Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer.

PURPOSE: To assess the efficacy of systemic intravenous-fluorouracil (5-FU) and subcutaneous recombinant human interferon alfa-2b (rIFN alpha-2b) in patients with measurable cancer of the biliary tree. PATIENTS AND METHODS: Thirty-five patients (25 with cholangiocarcinoma and 10 with gallbladder carcinoma) were registered onto this phase II protocol between 1992 and 1995. Patients received a continuous infusion of 750 mg/m2/d of 5-FU on days 1 through 5 through a centrally placed venous catheter and a subcutaneous injection of 5 MU/m2 of rIFN alpha-2b on days 1, 3, and 5. Treatment cycles were repeated every 14 days; one course of therapy included four treatment cycles. Disease status was assessed every 8 weeks. Dosages were lowered for grade III mucositis. Fourteen patients had prior treatment and, before initiating this therapy, 17 patients required decompression of the biliary tree. RESULTS: Eleven of 32 (34%) assessable patients had a partial response. The median time to disease progression was 9.5 months, and the median survival time 12 months. Grade III to IV toxic effects were granulocytopenia (14%), mucositis (20%), diarrhea (9%), and dermatitis (11%). Grade III to IV asthenia and fatigue were observed in 6% of patients. CONCLUSION: Drug tolerance was better among previously untreated patients. To achieve a complete response, additional chemotherapy or radiotherapy should be considered when liver resection or transplantation is not feasible. However, if these results can be reproduced by other investigators, the regimen should be studied for adjuvant treatment of gallbladder carcinoma incidentally identified in patients undergoing cholecystectomy.

Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.

PURPOSE: To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy. RESULTS: Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. CONCLUSION: Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.

Preoperative chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents.

PURPOSE: A recent multicenter study of preoperative chemoradiation and pancreaticoduodenectomy for localized pancreatic adenocarcinoma suggested that biliary stent-related complications are frequent and severe and may prevent the delivery of all components of multimodality therapy in many patients. The present study was designed to evaluate the rates of hepatic toxicity and biliary stent-related complications and to evaluate the impact of this morbidity on the delivery of preoperative chemoradiation for pancreatic cancer at a tertiary care cancer center. PATIENTS AND METHODS: Preoperative chemoradiation was used in 154 patients with resectable pancreatic adenocarcinoma (142 patients, 92%) or other periampullary tumors (12 patients, 8%). Patients were treated with preoperative fluorouracil (115 patients), paclitaxel (37 patients), or gemcitabine (two patients) plus concurrent rapid-fractionation (30 Gy; 123 patients) or standard-fractionation (50.4 Gy; 31 patients) radiation therapy. The incidences of hepatic toxicity and biliary stent-related complications were evaluated during chemoradiation and the immediate 3- to 4-week postchemoradiation preoperative period. RESULTS: Nonoperative biliary decompression was performed in 101 (66%) of 154 patients (endobiliary stent placement in 77 patients and percutaneous transhepatic catheter placement in 24 patients). Stent-related complications (occlusion or migration) occurred in 15 patients. Inpatient hospitalization for antibiotics and stent exchange was necessary in seven of 15 patients (median hospital stay, 3 days). No patient experienced uncontrolled biliary sepsis, hepatic abscess, or stent-related death. CONCLUSION: Preoperative chemoradiation for pancreatic cancer is associated with low rates of hepatic toxicity and biliary stent-related complications. The need for biliary decompression is not a clinically significant concern in the delivery of preoperative therapy to patients with localized pancreatic cancer.

Enhanced staging and all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma.

PURPOSE: Patients with local-regional gastric carcinoma have a low rate of curative resection (R0) because of the advanced stage at diagnosis and suboptimal clinical staging. This study was designed to improve clinical staging with the use of laparoscopy and endoscopic ultrasonography (EUS) and to improve R0 resection rates and tolerance by delivering all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma. PATIENTS AND METHODS: All patients with histologic proof of localized adenocarcinoma of the stomach underwent a staging laparoscopy before registration. EUS was performed when feasible. The intention was to administer up to five courses of preoperative chemotherapy consisting of fluorouracil (500 mg/m(2)/d as a continuous infusion on days 1 through 5 and as a bolus on days 12 and 19), interferon alfa-2b (3 million units subcutaneously three times a week for 3 weeks), and cisplatin (15 mg/m(2)/d as a bolus on days 1 through 5). After chemotherapy, surgery was attempted to remove the primary and regional lymph nodes. Clinical response and EUS staging were correlated with surgical pathology. The feasibility of this approach, resection rates, patient survival, and patterns of failure also were assessed. RESULTS: All 30 patients enrolled were assessed for toxicity, response, and survival. Nineteen men and 11 women were enrolled. The median number of courses delivered per patient was three (range, one to five courses). Fourteen patients (47%) received all five preoperative courses of chemotherapy. The overall clinical response rate was 34%. Twenty-nine patients (97%) underwent attempted resection. Twenty-five (83%) had an R0 resection. Two patients (7%) had no evidence of carcinoma in the surgical specimen, and three had only microscopic carcinoma (>/= 90% necrosis). Posttreatment EUS findings did not correlate well with surgical pathology. The median duration of follow-up was 30 months (range, 5 months to 65+ months). The median survival time for 30 patients, calculated by the Kaplan-Meier method, was 30 months (range, 5 months to 65+ months). There were no cases of grade 4 toxicity. CONCLUSION: It is feasible to administer prolonged preoperative therapy in patients with potentially resectable gastric carcinoma. Enhanced staging with laparoscopy and EUS helped in proper selection of patients and better characterization of the stage.

Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer.

The aim of this study was to test the efficacy of a chemotherapy combination of cisplatin, IFN alpha-2b, doxorubicin, Adriamycin, and 5-fluorouracil (PIAF) as treatment for radiologically measurable cancer of the biliary tree. Forty-one patients (19 gallbladder carcinoma and 22 cholangiocarcinoma) with unresectable, histologically confirmed adenocarcinoma were registered. Starting chemotherapy doses were as follows: cisplatin, 80 mg/m(2) i.v. over 2 h; doxorubicin, 40 mg/m(2) i.v. over 2 h; and 5-fluorouracil, 500 mg/m(2) by continuous infusion daily for 3 days. IFN alpha-2b (5 x 10(6) units/m(2)) was administered s.c. before the cisplatin and daily thereafter for a total of four doses. The overall response rate was 21.1% [95% confidence interval (CI), 10-37]. For cholangiocarcinoma and gallbladder carcinoma patients, the response rates were 9.5% (95% CI, 1-32%) and 35.3% (95% CI, 14-62%), respectively. Overall median survival time was 14 months (95% CI, 9.5-18.5), 18.1 months (95% CI, 12.1-24.1) for the cholangiocarcinoma patients, and 11.5 months (95% CI, 5.9-17.1) for the gallbladder carcinoma patients. This difference was not statistically significant. The most common grade III and IV toxicities were neutropenia (41%), thrombocytopenia (20%), nausea and vomiting (34%), and fatigue (20%). In conclusion, the PIAF combination seemed more active against gallbladder carcinoma than against cholangiocarcinoma but was associated with significant toxicity. Therefore, this regimen cannot be recommended for cholangiocarcinoma, but it may have a role in the treatment of gallbladder carcinoma, particularly among patients who were refractory to higher priority investigational agents.

Detection of mutated c-Ki-ras in the bile of patients with pancreatic cancer.

BACKGROUND: Because treatment of advanced pancreatic cancer is often unsuccessful, early detection is important. Codon 12 c-Ki-ras mutations have been found in 80-90% of pancreatic cancer cases and are a potential early marker for pancreatic cancer, but obtaining tissue or fluid for analysis can be difficult. We therefore evaluated whether mutant c-Ki-ras could be detected in bile samples obtained from pancreatic cancer patients. METHODS: DNA was isolated from bile specimens obtained from 20 patients with pancreatic cancer. The mutant-enriched PCR technique (ME-PCR) was used to amplify and detect point mutations at codon 12 of the c-Ki-ras oncogene. RESULTS: In 17 cases sufficient DNA for amplification was obtained; 14 had mutant c-Ki-ras alleles. Cytological evaluation of the bile was performed in 11 of these cases, but was positive in only two cases; both were positive for codon 12 c-Ki-ras mutations. Of the 9 cytologically negative biliary specimens, ME-PCR was positive in six. CONCLUSIONS: Codon 12 c-Ki-ras mutations can be successfully identified in PCR-amplified DNA from bile samples obtained from patients with advanced pancreatic cancer. This technique may supplement cytologic techniques for diagnosing pancreatic cancer and may be capable of identifying individuals at risk for this disease.

Phase I study of irinotecan and concurrent radiation therapy for upper GI tumors.

Irinotecan (Camptosar) is an active chemotherapeutic agent for lung, gastric, esophageal, and colorectal cancers and a potent radiosensitizer. This phase I study was designed to assess the maximum tolerated dose of weekly irinotecan combined with concurrent radiotherapy for patients with locally advanced, unresectable gastric, gastroesophageal junction, or esophageal cancer. Patients who received previous chemotherapy (excluding irinotecan) or who experienced recurrent cancer after surgery were eligible for this protocol. The total dose of radiation did not exceed 50.4 Gy (28 fractions of 1.8 Gy each). The starting dose level of irinotecan was 30 mg/m2 infused over 90 minutes given weekly for 5 weeks. Subsequent dose levels were increased in 10 mg/m2 increments to 40, 50, 60, and 70 mg/m2. Of 15 patients who have been enrolled to date, all are evaluable for toxicities and 12 for response. Major hematologic toxicities (grade 3/4) were neutropenia, chills, hemorrhage, and anemia. Grade 3/4 gastrointestinal toxicities included nausea, vomiting, dehydration, anorexia, and constipation. Other severe nonhematologic toxicities included fatigue, hypotension, and hypothermia, as well as cardiovascular toxicities. There was no severe diarrhea and no treatment-related deaths. Of the 12 evaluable patients, 7 (58%) responded, including 2 complete responses; 4 (30%) had no change and 1 had progressive disease. Survival ranged from 1 month to 15 months, with a median survival of 8 months. When the total dose of irinotecan given concurrently with radiotherapy was higher than 250 mg/m2, patients experienced significantly more severe grade 3/4 toxicities than with lower doses (P = .04), with no improvement in response rate. It was concluded that weekly doses of irinotecan of up to 60 mg/m2 with concurrent radiotherapy given over 5 weeks was feasible and demonstrated good response. This regimen did not cause severe diarrhea or pneumonitis, but neutropenia and fatigue were major toxicities. The study continues to accrue.

Nutritional aspects of strictures.

Malnutrition is common and often undiagnosed in affected patients, especially those in the hospital, and is associated with impaired organ function, increased morbidity, and prolongation of hospital stay. It should be recognized and treated appropriately, because artificial nutritional support in malnourished patients leads to improvement in nutritional status and clinical outcome. There are multiple methods to provide nutrition, some by simply keeping the esophageal lumen patent, others by providing additional or all nutrients, including enteral and parenteral routes. The enteral route is preferred due to patient acceptance, lesser expense, and lower risk of complications. The addition of specific nutrients over standard diets may add benefit. Preoperative nutrition may reduce the risk of postoperative complications. Lastly, in the terminally ill patient, minimal intervention may be all that is needed to achieve the patient's comfort, perhaps the most important goal.

The wallstent for benign biliary obstruction.

Endoscopic stent placement for biliary strictures is well-established. The majority of biliary strictures, particularly benign, are treated with plastic stents. The role of permanent expandable stents in the treatment of benign biliary strictures is still questionable. When expandable stents are used, it appears that those with a wider mesh have a better long-term response. In this article, the authors present data on the Wallstent for benign biliary strictures.

Intracorporeal lithotripsy in the management of biliary stone disease.

Choledocholithiasis accounts for approximately 4% to 10% of patients with biliary tract disease. The incidence of intrahepatic biliary disease is less common in the Western world and greater in Asian countries. The overwhelming majority of patients are treated by means of peroral endoscopy. In expert hands, standard techniques will clear the biliary tree from stones in approximately 90% of patients. However, 10% will require nonstandard management, including peroral or percutaneous mechanical, electrohydraulic, or laser lithotripsy. Very few patients will necessitate surgical intervention. Following is a review of the current status of intracorporeal lithotripsy, including principles and techniques, peroral and percutaneous applications, and its overall success.

Coated expandable esophageal stents in the treatment of digestive-respiratory fistulas.

BACKGROUND: Malignant digestive-respiratory fistula (DRF) is associated with significant morbidity and mortality. In addition to the other recognized advantages of expandable stents, coated expandable stents can seal off DRF. METHODS: Eight men and five women, mean age 52 yr, with endoscopically and radiographically proven DRF were treated with the coated Wallstent (Schneider). Eleven had dysphagia, 11 postprandial cough, and two required mechanical ventilation. The DRF was proximal in four, mid-esophageal in seven, and distal in two. Two had a normal esophagus and 11 had stricture. RESULTS: Stent placement and DRF obliteration were successful in all. During a median follow-up of 157 days (range 30-423), no recurrent DRF were noted. The median dysphagia score improved from 3.4 to 1.3. Respiratory symptoms were corrected in all. A gastrostomy tube was required in three. The only complications were transient chest pain and foreign body sensation in three patients and constant sensation of belching in one. There was no procedure-related mortality. CONCLUSION: In this small group of patients, the coated Wallstent demonstrated excellent palliation of DRF with minimal morbidity and no mortality.

Use of an expandable Ultraflex stent in the treatment of malignant rectal stricture.

Obstructive colorectal cancer is usually an indication for surgical intervention. For patients with metastatic disease, medical contraindications, or those who refuse surgery, palliation by nonoperative means is necessary. The advent of expandable metallic stents may allow for speedy palliation. We have treated one patient with unresectable colon cancer with a new selfexpanding endoprosthesis made of nitinol (Ultraflex, Microvasive, Watertown, MA, U.S.A.).

Does chemoradiation therapy increase the incidence of complications with self-expanding coated stents in the management of malignant esophageal strictures?

BACKGROUND: Expandable stents offer excellent palliation of malignant dysphagia and digestive-respiratory fistula. There are insufficient data regarding factors that may affect the complication rate of expandable stents, but an association between previous treatment with chemotherapy and/or radiation therapy and stent-related life-threatening complications has been suggested. METHODS: We retrospectively analyzed our data on 60 patients; in all of them, a coated Wallstent had been successfully placed for malignant dysphagia and/or digestive-respiratory fistula. Our objective in this study was to determine the overall complication rate as well as whether previous or ongoing chemoradiation therapy increased the rate of life-threatening complications. RESULTS: Among 21 patients with no previous chemotherapy or radiation therapy, two (9.5%) had life-threatening complications (both had bleeding tumors; blood transfusions were required in two and endoscopic hemostasis in one). Among 39 patients who had had either radiation therapy, chemotherapy, or both, life-threatening complications occurred in three (8%). Two of the three had gastrointestinal bleeding (two received blood transfusions, and one had external radiation therapy), and in the third, an esophageal tear was treated with the stent. There was no procedure- or stent-related mortality in either group. CONCLUSIONS: Palliation of malignant dysphagia or digestive-respiratory fistulas with the coated Wallstent in patients with previous chemotherapy and/or radiation therapy is not associated with an increased risk of life-threatening complications.

Hormonal and pharmacologic regulation of sodium absorption in rabbit cecum in vitro.

The rabbit cecum is a moderately tight epithelium with amiloride-resistant but phenamil-sensitive electrogenic Na absorption. We performed flux and electrical studies under short-circuit conditions in vitro to further characterize the mechanisms of ion transport in cecum in normal and animals pretreated with methylprednisolone (MP) and deoxycorticosterone acetate (DOCA). MP treatment increased Na absorption and decreased tissue conductance. In contrast, DOCA increased Isc but did not significantly alter Na or Cl fluxes. Amiloride analogs with primary specificity for Na channel and Na/H exchanger both inhibited Isc and Na absorption. Ethacrynic acid, but not bumetanide, inhibited Isc. Nystatin and amphotericin B increased Isc. We conclude that: (1) Steroids have a differential effect on cecal ion transport; methylprednisolone increases Na absorption, but DOCA does not. (2) The response to amiloride analogs is different from other electrogenic transport systems, suggesting a distinct mechanism of Na transport in cecum. (3) The effect of ethacrynic acid was unexpected, suggesting an inhibitory response on an alternate transport system. (4) The effects of polyene antibiotics are similar to those found in other tight epithelia. Electrogenic Na absorption in rabbit cecum represents a distinct transport system, significantly different from Na absorptive mechanisms in other segments of the gut.

Gastric cancer after gastric bypass for obesity. Case report.

We describe a patient in whom gastric cancer developed after gastric bypass for morbid obesity. In addition, we review the literature to emphasize the technical problems involved in diagnosing disease in the excluded portion of the stomach.

Appendiceal mucocele: endoscopic appearance.

Appendiceal mucocele is a rare disorder of the vermiform appendix, occurring predominantly in the sixth or seventh decades, and has a distinct female predominance. Very few cases have been reported in the endoscopic literature. We report two patients with appendiceal mucocele, describe and show the colonoscopic appearance of these tumors, and review the literature.

Palliation of malignant dysphagia and fistulae with coated expandable metal stents: experience with 101 patients.

BACKGROUND: Insertion of coated expandable esophageal stents is the preferred endoscopic palliative treatment for malignant dysphagia and digestive-respiratory fistulae. METHODS: One hundred one patients with malignant dysphagia and digestive-respiratory fistulae, 83 due to esophageal cancer and 18 due to metastatic disease, underwent placement of a coated expandable metal stent. Thirteen patients had a digestive-respiratory fistula. The stricture location (99 patients) was proximal in 11, mid in 29, distal in 37, and at the gastroesophageal junction in 24. The endoscopic appearance was exophytic in 80, infiltrative in 19, single ulcer in 1, and normal in 1. The mean stricture length was 6.7 cm. RESULTS: Initial stent placement was successful in 100 patients; a second stent was required in 1. The median dysphagia grade improved from 3.6 to 1.4 and sealing-off of the digestive-respiratory fistula was successful in all cases. The overall complication rate was 37.9%. Life-threatening complications occurred in 7.9%. There were no procedure-related deaths. During a mean follow-up of 201 days, 99 patients died-none from stent-related problems. CONCLUSIONS: This large series confirms the efficacy of the coated metal expandable stent in the palliation of malignant dysphagia and digestive-respiratory fistula with an acceptable complication rate.

Concomitant placement of percutaneous endoscopic gastrostomy and jejunostomy.

Percutaneous endoscopic gastrostomies have gained wide use for long-term enteral nutrition. However, gastroesophageal reflux and aspiration pneumonia have occurred following this procedure. Initial enthusiasm concerning the ability of intrajejunal feeding to negate the risk of aspiration has been challenged by some reports. In this report, a new method is described for concomitant placement of endoscopic gastrostomy and feeding jejunostomy wherein the tip of the feeding jejunostomy is placed at least 40 cm distal to the pylorus while the gastrostomy tube is used for drainage. Twenty critically ill patients underwent the procedure utilizing general or local anesthesia. Sixty-day follow-up showed one uneventful episode of pulmonary aspiration (5%) after retrograde migration of the jejunal tube into the duodenum. All but two patients (90%) tolerated their tube feedings well. This technique can be easily performed with accurate placement of the PEJ tube distal to the pylorus and is associated with minimal risk of aspiration.

Mucinous ductal ectasia: cholangiopancreatographic and endoscopic findings.

Mucinous ductal ectasia (MDE) is an uncommon disease characterized by a patulous duodenal papilla extruding mucus, and a pancreatogram showing dilation with amorphous filling defects, communication of the mass with the pancreatic duct, the mass usually being located in the head of the pancreas. We have recently treated three men and three women, mean age 66 years, with MDE. All had abdominal pain, while 33% had the clinical picture of pancreatic insufficiency. Three patients had recurrent pancreatitis, and three had biliary obstruction. Endoscopic retrograde cholangiopancreatography and imaging studies showed a patulous papilla draining mucus in six, pancreatic duct dilation in six, filling defects in six, and communication between the cystic mass and the pancreatic duct in five. A distinct finding not previously reported was a separate pancreatic and biliary orifice in two. Three patients had cancer, two cases being metastatic and one being found at surgery (not suspected preoperatively). Therapy included endoscopic biliary drainage in two, surgery in three, while one refused surgery. Of the operated patients, two underwent resection, one of whom had benign disease and the other cancer; both patients are doing well 14 and 32 months after surgery, respectively. One patient underwent pancreatojejunostomy without symptomatic relief, and developed cholangitis 18 months after surgery that was successfully treated with endoscopic drainage. The other two patients treated with biliary drainage died one and 13 months later, respectively. We conclude that MDE has characteristic pancreatographic and endoscopic findings, and that it is commonly associated with malignant degeneration. Surgical resection is the treatment of choice, since MDE is premalignant, and surgery may be curative when the malignancy is resectable.