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

BACKGROUND: Definitive 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 fluoropyrimidine-based definitive 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 confirmed carcinoma of the oesophagus (adenocarcinoma, squamous-cell, or undifferentiated; WHO status 0-1; stage I-III disease) and been selected to receive definitive CRT. Patients were randomly assigned (1:1) via a central computerised system using stratified minimisation (with an 80:20 random element) to receive CRT alone or CRT with cetuximab (400 mg/m(2) on day 1 followed by 250 mg/m(2) weekly), stratified by recruiting hospital, primary reason for not having surgery, tumour histology, and tumour stage. CRT consisted of cisplatin 60 mg/m(2) (day 1) and capecitabine 625 mg/m(2) 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 definitive CRT. FUNDING: Cancer Research UK.

Case of carcinoid crisis following a fine-needle biopsy of hepatic metastasis.

Fine-needle biopsy of hepatic lesions in a patient with carcinoid liver metastasis can precipitate carcinoid crisis. We report a case of carcinoid crisis following a liver biopsy. Recognition of this unusual presentation of this condition is important to enable all appropriate preparatory measures to be taken and resuscitative equipment to be available.

Systematic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: evidence of a radiation and chemotherapy dose response.

BACKGROUND AND PURPOSE: Numerous trials have shown that pathological complete response (pCR) following preoperative chemoradiotherapy (CRT) and surgery for oesophageal cancer is associated with improved survival. However, different radiotherapy doses and fractionations and chemotherapy drugs, doses and scheduling were used, which may account for the differences in observed pCR and survival rates. A dose-response relationship may exist between radiotherapy and chemotherapy dose and pCR. PATIENTS AND METHODS: Trials using a single radiotherapy and chemotherapy regimen (5FU, cisplatin or mitomycin C-based) and providing information on patient numbers, age, resection and pCR rates were eligible. The endpoint used was pCR and the covariates analysed were prescribed radiotherapy dose, radiotherapy dosexdose per fraction, radiotherapy treatment time, prescribed chemotherapy (5FU, cisplatin and mitomycin C) dose and median age of patients within the trial. The model used was a multivariate logistic regression. RESULTS: Twenty-six trials were included (1335 patients) in which 311 patients (24%) achieved pCR. The probability of pCR improved with increasing dose of radiotherapy (P=0.006), 5FU (P=0.003) and cisplatin (P=0.018). Increasing radiotherapy treatment time (P=0.035) and increasing median age (P=0.019) reduced the probability of pCR. The estimated alpha/beta ratio of oesophageal cancer was 4.9 Gy (95% confidence interval (CI) 1.5-17 Gy) and the estimated radiotherapy dose lost per day was 0.59 Gy (95% CI 0.18-0.99 Gy). One gram per square metre of 5FU was estimated to be equivalent to 1.9 Gy (95% CI 0.8-5.2 Gy) of radiation and 100mg/m2 of cisplatin was estimated to be equivalent to 7.2 Gy (95% CI 2.1-28 Gy). Mitomycin C dose did not appear to influence pCR rates (P=0.60). CONCLUSIONS: There was evidence of a dose-response relationship between increasing protocol prescribed radiotherapy, 5FU and cisplatin dose and pCR. Additional significant factors were radiotherapy treatment time and median age of patients within the trial.

Pituitary carcinoma with a single metastasis causing cervical spinal cord compression. Case report.

Pituitary carcinoma is rare, with fewer than 100 cases having been reported in the English-language literature. The diagnosis of pituitary carcinoma requires the demonstration of cerebrospinal and/or systemic metastases rather than local invasion. The lesion carries a poor prognosis; fewer than 50% of patients survive beyond 1 year after diagnosis. In this report the authors describe the case of a 68-year-old man who had undergone transsphenoidal debulking surgery and pituitary radiotherapy 4 years earlier for a pituitary adenoma. He presented with cervical cord compression due to a single metastasis from pituitary carcinoma. The authors discuss the management of this entity and review the literature for current opinion on the pathogenesis of these tumors, factors resulting in malignant transformation, and the reliability of markers that predict future malignant behavior. Evidence for the various treatment modalities is also appraised.

Cancer of the anal canal.

Anal cancer is an uncommon tumour that represents 4% of all cancers of the lower gastrointestinal tract. Its pathogenesis and treatment have undergone substantial reassessment over the past two decades, and this is likely to continue. Anal cancer can be cured by synchronous chemoradiotherapy, a treatment that both enables anal continence to be retained and reserves abdominoperineal resection of the rectum and anal canal (with formation of a permanent colostomy) for recurrent or residual disease after primary chemoradiotherapy. Overall, survival from anal cancer is now around 70-80% at 5 years. Future challenges will be influenced by an increasing incidence due to human papillomavirus and HIV infection, more accurate characterisation and treatment of early (in situ) disease, and optimisation of chemoradiation regimens.