Impact of postoperative complications on disease recurrence and long-term survival following oesophagogastric cancer resection.

BACKGROUND: Postoperative complications after resection of oesophagogastric carcinoma can result in considerable early morbidity and mortality. However, the long-term effects on survival are less clear. METHODS: All patients undergoing intentionally curative resection for oesophageal or gastric cancer between 2006 and 2016 were selected from an institutional database. Patients were categorized by complication severity according to the Clavien-Dindo classification (grades 0-V). Complications were defined according to an international consensus statement. The effect of leak and severe non-leak-related complications on overall survival, recurrence and disease-free survival was assessed using Kaplan-Meier analyses to evaluate differences between groups. All factors significantly associated with survival in univariable analysis were entered into a Cox multivariable regression model with stepwise elimination. RESULTS: Some 1100 patients were included, with a median age of 69 (range 28-92) years; 48·1 per cent had stage III disease and cancer recurred in 428 patients (38·9 per cent). Complications of grade III or higher occurred in 244 patients (22·2 per cent). The most common complications were pulmonary (29·9 per cent), with a 13·0 per cent incidence of pneumonia. Rates of atrial dysrhythmia and anastomotic leak were 10·0 and 9·6 per cent respectively. Patients with a grade III-IV leak did not have significantly reduced overall survival compared with those who had grade 0-I complications. However, patients with grade III-IV non-leak-related complications had reduced median overall survival (19·7 versus 42·7 months; P < 0·001) and disease-free survival (18·4 versus 36·4 months; P < 0·001). Cox regression analysis identified age, tumour stage, resection margin and grade III-IV non-leak-related complications as independent predictors of poor overall and disease-free survival. CONCLUSION: Beyond the acute postoperative period, anastomotic leak does not adversely affect survival, however, other severe postoperative complications do reduce long-term overall and disease-free survival.

Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma.

BACKGROUND: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma. METHODS: A questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Records of consecutive patients undergoing oesophagogastric resection at seven centres between January 2000 and December 2013 were reviewed. Pathological response to neoadjuvant chemotherapy was assessed using the Mandard Tumour Regression Grade (TRG) and lymph node downstaging. RESULTS: TRG (8 of 11 centres) was the most widely used system to assess response to neoadjuvant chemotherapy, but there was discordance on how it was used in practice. Of 1392 patients, 1293 had TRG assessment; data were available for clinical and pathological nodal status (cN and pN) in 981 patients, and TRG, cN and pN in 885. There was a significant difference in survival between responders (TRG 1-2; median overall survival (OS) not reached) and non-responders (TRG 3-5; median OS 2·22 (95 per cent c.i. 1·94 to 2·51) years; P < 0·001); the hazard ratio was 2·46 (95 per cent c.i. 1·22 to 4·95; P = 0·012). Among local non-responders, the presence of lymph node downstaging was associated with significantly improved OS compared with that of patients without lymph node downstaging (median OS not reached versus 1·92 (1·68 to 2·16) years; P < 0·001). CONCLUSION: A clinically meaningful local response to neoadjuvant chemotherapy was restricted to the small minority of patients (14·8 per cent) with TRG 1-2. Among local non-responders, a subset of patients (21·3 per cent) derived benefit from neoadjuvant chemotherapy by lymph node downstaging and their survival mirrored that of local responders.

Analysis of lymphatic and blood vessel invasion biomarkers in T1 esophagogastric adenocarcinomas for improved patient prognostication.

Lymphovascular invasion (LVI) in T1 esophagogastric adenocarcinoma may predict risk of recurrence despite definitive treatment with surgery or endoscopic resection. Podoplanin and CD34 are emerging biomarkers of lymphatic and blood vessel invasion, respectively, and could be adopted to refine LVI assessment. A consecutive series of 65 patients with T1 adenocarcinomas diagnosed at Nottingham University Hospitals were investigated. T1 tumors from 43/65 patients who received primary surgery only were suitable for LVI evaluation by hematoxylin and eosin (H&E) staining as well as by CD34 and Podoplanin immunohistochemistry. LVI was correlated to clinicopathological features and recurrence free survival. H&E staining detected LVI in 11.6% (5/43) of T1 tumors. CD34 and Podoplanin immunohistochemistry significantly improved LVI detection to 25.6% (11/43). Compared with LVI by H&E, immunohistochemical evaluation of blood vessel invasion (CD34) or lymphatic vessel invasion (Podoplanin) was significantly associated with higher grade (P = 0.005), submucosal invasion (T1b) (P = 0.018), lymph node positivity (N1) (P = 0.029) and poor recurrence free survival (P = 0.0003). Our study provides evidence that CD34 and Podoplanin immunohistochemistry could improve LVI detection and allow better prognostication of patients and optimum selection of definitive treatment. Larger multicenter studies are required for further validation that could have significant clinical implications.

Venous thromboembolism in patients receiving perioperative chemotherapy for esophagogastric cancer.

The association between venous thromboembolism and chemotherapy for esophagogastric cancer is well known in patients treated with palliative intent. Whether this risk extends to the neoadjuvant and perioperative setting is unclear. A retrospective interrogation of databases of patients receiving perioperative chemotherapy for potentially curative intent at the Leicester (2006-2011) and Nottingham (2004-2011) esophagogastric cancer centers was performed. Thromboembolic events were diagnosed in 48 of 384 patients (12.5%), 21 (5.5%) at presentation, 12 (3%) during neoadjuvant chemotherapy, and 15 (3.9%) in the postoperative period. There were no deaths from thromboembolic disease. By site these comprised catheter-related axillary vein thrombosis in 7 patients, deep venous thrombosis in 12 patients, and pulmonary embolism in 29 patients. Twenty-five of the 29 pulmonary emboli were incidental findings on staging computed tomography imaging. Combination chemotherapy with epirubicin, cisplatin, and capecitabine appeared to carry the greatest risk for the development of thromboembolism. Seven of the 12 patients (58%) who developed thromboembolism during neoadjuvant chemotherapy did not proceed to surgery because of deterioration in performance status. Preoperative thromboembolic disease resulted in a significant increase in the interval between chemotherapy and surgery, but did not influence either length of hospital stay or survival. Venous thromboembolism will develop in 12.5% of patients treated with potentially curative intent. This adverse event can occur at any time during the patient journey. In contrast to the commonly held view, this did not translate into a poorer prognosis.

Deterioration in quality of life (QoL) in patients with malignant ascites: results from a phase II/III study comparing paracentesis plus catumaxomab with paracentesis alone.

BACKGROUND: Malignant ascites (MA) is associated with poor prognosis and limited palliative therapeutic options. Therefore, quality of life (QoL) assessment is of particular importance to demonstrate new treatment value. Following the demonstration of the superiority of catumaxomab and paracentesis over paracentesis on puncture-free survival, this analysis aimed at comparing deterioration in QoL between both the treatment options. PATIENTS AND METHODS: In a randomised, multicentre, phase II/III study of patients with MA due to epithelial cell adhesion molecule (EpCAM) positive cancer, the QoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items (EORTC QLQ-C30) questionnaire at screening, 1, 3 and 7 months after treatment and in the case of re-puncture on the day of paracentesis. Time to first deterioration in QoL was defined as a decrease in the QoL score of at least five points and compared between the catumaxomab (n=160) and control (n=85) groups using the log-rank test and Cox proportional hazards models adjusted for baseline score, country and primary tumour type. RESULTS: Deterioration in QoL scores appeared more rapidly in the control than in the catumaxomab group (median 19-26 days versus 47-49 days). The difference in time to deterioration in QoL between the groups was statistically significant for all scores (P<0.01). The hazard ratios ranged from 0.08 to 0.24 (P<0.01). CONCLUSIONS: Treatment with catumaxomab delayed deterioration in QoL in patients with MA. Compared with paracentesis alone, catumaxomab enabled patients to benefit from better QoL for a prolonged survival period.

MAGIC in practice: experience of peri-operative ECF/X chemotherapy in gastro-esophageal adenocarcinomas.

BACKGROUND: The MAGIC trial demonstrated the perioperative regimen of Epirubicin (E), Cisplatin (C) and 5-Fluorouracil (F) to have an overall survival benefit for patients with gastro-esophageal adenocarcinomas. We present our experience of the peri-operative regimen of ECF/ECX(X = Capecitabine) in operable gastro-esophageal adenocarcinoma. METHODS: Analysis of retrospective data of patients treated with MAGIC style therapy between May 2006 and August 2008 with potentially operable gastro-esophageal adenocarcinoma. RESULTS: One hundred patients underwent peri-operative chemotherapy according to the MAGIC protocol. Median age was 66 years, with 39% above the age of 70 years. The tumours were evenly distributed between the lower esophagus, gastro-esophageal junction and stomach. Seventy-nine percent completed all pre-operative cycles of chemotherapy and 81% proceeded to surgery, whilst 24% did not receive curative surgery. The median survival on an intention to treat analysis is 31.7 months from diagnosis. The median survival of patients who underwent resection has not yet been reached after a median follow-up of 41.4 months. CONCLUSION: Our patient population is older than the patients in the MAGIC trial (age 66 years vs. 62 years) with a much higher proportion of esophageal and GEJ tumours. Overall, curative resection rate was comparable to the MAGIC trial. Overall survival is superior to that found in the MAGIC trial.

Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy.

AIMS: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response. METHODS AND RESULTS: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry. In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P=0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P=0.006) and was associated with poor disease-specific (P=0.020) and overall survival (P=0.040). CONCLUSIONS: We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy.

Biomarkers of response to therapy in oesophago-gastric cancer.

Cancer of the oesophagus, gastro-oesophageal junction (GOJ) and stomach remains a major health problem worldwide. The evidence base for the optimal management of patients with operable oesophago-gastric cancer is evolving. Accepted approaches include preoperative chemotherapy followed by surgery (oesophageal cancer), chemo-radiotherapy alone (oesophageal cancer) and perioperative chemotherapy (gastric and gastro-oesophageal adenocarcinomas). The underlying principles behind neoadjuvant therapy are to improve resectability of the tumour by tumour shrinkage/downstaging and to treat occult metastatic disease as early as possible. The response rate to cytotoxic therapy is about 40% in oesophago-gastric cancer. Available evidence suggests that a favourable histopathological response to cytotoxic therapy may be a useful positive predictive marker in oesophago-gastric cancer. However, the ability to predict tumour response in routine clinical practice is difficult and is an area of intense investigation. There is evolving evidence for the role of predictive biomarkers in cancer in general and oesophago-gastric cancer in particular. We provide an overview on the current status of radiological and biological predictive biomarkers. We have focussed on clinical translational investigations and, where appropriate, provided pre-clinical insights. Whether predictive markers will be routinely incorporated in clinical practice remains to be seen as biomarker research is expensive and the data generated from these investigations are complex. It is clear that a concerted international effort between academia and industry is critical if personalised medicine as a practical reality for our cancer patients is to be realised.

Adjuvant statin therapy for oesophageal adenocarcinoma: the STAT-ROC feasibility study.

BACKGROUND: Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT. METHODS: For this multicentre, double-blind, parallel-group, randomized, placebo-controlled feasibility trial, adults with OAC (including Siewert I-II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival. RESULTS: A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26·7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low-density lipoprotein cholesterol levels by 3 months (adjusted mean difference -0·83 (95 per cent c.i. -1·4 to -0·22) mmol/l; P = 0·009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow-up. Adverse events were similar between the groups. Quality-of-life data were complete for 98·3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non-randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise. CONCLUSION: This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (www.isrctn/com).

ANTECEDENTES: Las estatinas inhiben las señalizaciones proliferativas en el adenocarcinoma de esófago (oesophageal adenocarcinoma, OAC) y su uso se asocia con mejor supervivencia en estudios observacionales. El presente estudio se llevó a cabo para examinar la viabilidad de evaluar el tratamiento adyuvante con estatinas en pacientes con OAC operable en un ensayo aleatorizado y controlado de fase III. MÉTODOS: En este ensayo de viabilidad controlado por placebo, aleatorizado, de grupos paralelos, doble ciego y multicéntrico, los pacientes adultos con OAC (incluyendo lesiones Siewert I/II) que fueron sometidos a esofaguectomía se asignaron de forma centralizada (1:1) a tratamiento con simvastatina 40 mg o placebo equivalente mediante aleatorización en bloques, estratificados por centro. Los participantes, los clínicos y los investigadores desconocían la asignación del tratamiento. Los pacientes recibieron el tratamiento hasta un año. Los resultados de viabilidad fueron reclutamiento, retención, absorción del fármaco, adherencia, seguridad, calidad de vida, generalización, y supervivencia. RESULTADOS: Un total de 120 pacientes fueron evaluados para elegibilidad en 4 centros, de los cuales 32 (26,7%) fueron aleatorizados, 16 en cada grupo. Siete pacientes abandonaron el ensayo. Los pacientes asignados a tratamiento con simvastatina tenían niveles de colesterol LDL más bajos a los 3 meses (diferencia media ajustada, −0,83 mmol/L, i.c. del 95% −1,4 a −0,22, P = 0,009). La mediana de la adherencia a la medicación fue mayor del 90% entre los 3-12 meses de seguimiento. Los eventos adversos fueron similares entre los grupos. Los datos de calidad de vida estaban completos en el 98,3% de las preguntas del cuestionario. Enfermedad cardiovascular, diabetes y uso de aspirina eran más prevalentes en el grupo no aleatorizado, mientras que la localización del tumor, el estadio y el grado fueron similares entre los grupos. Las estimaciones de supervivencia fueron imprecisas. CONCLUSIÓN: Este RCT apoya la realización e informa de las consideraciones de diseño para un futuro ensayo de fase III de tratamiento adyuvante con estatinas en pacientes con OAC.

The role of staging laparoscopy in oesophagogastric cancers.

AIMS: Selection of patients for treatment of oesophagogastric cancers rests on accurate staging. Laparoscopy has become a safe and effective staging tool in upper gastrointestinal cancers because of its ability to detect small peritoneal and liver metastases missed by imaging techniques. The aim of this study was to evaluate the role of staging laparoscopy (SL) in determining resectability of oesophagogastric cancers. METHODS: A review of 511 patients with oesophagogastric cancers referred to our centre during a 7-year period was performed. Four hundred and sixteen of them assessed to have resectable tumours after preoperative staging with CT and/or ultrasound underwent SL. The main outcome measure was the number of patients in whom laparoscopy changed treatment decision. RESULTS: Staging laparoscopy changed treatment decision in 84 cases (20.2%): locally advanced disease in 17, extensive lymph node disease in four and distant metastases (liver and peritoneum) in 63 cases. The sensitivity of laparoscopy for resectability was 88%. Eighty-one percent of patients who had combined CT scan and EUS were resectable at surgery compared with 65% of those who had CT scan alone (statistically significant with P-value<0.05). Of those patients deemed resectable by SL 8.1% were found to be unresectable at laparotomy, 16 with locally advanced disease and 11 with metastases. CONCLUSION: Staging laparoscopy avoided unnecessary laparotomy in 20.2% of our patients and was most useful in adenocarcinoma, distal oesophageal, GOJ and gastric cancers and probably not necessary in lesions of the upper two-third of the oesophagus.

The front-line general surgery consultant as a new model of emergency care.

Introduction Emergency general surgery services in England are undergoing rapid structural change with the aim of improving care. In our centre, the key issues identified were high numbers of admissions, inappropriate referrals, prolonged waiting times, delayed senior input and poor patient satisfaction. A new model was launched in January 2015 to address these issues: the surgical triage unit (STU). This study assesses the success of the new service. Methods All emergency general surgical admissions during a five-month period before introduction of the STU were compared with those of a comparable five-month period after its introduction. Process, clinical and patient experience outcomes were assessed to identify improvement. Results Attendance fell from 3,304 patients in the 2014 cohort to 2,830 in the 2015 cohort. During the 2015 study period, 279 more patients were discharged on the same day. Resource requirement fell by 2,635 bed days (23%). The number of true surgical emergencies remained consistent. Rates for reattendance (7.8% for 2014 vs 8.1% for 2015) and readmission (5.7% for 2014 vs 5.7% for 2015) showed no significant difference. Patient experience data demonstrated a significant improvement in both net promoter score (64.1 vs 82.2) and number of complaints (34 vs 5). Clinical outcomes for low risk procedures remained similar. Emergency laparotomy in-hospital mortality fell (11.4% vs 10.3%) despite preoperative risk stratification suggesting a risk burden that was significantly higher than the national average. Conclusions This novel model of emergency general surgery provision has improved clinical efficiency, patient satisfaction and outcomes. We encourage other units to consider similar programmes of service improvement.

Postoperative survival following perioperative MAGIC versus neoadjuvant OE02-type chemotherapy in oesophageal adenocarcinoma.

The optimal management of resectable oesophageal adenocarcinoma is controversial, with many centres using neoadjuvant chemotherapy following the Medical Research Council (MRC) oesophageal working group (OE02) trial and the MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. The more intensive MAGIC regimen is used primarily in gastric cancer but some also use it for oesophageal cancer. A database of cancer resections (2001-2013) provided information on survival of patients following either OE02 or MAGIC-type treatment. The data were compared using Kaplan-Meier analysis. Straight-to-surgery patients were also reviewed and divided into an 'early' cohort (2001-2006, OE02 era) and a 'late' cohort (2006-2013, MAGIC era) to estimate changes in survival over time. Subgroup analysis was performed for responders (tumour regression grade [TRG] 1-3) versus non-responders (TRG 4 and 5) and for anatomical site (gastro-oesophageal junction [GOJ] vs oesophagus). An OE02 regimen was used for 97 patients and 275 received a MAGIC regimen. Those in the MAGIC group were of a similar age to those undergoing OE02 chemotherapy but the proportion of oesophageal cancers was higher among MAGIC patients than among those receiving OE02 treatment. MAGIC patients had a significantly lower stage following chemotherapy than OE02 patients and a higher median overall survival although TRG was similar. On subgroup analysis, this survival benefit was maintained for GOJ and oesophageal cancer patients as well as non-responders. Analysis of responders showed no difference between regimens. 'Late' group straight-to-surgery patients were significantly older than those in the 'early' group. Survival, however, was not significantly different for these two cohorts. Although the original MAGIC trial comprised few oesophageal cancer cases, our patients had better survival with MAGIC than with OE02 chemotherapy in all anatomical subgroups, even though there was no significant change in operative survival over the time period in which these patients were treated. The use of the MAGIC regimen should therefore be encouraged in cases of operable oesophagogastric adenocarcinoma.

Inhibition of matrix metalloproteinase activity and growth of gastric adenocarcinoma cells by an angiotensin converting enzyme inhibitor in in vitro and murine models.

INTRODUCTION: Angiotensin converting enzyme (ACE) shares structural homology with the matrix metalloproteinase family of proteolytic enzymes (MMPs) responsible for degradation of the extracellular matrix (ECM). ACE inhibitors have been reported to protect against cancer in patients. The aim of this study was to determine whether the ACE inhibitor, captopril, could impair the activity of MMPs and impact on tumour invasion and growth in a cell line and murine model. METHODS: For proof of principle, the protein activity of human MMP-2 and MMP-9 produced by the HT1080 fibrosarcoma cell line was detected using gelatin zymography. Gene expression was determined by real time reverse transcriptase PCR and tumour cell invasion using Matrigel invasion chambers. The effect of captopril on the in vivo growth of MGLVA-1 human gastric adenocarcinoma xenografts was evaluated in a nude mouse model. RESULTS: Captopril inhibited activity of secreted MMP-9 and MMP-2, however, gene expression in HT1080 remained unaltered. Invasion of HT1080 cells was inhibited by 48% (p<0.001). Tumour size was reduced by 40-50% with 0.4 mg/ml captopril (p<0.01) and when combined with cisplatin the inhibition increased to 71% (p<0.05). DISCUSSION: ACE inhibitors inhibit the activity of secreted MMP-2 and -9 by a mechanism similar to synthetic MMP inhibitors. ACE inhibitors have previously been shown to inhibit tumour growth, however; this is the first study to demonstrate inhibition of a human gastric xenograft, both alone and in combination with cisplatin. These results support further investigation into the anticancer effects of ACE inhibitors.

Appendix mass: do we know how to treat it?

INTRODUCTION: The traditional management of appendiceal mass has been an initial conservative approach followed by interval appendicectomy. More recently, the necessity of interval appendicectomy has been questioned by a growing amount of evidence in the surgical literature. The aim of this study was to review the available scientific evidence and to determine how appendiceal masses are currently being managed in the Mid-Trent region by general surgeons. PATIENTS & METHODS: A literature search using Medline, Embase, Cinahl, HMIC and Biosis was carried out. A personal or telephonic survey of all consultants and specialist registrars working in general surgery in the Mid-Trent region (n = 67) was conducted recording their management protocol of 3 different clinical scenarios--a 14-year-old boy, a 29-year-old female and a 68-year-old male. Responses of the questionnaire were entered to a database in Microsoft Access 2000 and analysed. RESULTS: The results showed that there was difference of opinion on the management of appendix mass in either scenario. Appendectomy (interval or emergency) is still practised by 75% of general surgeons in the Mid-Trent region and less that 25% manage asymptomatic appendix mass without interval appendectomy. Additionally, specialist registrars appear more likely not to offer patients interval appendicectomy after successful conservative management (P < 0.05). CONCLUSIONS: At present, there is no agreed consensus on the management of appendiceal mass. There is a need to develop a protocol for the management of this common problem.

Sarcopenia is associated with toxicity in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer.

BACKGROUND: Patients with potentially curative oesophago-gastric cancer typically undergo neo-adjuvant chemotherapy prior to surgery. The majority of anti-cancer drugs have a narrow therapeutic index. The aim of this study was to determine if features of body composition, assessed using computed tomography (CT) scans, may be predictive of dose-limiting toxicity (DLT) in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer. The influence of sarcopenia and DLT on overall survival was also evaluated. METHODS: 89 Patients having potentially curative oesophago-gastric cancer surgery were studied. Patients studied had histologically confirmed oesophago-gastric cancer with no evidence of distant metastasis on pre-operative staging. CT scan was performed in all cases at diagnosis. DLT was defined as toxicity leading to postponement of treatment, a drug dose reduction or definitive interruption of drug administration. RESULTS: DLT occurred in 37 out of 89 patients (41.6%) undergoing chemotherapy. Sarcopenia (odds ratio, 2.95; 95% confidence interval, 1.23-7.09; p = 0.015) was associated with DLT on multivariate analysis. Median overall survival for patients who were sarcopenic was 569 days (IQ range: 357-1230 days) vs. 1013 days (IQ range: 496-1318 days) for patients who were not sarcopenic (p = 0.04). There was no significant difference in overall survival in patients who experienced DLT compared with those that did not (p = 0.665). CONCLUSIONS: Sarcopenia is a significant predictor of DLT in oesophago-gastric cancer patients undergoing neo-adjuvant chemotherapy. These results raise the potential for use of assessment of skeletal muscle mass using CT scans to predict toxicity and individualize chemotherapy dosing.

A pilot study of the safety and effects of the matrix metalloproteinase inhibitor marimastat in gastric cancer.

The aim of this study was to evaluate the safety and tolerability of 4 weeks administration of marimastat, and to seek evidence of biological activity as observed by changes in the endoscopic appearance of the gastric tumours. 35 patients with advanced, inoperable gastric or gastro-oesophageal tumours were recruited. The dose of marimastat was reduced from the starting dose of 50 mg twice daily (6 patients) to 25 mg once daily (29 patients). 31 completed the 28 day study period. Marimastat was generally well tolerated, with the principal treatment-related toxicity being pain and stiffness of the musculoskeletal system. These symptoms occurred more frequently at the higher-dose, and increased to involve a total of 13 patients (37%) with longer-term treatment. The events were usually rapidly reversible on drug discontinuation. 3 patients receiving prolonged treatment experienced more severe symptoms, with the development of skin thickening and contractures in the hands. At endoscopy, 10 patients showed an increased fibrotic cover of the tumour, 8 had decreased haemorrhagic appearance, and in at least 2 cases where comparative tumour histology was assessable, there was evidence of increased stromal fibrotic tissue.

Phase I/II trial of batimastat, a matrix metalloproteinase inhibitor, in patients with malignant ascites.

Matrix metalloproteinases have been shown to be important in tumour invasion and metastasis, and the use of matrix metalloproteinase inhibitors in animal models has suggested that these agents may be useful in the control of malignant disease. This article reports the results of an early clinical trial of batimastat, one of the first generation of metalloproteinase inhibitors, in patients with malignant ascites. The drug was well absorbed via the intraperitoneal route and associated with few side-effects. Furthermore, a response to treatment was seen in about half the evaluable patients with advanced malignant disease. The results suggest that further research on the use of matrix metalloproteinase inhibitors in patients with malignant disease is worthwhile.

Malignant ascites: a 2-year review from a teaching hospital.

In this retrospective review of 164 consecutive patients with malignant ascites it has been shown that ovarian ascites accounts for 28% of the total and is associated with a significantly improved survival compared with other groups (P<0.001). Non-ovarian ascites is associated with a very poor prognosis and many patients in this group are unsuitable for aggressive treatment. In 49% of patients, ascites will be the presenting feature requiring further investigation to ascertain the primary tumour. Thorough investigation of female patients should be performed in order to identify all patients with an ovarian primary so that appropriate chemotherapy can be given. However, thorough investigation in male patients is not justifiable.