SCOPE1-全文

来源：飒榕旅游知识分享网

Articles

Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial

Thomas Crosby*, Christopher N Hurt*, Stephen Falk, Simon Gollins, Somnath Mukherjee, John Staﬀ urth, Ruby Ray, Nadim Bashir, John A Bridgewater, J Ian Geh, David Cunningham, Jane Blazeby, Rajarshi Roy, Tim Maughan†, Gareth Griﬃ ths†

Summary

Background Deﬁ nitive chemoradiotherapy (CRT) is an alternative to surgery for the curative treatment of oesophageal carcinoma. The SCOPE1 trial aimed to investigate the addition of cetuximab to cisplatin and ﬂ uoropyrimidine-based deﬁ nitive CRT in patients with localised oesophageal squamous-cell cancer and adenocarcinomas to assess activity, safety, and feasibility of use.

Methods In this multicentre, randomised, open-label, phase 2/3 trial, we recruited patients aged 18 years and older from UK radiotherapy centres who had non-metastatic, histologically conﬁ rmed carcinoma of the oesophagus (adenocarcinoma, squamous-cell, or undiﬀ erentiated; WHO status 0–1; stage I–III disease) and been selected to receive deﬁ nitive CRT. Patients were randomly assigned (1:1) via a central computerised system using stratiﬁ ed minimisation (with an 80:20 random element) to receive CRT alone or CRT with cetuximab (400 mg/m² on day 1 followed by 250 mg/m² weekly), stratiﬁ ed by recruiting hospital, primary reason for not having surgery, tumour histology, and tumour stage. CRT consisted of cisplatin 60 mg/m² (day 1) and capecitabine 625 mg/m² twice daily (days 1–21) for four cycles; cycles three and four were given concurrently with 50 Gy in 25 fractions of radiotherapy. The primary endpoint was the proportion of patients who were treatment failure free at week 24 for the phase 2 trial and overall survival for the phase 3 trial, both measured from randomisation. We analysed data by intention to treat. This trial is an International Standard Randomised Controlled Trial, number 47718479.

Findings 258 patients (129 assigned to each treatment group) from 36 UK centres were recruited between Feb 7, 2008, and Feb 22, 2012. Recruitment was stopped without continuation to phase 3 because the trial met criteria for futility, but we continued to follow-up recruited patients until all had reached at least 24-week follow-up (median follow-up of patients who survived was 16·8 months [IQR 11·2–24·5]). Fewer patients were treatment failure free at 24 weeks in the CRT plus cetuximab group (79 of 119 patients [66·4%, 90% CI 58·6–73·6]) than in the CRT only group (93 of 121 patients [76·9%, 69·7–83·0]). The CRT plus cetuximab group also had shorter median overall survival (22·1 months [95% CI 15·1–24·5] vs 25·4 months [20·5–37·9]; adjusted HR 1·53 [95% CI 1·03–2·27]; p=0·035). Patients who received CRT plus cetuximab had more non-haematological grade 3 or 4 toxicities (102 [79%] of 129 patients vs 81 [63%] of 129 patients; p=0·004). The most common grade 3 or 4 toxicities were low white blood cell count (14 [11%] in the CRT plus cetuximab group vs 21 [16%] in the CRT only group), low absolute neutrophil count (15 [12%] vs 24 [19%]), fatigue (26 [20%] vs 25 [19%]), and dysphagia (35 [27%] vs 37 [29%]).Interpretation The addition of cetuximab to standard chemotherapy and radiotherapy cannot be recommended for patients with oesophageal cancer suitable for deﬁ nitive CRT.Funding Cancer Research UK.

Lancet Oncol 2013; 14: 627–37Published OnlineApril 25, 2013http://dx.doi.org/10.1016/S1470-2045(13)70136-0See Comment page 569*Joint ﬁ rst authors†Joint last authorsVelindre Cancer Centre, Velindre Hospital, Cardiﬀ , UK (T Crosby FRCR); Wales Cancer Trials Unit, School of Medicine, Heath Park (C N Hurt MSc, R Ray PhD, N Bashir BSc, G Griﬃ ths MSc), Cardiﬀ NCRI RTTQA Centre, Velindre NHS Trust (J Staﬀ urth MD, G Griﬃ ths), and Institute of Cancer and Genetics, Velindre Cancer Centre (J Staﬀ urth), Cardiﬀ University, Cardiﬀ , UK; Bristol Haematology and Oncology Centre, Bristol, UK (S Falk MD); North Wales Cancer Treatment Centre, Rhyl, UK (S Gollins FRCR); Gray Institute for Radiation Oncology and Biology, Oxford University, Oxford, UK (S Mukherjee FRCP, Prof T Maughan FRCP); UCL Cancer Institute, London, UK (J A Bridgewater FRCP); Queen Elizabeth Hospital, Birmingham, UK (J I Geh FRCP); The Royal Marsden Hospital NHS Foundation Trust, London, UK (Prof D Cunningham FRCP); Centre for Surgical Research, School of Social and Community Medicine, University of Bristol, Bristol, UK (Prof J Blazeby MD); and Diana Princess of Wales Hospital, Grimsby, UK (R Roy FRCR)Introduction

In the UK, oesophageal cancer is the sixth most common cause of cancer death, accounting for around 5% of all cancer deaths.1 Worldwide, oesophageal cancer is the eighth most common cancer—an estimated 482 300 new cases and 406 800 deaths occurred in 2008—and it has the ﬁ fth highest mortality

rate of all tumour sites. The incidence of oesophageal adenocarcinomas predom inantly aﬀ ecting the lower oesophagus and gastro-oesophageal junction has increased substantially in recent decades, especially in Europe and the USA.2 The incidence of squamous-cell carcinoma is stable or falling in the UK, but is much

www.thelancet.com/oncology Vol 14 June 2013 more prevalent in southern and east Africa and east Asia.

Surgery has been the cornerstone of curative treatment for this disease for the past 50 years, but is only appropriate

for 10–20% of the patient population, and despite Correspondence to:improvements in patient selection, perioperative care, and Mr Christopher N Hurt, Wales adjuvant treatment, less than 25% will survive 5 years Cancer Trials Unit, School of Medicine, Heath Park, Cardiﬀ after treatment3,4 and those who relapse within 2 years of University, Cardiﬀ CF14 4YS, UKsurgery never regain their former quality of life.5hurtcn@cardiﬀ .ac.ukChemoradiotherapy when given as deﬁ nitive treat-ment is more eﬀ ective than radiotherapy6 or chemo-therapy alone.7 In the UK, this treatment is usually oﬀ ered to patients who are unsuitable for surgery.

627

Articles

See Online for appendixUnsuitability for surgery might be due to the extent of local control, quality of life, and overall survival in patients disease precluding the likelihood of a curative resection, with localised oesophageal squamous-cell cancer and or because the patient is physiologically not ﬁ t for adenocarcinomas. On behalf of the UK National Cancer surgery because of comorbidities or poor performance Research Institute (NCRI) Upper GI Clinical Studies status. Less often, patients or clinicians will opt for this Group we designed the SCOPE1 trial (Study of strategy.8 Increasingly, deﬁ nitive chemoradiotherapy is Chemoradiotherapy in OesoPhageal cancer with Erbitux) being considered as a standard of care in patients with to test this hypothesis. oesophageal squamous-cell carcinoma, because

evidence suggests that outcomes are similar to those of Methods

surgical treatment.3,6,9 By contrast, for adenocarcinomas, Study design and patientsevi dence to support the use of deﬁ nitive In this multicentre, randomised, open-label, parallel, chemoradiotherapy is less strong and is restricted to two-arm, phase 2/3 trial, we recruited patients from studies of chemo radiotherapy in patients who are radiotherapy centres in the UK who had the following unsuitable for surgery.key eligibility criteria (for full inclusion and exclusion Concurrent chemoradiotherapy regimens have been criteria see appendix): non-metastatic, histologically based on cisplatin and ﬂ uorouracil. Both drugs have conﬁ rmed carcinoma of the oesophagus (adenocar-good single-agent activity in oesophageal malignant cinoma, squamous-cell, or undiﬀ erentiated carcinoma) disease and are two of the best radiosensitisers in tumour or gastro-oesophageal junction (Siewert type 1 or 2 with models.10,11 The regimen used most frequently in the UK <2 cm extension into the stomach); selected for deﬁ nitive consists of conformal external beam radio therapy (50 Gy chemoradiotherapy by a designated multidisciplinary in 25 fractions for 5 weeks) with two cycles of cisplatin team; aged 18 years or older; WHO performance status and ﬂ uorouracil given concurrently, with or without a 0 or 1; stage I–III disease (TNM stage 6); and disease

ned by endoscopic further two cycles of the same chemo therapy, given in a length of less than 10 cm deﬁ

neoadjuvant phase. This neoadjuvant phase, as well as ultrasound. Patients with M1a or M1b were not eligible delivering additional systemic therapy, allows time for for this study. The protocol for the study has been careful radiotherapy planning, frequently improves published elsewhere18 and the trial was coordinated by patients’ dysphagia, and debulks the tumour before the Wales Cancer Trials Unit (WCTU).

radiotherapy. Capecitabine has been shown to be as Patients were required to have staging investigations eﬀ ective as ﬂ uorouracil in locally advanced and meta-that consisted of endoscopic ultrasound and contrast-static oesophagogastric cancer.7 Encouraging outcomes enhanced spiral CT scan of the thorax and abdomen.

uorodeoxyglucose CT-PET scan was optional. In with deﬁ nitive chemoradiotherapy regimens were ¹⁸F-ﬂ

8,12

reported in single-centre series, but whether the patients in whom endoscopic ultrasound was not possible ﬁ ndings could be replicated in a prospective, multicentre because of advanced malignant oesophageal stricturing,

patients were staged with CT with or without CT-PET. trial was unclear.

Although deﬁ nitive chemoradiotherapy in patients Patients were physiologically assessed to identify those with a poor outlook can lead to useful long-term disease with eligible lung function (forced expiratory volume in 1 s control, most patients still succumb to the disease. The >1·0), cardiac function (left ventricular ejection fraction pattern of treatment failure diﬀ ers from that after >40% on echocardiogram or multigated acquisition scan),

ltration rate [GFR] surgery, with a higher rate of locoregional recurrence.6,8,9,12 renal function (EDTA glomerular ﬁ

Improvements to both the systemic and locoregional >40 mL/min, or estimated by Cockcroft-Gault formula to components of this treatment strategy are therefore be >60 mL/min), liver function (serum bilirubin

≤1·5×upper limit of normal [ULN], aspartate amino-urgently needed.

EGFR is overexpressed in up to 55% of oesophago-transferase to alanine aminotransferase ratio ≤2·5×ULN, gastric cancers and is associated with poor prognosis.13 alkaline phosphatase ≤3×ULN) and haematological Cetuximab, a monoclonal EGFR antagonist, improved assessment (haemoglobin >100 g/L, white blood cells outcomes when given in combination with chemo therapy >3×10⁹/L, absolute neutrophil count [ANC] >1·5×10⁹/L, in other tumours—eg, advanced colorectal adeno-platelet count >100×10⁹/L). All treatment and assessments carcinomas14 and squamous-cell head and neck cancer.15 were done in UK radiotherapy centres.

All patients had to provide written informed consent More importantly, preclinical studies have shown that

cetuximab can overcome an important mechanism of before registration and the trial protocol was approved radioresistance,16 and results of a phase 3 trial by Bonner by the UK Medicines and Healthcare products and colleagues17 in squamous-cell carcinoma of the head Regulatory Agency and a multicentre research ethics and neck showed that cetuximab in combination with committee. The SCOPE1 trial was sponsored by radiotherapy can improve local control and overall survival Velindre NHS Trust and coordinated by the WCTU at

University. Cancer Research UK’s Clinical Trials compared with radiotherapy alone. We therefore Cardiﬀ

postulated that cetuximab in combination with con-Awards and Advisory Committee (CTAAC) approved the ventional deﬁ nitive chemoradiotherapy might improve trial design.

www.thelancet.com/oncology Vol 14 June 2013628

Articles

resolution to grade 0–1. Further chemotherapy was

Eligible patients were randomly assigned (1:1) to chemo-omitted for grade 4 toxicity, and given at 75% and 50%

rst and second occurrences of radiotherapy with cetuximab (CRT plus cetuximab) or dose reductions after the ﬁ

chemoradiotherapy without cetuximab (CRT only) by grade 3 toxicity. For grade 2 toxicity, subsequent stratiﬁ ed minimisation with a random element (80:20). chemotherapy was given at 100%, 75%, and 50% dose

rst, second, and third occurrences of Randomisation was stratiﬁ ed by recruiting hospital, reductions after the ﬁ

primary reason for not having surgery, tumour histology, toxicity. For cetuximab-induced skin toxicity, cetuximab Randomisation and masking

and tumour stage. To conceal the sequence until inter-ventions were assigned, research nurses (who recruited the patients) telephoned the WCTU where the random allocation sequence was generated by a trial or data manager interacting with a computerised system. The study had an open-label design. Participants, those administering the interventions, and those assessing the outcomes were aware of which treatment had been allocated.

Procedures

Both study groups received the same chemotherapy, which consisted of four 3-weekly cycles of cisplatin (60 mg/m² intravenously on day 1) and capecitabine (625 mg/m² orally twice daily from day 1 to day 21); cycles one and two were given as neoadjuvant treatment. Cycles three and four were given concurrently with radiotherapy. This regimen is the most frequently used regimen in the UK. Patients randomly assigned to the CRT plus cetuximab group also received intravenous cetuximab 400 mg/m² on day 1 of chemotherapy and 250 mg/m²

weekly for the 12 weeks of treatment. If patients were unable to swallow capecitabine, investi gators could use a protracted intravenous infusion of ﬂ uorouracil at a rate of 225 mg/m² per day from day 1 to day 21 of each cycle. Full details of protocol treatment and dose reductions are detailed in the trial protocol.

Dose modiﬁ cation for haematological toxicity was based on a full blood counts taken within the 3 days before the

start of each cycle of chemotherapy. Full-dose chemotherapy was given if ANC was 1×10⁹/L or higher and platelet count was 75×10⁹/L or higher. For ANC 0·5×10⁹/L to less than 1×10⁹/L or a platelet count 50×10⁹/L to less than 75×10⁹/L, chemotherapy was stopped until recovery of counts and restarted with a 25% dose

reduction of cisplatin and capecitabine. For ANC below

0·5×10⁹/L or platelet count below 50×10⁹/L, chemotherapy was restarted with a 50% dose reduction. Renal

modiﬁ cation was based on GFR at baseline and before day 1 of chemotherapy. Patients received full-dose chemotherapy if their GFR was 50 mL/min or higher.

Cisplatin was given at a 75% dose reduction to patients with GFR of 40–50 mL/min, and replaced by carboplatin

(at a concentration to achieve an area under the con-centration–time curve of 5) if GFR was below 40 mL/min. Capecitabine was given at a 75% dose reduction if GFR

was below 50 mL/min, a 50% dose reduction if GFR was

below 40 mL/min, and omitted if GFR was below 30 mL/min. For other non-haematological toxicities of

grade 2 or higher, chemotherapy was withheld until www.thelancet.com/oncology Vol 14 June 2013 was continued along with topical emollient and antibiotics if the patient had a grade 1 acneiform rash. Oral antibiotics were mandated for grade 3 rash and recommended for grade 2 rash. Sequential dose reduction of cetuximab to 200 mg/m² and 150 mg/m² was advised for second and third occurrences of grade 3 skin rash, respectively; it was permanently discontinued after a fourth appearance.

The radiotherapy protocol and planning guidance

document mandated the use of intravenous contrast CT simulation with minimum 3-mm CT slices. 50 Gy in 25 fractions, prescribed according to recommendations by the Inter

national Commission on Radiation Units and Measure

ments (ICRU-50/62), was delivered Monday to Friday as a three-dimensional (3D) conformally planned single-phase treatment, usually with four radiotherapy

ﬁ

elds to achieve the following normal organ dose constraints: less than 30% of the heart volume to receive at least 40 Gy, less than 25% of the lung volume to receive at least 20 Gy, and a maximum dose in the spinal cord of

less than 40 Gy. Gross tumour volume was deﬁ

ned by diagnostic CT scan, endoscopy and endoscopic ultrasound, and PET scan information (when available).

The clinical target volume was cal

culated by adding 2 cm manually along the oesophagus superiorly–inferiorly

and 1 cm radially. The ﬁ

nal planning target volume was then created by adding 1 cm superiorly–inferiorly and

0·5 cm radially to the clinical target volume. Elective For the trial protocol see http://nodal irradiation was not done.

www.wctu.org.uk/trial.All potential principal investigators and radiotherapy php?trial=scope1centres received a CD-ROM containing the detailed

radiotherapy protocol, a radio

therapy planning guidance document, and example planning cases. All principal investigators had to outline a benchmark case 0 patients were assessed for eligibility282 excluded 213 did not meet inclusion criteria 66 refused 3 other reasons258 were randomly assigned129 were assigned to129 assigned to chemoradiotherapy pluschemoradiotherapy onlycetuximabFigure 1: Trial proﬁ

le629

Articles

During treatment, patients were reviewed within the and radiotherapy centres then planned the same case,

which had to pass central review before patient 3 days before day 1 of each cycle of chemotherapy during

nitive recruitment.19 On-trial radiotherapy trials quality the neoadjuvant phase and weekly during the deﬁ

assurance (RTTQA) consisted of all principal investi-chemoradiotherapy phase. Assessment at each review gators’ ﬁ rst plans, 10% of all subsequent plans, and consisted of medical examination and assessment of trial-speciﬁ c planning assessment forms for each WHO performance status, dysphagia score, and toxicity patient submitted for central review that outlined and according to the US National Cancer Institute’s Common 630

assessed the 3D dose distribution before treatment. SCOPE1 RTTQA was coordinated by the NCRI RTTQA centre in Cardiﬀ , UK.

CRT plus cetuximab CRT only (n=129)(n=129)Age (years)Median66·966·6Range (IQR)44·9–84·1 (61·3–73·7)35·7–81·9 (60·2–72·3)Aged ≥70 years50 (39%)48 (37%)SexMale71 (55%)74 (57%)Female58 (45%)55 (43%)WHO performance status061 (47%)70 (%)168 (53%)59 (46%)Reason for no surgeryLocal extent of disease60 (47%)62 (48%)Patient choice48 (37%)49 (38%)Comorbidity/poor 21 (16%)18 (14%)performance statusPET used in stagingYes109 (84%)112 (87%)No17 (13%)16 (12%)Missing data3 (2%)1 (<1%)Site of predominant tumourUpper15 (12%)12 (9%)Middle56 (43%)58 (45%)Lower (42%)58 (45%)Missing data4 (3%)1 (<1%)Tumour typeAdenocarcinoma33 (26%)32 (25%)Squamous cell92 (71%)96 (74%)Undiﬀ erentiated4 (3%)1 (<1%)StageI4 (3%)4 (3%)IIa36 (28%)36 (28%)IIb12 (9%)11 (9%)III77 (60%)78 (60%)Total EUS disease length (cm)Mean (SD)5·6 (2·7)5·6 (2·4)Missing data37 (29%)28 (22%)Time of start of treatment from randomisation (days)MedianRange (IQR)0–34 (2–7)0–22 (2–7)Data are number (%) unless otherwise speciﬁ ed. CRT=chemoradiotherapy. EUS=endoscopic ultrasound.Table 1: Baseline characteristics of randomly assigned patients Terminology Criteria for Adverse Events (CTCAE version 3.0). Capecitabine compliance was assessed by counting

the number of tablets at each visit. Blood tests including full blood count and biochemical proﬁ le were done at each clinic visit. Blood and biopsy samples were obtained at both baseline and week 24, but the processing of these

samples is still in progress, and correlations with treat-ment response will be the subject of a future paper.Follow-up was at 24 weeks, then every 3 months after that during the ﬁ rst year, every 4 months during the second year, and yearly thereafter for a minimum of 5 years from randomisation. All patients had an endoscopic assessment, biopsy, and CT scan 12 weeks after com pletion of deﬁ nitive chemoradiotherapy (at week 24). No further CT scan was mandated, and further investigations (endoscopy or CT scan) were done according to patient symptoms. The choice of second-line treatment, in cluding salvage surgery in the case of locoregional recurrence, was left to the discretion of the treating clinician. Patients completed validated quality-of-life questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C3020 and QLQ-OES18,21 dermatology life-quality index, and EQ-5D) and a health-care resource utilisation log at baseline and weeks 7, 13, 24, and 52, and yearly thereafter (to 5 years after randomisation). We postulated that scores for physical and role function, fatigue, dysphagia, and eating restrictions would be better over time in the CRT plus cetuximab group than in the CRT only group. Missing data were managed according to the standard guidelines associated with each questionnaire.The primary endpoint of the phase 2 trial was the

proportion of patients who were treatment failure free at

24 weeks (12 weeks after completion of treatment).

A patient was deemed treatment failure free if they were

still alive with no evidence of residual malignancy in the

endoscopic biopsy sample, and no evidence of disease

progression outside the radiotherapy ﬁ eld on CT scan.

Secondary endpoints were toxicity, quality of life, health

economics, progression-free survival (overall, local, and

distant), treatment compliance, and feasibility of

recruitment. Local progression-free survival was deﬁ ned

as the time to progression within the radiotherapy ﬁ eld (with or without metastatic disease) or death by any cause. Distant progression-free survival was deﬁ ned as time to progression with metastases or death by any cause.

Statistical analysis

With the addition of cetuximab to the intervention group, we felt that a treatment-failure-free rate of less than 60%

www.thelancet.com/oncology Vol 14 June 2013Articles

at week 24 would not be suﬃ ciently large enough to randomisation at which a CT scan or endoscopic biopsy warrant further investigation in a phase 3 setting, but was done. We calculated survival from date of

gression that a rate of 75% or higher would warrant further randomisation to when an event occurred (ie, pro

investigation. Using a Fleming’s single-stage design (p1=0·60; p2=0·75; α=0·05; 90% power; 10% loss to CRT plus cetuximab (n=129)follow up), we needed to recruit 90 patients in the CRT

Haematological27 (21%)plus cetuximab group (180 patients overall). Subject to

CRT only (n=129)36 (28%)the independent data monitoring committee’s review of

the phase 2 analysis, the study would proceed to phase 3

with a primary endpoint of overall survival from date of

randomisation. However, we were to continue recruiting

patients until the phase 2 trial was analysed. For the

phase 3 trial, we needed to recruit 420 patients (269 events) to detect an improvement in 2-year overall

survival from 35% to 47·5% (hazard ratio [HR] 0·71) in

patients assigned to CRT plus cetuximab, with 80%

power at 5% signiﬁ cance.

Data were analysed with the Stata 11 statistical package

according to intention to treat. We used the Clopper-Pearson exact binomial method to calculate 90% CIs for

the phase 2 primary endpoint. Analyses of the proportion

of patients who were treatment failure free were done

using the number of patients who died or progressed

before 24 weeks, or those with a valid 24-week assess ment, as the denominator. A valid 24-week assessment was deﬁ ned as a follow-up visit between 20 and 28 weeks after CRT plus CRT only cetuximab (n=129)(n=129)CisplatinCompleted cycles 1–4 at full dose73 (57%)69 (53%)Completed cycles 1–4 at full or reduced dose99 (77%)116 (90%)Stopped before cycle 4 due to patient choice4 (13%)*1 (8%)†Stopped before cycle 4 due to toxicity/illness 26 (87%)*12 (92%)†CapecitabineCompleted cycles 1–4 at full dose32 (25%)44 (34%)Completed cycles 1–4 at full or reduced dose (69%)110 (85%)Stopped before cycle 4 due to patient choice4 (10%)‡0§Stopped before cycle 4 due to toxicity/illness36 (90%)‡19 (100%)§Switched to ﬂ uorouracil before cycle 47 (5%)7 (5%)Number of cycles of cetuximab completed at full or reduced dose01 (<1%)NA19 (7%)NA216 (12%)NA314 (11%)NA4 (69%)NARadiotherapyFull protocol dose100 (78%)116 (90%)Dose reduction4 (3%)3 (2%)No radiotherapy given25 (19%)10 (8%)CRT=chemoradiotherapy. NA=not applicable. *Out of 30 patients who stopped cisplatin before cycle 4. †Out of 13 patients who stopped cisplatin before cycle 4. ‡Out of 40 patients who stopped capecitabine before cycle 4. §Out of 19 patients who stopped capecitabine before cycle 4. Table 2: Treatment compliance in randomly assigned patientswww.thelancet.com/oncology Vol 14 June 2013 Haemoglobin3 (2%)3 (2%)WBC14 (11%)21 (16%)ANC15 (12%)24 (19%)Platelets11 (9%)6 (5%)Lymphocytes5 (4%)3 (2%)Non-haematological102 (79%)81 (63%)Cardiac disorders8 (6%)2 (2%)Cardiac ischaemia/infarction3 (2%)1 (<1%)Other5 (4%)1 (<1%)Dermatological28 (22%)5 (4%)Acne9 (7%)0Hand-foot syndrome7 (5%)4 (3%)Rash14 (11%)0Other9 (7%)1 (<1%)Metabolic/laboratory31 (24%)14 (11%)Hypomagnesia9 (7%)2 (2%)Hypokalaemia9 (7%)7 (5%)Hypophosphataemia6 (5%)1 (<1%)Hyponatraemia2 (2%)1 (<1%)Bilirubin2 (2%)0Hyperuricaemia2 (2%)0Other13 (10%)6 (5%)Pulmonary8 (6%)4 (3%)Dyspnoea8 (6%)3 (2%)Other2 (2%)1 (<1%)Constitutional symptoms27 (21%)26 (20%)Fatigue26 (20%)25 (19%)Weight loss3 (2%)3 (2%)Gastrointestinal55 (43%)57 (44%)Diarrhoea12 (9%)8 (6%)Dysphagia35 (27%)37 (29%)Stomatitis4 (3%)2 (2%)Nausea6 (5%)11 (9%)Oesophagitis3 (2%)7 (5%)Vomiting7 (5%)11 (9%)Anorexia12 (9%)13 (10%)Other7 (5%)9 (7%)Infection8 (6%)9 (7%)Febrile neutropenia3 (2%)3 (2%)Infection with normal ANC5 (4%)6 (5%)Neurological5 (4%)5 (4%)Vascular14 (11%)13 (10%)Thrombosis/thrombus/embolism14 (11%)12 (9%)Other2 (2%)1 (<1%)Other12 (9%)10 (8%)All randomly assigned patients received at least one dose of treatment. CRT=chemoradiotherapy. WBC=white blood cell. ANC=absolute neutrophil count. CTCAE=Common Terminology Criteria for Adverse Events.Table 3: CTCAE grade 3 or 4 toxicity in patients during treatment (weeks 1 to 12)631

Articles

or any death for progression-free survival, and any death for overall survival). Patients who were event free were censored at the time they were last assessed. We estimated event time distributions with the Kaplan-Meier method and compared overall survival and progression-free survival with an unadjusted log-rank test and HRs from Cox regression, both unadjusted and adjusted for dose of treatment. We compared quality-of-life score diﬀ erences with Wilcoxon rank sum tests. We prespeciﬁ ed all the analyses that we have presented below. Detailed quality-of-life analyses, health economic analyses, and correl ation of outcomes with radiotherapy treatment delivery will be presented in future reports.

This trial is an International Standard Randomised randomisation strati ﬁ cation factors (we tested the proportional hazards assumption with Cox-Snell residuals and Schoenfeld’s global test). We included all randomly assigned patients who met the eligibility criteria in the analysis of their allocated group. We assessed toxicity by comparing proportions of haematological and non-haematological toxicities during chemoradiotherapy with Pearson’s χ² tests in all patients who received at least one

CRT plus cetuximab CRT only (n=129)(n=129)Lost to follow-up before 24 weeks10 (8%)8 (6%)Too ill for assessments/withdrew/moved away8 (80%)6 (75%)Invalid 24 week assessment (too early/late)2 (20%)2 (25%)Died before 24 weeks17 (13%)8 (6%)Oesophageal cancer11 (65%)4 (50%)Treatment related3 (18%)0 Other3 (18%)4 (50%)Valid 24-week assessment102 (79%)113 (88%)Failure at 24-week assessment23 (23%)20 (18%)By biopsy20 (87%)10 (50%)By endoscopy03 (15%)By CT scan3 (13%)7 (35%)Failure free at 24 weeks79 (66%)93 (77%)Alive and without progression at last follow-up49 (62%)58 (62%)Progressed at last follow-up17 (22%)23 (25%)Local7 (41%)10 (43%)Metastatic2 (12%)6 (26%)Both8 (47%)7 (30%)Died of any cause before progression13 (16%)12 (13%)Oesophageal cancer13 (100%)8 (67%)Pulmonary embolism01 (8%)Stroke01 (8%)Cardiac failure/heart disease01 (8%)Liver disease01 (8%)Post-trial treatments up to 12 months after randomisation*Patients with completed treatment follow-up data88 (68%)97 (75%)Surgery03 (3%)Palliative chemotherapy7 (8%)2 (2%)Radiotherapy1 (1%)2 (2%)Endoscopic interventionOesophageal stent2 (2%)2 (2%)Oesophageal dilatation1 (1%)6 (6%)Oesophageal laser therapy1 (1%)0 Stent plus dilation1 (1%)1 (1%)CRT=chemoradiotherapy. *No patients started more than one of the treatments listed here. Table 4: Failure-free rate at 24 weeks, and subsequent pattern of treatment failure and treatments given632

Controlled Trial, number 47718479.

Role of funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The statistician (CH) had full access to all the data and the corresponding author (TC) and statistician (CH) had ﬁ nal responsibility for the decision to submit for publication. Merck Serono provided the cetuximab free of charge but had no role in study design, data collection, data analysis, data interpretation or writing of the report.

Results

258 patients were recruited from 36 of the 56 radiotherapy centres in the UK between Feb 7, 2008, and Feb 22, 2012 (ﬁ gure 1). In February, 2012, the independent data monitoring committee undertook a preplanned analysis of the ﬁ rst 180 patients recruited who had completed 24 weeks of follow up, and recommended stopping recruitment because the trial had met predetermined criteria for futility. When making this decision, they also took into account toxicity, treatment compliance, and overall survival, and recommended completion of treat-ment and follow-up of all recruited patients. The data presented here are those from all 258 patients (129 pa-tients allocated to each treatment group) who were recruited up until the independent data monitoring committee’s decision, analysed after the last patient had undergone assessment at week 24. The median length of follow-up for patients who had survived by the time of analysis was 16·8 months (IQR 11·2–24·5).

Patient and tumour baseline characteristics were well balanced between groups (table 1). Patients who were assigned to receive CRT plus cetuximab were less likely to com plete standard protocol treatment than were those assigned to the CRT only group (table 2). The com pliance diﬀ erence between groups was signiﬁ cant for completion (at full or reduced dose) of four planned cycles of cisplatin (p=0·005), completion of four cycles of capecitabine (p=0·002), and delivery of any radiotherapy (104 [81%] of 129 patients in the CRT plus cetuximab group vs 119 [92%] of 129 patients in the CRT only group; p=0·006; table 2). The number of patients whose cisplatin dose was reduced (or stopped) was similar in each group (56 [43%] in the CRT plus cetuximab group vs 60 (47%) in the CRT only group). The number of patients whose capecitabine dose was reduced was higher in the CRT plus cetuximab group than in the CRT only group (97 [75%] vs 85 [66%]). More patients in the CRT plus cetuximab group stopped both cisplatin and capecitabine treatment early because

www.thelancet.com/oncology Vol 14 June 2013Articles

of toxicity or illness than did those in the CRT only group CRT plus cetuximab100(cisplatin stopped, 26 [20%] vs 12 [9%]; capecitabine CRT onlystopped, 36 [28%] vs 19 [15%]).

All CTCAE grade 3 or 4 toxicities (including serious

75adverse reactions and suspected unexpected serious adverse reactions) reported during treatment are shown in table 3. Patients who received CRT plus cetuximab had

ival (%)more non-haematological toxicity (p=0·004). These

toxicities were mainly dermatological, biochemical (metabolic or laboratory tests), and cardiac disorders (table 3).The proportion of patients who were treatment failure free at 24 weeks was lower in the CRT plus cetuximab group than in the CRT only group (79 of 119 patients [66·4%, 90% CI 58·6–73·6] vs 93 of 121 patients [76·9%, 69·7–83·0]). Patients who were failure free at 24 weeks

had signiﬁ cantly better median overall survival than did those who were not failure free (8·3 months [95% CI 6·7–12·5] vs 26·7 months [24·5–42·7]). Of those patients

who were failure free at 24 weeks, 107 (62%) of 172 were still alive without progression at the end of the study follow-up, whereas 40 (23%) were alive with progression

and 25 (15%) had died. Of patients who died before

24 weeks, more were recorded as having oesophageal

cancer as the cause of death in the CRT plus cetuximab group than in the CRT only group (table 4). Three

treatment-related deaths occurred in the CRT plus cetuximab group (one stroke, one multiorgan failure, one pulmonary embolism). 29 patients are known to

have had further treatment during the 12 months after

randomisation (table 4).

Overall survival was signiﬁ cantly worse in the CRT plus cetuximab group than in the CRT only group (unadjusted HR 1·45 [95% CI 1·01–2·09], log-rank

p=0·043; adjusted HR 1·53 [1·03–2·27], p=0·035;

ﬁ gure 2). Median overall survival was 22·1 months

(95% CI 15·1–24·5) in the CRT plus cetuximab group

and 25·4 months (20·5–37·9) in the CRT only group. This pattern was consistent across randomisation strati-ﬁ cation characteristics (ﬁ gure 3). 2-year overall sur

vival was also lower in the CRT plus cetuximab group than in the CRT only group (41·3% [95% CI 30·9–51·4] vs 56·0% [45·1–65·6]), as well as median progression-free survival,

but not signiﬁ cantly so (15·9 months [95% CI 11·0–21·1] vs 21·6 months [16·2–27·8]; un adjusted HR 1·26 [95% CI 0·90–1·77], log-rank p=0·17; adjusted HR 1·29 [0·–1·85], p=0·18), median distant progression-free survival (18·4 months [13·3–23·2] vs 25·4 months [18·4–29·3]), and local progression-free survival (15·9 months [11·0–21·1] vs 21·6 [16·2–27·8]).

Figures 4 and 5 show the results of the quality-of-life analysis. At baseline, 246 (95%) patients completed the

QLQ-C30 and 240 (93%) patients completed QLQ-OES18. A completion rate of 69% or above was maintained at week 13 (184 [71%] completed QLQ-C30 and 178 [69%] completed QLQ-OES18); the major reason for loss to follow-up was attrition. The change in the fol lowing www.thelancet.com/oncology Vol 14 June 2013 vrus50 llarevO25006121824303248Number at riskMonths from randomisationCRT plus cetuximab129106704525161241CRT only12911487563112832Figure 2: Kaplan-Meier curves of overall survival by treatment group

CRT=chemoradiotherapy.

nDeathsSurvival (months)Reason for no surgeryLocal extent of disease1225622·2 (16·1−25·4)Patient choice974524·7 (20·0−30·3)Comorbidity/poor performance status391823·2 (12·8−NC)Tumour typeAdenocarcinoma653419·7 (14·7−25·8)Squamous cell1888324·0 (20·5−27·8)Other52·· StageI81·· II953630·3 (19·7−NC)III1558220·7 (16·9−24·7)0·51·02·04·0Favours CRTFavours CRT only+ cetuximabFigure 3: Hazard ratio plots for overall survival, by baseline characteristics

Survival data are median number of months (95% CI) in all patients. Positions of squares show hazard ratio of

death in the CRT plus cetuximab group compared with death in the CRT only group; the area of each square represents the amount of information (ie, the number of patients) in each category. Lines show 95% CIs.

CRT=chemoradiotherapy. NC=not calculable because of small numbers of patients.scores from baseline to week 13 did not diﬀ

er signiﬁ cantly between groups: physical function (z=−1·139, p=0·25; n=177), role function (z=−1·207,p=0·23; n=177), fatigue (z=0·520, p=0·60; n=177), dysphagia (z=1·395, p=0·16; n=167), and eating restrictions (z=0·031, p=0·98; n=167). In each case, n represents the number of patients who

had completed questionnaires at both baseline and week 13. Full quality-of-life data will be reported elsewhere.Discussion

As the result of a preplanned assessment, the inde-pendent data monitoring committee reported that the primary endpoint of the phase 2 stage of the SCOPE1 trial had not been met and recommended closing the

633

Articles

100CRT plus cetuximab)CRT only03C−QL80Q( erocs gn60inoitcnuf 40lacisyhp na20eM007132652Number of patientsWeeks from randomisationCRT plus cetuximab12492858460CRT only122103998871Figure 4: Physical functioning score from QLQ-C30 in each treatment group at ﬁ ve timepoints over 52 weeksThe number of patients shows the amount who completed QLQ-C30 at each timepoint. A higher score indicates better function. Bars show 95% CI. QLQ-C30=European Organisation for Research and Treatment of Cancer’s Quality of Life Questionnaire C30.

100CRT plus cetuximabCRT only)81EO−80QLQ( erocs60 snoitcirtse40r gnitae na20eM007132652Weeks from randomisationNumber of patientsCRT plus cetuximab12190828158CRT only117100968870Figure 5: Eating restrictions score from QLQ-OES18 in each treatment group at ﬁ ve timepoints over 52 weeksThe number of patients shows the amount who completed QLQ-OES18 at each timepoint. A higher score indicates a greater number of problems. Bars show 95% CI. QLQ-OES18=European Organisation for Research and Treatment of Cancer’s Quality of Life Questionnaire OES18.

trial to further recruitment and not proceeding to phase 3. The addition of cetuximab to chemoradiotherapy resulted in more toxicity, less protocol treatment being delivered, and worse overall survival than with chemo-radiotherapy alone, although quality of life was not reduced compared with chemoradiotherapy alone. This eﬀ ect on overall survival was consistent across pre-determined subgroups—ie, histological subtype, tumour stage, and the reason for not undergoing surgery. There-fore, the addition of cetuximab to standard deﬁ nitive chemoradiotherapy cannot be recommended.

634

The outcome of SCOPE1 is consistent with recent results from other randomised trials comparing the addition of anti-EGFR therapy to standard treatment across several tumour sites (panel). In the REAL3 study,23 patients with advanced oesophagogastric cancer received epirubicin, oxaliplatin, and capecitabine with or without panitumumab. Patients who received the monoclonal antibody received a lower protocol dose of capecitabine and oxaliplatin. Despite this prespeciﬁ ed dose modi-ﬁ cation, patients in the chemotherapy plus panitumumab group received a lower median number of cycles than did the control group (ﬁ ve vs six), a lower median dose intensity of capecitabine, and had worse overall survival (8·8 months vs 11·3 months; HR 1·37; p=0·01). The Radiation Therapy Oncology Group (RTOG) 0522 trial24 sought to build on the results of Bonner and colleagues’ study17 by adding cetuximab to cisplatin or ﬂ uoro-pyrimidine-based chemoradiation in a similar patient population with squamous-cell head and neck cancer. Once again, no beneﬁ t was reported in terms of progression-free survival or overall survival, although an increased rate of mucositis was noted in the patients treated with cetuximab.24 In the COIN trial,25 which randomly assigned 2445 patients with metastatic colo-rectal cancer to oxaliplatin–ﬂ uoropyrimidine (ﬂ uoro-uracil or capecitabine) chemotherapy with or without cetuximab, a higher than anticipated incidence of grade 3 or 4 diarrhoea (30%) in the experimental group resulted in a dose modiﬁ cation of capecitabine during the course of the trial. No overall improvement in survival was reported in patients randomly assigned to receive cetuximab. The EXPAND study26 also showed no beneﬁ t from adding cetuximab to ﬁ rst-line chemotherapy in advanced gastric cancer. In the SCOPE1 trial, the REAL3 trial,23 and for most patients in the COIN trial,25 a capecitabine backbone was used and the resultant reduction in doses of standard therapy might have contributed to the worse outcome in the cetuximab groups of these trials. As seen in the REAL3 study,23 patients receiving cetuximab had a lower rate of haematological toxicity, possibly as a result of the lower chemotherapy dose intensity delivered.

Perhaps more importantly—with respect to this study of an investigational drug in deﬁ nitive treatment of oesophageal cancer—was the eﬀ ect on the dose of radiotherapy delivered. More than twice the number of patients in the CRT plus cetuximab group than in the CRT only group did not receive any radiotherapy (25 vs 10). As systemic therapies move from palliative, through to adjuvant, to deﬁ nitive treatment protocols, evidence-based treatment regimens should be vigilantly protected, especially if such treatments are intensiﬁ ed.

Another explanation for these results, independent of dose intensity, is the possible occurrence of a negative interaction between cetuximab and chemoradiotherapy. The proinﬂ ammatory and antitumour proliferative eﬀ ects of cetuximab have been proposed as the cause of

www.thelancet.com/oncology Vol 14 June 2013Articles

reduced eﬃ cacy in combination with chemoradiation in rectal cancer.27 A similar interaction between oxaliplatin and cetuximab has been proposed, speciﬁ cally that cetuximab might protect against free-radical damage by platinum drugs,28 and again could explain the negative outcome in this and other studies.25,29 Despite this reduction in survival, however, and increased toxicity, we Panel: Research in context

Systematic review

We identiﬁ ed a systematic review22 on combined modality radiotherapy and chemotherapy in non-surgical

management of localised carcinoma of the oesophagus that searched Medline (1996–2001), Cancerlit (1983–2001), did not record an eﬀ ect on quality of life according to standard EORTC generic and disease-speciﬁ c measures.The EGFR pathway seems to be important in the carcinogenesis of oesophagogastric malignancy30 and a beneﬁ t of anti-EGFR therapy has been shown in head and neck cancer in combination with radiotherapy17 and in advanced disease.15 The negative outcome in this study therefore seems to be a result of tumour-speciﬁ c interactions and biology that are not fully understood, or overlapping toxicities that preclude the delivery of eﬀ ective standard treatment.

An understanding of why the overall survival in this trial was better than anticipated will be important; 2-year overall survival was predicted to be 35% in the CRT only group in the phase 3 design. Despite the fact that most patients had stage III disease, 38% of patients were older than 70 years, and 15% of patients had comorbidities that precluded surgery, the 2-year overall survival in all patients was 49%, and was 56% in those receiving CRT only. Indeed, the overall survival in the CRT only group exceeded that which was hoped to be seen by the addition of cetuximab and was better than that seen in the US and UK studies exploring the role of the addition of neoadjuvant chemotherapy to surgery.3 Although one of the lead authors in our investigation (TC) has previously published encouraging out comes of single centre,

retrospective series,8,12

whether these outcomes could be reproduced in a multicentre, prospective study was unclear. Before this trial, concerns had been raised about the quality of radiotherapy delivered in multicentre UK studies of radiotherapy in upper gastrointestinal cancers.31 Such studies did not have detailed radiotherapy treatment protocols and had near-absent radiotherapy quality assurance. Standard practice throughout the UK varied substantially before this study;32 therefore, we made RTTQA an important aspect of the study design. We developed a detailed protocol mandating the use of endoscopic ultrasound and intravenous contrast to aid localisation of target volume and used a single-phase conformal treatment plan.33 This plan, together with a comprehensive radiotherapy planning protocol and test cases, was sent to all principal investigators and radiotherapy centres before patients were recruited.19 We propose that this protocol, together with the on-trial quality assurance programme providing a positive dialogue between recruiting units and the RTTQA central team, was a crucial component to the successful outcomes seen in the CRT only group. The beneﬁ t of

RTTQA has been reported in other studies.34

To the best of our know ledge, this trial is the largest prospective

www.thelancet.com/oncology Vol 14 June 2013 Cochrane Library databases (2001), and abstracts published in the American Society of Clinical Oncology and the

American Society for Therapeutic Radiology and Oncology (1999–2001) for articles published in any language. Search terms included “esophageal neoplasms” with the

subheadings “drug therapy”, “radiotherapy”, or “therapy”. The review reported the beneﬁ ts of chemoradiotherapy (CRT) compared with radiotherapy alone; however, it also showed that most patients still relapse with locoregional or metastatic disease. We also identiﬁ ed studies that reported that cetuximab, a monoclonal EGFR antagonist, improved outcomes when given in combination with: chemotherapy in advanced colorectal adenocarcinomas and squamous-cell head and neck cancer; and radiotherapy in squamous-cell head and neck cancer.

Interpretation

Cetuximab should not be given in addition to chemoradiation in an unselected patient population. The results of our study do, however, support the use of chemoradiation alone as a standard of care in patients with non-metastatic

squamous-cell carcinoma of the oesophagus and in patients with non-metastatic adenocarcinoma who are not suitable for surgery. Indeed, the outcomes of this study would support the increased use of this treatment in patients who have a higher risk of failure of surgical treatment, either due to the existence of comorbidities or where surgical excision is likely to be incomplete. A randomised trial to compare surgical and radiotherapy-based treatments in patients with oesophageal cancer with a better outlook is warranted.

study with a comprehensive assessment of quality of life with disease and cancer-speciﬁ c questionnaires in patients under going deﬁ nitive chemoradiotherapy. Scores achieved in patients surviving for 2 years in our study are compatible with that achieved by surgical-based treatments.5

Other factors that could have contributed to improved outcomes in this study are patient selection and organ-isation of cancer services throughout the UK. Although not mandated, 86% of patients had a PET scan before starting radiotherapy. PET has been shown to both exclude patients with metastatic disease not otherwise seen with endoscopic ultrasound and CT scan35 and be useful in radiotherapy planning.36 Substantial recon-ﬁ guration of oesophagogastric cancer treatment ser vices in the UK has also taken place in the past decade.37,38 Although the changes have mainly been in centralisation of surgical services, they have led to the development of regional specialist multidisciplinary teams, which has

635

Articles

636

undoubtedly added rigour to treatment decisions and with cisplatin and capecitabine-based deﬁ nitive chemo-patient selection. The 2012 annual report of the UK radiotherapy in patients with localised oesophageal National Oesophago-gastric Cancer Audit38 has showed cancer cannot be recommended. However, the very an improvement in outcomes for patients undergoing encouraging outcomes seen with deﬁ nitive chemoradio-surgery, with 45% of patients surviving for 3 years. Both therapy alone should provide an excellent platform to test of these areas have scope for further development, more targeted therapeutic approaches, incorporating namely the incorporation of CT-PET more directly into biomarker-driven systemic therapies and newer radio-radiotherapy planning and assessment of caseload, with therapy technologies to safely intensify treatment, in-outcomes in specialist non-surgical services.

cluding increases to radiotherapy doses.

How can we build further on the encouraging clinical outcomes reported in the CRT only group of this study? Contributors

TC, CNH, SF, SG, JS, JAB, JIG, JB, TM, and GG were involved in the Clearly, as patients continue to relapse with both meta-design and development of the trial and the writing and review of the static and locoregional disease, systemic and local com-protocol. CNH, NB, and RRa were involved in the day-to-day running of ponents of this treatment strategy need to be improved the trial. CNH was responsible for the statistical analysis. TC, CNH, SM, JB, and GG were responsible for preparing the manuscript. All authors and intensiﬁ ed. Systemic treatments should either have have contributed to, seen, and approved the ﬁ nal draft. TC, SF, SG, RRo, independent activity in oesophageal cancer or have JIG, and DC were principal investigators at centres recruiting more than synergistic eﬀ ects with radiotherapy in the form of 5% of patients. A full list of all SCOPE1 study investigators is listed in radiosensitisation or overcoming mechanisms of radio-the appendix.

resistance. However, newer therapies need to be carefully Conﬂ icts of interest

integrated so as not to compromise the dose intensity We declare that we have no conﬂ icts of interest.

of standard chemoradiotherapy. High concentrations of Acknowledgments

tumoral ERCC1 might predict platinum resistance,39 The SCOPE1 trial was sponsored by Velindre NHS Trust, funded by Cancer Research UK (CRUK), and CRUK core funding at the Wales which might be overcome with alternative chemotherapy Cancer Trials Unit (WCTU). Merck provided free cetuximab, labelling, such as taxane-containing regimens. The overexpression and distribution for the study. The radiotherapy trials quality assurance of HER2 (also known as ERBB2) predicts whether the (RTTQA) was funded by CRUK and the Cardiﬀ National Cancer addition of trastuzumab will beneﬁ t patients with

Research Institute RTTQA Centre at Velindre NHS Trust which are funded by the National Institute of Social Care and Health Research advanced oesophagogastric cancer.40

The safety and (NISCHR; Wales) and Department of Health (England). TC is partly eﬃ cacy of anti-HER2 therapy should be tested as part of supported by NISCHR Academic Health Science Collaboration

chemoradiotherapy treatment in this patient population.fellowship funding. JB is supported by the Medical Research Council A radiotherapy dose–response eﬀ ect in patients with ConDuCT Hub for Trials Methodology Research. DC receives funding from the Biomedical Research Centre at the Royal Marsden Hospital oesophageal cancer has been known for some time.41 and Institute of Cancer Research. JAB is in part supported by the However, a study designed to test the beneﬁ t of a University College London Hospital (UCLH)/UCL Biomedical

higher radiation dose given concurrently with cisplatin Research Centre. We thank all the patients who participated in the trial, and ﬂ uoropyrimidine chemotherapy was prematurely the doctors, nurses, pathologists, other members of the

multidisciplinary teams, radiotherapy team, and research team from stopped for futility as a result of an excess of treatment-the participating centres. We thank members of the independent data related deaths occurring in the high-dose treatment group.9 monitoring committee and the independent trial steering committee We believe, however, that by using newer radiotherapy for their oversight of the trial. We also thank Lisette Nixon (WCTU trial techniques, such as intensity-modulated and image-manager), Bethan Tranter (trial pharmacist), David Kirby (patient representative), Wendy Wade (research nurse), and Ashley Roberts guided radiotherapy, we can now safely deliver a higher (radiologist) for their input into the trial management group.

dose of radiation to a highly conformal target volume References

within the context of a high-quality RTTQA programme.1 Cancer Research UK. Oesophageal cancer: statistical information

This trial was a phase 2/3 study that ended on on gullet cancer. http://publications.cancerresearchuk.org/cancerstats/statsoesophapgeal (accessed Feb 28, 2013).

completion of phase 2. The study did not reach the full 2 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global

sample size needed for the comparison of overall survival cancer statistics. CA Cancer J Clin 2011, 61: 69–90.

powered for under the phase 3 design. However, we do 3 Medical Research Council Oesophageal Cancer Working Group.

plan to follow-up patients for 5 years. Additionally, Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002; although the study stratiﬁ ed patients according to 359: 1727–33.

tumour histology, it was not powered to assess with 4 Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy

certainty the beneﬁ t of cetuximab in each of the two compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III main histological variants of this disease.

trial. J Clin Oncol 2011; 29: 1715–21.

This trial has not shown that the addition of cetuximab 5 Blazeby J, Farndon J, Donovan J, Alderson D. A prospective

to standard deﬁ nitive chemoradiotherapy beneﬁ ts pa-longitudinal study examining the quality of life of patients with esophageal carcinoma. Cancer 2000; 88: 1781–87.

tients with locally advanced oesophageal cancer. In fact, 6 Cooper JS, Guo MD, Herskovic A, et al. Chemotherapy of locally

the addition of cetuximab increased toxicity, reduced advanced esophageal cancer: long term follow-up of a prospective delivery of all components of standard chemoradio-randomized trial (RTOG 85-01). JAMA 1999; 281: 1623–27.therapy, and was associated with a signiﬁ cant reduction 7 Cunningham D, Starling N, Rao S, et al. Capecitabine and

oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008; in overall survival. The use of cetuximab in combination

358: 36–46.

www.thelancet.com/oncology Vol 14 June 20138

Crosby TD, Brewster AE, Borley A, et al. Deﬁ nitive chemoradiation in patients with inoperable oesophageal carcinoma. Br J Cancer 2004; 90: 70–75.

9 Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation

Therapy Oncology Group 94-05) phase III trial of

combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002; 20: 1167–74.10 Tsutsumi K, Yasuda M, Nishioka T. X-ray irradiation altered

chemosensitivity of a p53-null non-small cell lung cancer cell line. Cell Struct Funct 2006; 31: 47–52.11 Byﬁ eld JE, Calabro-Jones P, Klisak I, Kulhanian F. Pharmacologic

requirements for obtaining sensitization of human tumor cells in vitro to combined 5-Fluorouracil or ftorafur and X rays. Int J Radiat Oncol Biol Phys 1982; 8: 1923–33.

12 Gwynne S, Hurt C, Evans M, Holden C, Vout L, Crosby T. Deﬁ nitive

chemoradiation for oesophageal cancer—a standard of care in patients with non-metastatic oesophageal cancer. Clin Oncol (R Coll Radiol) 2011; 23: 182–88.

13 Wang KL, Wu TT, Choi IS, et al. Expression of epidermal growth

factor receptor in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Cancer 2007; 109: 658–67.

14 Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy

and cetuximab plus irinotecan in irinotecan-refractory metastic colorectal cancer. N Engl J Med 2004; 351: 337–45.

15 Vermorken JB, Mesia R, Rivera F, et al. Platinum-based

chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–27.

16 Baumann M, Krause M. Targeting the epidermal growth factor

receptor in radiotherapy: radiological mechanisms, preclinical and clinical results. Radiother Oncol 2004; 72: 257–66.

17 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab

for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 3: 567–78.

18 Hurt CN, Nixon LS, Griﬃ ths GO, et al. SCOPE1: a randomised

phase II/III multicentre clinical trial of deﬁ nitive chemoradiation, with or without cetuximab, in carcinoma of the oesophagus. BMC Cancer 2011; 11: 466.

19 Gwynne S, Spezi E, Wills L, et al. Toward semi-automated

assessment of target volume delineation in radiotherapy trials: the SCOPE 1 pretrial test case. Int J Radiat Oncol Biol Phys 2012; 84: 1037–42.

20 Aaronson NK, Ahmedzai S, Bergman B, et al. The European

Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–76.

21 Blazeby JM, Conroy T, Hammerlid E, et al. Clinical and

psychometric validation of an EORTC questionnaire module, the EORTC QLQ-OES18, to assess quality of life in patients with oesophageal cancer. Eur J Cancer 2003; 39: 1384–94.

22 Wong RK, Malthaner RA, Zuraw L, Rumble BR, for the Cancer Care

Ontario Practice Guidelines Initiative Gastrointestinal Cancer Disease Site Group. Combined modality radiotherapy and

chemotherapy in nonsurgical management of localized carcinoma of the esophagus: a practice guideline. Int J Radiat Oncol Biol Phys 2003; 55: 930–42.

23 Waddell T, Chau I, Cunningham D, et al. Epirubicin, oxaliplatin, and

capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 2013; 14: 481–.24 Ang KK, Zhang QE, Rosenthal DI, et al. A randomized phase III

trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). Proc Am Soc Clin Oncol 2011; 29 (suppl): abstr 5500.

25 Maughan TS, Adams RA, Smith CG, et al, on behalf of the MRC

COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based ﬁ rst-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377: 2103–14.

www.thelancet.com/oncology Vol 14 June 2013 26 Lordick F, Kang Y-K, Chung H-C, on behalf of the

Arbeitsgemeinschaft Internistische Onkologie (AIO) and EXPAND Investigators. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 2013; 14: 490–99.

27 Glynne-Jones R, Mawdsley S, Harrison M. Cetuximab and

chemoradiation for rectal cancer—is the water getting muddy? Acta Oncol 2010; 49: 278–86.

28 Dahan L, Sadok A, Formento J-L, Seitz JF, Kovacic H. Modulation

of cellular redox state underlies antagonism between oxaliplatin and cetuximab in human colorectal cancer cell lines. Br J Pharmacol 2009; 158: 610–20.

29 Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab

with continuous or intermittent ﬂ uorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in ﬁ rst-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 2012; 30: 1755–62.

30 Paterson AL, O’Donovan M, Provenzano E, et al. Characterisation

of the timing and prevalence of receptor tyrosine kinase expression changes in esophageal carcinogenesis. J Pathol 2012; 230: 118–28. 31 Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of

chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200–10.32 Button M, Staﬀ urth J, Crosby T. National variations in the treatment

of oesophageal carcinoma with chemo-radiotherapy. Clin Oncol (R Coll Radiol) 2007; 19: S25.33 Nixon L, Wills L, Staﬀ urth J, Crosby T, Casbard A, Griﬃ ths G.

Implementation of a QA RT substudy for SCOPE 1: preliminary results for test cases. Clin Oncol 2009; 21: 255.

34 Peters LJ, O’Sullivan B, Giralt J, et al. Critical impact of radiotherapy

protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02. J Clin Oncol 2010; 28: 2996–3001.

35 Flamen P, Lerut A, Van Cutsem E, et al. Utility of positron emission

tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 2000; 18: 3202.

36 Leong T, Everitt C, Yuen K, et al. A prospective study to evaluate the

impact of FDG-PET on CT-based radiotherapy treatment planning for oesophageal cancer. Radiother Oncol 2006; 78: 2–61.

37 NHS Executive. Guidance on commissioning cancer services:

improving outcomes in upper gastro-intestinal cancers. NHS

Executive Catalogue Number 23943. London: NHS Executive, 2001.38 Groene O, Cromwell DA, Hardwick R, Riley S, Crosby T,

Greenaway K. The National Oesophageal-Gastric Cancer Audit: 2012 annual report. London: The Royal College of Surgeons of England, 2012.

39 Leichman LP, Goldman BH, Bohanes PO, et al. S0356: a phase II

clinical and prospective molecular trial with oxaliplatin, ﬂ uorouracil, and external-beam radiation therapy before surgery for patients with esophageal adenocarcinoma. J Clin Oncol 2011; 29: 4555–60.

40 Bang Y-J, Van Cutsem E, Feyereislova A, et al, for the ToGA Trial

Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687–97.

41 Geh JI, Bond SJ, Bentzen SM, Glynne-Jones R. Systematic overview

of preoperative (neoadjuvant) chemoradiotherapy trials in

oesophageal cancer: evidence of a radiation and chemotherapy dose response. Radiother Oncol 2006; 78: 236–44.

637

Articles

因篇幅问题不能全部显示，请点此查看更多更全内容

查看全文