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.

Figure 11.4 Management of recurrence.

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).

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.

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.

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.

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).