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.

Human model of duodenogastro-oesophageal reflux in the development of Barrett's metaplasia.

BACKGROUND: Patients with an intrathoracic oesophagogastrostomy after subtotal oesophagectomy experience profound duodenogastro-oesophageal reflux (DGOR). This study investigated the degree of mucosal injury and histopathological changes in oesophageal squamous epithelium after subtotal oesophagectomy with gastric interposition in relation to the extent of postoperative DGOR. METHODS: Serial endoscopic assessment and systematic biopsy at the oesophagogastric anastomosis was undertaken in 40 patients following curative radical subtotal oesophagectomy and reconstruction with a gastric conduit subjected to a pyloroplasty. Thirty patients subsequently underwent combined 24-h ambulatory pH and bilirubin monitoring. RESULTS: Grade I-III oesophagitis was identified in 14 patients and oesophageal columnar epithelium in 19 patients. Biopsies from columnar regeneration revealed cardiac-type epithelium in ten patients and intestinal metaplasia in nine. Seven patients followed serially showed progression from cardiac-type epithelium to intestinal metaplasia. The incidence of Barrett's metaplasia was similar irrespective of the histological subtype of the resected tumour. Patients with oesophageal columnar epithelium had significantly higher acid (P = 0.015) and bilirubin (P = 0.011) reflux. CONCLUSION: Severe DGOR occurs following subtotal oesophagectomy and provides an environment for the acquisition of Barrett's metaplasia via a sequence of cardiac epithelium and eventual intestinal metaplasia.

Diagnosis and management of a mediastinal leak following radical oesophagectomy.

BACKGROUND: The aim of this study was to evaluate the diagnosis, management and outcome of mediastinal leaks following radical oesophagectomy with a stapled intrathoracic anastomosis. METHODS: Some 291 consecutive patients underwent two-phase subtotal oesophagectomy with gastric interposition for malignancy. Patients with clinical suspicion of a leak were investigated with contrast radiology and flexible upper gastrointestinal endoscopy. RESULTS: Nineteen patients (6.5 per cent) developed a proven mediastinal leak at a median of 8 (range 3-30) days following surgery. Contrast radiology and flexible upper gastrointestinal endoscopy identified that 13 patients had an isolated leak from the oesophagogastric anastomosis and two had widespread leakage secondary to gastrotomy-line dehiscence. Endoscopy revealed a further four patients with gastric necrosis in whom contrast radiology was normal. In six patients the diagnosis of leakage followed an apparently normal routine contrast examination on day 5-8. All 13 isolated anastomotic leaks were managed non-operatively with targeted mediastinal drainage, intravenous antibiotics and antifungal therapy, nasogastric decompression and enteral nutrition; the mortality rate was 15 per cent (two of 13). Patients with gastrotomy dehiscence or gastric necrosis had a more severe clinical picture; they were managed with repeat thoracotomy and either revision of the conduit or resection and exclusion. Despite early intervention four of the six patients died. CONCLUSION: Routine postoperative contrast radiology cannot be recommended. On clinical suspicion of a leak patients require both contrast radiology and endoscopic evaluation. Isolated anastomotic leaks can be managed successfully with non-operative treatment, whereas more extensive leaks from the gastric conduit require revisional surgery which carries a high mortality rate.

The pattern of metastatic lymph node dissemination from adenocarcinoma of the esophagogastric junction.

BACKGROUND: The incidence of adenocarcinoma of the esophagogastric junction is rapidly increasing, and the extent of lymphadenectomy for such tumors remains controversial. The aim of this study was to identify the pattern of dissemination by examination of all lymph nodes retrieved from resected tumors of the esophagogastric junction. METHODS: The endoscopic and pathologic reports of patients who underwent RO resection for adenocarcinoma of the esophagogastric junction between January 1996 and November 1999 were examined. Patients with type 1 tumors (distal esophagus) underwent subtotal esophagectomy with 2-field lymphadenectomy. Patients with type 2 (gastric cardia) tumors underwent transhiatal D2 total gastro-esophagectomy. Lymph node groups were dissected from the main specimens and examined separately. RESULTS: One hundred and four type 1 and 48 type 2 tumors were studied. Median nodal recovery was 23 lymph nodes (type 1, 22 lymph nodes; type 2, 23 lymph nodes). Seventy-eight percent of the type 1 tumors with nodal metastases had dissemination in both the abdomen and mediastinum. The common abdominal sites were the paracardiac and the left gastric stations. Within the mediastinum, paraesophageal, paraaortic and tracheobronchial metastases were more often encountered. Type 2 tumors had positive lymph nodes most frequently in the left and right paracardiac, lesser curve (N1 group), and left gastric (N2 group) territories. Nodal status correlated with increasing depth of tumor invasion (P =.002). CONCLUSIONS: The pattern of nodal dissemination for cardia tumors concurs with that described by other studies. The current definition of nodal fields in the abdomen and mediastinum for esophageal tumors relates to experience with squamous carcinomas. Our results demonstrate a different pattern of dissemination for junctional esophageal adenocarcinomas. The nodal stations to be resected in radical lymphadenectomies for such tumors should be redefined.

Prognostic significance of peri-operative blood transfusion following radical resection for oesophageal carcinoma.

INTRODUCTION: Peri-operative allogeneic blood transfusion may exert an immunomodulatory effect and has been associated with early recurrence and decreased survival following resection for several gastro-intestinal malignancies. The aim of this study was to evaluate the prognostic influence of transfusion requirements following radical oesophagectomy for cancer. METHODS: A consecutive series of 235 patients undergoing subtotal oesophagectomy with two-field lymphadenectomy in a single centre from April 1990 to June 1999 were studied. RESULTS: The median age was 64 years (30-79) with a male to female ratio of 3:1. The predominant histological subtype was adenocarcinoma (n = 154) compared to squamous carcinoma (n = 81). To avoid the influence of surgical complications data were excluded from the 5.5% of patients suffering in-hospital mortality. In the remaining patients, median blood loss was 900 ml (200-5500) with 46% (103/222) requiring transfusion (median 3 units, range 2-21). Median survival of non-transfused patients was 36 months compared to only 19 months for those receiving transfusion (log-rank = 4.44; 1 df, P = 0.0352). Non-transfused patients had significantly higher 2 and 5-year survival rates of 62% and 41% respectively in contrast to only 40% and 25% in those receiving blood transfusion. Even after stratification of results according to disease stage or the presence of major complications, survival was significantly worse in those receiving transfusion. Multivariate analysis demonstrated that in addition to nodal status, > 4 units transfusion was an independent prognostic indicator. CONCLUSION: Post-operative transfusion is associated with a significantly worse prognosis following radical oesophagectomy. Meticulous haemostasis and avoidance of unnecessary transfusion may prove oncologically beneficial.

Pattern of recurrence following radical oesophagectomy with two-field lymphadenectomy.

BACKGROUND: Despite increasingly radical surgery for oesophageal cancer, many patients continue to develop recurrent disease. The aim of this study was to evaluate the pattern of failure following attempted curative oesophagectomy with two-field lymphadenectomy for adenocarcinoma and squamous cell carcinoma of the middle and lower third of the oesophagus. METHODS: A total of 176 consecutive patients discharged from hospital following R0 resection between 1 April 1990 and 31 December 1999 were followed for evidence of recurrence over a mean interval of 26 months. RESULTS: Adenocarcinoma was the predominant histological subtype (n = 113) compared with squamous cell carcinoma (n = 63). Sex and age distribution were similar for both histological subtypes (M:F ratio 2.5:1, median age 64 (range 40-77) years). Overall 2- and 5-year survival rates were 54 and 31 per cent respectively. Some 85 patients (48 per cent) developed proven recurrence, of whom five are alive and 80 dead. The median time to recurrence was 11.7 (range 1. 5-67) months, with a median survival thereafter of only 2.7 (0-25.9) months. The pattern of recurrence was locoregional in 27 per cent (mediastinal 21 per cent and cervical 6 per cent) and distant in 18 per cent (liver 6 per cent, bone 6 per cent, cerebral 2 per cent, peritoneal 2 per cent, lung 1 per cent, skin 1 per cent). There was no difference in the overall pattern of dissemination or timing of recurrence for either histological subtype. Over 50 per cent of all recurrences occurred within 12 months of surgery, with local, regional and distant recurrence occurring at a median of 11.9 (range 1.8-52), 11.0 (range 5-67) and 11.0 (1.5-58) months respectively. CONCLUSION: The low incidence of cervical recurrence suggests that a more extensive 'three-field' lymphadenectomy is unlikely to improve survival rates. Better staging modalities are needed to identify patients who will have recurrence within 12 months of operation, so that they may be either entered into trials of multimodality treatment or offered non-surgical palliation. British Journal of Surgery prize-winning paper, presented to the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, London, UK, September 1999

Percutaneous endoscopic duodenostomy: the relief of obstruction in advanced gastric carcinoma.

Nausea and vomiting in patients with advanced gastric malignancy and mechanical obstruction are distressing and difficult to manage. We describe a patient with linitis plastica and gastric stasis who was treated with a percutaneous endoscopic duodenostomy as the stomach could not be used for percutaneous endoscopic gastrostomy (PEG) formation. A Conflo PEG tube was inserted into the second part of the duodenum using the Ponsky-Gauderer technique without complication. The patient experienced excellent symptomatic relief and tolerated enteral nutrition extremely well, regaining some weight. This manoeuvre can produce effective symptom palliation allowing the patient to be managed at home during the terminal phase of their illness.

Transhiatal approach to total gastrectomy for adenocarcinoma of the gastric cardia.

BACKGROUND: A thoracoabdominal approach has traditionally been described for the resection of tumours of the gastric cardia. The aim of this study was to evaluate a transhiatal approach for resection of cancers of the gastric cardia. METHODS: Twenty consecutive patients undergoing transhiatal gastro-oesophagectomy for cancer of the gastric cardia were studied. Data were collected prospectively with regard to operating time, operative blood loss, intensive care unit (ICU) stay, analgesia use, duration of hospital stay, and pathological details of resection margin clearance and lymph node yield. Results were compared with those of the 20 preceding patients for whom the same prospective information had been recorded following resection via the standard thoracoabdominal approach. RESULTS: The transhiatal approach required a shorter operating time (median 190 (range 105-255) versus 280 (225-330) min; P = 0.004). It resulted in less blood loss (median 405 (180-2000) versus 1000 (420-3200) ml; P = 0.03) and fewer days in the ICU (median 0 (0-31) versus 2 (1-8) days; P = 0.005) despite being performed in an older patient population (median 71 (43-78) versus 63 (59-70) years; P = 0.016). There was no difference in either the lymph node harvest or length or involvement of upper resection margins. CONCLUSION: The transhiatal approach to the resection of tumours at the gastric cardia is a valid and safe alternative to the standard thoracoabdominal technique. This technique avoids thoracotomy and its associated morbidity and is accompanied by reduced blood loss, decreased operating time and a shorter ICU stay.

Incidence and prognostic significance of lymphatic and vascular invasion in radical prostatectomy specimens.

A review of 55 radical prostatectomy specimens from patients with clinically localized carcinoma of the prostate was performed. Blinded review of slides was performed by a single pathologist and urologist. Criteria for invasion were encroachment by tumor of the lymphatic or vascular lumen and evidence of reaction around or in the lymphatic or vascular channel. Notation was made of the degree and location of lymphatic and vascular invasion. All patients had a minimum of 5 years of follow-up. Twenty-one of 55 (38%) patients either had lymphatic or vascular invasion, and seven (13%) had both findings. In the majority of these patients the degree of invasion was rare (71%), while multifocal (19%) and diffuse (10%) involvement were seen less frequently. Nine patients experienced either progression of their tumors or death from disease. Those patients with evidence of lymphatic or vascular invasion had a fourfold greater incidence of progression and or death. However, the presence of lymphatic or vascular invasion was clearly related to both tumor grade and stage, and multivariate statistical analysis demonstrated that its prognostic significance was dependent upon tumor grade.

Results of 6 weekly intravesical bacillus Calmette-Guerin instillations on the treatment of superficial bladder tumors.

We evaluated 104 patients with superficial bladder tumors for response to intravesical bacillus Calmett-Guerin therapy. Patients received 6 weekly intravesical bacillus Calmette-Guerin instillations and they were followed for response every 3 months with urinary cytology, cystoscopy and bladder biopsy. Patients were considered treatment failures if either the cytology studies or biopsies were positive for tumor. Of 65 patients who failed the initial treatment course 57 were given an additional 6-week course of therapy. One 6-week course of bacillus Calmette-Guerin was successful in 20 of 55 patients (36 per cent) treated for prophylaxis, 12 of 32 (37 per cent) treated for carcinoma in situ and 7 of 17 (41 per cent) treated for residual tumor. The response rate for the total patient population treated with 1, 6-week course was 37.5 per cent (39 of 104). A second 6-week course was successful in 19 of 29 patients (65 per cent) treated for prophylaxis, 11 of 18 (71 per cent) treated for carcinoma in situ and 4 of 10 (40 per cent) treated for residual tumor. The response rate for all patients receiving a second course of bacillus Calmette-Guerin was 59.6 per cent (34 of 57). Of 6 patients who refused another 6-week course of bacillus Calmette-Guerin 4 had additional recurrences and 3 of these 4 suffered invasive disease. The over-all therapeutic response rate for patients treated with either 6 or 12 weeks of therapy was 70 per cent. These results suggest that 6 weeks of intravesical bacillus Calmette-Guerin do not provide optimal therapy for superficial bladder tumors. The data further suggest that more intensive regimens may increase therapeutic efficacy.

Single course versus maintenance bacillus Calmette-Guerin therapy for superficial bladder tumors: a prospective, randomized trial.

A total of 42 patients with recurrent superficial bladder tumors or carcinoma in situ entered a prospective, randomized trial to compare the efficacy of bacillus Calmette-Guerin therapy with and without quarterly maintenance instillations of bacillus Calmette-Guerin. Maintenance therapy did not reduce further bladder tumor recurrence rates or the interval to recurrence in patients who responded to the initial course of therapy. However, prolongation of toxicity was observed with maintenance bacillus Calmette-Guerin therapy.

Two courses of intravesical bacillus Calmette-Guerin for transitional cell carcinoma of the bladder.

Bacillus Calmette-Guerin intravesical immunotherapy is becoming the adjunctive treatment of choice for patients with recurrent superficial transitional cell carcinoma of the bladder. The recurrence rates following bacillus Calmette-Guerin therapy reported to date vary widely but generally they fall within the 20 per cent range. The results of retreatment of bacillus Calmette-Guerin failures with a second 6-week course of intravesical bacillus Calmette-Guerin have not been reported previously. We report the response rates of 61 patients treated with a single 6-week course of intravesical bacillus Calmette-Guerin, and 25 patients who failed to respond to the initial course and were treated with a second 6-week course. Intravesical bacillus Calmette-Guerin therapy (120 mg. Pasteur strain) was administered weekly for 6 weeks. No intradermal injections of bacillus Calmette-Guerin were given. Patients were followed with urinary cytology and bladder biopsy every 3 months. Patients with tumor at followup were treated with a second 6-week course of intravesical bacillus Calmette-Guerin. Of 19 patients with carcinoma in situ 8 (42 per cent) responded to the initial course of bacillus Calmette-Guerin, while 5 of 9 (56 per cent) became free of tumor after the second course, for a cumulative response rate of 68 per cent (mean followup 13.5 +/- 2.1 months). Of 13 patients treated for residual papillary tumors 6 (46 per cent) responded to the initial course of bacillus Calmette-Guerin and 3 of 7 (43 per cent) to the subsequent course, providing a cumulative response rate of 69 per cent (mean followup 14.8 +/- 2.8 months). Of 29 patients treated for prophylaxis against tumor recurrence 20 (69 per cent) remained free of tumor after a single 6-week course, while 6 of 9 (67 per cent) were free of tumor after the second treatment course. A 90 per cent cumulative response rate was observed in the prophylaxis category (mean followup 12.8 +/- 1.3 months). Over-all 48 of 61 patients (79 per cent) were observed to respond when all 3 categories and both treatment courses were considered. Individually, the response rate for each 6-week treatment course was 56 per cent (34 of 61 and 14 of 25, respectively). Toxicity for each treatment course was well tolerated and consisted of dysuria/frequency, hematuria and a flu-like syndrome. Toxicity was progressively more severe with prolonged treatment. Retreatment with a second course of bacillus Calmette-Guerin is warranted for patients failing the initial treatment course.(ABSTRACT TRUNCATED AT 400 WORDS)

Prognostic value of purified protein derivative skin test and granuloma formation in patients treated with intravesical bacillus Calmette-Guerin.

We evaluated the prognostic value of purified protein derivative skin test reactivity and a granulomatous response in intravesical bacillus Calmette-Guerin therapy. We treated 62 patients with intravesical bacillus Calmette-Guerin once a week for 6 weeks. Purified protein derivative skin tests were performed before and after therapy. Cold cup bladder biopsies were examined in a blind retrospective manner for the presence of granulomas 6 weeks after completion of therapy. A significant correlation between status free of tumor and the presence of either granulomas or positive purified protein derivative skin tests was observed for the total patient population. Of 25 patients whose purified protein derivative test was converted from negative to positive 19 (77 per cent) remained free of tumor, while only 11 of 32 (34 per cent) whose test did not convert to purified protein derivative positive remained free of tumor (p equals 0.0006, chi-square). Similarly, 28 of 37 patients (77 per cent) who had a granulomatous response remained free of tumor, while only 8 of 25 (32 per cent) without a granulomatous response remained free of tumor (p less than 0.003, chi-square). The correlation was similar for each parameter when the total patient population was subdivided into patients treated for carcinoma in situ, residual tumor or prophylaxis. Calculation of predictive values showed that neither purified protein derivative responsiveness, granuloma formation nor a combination of both provided a highly accurate predictive index of therapeutic response in individual patients. False positive or negative rates, ranging from 23 to 24 per cent and 32 to 39 per cent, respectively, were observed. These results suggest that a link between immunological responsiveness and response to therapy exists but that neither the purified protein derivative skin test nor the granulomatous response exhibits sufficient immunological specificity to serve as accurate prognostic indicators in individual patients.

Nerve-sparing radical prostatectomy: extraprostatic tumor extension and preservation of erectile function.

A total of 52 patients underwent a nerve-sparing radical retropubic prostatectomy for clinical stage A or B prostatic cancer. The incidence of positive surgical margins (18 per cent of the patients with stages A and B1, and 57 per cent with stage B2 disease) was not significantly different (p less than 0.5) from that of 25 patients who underwent a standard radical retropubic prostatectomy by the same surgeon (18 per cent with stages A and B1, and 50 per cent with stage B2 cancer). Of 42 patients who were sexually potent preoperatively 41 (98 per cent) have had partial return of erectile function and 22 (52 per cent) have had return of erections sufficient for vaginal penetration. No correlation between clinical or pathological stage and postoperative potency was observed. Erections sufficient for penetration returned in 67 per cent of the patients less than 60 and 43 per cent of those more than 60 years old. The results suggest that with the nerve-sparing modification of radical retropubic prostatectomy sexual function can be preserved in the majority of patients with clinical stage A or B prostatic cancer without compromising the adequacy of tumor excision.

Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results.

We treated 40 patients with superficial bladder cancer via intravesical bacillus Calmette-Guerin for 1) prophylaxis against tumor recurrence, 2) residual carcinoma or 3) flat carcinoma in situ. A single course of intravesical bacillus Calmette-Guerin therapy was successful in 6 of 11 patients (55 per cent) treated for residual carcinoma and 6 of 12 (50 per cent) treated for carcinoma in situ. Of 17 patients receiving a single course of bacillus Calmette-Guerin for prophylaxis 11 remained free of tumor during short-term followup. A second course of therapy was administered to failures in each treatment category, which resulted in favorable responses in 5 of 6 patients treated for prophylaxis, 2 of 5 treated for residual tumor and 3 of 6 treated for carcinoma in situ. Over-all complete responses were achieved in 16 of 17 patients (94 per cent) treated for prophylaxis, 8 of 11 (73 per cent) for residual carcinoma and 8 of 12 (66 per cent) for carcinoma in situ, with a mean followup from the final treatment of 9.3, 12.3 and 7.9 months, respectively. Favorable results occurred more frequently among patients who exhibited a granulomatous inflammatory response in the bladder and delayed hypersensitivity skin test response to purified protein derivative. Marked variability in viability of bacillus Calmette-Guerin organisms was observed among different lots of bacillus Calmette-Guerin, and a direct relationship was observed between bacillus Calmette-Guerin vaccine viability and therapeutic efficacy. Most patients who failed initial therapy with a low viability lot of bacillus Calmette-Guerin responded favorably to re-treatment with a higher viability lot. The results suggest that the level of viability of each lot of bacillus Calmette-Guerin vaccine should be verified before clinical use.