Worldwide, oesophageal cancer is the eighth most common cancer, responsible for an estimated 482,300 new cases and 406,800 deaths in 2008 and is the fifth highest in mortality rate among tumour sites . In the UK, there were 7,966 new cases of oesophageal cancer diagnosed in 2007 and it is responsible for approximately 4% of all cancer deaths with over 7,600 people dying in 2008 . There are two main histological types of oesophageal cancer, squamous cell carcinoma (SCC) and adenocarcinoma (AC). Recently there has been an increase in the numbers of adenocarcinomas of the lower oesophagus and gastro-oesophageal junction in populations of the western world  whilst the incidence of squamous carcinoma has fallen slightly. In the UK, there has been a 60% increase in oesophageal carcinoma incidence in males over the past 30 years .
Surgery has long been, and remains, the cornerstone for cure of oesophageal cancer and is considered for all patients with potentially resectable oesophageal cancer who are fit for surgery and have no evidence of distant disease. Approximately 23% of patients survive 5 years with the most commonly used surgical treatment strategy . However, rates of surgical intervention in the UK are as low as 20% of all cases. The most recent figures (for patients diagnosed between 2001 and 2006) show that the 5-year survival of all patients with oesophageal cancer is 10 per cent .
Chemoradiotherapy (CRT) in oesophageal cancer
In a pivotal study , US Intergroup RTOG-8501 randomised 121 patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC) to receive CRT (4 cycles cisplatin and 5-Fluorouracil (5FU), the first 2 cycles given concurrently with 50Gy radiotherapy in 25 fractions) or radiotherapy alone (64Gy in 32 fractions). This trial, together with a subsequent systematic review , demonstrated a survival superiority of CRT over radiotherapy alone (1-year mortality odds ratio 0.61, 95% CI 0.31-0.89, P < 0.001), albeit at the expense of increased toxicity. This and other reported studies [5, 7–12] have been predominantly in patients with SCC and have demonstrated a remarkably consistent median survival of 14-18 months and 2 year overall survival of 30-40% with CRT.
In the UK, most experience has been gained in those patients, both with SCC and AC, deemed unsuitable for surgery due to the presence of co-morbidity or extent of disease [8, 13]. Despite the expected poor prognosis of this patient group, of the 266 patients who were deemed inoperable at one UK centre between 1995 and 2009, the median survival was 20.6 months (2 and 5 year survival 44% (95% CI: 37, 50%) and 20% (95% CI: 14, 26%) respectively) . In this study 42% of patients suffered grade 3 and 7% grade 4 toxicities, mainly mucosal and haematological due to the chemotherapy.
Rational for standard chemotherapy agents
Concurrent CRT regimens have been based upon cisplatin and 5FU. Both have good single agent activity in oesophageal malignant disease and are amongst the best radio-sensitisers in tumour models [14, 15]. The regimen used most frequently in the UK involves conformal external beam radiotherapy, 50Gy in 25 fractions over 5 weeks, with 2 cycles cisplatin and 5FU given concurrently, with or without a further 2 cycles of the same chemotherapy, given as a neo-adjuvant phase . The latter, as well as delivering additional systemic therapy, allows time for careful radiotherapy planning, frequently improves the patients' dysphagia and 'debulks' the tumour prior to radiotherapy.
5FU has historically been given as a continuous infusion throughout treatment. Capecitabine (Xeloda™), an oral fluoropyrimidine, sequentially converted to 5FU via 3 enzymes located in liver and tumour tissue, mimics the effect of continuous infusional 5FU. Capecitabine has been shown to be at least as effective as infusional 5FU in advanced oesophago-gastric cancer  and the use of capecitabine instead of infusional 5FU during Upper GI concurrent CRT has now become standard practice in some centres e.g. Velindre Cancer Centre, Cardiff and the Royal Marsden Hospital, Sutton. Capecitabine is also being used concurrently with radiotherapy to treat other Upper GI tumour sites . In patients with significant dysphagia capecitabine can be dissolved in warm water and swallowed or even administered via a naso-gastric tube.
Cetuximab and anti-EGFR therapies
The majority of patients who relapse do so within the previously irradiated area [5, 10, 19]. The reported local failure rate in recent studies is 45-58% of patients treated with CRT. This may reflect the advanced nature of the disease, however factors such as tumour cell repopulation during radiation therapy have long been known to be an important mechanism of radio-resistance [20, 21]. Radiotherapy stimulates tumour cell growth through activation of the EGF receptor complex causing homodimerisation of the extracellular receptor inducing autophosphorylation of the intracellular tyrosine kinase (TK) domain , in turn stimulating a number of intracellular signal transduction pathways such as the ras-raf-MAPK pathway . This activation sequence can be blocked by the monoclonal antibody, cetuximab, preventing radiotherapy induced growth stimulation.
Bonner et al  reported results of a trial in patients with locally advanced squamous cell carcinoma of the head and neck, a disease with many similarities to oesophageal cancer, which tested the benefits of the addition of cetuximab to radiotherapy. 424 patients were randomised to receive 70-76.8Gy of radiotherapy with or without cetuximab. Patients were followed up for a minimum of 2 years. The addition of the antibody was well tolerated, notably without an increase in mucositis, although 34% developed predictable and mostly manageable G3-4 acute skin reactions (compared to 18%). With the addition of cetuximab there was improved local control (47% vs 34% at 3 year, P < 0.01) and overall survival (55% vs 45% at 3 years, p = 0.05) with nearly a doubling in median survival (49 vs 29 months). More recently, a phase II study combining adjuvant cetuximab and CRT after surgery in patients with head and neck cancer has shown the addition of cetuximab to be feasible and tolerated with predictable toxicity .
In patients with metastatic colorectal cancer, cetuximab has shown significant activity in combination with chemotherapy in patients who have relapsed on the same chemotherapy regimen given alone . EXPERT-C, a randomised phase II study comparing neoadjuvant chemotherapy before CRT and TME with and without cetuximab in patients with MRI selected high-risk operable rectal adenocarcinoma, has shown significant improvement in 3 year OS with the addition of cetuximab (81% vs 96%; HR 0.27, p = 0.035) in the KRAS + BRAF wild type population although in the all treated population there was no difference . Skin toxicity was increased with cetuximab during neoadjuvant chemotherapy and CRT and diarrhoea was increased during CRT. XERXES, a multicentre pilot trial to examine the role of cetuximab when added to a schedule of capecitabine plus pelvic radiation in patients who have locally advanced primary rectal cancers, is still recruiting.
Anti-EGFR therapies have been combined with CRT in the treatment of thoracic malignancies. 15 patients with stage III non-small cell lung cancer received gefitinib with 60Gy radiotherapy, given concurrently with carboplatin and escalating doses of paclitaxel. This anti-EGFR small molecular agent was well tolerated even in the cohort receiving full dose chemotherapy, with an impressive response rate of 91% . RTOG 0324, a Phase II study of primary CRT and cetuximab in Stage IIIA/B non-small cell lung cancer, enrolled 93 patients of whom 87 were evaluable . Response rate was 62%, median survival was 22.7 months, and 24-month overall survival was 49.3%. Adverse events related to treatment included 20% grade 4 hematologic toxicities, 8% grade 3 esophagitis, and 7% grade 3 to 4 pneumonitis. It concluded that the combination of cetuximab with CRT is feasible and shows promising activity.
In oesophageal cancer, cetuximab has been tested in combination with irinotecan, cisplatin and concurrent radiotherapy in Phase II studies: a single centre study (NCT00165490, 02-012) and in the SWOG-SO414 study. In the former study, in resectable tumours, 17 of 39 planned patients had completed the protocol by the ASCO 2006 meeting . Grade 3/4 toxicities seen were diarrhoea (9 patients), neutropenia (9 patients), febrile neutropenia (5 patients), anorexia (5 patients), vomiting (4 patients), fatigue (3 patients) and mucositis (1 patients). The study is still in follow up. The SWOG-S0414 study, in unresectable tumours, closed due to slow accrual after recruiting 21 patients. 48% and 29% of patients had Grade 3 and 4 toxicity respectively .
In a larger series, 37 patients with oesophago-gastric cancer underwent carboplatin AUC = 2, paclitaxel 50 mg/m2, cetuximab 250 mg/m2 weekly concurrently with 50.4Gy radiotherapy. There were no Grade 4 non-haematological toxicities, 20% of patients had Grade 3 oesophagitis. Eighteen of 27 (67%) had no residual disease on endoscopic biopsy after treatment and 7 of 16 (43%) who underwent surgery had a complete pathological response . Building on their pivotal work with cetuximab and radiotherapy in head and neck cancer, Dobelbower et al have performed a Phase 1 study of cisplatin, infusional 5FU, erlotinib (anti-EGFR small molecule) with 50.4Gy radiotherapy in 11 patients with oesophageal cancer. There were no unexpected toxicities .
Since the start of the SCOPE1 trial, a phase II study of neoadjuvant CRT with oxaliplatin and infusional 5-FU plus cetuximab followed by postoperative docetaxel and cetuximab has completed in patients with operable adenocarcinoma of the oesophagus . It was stopped after 22 patients had been recruited due to unacceptable toxicity (4 post operative deaths all from ARDS) although it showed promising activity based on pathological complete response rate (pCR) rate (7 patients). However, a Phase II study of CRT with FOLFOX plus cetuximab in 79 patients with locally advanced cardia or oesophageal cancer has also completed recently and concluded that it is active (overall response rate after CRT was 77.2%) and has an acceptable toxicity profile in patients with locally advanced cardia or oesophageal cancer .
Other Phase I/II studies of cetuximab in oesophageal cancer are still ongoing: EXCEL (NCT00815308, 44 patients in China), FFCD 0505 (NCT00544362, 45 patients in France), and NCT00425425 (43 patients in Germany). RTOG 0436, a Phase III trial (420 patients) evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with oesophageal cancer who are treated without surgery, is still in recruitment. A Swiss Phase III trial (NCT01107639, 300 patients) giving CRT with or without cetuximab followed by surgery is also in recruitment.
Assessing response to CRT, without surgically removing the oesophagus for histological examination, is notoriously difficult. Endoscopy negative rates following CRT range from 30-80% (mean 61%) [35–42]. Although not a reliable marker for pCR within the surgically resected specimen [38, 42] endoscopic response is strongly correlated with long-term survival [35–37]. No other technique has been shown to be more reliable though trials are ongoing into the role of 18-FDG PET and EUS guided FNA in this setting. PET assesses metabolic activity (as opposed to size) so is able to determine benign from malignant lesions and is not only effective in detecting the primary tumour, but also is more sensitive in detecting small nodal and distant metastases . It is likely to become more commonly used after the results of larger trials and availability of equipment. It is not clear whether the presence of the EGF receptor predicts for response to cetuximab. Although not a pre-requisite for entry into this study, this and other predictors of response will be the subject of associated translational research.
Main research question
The main study aim of the SCOPE1 trial is to assess the effect on overall survival of adding cetuximab to the standard treatment. We will also examine the effect on toxicity, health related quality of life (HRQL), and cost effectiveness. In this paper we describe the study protocol.