction and haemoptysis are less frequent. Pleural effusions and ascites and bone pain secondary to metastases can occur. Anorexia and right upper quadrant discomfort/pain may suggest liver metastases. Clinical examination should be directed at any presence of obvious metastatic disease, such as neck or supraclavicular lymph nodes, hepatomegaly, pleural effusions and ascites.


A thorough nutritional assessment by a specialist oncology dietician at baseline and at regular intervals while on treatment is mandatory.



Diagnostic evaluation (Tables 24.1–24.3)


Any patient who presents with recent onset dysphagia and weight loss should be investigated for a possible esophageal cancer. Many major centres have a fast track dysphagia endoscopy service available to minimize the delay in the diagnosis of the cancer.


Table 24.1 Staging esophageal carcinoma






































































TNM staging system applies only for esophageal carcinomas
T: Primary tumour
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour invades the lamina propria or submucosa
T2 Tumour invades the muscularis propria
T3 Tumour invades the adventitia
T4 Tumour invades the adjacent structures
N: Regional nodes (see below)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Regional lymph node metastases
M: Distant metastases
MX Distant metastases cannot be assessed
M0 No distant metastases
M1 Distant metastases
For tumours of the upper thoracic oesophagus
M1a Metastases in cervical lymph nodes
M1b Other distant metastases
For tumours of the mid-thoracic oesophagus
M1a Not applicable
M1b Non-regional lymph nodes or other distant metastases
For tumours of the lower thoracic oesophagus
M1a Metastases in coeliac axis lymph nodes
M1b Other distant metastases
The regional lymph nodes depend on the anatomical subsite of the oesophagus (cervical or intrathoracic)
Cervical oesophagus
Scalene, internal jugular, upper and lower cervical, periesophageal and supraclavicular nodes
Intrathoracic oesophagus
Upper periesophageal (above the azygos vein), subcarinal, lower periesophageal (below the azygos vein), mediastinal, perigastric except coeliac axis nodes
pTNM Pathological classification


Table 24.2 Stage grouping for esophageal cancer

image

Table 24.3 Diagnostic evaluation of patients with esophageal cancer






Full blood count & renal & liver chemistry


CT scan of the chest & abdomen


Endoscopic ultrasound (EUS ± FNA)


Bronchoscopy (in selected cases)


FDG PET-CT


Isotope bone scan (if indicated)


In the majority of cases, upper GI endoscopy visualizes the tumour and its distance from the incisor teeth. The endoscopist should also define the lower extent of the tumour (if the lumen is traversable) and evaluate the esophagogastric junction. Multiple biopsies should be taken to maximize the yield. Any associated Barrett’s segment, its length and relation to the invasive cancer should be noted.


In patients who are fit for curative treatment, the first step is a multislice computed tomography (CT) scan of the chest and abdomen to exclude obvious metastatic disease. CT has poor sensitivity in predicting the T or N stage. The sensitivity and specificity of CT for T4 disease are 25% and 94% respectively and for coeliac node involvement are 30% and 90% respectively.


In patients with localized disease, further evaluation of the T and N stage is best done by endoscopic ultrasound (EUS) by an experienced endoscopist. EUS has a high sensitivity and specificity in evaluating the T and N stage in esophageal cancer and has improved the preoperative staging of esophageal cancer. The overall accuracy of EUS is 85% for T staging and 75% for N staging. EUS fine needle aspiration (FNA) enhances the accuracy of nodal staging and, in particular, is useful in confirming coeliac axis nodal status on cytology. EUS is less reliable in assessing T and N stage following preoperative chemoradiation because it may not be able to differentiate between residual tumour and post-radiation inflammation/fibrosis.


In patients with hoarseness of voices or hemoptysis/unexplained cough, bronchoscopy is recommended to rule out recurrent laryngeal nerve involvement or tracheobronchial fistula.


The role of 2-fluorodeoxy-D-glucose positron emission tomography (FDG PET-CT) in the initial staging of potentially operable esophageal cancer has been the subject of numerous studies. In a recent systematic review, the pooled sensitivity and specificity of FDG PET for distant nodal and hematogenous metastases was 67% and 97%, respectively. The change in patient management as a result of FDG PET ranged from 3 to 20%. Preliminary data suggest that early FDG PET following neoadjuvant chemotherapy may predict pathologic response and overall survival and thus may define a subset of patients who are more likely to benefit from surgery.



Therapy



Surgery


Surgery remains the mainstay of treatment for all T stages of resectable esophageal cancer. The surgery involves resection of the primary tumour with an adequate margin along with regional lymph nodes. Two standard surgical techniques have been described for surgical resection of esophageal cancers – transthoracic (Ivor-Lewis technique) and trans-hiatal approach. The aim is complete resection. The margin status and the extent of nodal burden are powerful prognostic indicators for relapse-free survival.



Radiotherapy


External beam radiation alone or as part of combined modality treatment has been evaluated in both squamous cell and adenocarcinoma of the oesophagus. Primary radiation treatment alone for treatment of clinically localized esophageal cancer is not recommended in the curative setting. Both local and distant failure rates remain too high despite higher doses of radiation. Five-year survival is reported to be less than 5%. Preoperative radiation (i.e. without chemotherapy) has not shown any significant survival advantage. These two approaches are not recommended for patients fit for a potentially curative approach.



Definitive chemoradiation


Chemoradiation protocols typically use cisplatin and 5-fluorouracil (5FU) (recent studies have explored additional agents such as paclitaxel) with fractionated external beam radiation to a dose of 45–60   Gy. In two phase III trials in squamous cell carcinomas, definitive chemoradiation gave comparable median survival figures around 15–19 months with a 25–40% 2–year survival. Paclitaxel-based preoperative chemoradiation though has resulted in higher response rates; there is significant risk of postoperative complications, therefore, taxane-based chemotherapy with radiation has not become a standard of care.


Palliative radiotherapy can be recommended for local pain, bleeding or dysphagia; 8–10   Gy single fraction or 20–30   Gy in 5–10 fractions is given as a parallel-opposed pair. For patients with dysphagia, an esophageal stent may be more appropriate for providing good palliation.



Adjuvant radiation or chemoradiation


There are no prospective randomized trial data to support the routine use of adjuvant chemoradiation in resected esophageal cancer. Single institute series have shown some improvement in local control rates and progression-free survival but this could due to the inherent bias in the studies that the patients were fit enough to receive the adjuvant treatment.



Radiation therapy techniques



External beam radiation


Radiation planning using oral contrast (barium or gastrograffin) underestimates the tumour length. Three-dimensional conformal radiotherapy with CT planning is recommended. Joint planning with the endoscopist/radiologist to delineate the primary tumour based on the endoscopic ultrasound information will help to minimize the risk of a geographic miss. EUS can detect submucosal spread and gives a more accurate extent of the disease. Conventional margins above and below the tumour used to be 5   cm but, with modern imaging, this margin can be reduced to 3   cm and a 1.5–2   cm margin around the gross tumour volume (GTV) is adequate. A 3D conformal plan is generated with dose volume histograms defining the doses for the planned target volume, regions of interest including the spinal cord and lungs. A single phase three-field (anterior and two obliques) is the standard field arrangement to deliver a dose of 45–50   Gy in 1.8–2   Gy fractions. Chemoradiation patients will have concomitant intravenous 5-fluorouracil (5FU) or oral capecitabine and cisplatin during their radiation treatment. A widely used regimen is cisplatin 75   mg/m2 day 1 plus 5-fluorouracil 1000   mg/m2 infused over 24 hours on days 1–4 repeated every 3 weeks. Two to four cycles are given during radiotherapy. Weekly blood count and renal function monitoring is mandatory. Continuing dietary assessment prior to, during and after radiation, with nutritional support if necessary, is strongly recommended. Parallel-opposed fields (anterior/posterior) can be used for palliative radiotherapy.



Brachytherapy


Intracavitary treatment can be used for palliation of dysphagia and bleeding. Radiation dose can be delivered either through a low dose rate or a high dose rate technique. Doses of 5–20   Gy are delivered to a depth of 1   cm. Local control rates vary from 40 to 90%. The reported risk of stricture and/or fistula formation ranges from 2 to 38% and is known to be associated with the increasing brachytherapy fraction size. The role of intracavitary brachytherapy in the curative setting remains to be defined and has to be considered experimental.



Chemotherapy



Neoadjuvant chemotherapy


Preoperative chemotherapy with cisplatin and 5-FU (two cycles) has been the standard of care in the UK for patients with resectable esophageal cancer. Updated results from the MRC OE-2 trial of preoperative chemotherapy in patients undergoing curative surgery showed 5-year overall survival rates of 23% in the combined modality arm compared to 17% in the surgery alone arm. Newer agents and longer duration of therapy are being explored in clinical trials.


Trimodality therapy, i.e. preoperative chemoradiation followed by surgery has been evaluated in adenocarcinoma of oesophagus within the CALGB 9781 randomized trial. A significant survival advantage for the trimodality arm 39% (95% CI 21–57%) versus 16% (95% CI 5–33%) 5-year survival) was reported compared to surgery alone. This may be accepted as a new standard of care in North America. However, despite the expected accrual of 500 patients, the trial was closed due to poor accrual, after only 54 patients were recruited into this study.



Palliative chemotherapy


Platinum and 5FU/oral capecitabine based regimens are the accepted standard of care. Newer chemotherapy agents and targeted therapy with epidermal growth factor receptor/vascular endothelial growth factor (EGFR/VEGF) inhibitors will be explored in future trials.



Other treatments


Endoluminal techniques have been used for the treatment of Barrett’s metaplasia and dysplasia. These include circumferential radiofrequency ablation, endoscopic mucosal resection (EMR) and photodynamic therapy. Endomucosal resection for early invasive mucosal lesions is fast gaining acceptance as a local curative treatment and is best performed in experienced centres. EMR is indicated for superficial lesions, i.e. high grade dysplasia and moderately to well differentiated carcinomas limited to lamina propria only.


Palliative treatment options are tailored to the individual patient and are best discussed in a multidisciplinary setting along with the palliative care team. Esophageal stenting provides palliation of dysphagia. Endoscopic laser treatment may be suitable for bulky endoluminal squamous tumours. Palliative radiation (external beam or brachytherapy) and chemotherapy are other alternative options for symptomatic benefit.



Esophagogastric junctional tumours


Adenocarcinomas of the esophagogastric junction have been divided into three subtypes as proposed by Siewert and Stein. Typ. 1 junctional tumours primarily arise from the distal oesophagus and involve the junction, typ. 2 junctional tumours straddle the junction and typ. 3 tumours are predominantly in the cardia of the stomach involving the junction. Typ. 1 junctional adenocarcinoma is treated using oesophagus protocols. Typ. 3 junctional tumours are thought to behave like gastric adenocarcinoma, therefore, are treated using gastric protocols.



Summary


Management of esophageal cancer has evolved over the past three decades. Treatment decisions should be made within a multidisciplinary team setting. Careful staging and selection of patients for curative treatments is vital and surgery should be performed in high volume specialist centres for best outcome. Combined modality treatments remain the standard of care in curative setting for all patients with oesophageal cancer except the very early tumours.



Stomach



Anatomy


The stomach begins at the esophagogastric junction and ends at the pylorus. It is divided into three parts: cardia (fundus), body and pyloric antrum. The blood supply of the stomach is derived from the branches of the coeliac axis. The regional lymphatics drain into the coeliac axis nodes, splenic hilar, porta hepatis, gastroduodenal and suprapancreatic nodal groups. Venous drainage is primarily through the portal venous system into the liver.



Epidemiology


There is a considerable variation in the worldwide incidence of gastric cancer. The highest incidence is seen in Japan, South America and eastern Europe. The incidence in western Europe is in decline. However, the incidence of tumours of the cardia and esophagogastric junction has increased. The incidence of stomach cancer has been declining in the UK since 1930. CRUK (2004) reported 9660 cases in the UK with an incidence of 16.5 per 100   000 making this the sixth most common cancer in Britain.



Aetiology


Environmental and genetic factors play a role in the pathogenesis of gastric cancer. Carcinogens implicated in the aetiology include nitrates and nitrites in food, smoking and industrial dust exposure. The role of alcohol remains uncertain. Increased risk has been reported with a specific strain of Helicobacter pylori (CAG+ve) especially in non-cardia lesions. Pernicious anaemia and previous subtotal gastrectomy for benign conditions, and villous adenomas are thought to be associated with increased risk of gastric cancer after a long period of latency.


Genetic factors include mutations in specific genes, CDH1 and p53. CDH1 encodes for E-cadherin and mutations in this gene are associated with hereditary diffuse gastric cancer. Another familial gastric cancer syndrome is associated with p53 mutations. Gastric cancer is also a component of Li-Fraumeni syndrome, hereditary non-polyposis colorectal cancer (HNPCC), Peutz-Jegher polyposis, BRCA-2 mutations and juvenile polyposis.



Pathology


Adenocarcinoma constitutes 95% of the gastric cancers. They are classified into intestinal and diffuse types (Lauren’s classification system). The intestinal type is more common in older patients, high-risk groups and men. The diffuse type is more commonly seen in women and younger patients and carries a poorer prognosis. Other histological types of gastric malignancies include carcinoids, lymphomas and gastrointestinal stromal tumours (GISTS). GISTS are the most common mesenchymal tumours of the gastrointestinal tract.



Clinical features


The most common presenting symptoms are anaemia, weight loss, anorexia, haematemesis, melena, upper abdominal pain/discomfort/mass, nausea/vomiting. Occult bleeding is more common than overt haematemesis. Possible clinical findings include anaemia, abdominal mass, left supraclavicular lymphadenopathy, and ascites.



Staging (Tables 24.4 and 24.5)


The initial investigations often include a barium meal/swallow and endoscopy. Gastroscopy and biopsy will confirm the diagnosis in the majority of patients. Multiple biopsies increase the sensitivity and yield. The TNM staging system is used for staging gastric cancer. Endoscopic ultrasound is of value in proximal cardia and junctional tumours. Cross-sectional imaging with a spiral CT is the first step to exclude overt metastatic disease. CT is not a sensitive tool for detecting peritoneal spread, therefore, laparoscopy is mandatory prior to surgery to detect any occult peritoneal spread. Laparoscopy may also help in identifying tumour in the lesser sac, on the surface of the liver and nodal disease. FDG-PET imaging may identify metastases not clearly seen on CT but 25–30% of primary gastric cancers are not FDG avid.


Table 24.4 Stomach cancer TNM clinical classification











































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Mar 7, 2016 | Posted by in GENERAL RADIOLOGY | Comments Off on Gastrointestinal cancer

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T: Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ: intraepithelial tumour without invasion of the lamina propria
T1 Tumour invades lamina propria or submucosa
T2 Tumour invades muscularis propria or subserosa
T3 Tumour penetrates serosa (visceral peritoneum) without invasion of adjacent structures
T4 Tumour invades adjacent structures
Notes:


1. A tumour may penetrate muscularis propria with extension into the gastro-perforation of the visceral peritoneum covering these structures. In this case, the tumour is classified as T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or omentum, the tumour is classified as T3.


2. The adjacent structures of the stomach are the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine and retroperitoneum.


3. Intramural extension to the duodenum or oesophagus is classified by the depth of greatest invasion in any of these sites including stomach

.
N: Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1 to 6 regional lymph nodes
N2