Phase II Trial of Sorafenib in Patients with Chemotherapy Refractory Metastatic Esophageal and Gastroesophageal (GE) Junction Cancer.

PURPOSE: Vascular endothelial growth factor receptor (VEGFR2) directed therapies result in a modest survival benefit for patients with advanced esophageal and gastroesophageal (GE) junction cancer. Platelet-derived growth factor receptor (PDGFR) may contribute to escape from VEGFR2 inhibition. We evaluated the efficacy of sorafenib, a broad spectrum tyrosine kinase inhibitor targeting VEGFR2 and PDGFR as well as RET and RAF1, in patients with metastatic chemotherapy refractory esophageal and GE junction cancer. PATIENTS AND METHODS: This phase II trial of sorafenib 400 mg twice daily enrolled chemotherapy refractory patients with metastatic esophageal and GE junction cancer with primary endpoint of progression-free survival (PFS) rate at two months. Secondary endpoints included overall survival, objective response rate and toxicity. RESULTS: Among 34 patients, 8 week Kaplan-Meier estimated PFS was 61% (90%CI 45 to 73%). Median PFS is 3.6 months (95% CI 1.8 to 3.9 months), with median overall survival OS 9.7 months (95% CI 5.9 to 11.6 months). Grade 3 toxicities were uncommon and included hand foot skin reaction, rash, dehydration and fatigue. One patient (3%) with ongoing complete response and remains on trial for over 5 years. Whole exome sequencing of this tumor revealed mutations in many cancer-associated genes including ARID1A, PIK3CA, and TP53, and focal amplifications of HMGA2 and MET. CONCLUSION: Sorafenib therapy results in disease stabilization and encouraging PFS in patients with refractory esophageal and GE junction cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00917462.

TOPGEAR: a randomised phase III trial of perioperative ECF chemotherapy versus preoperative chemoradiation plus perioperative ECF chemotherapy for resectable gastric cancer (an international, intergroup trial of the AGITG/TROG/EORTC/NCIC CTG).

BACKGROUND: The optimal management of patients with resectable gastric cancer continues to evolve in Western countries. Following publication of the US Intergroup 0116 and UK Medical Research Council MAGIC trials, there are now two standards of care for adjuvant therapy in resectable gastric cancer, at least in the Western world: postoperative chemoradiotherapy and perioperative epirubicin/cisplatin/fluorouracil (ECF) chemotherapy. We hypothesize that adding chemoradiation to standard perioperative ECF chemotherapy will achieve further survival gains. We also believe there are advantages to administering chemoradiation in the preoperative rather than postoperative setting. In this article, we describe the TOPGEAR trial, which is a randomised phase III trial comparing control arm therapy of perioperative ECF chemotherapy with experimental arm therapy of preoperative chemoradiation plus perioperative ECF chemotherapy. METHODS/DESIGN: Eligible patients with resectable adenocarcinoma of the stomach or gastroesophageal junction will be randomized to receive either perioperative chemotherapy alone (3 preoperative and 3 postoperative cycles of ECF) or perioperative chemotherapy plus preoperative chemoradiation. In the chemoradiation arm, patients receive 2 cycles of ECF plus chemoradiation prior to surgery, and then following surgery 3 further cycles of ECF are given. The trial is being conducted in two Parts; Part 1 (phase II component) has recruited 120 patients with the aim of assessing feasibility, safety and preliminary efficacy of preoperative chemoradiation. Part 2 (phase III component) will recruit a further 632 patients to provide a total sample size of 752 patients. The primary endpoint of the phase III trial is overall survival. The trial includes quality of life and biological substudies, as well as a health economic evaluation. In addition, the trial incorporates a rigorous quality assurance program that includes real time central review of radiotherapy plans and central review of surgical technique. DISCUSSION: TOPGEAR is an international, intergroup collaboration led by the Australasian Gastro-Intestinal Trials Group (AGITG), in collaboration with the Trans-Tasman Radiation Oncology Group (TROG), European Organisation for Research and Treatment of Cancer (EORTC) and the NCIC Clinical Trials Group. It addresses a globally significant question that will help inform future international standards for clinical practice in resectable gastric cancer. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000035224 . Registered 30 May 2009.

Effects on heart function of neoadjuvant chemotherapy and chemoradiotherapy in patients with cancer in the esophagus or gastroesophageal junction - a prospective cohort pilot study within a randomized clinical trial.

BACKGROUND: Neoadjuvant therapy for cancer of the esophagus or gastroesophageal (GE)-junction is well established. The pros and cons of chemoradiotherapy and chemotherapy are debated. Chemoradiotherapy might impair cardiac function eliciting postoperative morbidity. The aim of this pilot study was to describe acute changes in left ventricular function following chemoradiotherapy or chemotherapy. METHODS: Patients with esophageal and (GE)-junction cancer enrolled at our center into a multicenter trial comparing neoadjuvant chemoradiotherapy and chemotherapy were eligible. Patients were randomized to receive cisplatin and 5-fluorouracil with or without the addition of 40 Gy radiotherapy prior to surgery. Left ventricular function was evaluated using echocardiography and plasma N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) before and after neoadjuvant treatment. The primary outcome measure was left ventricular global strain (GS). Clinical effects were assessed using repeated exercise tests. Linear mixed models were used to analyze the effects of treatment group, and the interaction between groups. RESULTS: 40 patients participated (chemoradiotherapy, n=17; chemotherapy, n=23). In the chemoradiotherapy group there was no change in left ventricular global strain but mitral annular plane systolic excursion (MAPSE) of the ventricular septum, early diastolic filling velocity (E-velocity), and the ratio of early to late ventricular filling velocities (E/A ratio) decreased significantly (p=0.02, p=0.01, and p=0.03, respectively). No changes were observed in the chemotherapy group. There was a trend towards an interaction effect for MAPSE sept and E (p=0.09 and p=0.09). NT-proBNP increased following chemoradiotherapy (p=0.05) but not after chemotherapy (p>0.99), and there was a trend towards an interaction effect (p=0.07). Working capacity decreased following neoadjuvant treatment (chemoradiotherapy p = 0.001, chemotherapy p=0.03) and was more pronounced after chemoradiotherapy with a trend towards an interaction effect (p=0.10). CONCLUSIONS: Neoadjuvant chemoradiotherapy but not chemotherapy before surgery for cancer of the esophagus or GE-junction seems to induce an acute negative effect on both systolic and diastolic left ventricular function. Future studies on neoadjuvant treatment for esophageal cancer are suggested to add measurements of cardiac function. TRIAL REGISTRATION: Clinical Trials.gov NCT01362127 .

The postoperative component of MAGIC chemotherapy is associated with improved prognosis following surgical resection in gastric and gastrooesophageal junction adenocarcinomas.

AIMS: MAGIC chemotherapy has become the standard of treatment for patients undergoing curative resection for gastric and gastrooesophageal junction (GOJ) cancers. The importance of postoperative component of this regimen is uncertain. The aim of this study was to compare survival and cancer recurrence in patients who have received neoadjuvant and adjuvant chemotherapies according to MAGIC protocol with those patients completing only neoadjuvant chemotherapy. METHODS: 66 patients with gastric and GOJ adenocarcinomas treated with neoadjuvant and adjuvant chemotherapies according to the MAGIC protocol were studied. All patients underwent potentially curative surgical resection. The histological, demographic, and survival data were collected for all patients. RESULTS: The median number of neoadjuvant chemotherapy cycles received was 2 (range 1-3). Thirty-one (47%) patients underwent adjuvant chemotherapy with a median of 2 cycles (range 1-3). Patients who have completed both cycles of chemotherapy had significantly improved survival (P = 0.04). Patients with involved lymph nodes and positive longitudinal resection margins had increased incidence of recurrence (P = 0.02) and poor five-year survival (P = 0.03). CONCLUSIONS: Patients who received both neoadjuvant and adjuvant chemotherapies for gastric and gastro-oesophageal junction tumours have improved outcomes compared to patients who only received neoadjuvant chemotherapy.

Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy.

BACKGROUND: The aim of this study was to evaluate the impact of pathologic complete response (pCR) on outcome in patients with gastric or esophagogastric junction (EGJ) adenocarcinoma after neoadjuvant docetaxel/platin/fluoropyrimidine-based chemotherapy. PATIENTS AND METHODS: Patients received at least one cycle of chemotherapy for potentially operable disease. Pretreatment clinicopathologic factors and pCR were investigated. Disease-free survival (DFS), overall survival (OS) and tumor-related death were correlated with pCR. RESULTS: One hundred twenty patients were included in this analysis. Eighteen patients (15%) achieved a pCR. Tumor localization in the EGJ was identified as the only significant predictor of pCR (P = 0.019). Median follow-up was 41.1 months. Median DFS and OS for all patients were 24.1 and 48.6 months, respectively. Median DFS for patients with a pCR was not reached versus 22.1 months non-pCR patients (hazard ratio, HR 0.38; 3-year DFS: 71.8% and 37.7%, respectively, P = 0.018). While OS was not significantly different, the risk for tumor-related death was significantly lower for pCR patients compared with non-pCR patients (3-year cumulative incidences of 6.4% and 45.4%, respectively, P = 0.009). CONCLUSION: A pCR following preoperative docetaxel/platin/fluoropyrimidine indicates favorable outcome in patients with gastric or EGJ adenocarcinoma. Tumor location in the EGJ is associated with a higher pCR rate.

Postoperative chemoradiotherapy combined with epirubicin-based triplet chemotherapy for locally advanced adenocarcinoma of the stomach or gastroesophageal junction.

BACKGROUND: Due to low tolerance to chemotherapy, the maximum number of cycles of postoperative adjuvant chemotherapy is 4 in adjuvant gastric clinical trials. The aim of this study is to retrospectively evaluate the safety and efficacy of adjuvant epirubicin-based triplet chemotherapy and radiotherapy in the treatment of resected locally advanced stomach or gastroesophageal junction adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: From January 2004 to July 2008, ninety-seven consecutive gastric or gastroesophageal junction adenocarcinoma patients in stages T3-4/N+ were treated with postoperative radiotherapy and chemotherapy. The recommended treatment plan was radical resection followed by 1-2 cycles of adjuvant chemotherapy (ACT), postoperative chemoradiotherapy (CRT), and, finally, 4-5 cycles of ACT. The patients were classified into two groups depending on the number of cycles of ACT: group 1 received 4-6 cycles (n = 59), and group 2 received 0-3 cycles (n = 38). The detailed grouping is as follows: RT alone, 2; RT and CT, 18; concurrent RTCT and CT, 41; and CRT, 36. Of the 97 patients, 77 patients received concurrent therapy (CRT, (5-fluorouracil or capecitabine), and 20 received radiotherapy alone because of patient refusal (n = 15) or treatment toxicity (n = 5). After a median follow-up of 44 months, the 3-year disease free survival(DFS) and overall survival (OS) were 66.5% and 69.5% for group 1 and 45.5% and 50% for group 2, respectively (p = 0.005 and p = 0.024). Multivariate analysis revealed that 4-6 cycles of ACT, lymphovascular invasion, or peritoneal metastasis were independent prognostic factors for disease-free survival or overall survival (p<0.05). CONCLUSIONS/SIGNIFICANCE: This study demonstrates that concurrent chemoradiation with adjuvant epirubicin-based triplet chemotherapy is feasible and tolerable for gastric or gastroesophageal junction carcinoma patients. Patients can benefit from more cycles of ACT.

Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203.

PURPOSE: The combination of sorafenib with chemotherapy is well-tolerated and is associated with encouraging response rates in several malignances. Both docetaxel and cisplatin are active in gastric cancer. A phase II study was conducted to determine the efficacy and toxicity of combined sorafenib, docetaxel, and cisplatin in patients with metastatic or advanced adenocarcinoma of stomach or gastroesophageal junction (GEJ). PATIENTS AND METHODS: Forty-four chemotherapy-naïve patients with Eastern Cooperative Oncology Group performance status 0 or 1, of whom 80% had metastatic disease and two thirds had poorly differentiated gastric or GEJ adenocarcinoma, were enrolled. The treatment regimen was sorafenib 400 mg orally twice a day for 21 days, docetaxel 75 mg/m(2) intravenously on day 1, and cisplatin 75 mg/m(2) intravenously on day 1, repeated every 21 days. The primary end point was response rate to the combination. Toxicity, overall survival, and progression-free survival were assessed as secondary end points. RESULTS: Eighteen of the 44 eligible and treated patients showed partial responses (41%; 90% CI, 28% to 54%). The median progression-free survival was 5.8 months (90% CI, 5.4 to 7.4 months). The median overall survival was 13.6 months (90% CI, 8.6 to 16.1 month). The major toxicity of this regimen was neutropenia, which reached grade 3 to 4 in 64% of patients. One patient experienced hemorrhage at the tumor site. CONCLUSION: The combination of sorafenib, docetaxel, and cisplatin has an encouraging efficacy profile with tolerable toxicity. Additional studies of sorafenib with chemotherapy are warranted in gastric cancer.

A multi-center phase II study of oxaliplatin, irinotecan, and capecitabine in advanced gastric/gastroesophageal junction carcinoma.

BACKGROUND: There is no standard first-line therapy for advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma and the prognosis remains poor. Our institution conducted a phase I study of oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule. The regimen was tolerated; pharmacodynamic studies revealed no drug interactions, and there was one confirmed response in a gastric cancer patient. We performed a phase II trial in advanced gastric and GEJ adenocarcinoma to determine response rate and response duration. METHODS: This was a multi-center single treatment arm study involving six sites. Only prior adjuvant therapy was allowed. Patients had ECOG performance status of 0-2, adequate organ function, and were able to tolerate oral medications. All patients received oxaliplatin 60 mg/m(2) intravenously (IV) and irinotecan 50 mg/m(2) IV weekly times 4 weeks with a 2-week rest period. Capecitabine 450 mg bid orally was received on days 1 through 5 every week for 4 weeks, followed by a 2-week rest. Patients were assessed for response after the first two cycles; response duration, overall survival, and adverse events were also recorded. We estimated an improvement in historical response rate by 30% would have clinical meaning. RESULTS: A total of 39 patients were accrued and all were assessed for toxicity; 30 patients were evaluable for response. The median age was 57.8 years (31-79 years) and 74% were male. Two patients had a complete response, with nine patients achieving a partial response. The total response rate was 28%, with nine patients not evaluable for response. The median response duration was noted at 5.97 months and median overall survival was 8.98 months. There were no grade 5 treatment related events, with all deaths secondary to disease progression. Only five grade 4 events occurred (neutropenia, hyperkalemia, hypokalemia (2), thrombosis/embolism) without grade 4 diarrhea or sensory neuropathy. CONCLUSIONS: Oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule does induce responses in advanced gastric and GEJ adenocarcinoma. However, the total response rate is modest and not an improvement over other regimens.

Cholinergic innervation to the upper esophageal sphincter muscle in the eel, with special reference to drinking behavior.

To elucidate innervation in the upper esophageal sphincter (UES) muscle of the eel, a key muscle in swallowing, repetitive electrical field stimulation (EFS; 30 mA, 40 V, 300 micros, 10 Hz, 10 trains) was employed. Anatomically, the eel UES muscle consists of striated fibers. The EFS-induced contraction of the UES was completely blocked by tetrodotoxin and curare, and abolished in Ca2+ -free Ringer solution. These results suggest that the EFS stimulates nerve fibers specifically and releases acetylcholine as a neurotransmitter. In fact, acetylcholine and carbachol constricted the UES in a concentration-dependent manner. Even after blocking neuronal firing with tetrodotoxin, acetylcholine constricted the UES muscle, suggesting the existence of acetylcholine receptors on the UES muscle cells. Both EFS- and carbachol-evoked contractions of the UES were blocked by curare at a lower concentration than by atropine or hexamethonium, suggesting that the acetylcholine receptor is nicotinic. Even in Ca2+ -free Ringer solution, a direct current stimulus (2 s duration) constricted the UES muscle to an extent similar to that in the presence of Ca2+, indicating that the muscle contraction itself does not need extracellular Ca2+, i.e., the muscle can be constricted by a release of Ca2+ from the sarcoplasmic reticulum.

In vitro studies indicate that acid catalysed generation of N-nitrosocompounds from dietary nitrate will be maximal at the gastro-oesophageal junction and cardia.

BACKGROUND: Dietary nitrate increases saliva nitrite levels and swallowed saliva is the main source of nitrite entering the acidic stomach. In acidic gastric juice, this nitrite can generate potentially carcinogenic N-nitrosocompounds. However, ascorbic acid secreted by the gastric mucosa can prevent nitrosation by converting the nitrite to nitric oxide. METHODS: To study the potential for N-nitrosocompound formation in a model simulating salivary nitrite entering the acidic stomach and the ability of ascorbic acid to inhibit the process. Concentrations of ascorbic acid, total vitamin C, nitrite, nitrosomorpholine, oxygen and nitric oxide were monitored during the experiments. RESULTS: The delivery of nitrite into HCl containing thiocyanate resulted in nitrosation of morpholine, with the rate of nitrosation being greatest at pH 2.5. Under anaerobic conditions, ascorbic acid converted the nitrite to nitric oxide and prevented nitrosation. However, in the presence of dissolved air, the ascorbic acid was ineffective at preventing nitrosation. This was due to the nitric oxide combining with oxygen to reform nitrite and this recycling of nitrite depleting the available ascorbic acid. Further studies indicated that the rate of consumption of ascorbic acid by nitrite added to natural human gastric juice (pH 1.5) was extremely rapid with 200 micromol/l nitrite consumed 500 micromol/l ascorbic acid within 10 s. CONCLUSIONS: The rapid consumption of ascorbic acid in acidic gastric juice by nitrite in swallowed saliva indicates that the potential for acid nitrosation will be maximal at the GO junction and cardia where nitrite first encounters acidic gastric juice. The high incidence of mutagenesis and neoplasia at this anatomical location may be due to acid nitrosation arising from dietary nitrate.

Peppermint oil improves the manometric findings in diffuse esophageal spasm.

BACKGROUND: Diffuse esophageal spasm (DES) is an uncommon condition that results in simultaneous esophageal contractions. Current medical treatment of DES is frequently unsatisfactory. We hypothesized that, as a smooth muscle relaxant, peppermint oil may improve the manometric findings in DES. STUDY: Eight consecutive patients with chest pain or dysphagia and who were found to have DES were enrolled during their diagnostic esophageal manometry. An eight-channel perfusion manometry system was used. Lower esophageal sphincter pressure and contractions of the esophageal body after 10 wet swallows were assessed before and 10 minutes after the ingestion of a solution containing five drops of peppermint oil in 10 mL of water. Each swallow was assessed for duration (seconds), amplitude (mm Hg), and proportion of simultaneous and multiphasic esophageal contractions. RESULTS: Lower esophageal sphincter pressures and contractile pressures and durations in both the upper and lower esophagus were no different before and after the peppermint oil. Peppermint oil completely eliminated simultaneous esophageal contractions in all patients (p < 0.01). The number of multiphasic, spontaneous, and missed contractions also improved. Because normal esophageal contractions are characteristically uniform in appearance, variability of esophageal contractions was compared before and after treatment. The variability of amplitude improved from 33.4 +/- 36.7 to 24.9 +/- 11.0 mm Hg (p < 0.05) after the peppermint oil. The variability for duration improved from 2.02 +/- 1.80 to 1.36 +/- 0.72 seconds (p < 0.01). Two of the eight patients had chest pain that resolved after the peppermint oil. CONCLUSIONS: This data demonstrates that peppermint oil improves the manometric features of DES.

Cholinergic blockade inhibits gastro-oesophageal reflux and transient lower oesophageal sphincter relaxation through a central mechanism.

BACKGROUND: Atropine, an anticholinergic agent with central and peripheral actions, reduces gastro-oesophageal reflux (GOR) in normal subjects and patients with gastro-oesophageal reflux disease (GORD) by inhibiting the frequency of transient lower oesophageal sphincter relaxation (TLOSR). AIMS: To compare the effect of methscopolamine bromide (MSB), a peripherally acting anticholinergic agent, with atropine on the rate and mechanism of GOR in patients with GORD. METHODS: Oesophageal motility and pH were recorded for 120 minutes in 10 patients with GORD who were studied on three separate occasions. For the first two recording periods, either atropine (15 microg/kg bolus, 4 microg/kg/h infusion) or saline were infused intravenously. MSB (5 mg orally, four times daily) was given for three days prior to the third recording period. RESULTS: Atropine significantly reduced basal LOS pressure (12.6 (0.17) mm Hg to 7.9 (0.17) mm Hg), and the number of TLOSR (8.1 (0.56) to 2.8 (0. 55)) and reflux episodes (7.0 (0.63) to 2.0 (0.43)) (p<0.005 for all comparisons). MSB reduced basal LOS pressure (12.6 (0.17) to 8.7 (0. 15) mm Hg, p<0.005), but had no effect on the frequency of TLOSR (8. 1 (0.56) to 7.5 (0.59)) and reflux episodes (7.0 (0.63) to 4.9 (0. 60)) (p>0.05). CONCLUSION: In contrast to atropine, MSB has no effect on the rate of TLOSR or GOR in patients with GORD. Atropine induced inhibition of TLOSR and GOR is most likely mediated through a central cholinergic blockade.

Medical therapy of achalasia: A benefit reserved for few.

BACKGROUND: The rationale for medical therapy of initial achalasia and the results obtained over the last 20 years in our laboratory are presented. METHODS: Achalasic patients were selected as candidates for medical therapy on the basis of the presence of a slight esophageal dilation (<5 cm) on X-rays and a good manometric response to nifedipine administration. These patients were asked to take 10-20 mg of nifedipine sublingually 30-45 min before each meal for 2 weeks. Chronic medical therapy was continued only in those with an 'excellent' or 'good' clinical response to nifedipine and a lack of severe side effects. X-ray controls were planned every 6 months and manometric examination after the first 6 months. RESULTS: Of the 56 patients selected in the above-mentioned manner, 17 had an insufficient clinical response or severe side effects during the initial trial and did not continue medical therapy. Of the 39 patients who started chronic medical treatment, 13 are still on therapy and 26 stopped after an average of 2.8 years: 17 because they underwent dilation or myotomy; 4 for unknown reasons, and 5 apparently recovered. Esophageal manometry was carried out in 4 of the latter patients and revealed that the achalasic motor pattern had been replaced by a near-normal pattern. CONCLUSIONS: We believe that medical treatment of achalasia should be carried out not only in those patients who cannot undergo invasive procedures or do not respond well to them, but also in patients with initial achalasia selected using the above-mentioned criteria, because regression of the disease could take place in some of them.

Adenocarcinoma of the gastro-esophageal junction: CT for monitoring during neoadjuvant chemotherapy.

OBJECTIVE: A clinical study was performed to assess the diagnostic value of spiral CT for evaluation of response during neoadjuvant chemotherapy (CTx) in patients with adenocarcinoma of the gastro-esophageal-junction (GEJ). Results were compared to those of endoscopy. METHODS AND MATERIAL: Twenty-five patients with histologically proven adenocarcinoma of the GEJ scheduled to undergo neoadjuvant CTx were studied. Before CT examination, 1200 ml of a vanilla flavoured paraffin emulsion were applied orally to the fasting patients and 40 mg BuscopanR or 2 mg glucagon were injected i.v. for hypotonia. Iodine (100 ml) was injected automatically (3 ml/s) and the CT scan was started 10 s after complete administration of CM. For response evaluation to CTx, four standardized parameters were measured by two experienced, blinded radiologists. The results were categorized according to the WHO classification of 1981 and compared to those of endoscopy. RESULTS: In 24 of 25 patients endoscopic and computed tomographic response evaluation showed a close correlation (r = 0.96). CONCLUSION: Spiral CT with negative oral contrast agent is a suitable technique for monitoring of GEJ masses. In combination with standardized metric parameters it offers a quantitative response evaluation in patients with GEJ masses during neoadjuvant CTx.

Hypotension induced by haemorrhage impairs lower oesophageal sphincter function.

The effect of haemorrhage-induced hypotension on lower oesophageal sphincter (LOS) tone was studied in 11 adult mongrel dogs. Mean(s.e.m.) blood loss of 760(66) ml, corresponding to 42 per cent of estimated blood volume, was associated with a significant fall in LOS tone (14.2(1.0) versus 7.2(0.6) sphinctometer units, P < 0.002). This was associated with a reduction in mean(s.e.m.) arterial blood pressure (99(7) versus 53(3) mmHg, P < 0.002) and heart rate (113(6) versus 106(5) beats per min, P = 0.06). Group 1 animals (n = 6) received autotransfusion, restoring LOS tone to prehaemorrhage values. Dogs in group 2 (n = 5) were given intravenous erythromycin 4 mg/kg, which also restored LOS tone. This effect was transient, lasting a mean(s.e.m.) of only 67(7) min. Infusion of an equivalent volume of 0.9 per cent saline following cessation of the erythromycin effect restored LOS tone to control values although the animals remained hypotensive. Reduction in LOS tone with haemorrhage may be part of a vagal reflex mediated by myocardial afferent C fibres and may explain the high incidence of pulmonary aspiration in shocked patients.

Medical treatment of esophageal achalasia. Double-blind crossover study with oral nifedipine, verapamil, and placebo.

Calcium channel blockers have been previously shown to decrease lower esophageal sphincter (LES) pressure and improve symptoms in achalasia. We performed a placebo-controlled, double-blind, crossover study to assess the effects of oral nifedipine and verapamil on LES pressure, amplitude of esophageal body contraction, and clinical symptomatology in eight patients with symptomatic achalasia diagnosed by endoscopy, barium swallow, and manometry. Patients were randomized to receive up to 20 mg nifedipine, 160 mg verapamil, or placebo and underwent esophageal manometry before (baseline) and after four weeks on each drug. Diary cards were kept to record and grade symptoms and drug plasma level determinations were correlated with manometric and clinical findings. Both nifedipine and verapamil caused a statistically significant decrease in mean LES pressure, but only nifedipine caused a significant decrease in the amplitude of contractions of the smooth muscle portion of the esophagus. No statistically significant differences in the overall clinical symptomatology were noted with any of the drugs, although some individual improvements in dysphagia and chest pain were noted. We conclude that, despite the reduction in LES pressure and contraction amplitude of the distal esophageal body, oral nifedipine and verapamil do not significantly alter the clinical symptomatology of patients with achalasia.

The role of nifedipine therapy in achalasia: results of a randomized, double-blind, placebo-controlled study.

Utilizing the rationale that the calcium channel blocker nifedipine decreases lower esophageal sphincter pressure, we performed a double-blind, placebo-controlled, crossover trial of sublingual nifedipine in achalasia, a disorder whose treatment depends on reduction in lower esophageal sphincter pressure. Ten patients participated in this trial, completed diaries, underwent manometric determinations of lower esophageal sphincter pressure, and had testing of esophageal emptying rates by a solid-meal radionuclide method. Nifedipine, titrated to a dose of 10-30 mg before meals, was well tolerated. Compared with placebo, nifedipine significantly reduced the frequency of dysphagia, but some symptoms of dysphagia, regurgitation, or nocturnal cough were still present most days. Nifedipine significantly reduced lower esophageal sphincter pressure by 28%, a value approximately one-half that achieved by successful pneumatic dilatation or myotomy. Esophageal emptying rates, as determined by the radionuclide method, were unchanged by nifedipine. We concluded that 1) nifedipine reduces symptoms of achalasia, but substantial symptoms do remain during such therapy; 2) the suboptimal effect results from the limited, although statistically significant, effect of nifedipine on reduction of lower esophageal sphincter pressure; and 3) although we believe that nifedipine may be recommended as treatment for achalasia in the subset of patients whose overall medical condition places them at high risk for forceful dilatation or surgery, it cannot be recommended as a standard alternative to these other modalities.

Effects of nasopharyngeal cocaine or pharyngeal benzocaine on esophageal motility.

The esophageal effect of topical anesthetics applied to the nasopharynx was evaluated. Eight healthy volunteers underwent an esophageal motility study after each of the following: no anesthesia, 5% cocaine solution applied to the nasopharynx, and 20% benzocaine spray applied to the pharynx. Upper esophageal sphincter relaxation was prolonged after use of the 5% cocaine solution. No other significant effects on esophageal motility or pressures were noted.