Cardiopulmonary fitness before and after neoadjuvant chemotherapy in patients with oesophagogastric cancer.

BACKGROUND: Neoadjuvant chemotherapy may have a detrimental impact on cardiorespiratory reserve. Determination of oxygen uptake at the anaerobic threshold by cardiopulmonary exercise testing (CPET) provides an objective measure of cardiorespiratory reserve. Anaerobic threshold can be used to predict perioperative risk. A low anaerobic threshold is associated with increased morbidity after oesophagogastrectomy. The aim of this study was to establish whether neoadjuvant chemotherapy has an adverse effect on fitness, and whether there is recovery of fitness before surgery for oesophageal and gastric adenocarcinoma. METHODS: CPET was completed before, immediately after (week 0), and at 2 and 4 weeks after neoadjuvant chemotherapy. The ventilatory anaerobic threshold and peak oxygen uptake (Vo2 peak) were used as objective, reproducible measures of cardiorespiratory reserve. Anaerobic threshold and Vo2 peak were compared before and after neoadjuvant chemotherapy, and at the three time intervals. RESULTS: Some 31 patients were recruited. The mean anaerobic threshold was lower following neoadjuvant treatment: 15·3 ml per kg per min before chemotherapy versus 11·8, 12·1 and 12·6 ml per kg per min at week 0, 2 and 4 respectively (P < 0·010). Measurements were also significantly different at each time point (P < 0·010). The same pattern was noted for Vo2 peak between values before chemotherapy (21·7 ml per kg per min) and at weeks 0, 2 and 4 (17·5, 18·6 and 19·3 ml per kg per min respectively) (P < 0·010). The reduction in anaerobic threshold and Vo2 peak did not improve during the time between completion of neoadjuvant chemotherapy and surgery. CONCLUSION: There was a decrease in cardiorespiratory reserve immediately after neoadjuvant chemotherapy that was sustained up to the point of surgery at 4 weeks after chemotherapy.

Sorafenib for the Treatment of Advanced Hepatocellular Cancer - a UK Audit.

AIMS: Sorafenib is the current standard treatment for advanced hepatocellular carcinoma. We carried out a national audit of UK patients treated with sorafenib as standard-of-care and those treated with systemic therapy in first-line trials. MATERIALS AND METHODS: Sorafenib-treated and trial-treated patients were identified via the Cancer Drugs Fund and local databases. Data were collected retrospectively from medical records according to a standard case report form. The primary outcome measure was overall survival, estimated by the Kaplan-Meier method. RESULTS: Data were obtained for 448 sorafenib-treated patients from 15 hospitals. The median age was 68 years (range 17-89) and 75% had performance status ≤ 1. At baseline, 77% were Child-Pugh A and 16.1% Child-Pugh B; 38% were albumin-bilirubin grade 1 (ALBI-1) and 48% ALBI-2; 23% were Barcelona Clinic Liver Classification B (BCLC-B) and 72% BCLC-C. The median time on sorafenib was 3.6 months, with a mean daily dose of 590 mg. The median overall survival for 448 evaluable sorafenib-treated patients was 8.5 months. There were significant differences in overall survival comparing Child-Pugh A versus Child-Pugh B (9.5 versus 4.6 months), ALBI-1 versus ALBI-2 (12.9 versus 5.9 months) and BCLC-B versus BCLC-C (13.0 versus 8.3 months). For trial-treated patients (n=109), the median overall survival was 8.1 months and this was not significantly different from the sorafenib-treated patients. CONCLUSION: For Child-Pugh A patients with good performance status, survival outcomes were similar to those reported in global randomised controlled trials. Patients with ALBI grade > 1, Child-Pugh B or poor performance status seem to derive limited benefit from sorafenib treatment.

Prognostic impact of extracapsular lymph node involvement after neoadjuvant therapy and oesophagectomy.

BACKGROUND: The significance of extracapsular lymph node involvement (LNI) is unclear in patients with oesophageal cancer who have undergone neoadjuvant treatment followed by oesophagectomy. The aim of this study was to assess the incidence and prognostic significance of extracapsular LNI in a large multicentre series of consecutive patients with oesophageal cancer treated by neoadjuvant chemotherapy or chemoradiotherapy and surgery. METHODS: Data from a consecutive series of patients treated at two European centres were analysed. All patients with squamous cell carcinoma or adenocarcinoma of the oesophagus or gastro-oesophageal junction, who received neoadjuvant chemotherapy or chemoradiation followed by transthoracic oesophagectomy and two-field lymphadenectomy with curative intent, were included. RESULTS: Between January 2000 and September 2013, 704 patients underwent oesophagectomy after neoadjuvant therapy. A median of 28 (range 5-77) nodes per patient was recovered. Some 347 patients (49·3 per cent) had no LNI (ypN0). Of the remaining 357 patients (50·7 per cent) with LNI (ypN1-3), extracapsular LNI was found in 190 (53·2 per cent). Five-year overall survival rates were 62·7 per cent for patients with N0 disease, 44·9 per cent for patients without extracapsular spread and 14·0 per cent where extracapsular LNI was identified (P < 0·001). Multivariable analyses demonstrated the presence of extracapsular LNI as an independent prognostic factor. CONCLUSION: The presence of extracapsular LNI after neoadjuvant therapy carries a poor prognosis.

The impact of neoadjuvant chemotherapy on cardiopulmonary physical fitness in gastro-oesophageal adenocarcinoma.

Introduction Operable oesophagogastric adenocarcinoma management in the UK includes three cycles of neoadjuvant chemotherapy (NAC) followed by resection. Determination of oxygen uptake at the anaerobic threshold (AT) with cardiopulmonary exercise testing (CPET) is used to objectively measure cardiorespiratory reserve. Oxygen uptake at AT predicts perioperative risk, with low values associated with increased morbidity. Previous studies indicate NAC may have a detrimental impact on cardiorespiratory reserve. Methods CPET was completed by 30 patients before and after a standardised NAC protocol. The ventilatory AT was determined using the V-slope method, and the peak oxygen uptake and ventilatory equivalents for carbon dioxide measured. Median AT before and after chemotherapy was compared using a paired Student's t-test. Results Median oxygen uptake at AT pre- and post-NAC was 13.9±3.1 ml/kg/min and 11.5±2.0 ml/kg/min, respectively. The mean decrease was 2.4 ml/kg/min (95% confidence interval [CI] 1.3-3.85; p<0.001). Median peak oxygen delivery also decreased by 2.17 ml/kg/min (95% CI 1.02-3.84; p=0.001) after NAC. Ventilatory equivalents were unchanged. Conclusions This reduction in AT objectively quantifies a decrease in cardiorespiratory reserve after NAC. Patients with lower cardiorespiratory reserve have increased postoperative morbidity and mortality. Preventing this decrease in cardiorespiratory reserve during chemotherapy, or optimising the timing of surgical resection after recovery of AT, may allow perioperative risk-reduction.

Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study.

BACKGROUND: Clinical data showed promising antitumour activity with feasible tolerability for matuzumab plus epirubicin, cisplatin and capecitabine (ECX) chemotherapy in untreated advanced oesophago-gastric (OG) cancer. The aim was to evaluate the efficacy of matuzumab plus ECX versus ECX alone. PATIENTS AND METHODS: In this multicentre, randomised open-label phase II study, 72 patients with metastatic OG cancer were randomly assigned to either 800 mg matuzumab weekly plus epirubicin 50 mg/m², cisplatin 60 mg/m² on day 1 and capecitabine 1250 mg/m² daily in a 21-day cycle (ECX) or the same ECX regimen alone. The primary end point was objective response. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life, safety and tolerability. RESULTS: Following random assignment, 35 patients (median age 59 years) received ECX/matuzumab and 36 patients (median age 64 years) ECX. The addition of matuzumab to ECX did not improve objective response: 31% for ECX/matuzumab [95% confidence interval (CI) 17-49] compared with 58% for the ECX arm (95% CI 41-74) P = 0.994 (one sided). There was no significant difference in median PFS: 4.8 months (95% CI 2.9-8.1) for ECX/matuzumab versus 7.1 months (95% CI 4.4-8.5) for ECX, or in median OS: 9.4 months (95% CI 7.5-16.2), compared with 12.2 months (95% CI 9.8-13.8 months). Grade 3/4 treatment-related toxicity was observed in 27 and 25 patients in the ECX/matuzumab and ECX groups, respectively. CONCLUSION: Matuzumab 800 mg weekly combined with ECX chemotherapy does not increase response or survival for patients with advanced OG cancer. Therefore, ECX/matuzumab should not be examined further in phase III trials.

Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF.

The purpose of the study was to establish the optimal dose of capecitabine (X) to be used within a multicentre, randomised study evaluating the potential roles of oxaliplatin (O) and X in chemonaive patients (pts) with advanced oesophagogastric cancer. Two by two design was used, and pts were randomised to one of four regimens and stratified for extent of disease, performance status (PS) and centre. The treatment regimens are epirubicin, cisplatin, 5-fluorouracil (ECF), EOF, ECX or EOX. Doses: E 50 mg m(-2), C 60 mg m(-2) and O 130 mg m(-2) i.v. 3 weekly; F 200 mg m(-2) day(-1) i.v. and X 500 mg m(-2) b.i.d.(-1) (escalated to 625 mg m(-2) b.i.d.(-1) after results of first interim analysis) p.o., continuously. First interim analysis was performed when 80 pts had been randomised. Dose-limiting fluoropyrimidine toxicities were stomatitis, palmar plantar erythema (PPE) and diarrhoea; 5.1% of X-treated pts experienced grade 3/4 toxicity. Protocol planned dose escalation of X to 625 mg m(-2) b.i.d.(-1) was instituted and a second interim analysis has been performed; results are presented in this paper. A total of 204 pts were randomised at the time of the protocol planned 2nd interim analysis. Grade 3/4 fluoropyrimidine-related toxicity was seen in 13.7% pts receiving F, 8.4% pts receiving X 500 mg m(-2) b.i.d.(-1) and 14.7% pts receiving X 625 mg m(-2) b.i.d.(-1). Combined complete and partial response rates were ECF 31% (95% CI 18.7-46.3), EOF 39% (95% CI 25.9-53.1), ECX 35% (95% CI 21.4-50.3), EOX 48% (95% CI 33.3-62.8). Grade 3/4 fluoropyrimidine toxicity affected 14.7% of pts treated with X 625 mg m(-2) b.i.d.(-1), which is similar to that observed with F, confirming this to be the optimal dose. The replacement of C by O and F by X does not appear to impair efficacy. The trial continues to total accrual of 1000 pts.

Oxaliplatin and capecitabine chemotherapy for advanced colorectal cancer: a single institution's experience.

AIMS: To determine the efficacy of the combination of oxaliplatin and capecitabine in patients with advanced colorectal cancer. MATERIALS AND METHODS: A retrospective review of all patients with advanced colorectal cancer treated with oxaliplatin 130 mg/m2 on day 1 and capecitabine 2 g/m2 daily in two divided doses days 1-14 every 3 weeks, outside of a clinical trial at the Royal Marsden Hospital. Patients could have received any number of lines of previous treatment. RESULTS: Between September 2000 and March 2002, 47 patients were treated with the combination. Fifteen patients had not received previous chemotherapy for advanced disease, 10 had received one line of treatment and 21 had received two or more lines of previous treatment. The overall response rate was 27.6%, with a complete response rate of 2.1%. Overall response rates according to line of treatment were 33% for non pre-treated patients, 36% for second line and 19% for third and more lines. The median overall survival was 13.4 months and the median failure-free survival was 6.5 months. There were no treatment-related deaths and no grade 4 haematological toxicity. CONCLUSIONS: The combination of oxaliplatin and capecitabine is active in advanced colorectal cancer. It can result in down-staging of tumours to enable hepatic resection. In addition, it is a well-tolerated regimen.

Neoadjuvant systemic fluorouracil and mitomycin C prior to synchronous chemoradiation is an effective strategy in locally advanced rectal cancer.

This study was designed to evaluate the benefits of neoadjuvant chemotherapy prior to chemoradiation and surgery in patients with locally advanced rectal cancer. Patients with previously untreated primary rectal cancer, reviewed in a multidisciplinary meeting and considered to have locally advanced disease on the basis of physical examination and imaging (MRI+CT n=30, CT alone n=6), were recruited. Patients received protracted venous infusion 5-FU (300 mg m(-2) day(-1) for 12 weeks) with mitomycin C (MMC) (7 mg m(-2) i.v. bolus every 6 weeks). Starting on week 13, 5-FU was reduced to 200 mg m(-2) day(-1) and concomitant pelvic radiotherapy 45 Gy in 25 fractions was commenced followed by 5.4-9 Gy boost to tumour bed. Surgery was planned 6 weeks after chemoradiation. Postoperatively, patients received 12 weeks of MMC and 5-FU at the same preoperative doses. Between January 99 and August 01, 36 eligible patients were recruited. Median age was 63 years (range=40-85). Following neoadjuvant chemotherapy, radiological tumour response was 27.8% (one CR and nine PRs) and no patient had progressive disease. In addition, 65% of patients had a symptomatic response including improvement in diarrhoea/constipation (59%), reduced rectal bleeding (60%) and diminished pelvic pain/tenesmus (78%). Following chemoradiation, tumour regression occurred in 80.6% (six CRs and 23 PRs; 95% CI=64-91.8%) and only one patient still had an inoperable tumour. R0 resection was achieved in 28 patients (82%). When compared with initial clinical staging, the pathological downstaging rate in T and/or N stage was 73.5% and pathological CR was found in one patient. Neoadjuvant systemic chemotherapy as a prelude to synchronous chemoradiation can be administered with negligible risk of disease progression and produces considerable symptomatic response with associated tumour regression.

Oral idarubicin as a single agent therapy in patients with relapsed or resistant multiple myeloma.

The established treatment for multiple myeloma (MM) comprises induction with infusional chemotherapy, high dose chemotherapy (HDC) and autologous transplantation followed by maintenance interferon. On relapse, patients (pts) are reconsidered for this however some are unsuitable and in this situation the therapeutic options are limited. Between June 1995 and May 1997, 14 pts with previously treated relapsed or refractory MM were recruited. Using a prospective database, the tolerability and efficacy of chronic low dose oral idarubicin was evaluated. The median age of pts was 63 years. All had received previous anthracycline in the form of infusional cVAMP chemotherapy. 11/14 had received previous HDC. Median time from diagnosis to commencing idarubicin was 77 months. 10 mg idarubicin was administered 3 times/week for 3 weeks of a 5 week cycle. The maximum number of courses was 6. Three pts completed 6 courses, 5 pts 3 courses, 2 pts 2 courses and 4 pts 1 course. The reasons for stopping treatment were death due to progressive disease (PD) in 7 pts, persistent thrombocytopenia in 2 pts, PD in 1 pt and 1 pt suffered a cerebral infarction not considered to be related to the idarubicin therapy. Two pts showed evidence of response, neither amounting to a partial response. One had stabilisation of paraprotein with a reduction in bone marrow infiltration (47% to 7% plasma cells), the other had a reduction in bone marrow infiltration after 3 course but an increase after 6 courses. In total forty-one courses of treatment were administered. Grade 3/4 haematological toxicities were noted in a minor fraction of cases and were as follows: anaemia 6/41, neutropenia 10/41 and thrombocytopenia 11/41. Our data therefore shows a minor response in 2/14 (14%) of heavily pretreated patients with MM, without evidence of severe toxicity. It provides the rationale for using oral idarubicin as either single agent or in combination therapy for patients earlier on in their disease course especially if they are unsuitable for standard therapy.