Is glucagonoma of the pancreas a curable disease?

BACKGROUND: Glucagonomas are rare neuroendocrine tumors of the pancreas. Because of its rarity, its natural history is not well understood. AIM: We evaluated the natural history of glucagonomas treated at a tertiary care cancer center. METHODS: A retrospective analysis of 12 patients during 1970 to 2000 was performed. Six patients (50%) had a tumor located in the head of the pancreas. RESULTS: Abdominal pain (83%) and weight loss (75%) were the most common symptoms. Median tumor size was 6 cm (range 0.04-10). Seven patients (58%) had liver metastases. Five patients (42%) underwent curative resection. Overall median survival was 66 mo, and 5-yr overall survival was 66%. Five-yr overall survival was 83% for patients who had resection versus 50% for the non-resected patients (p = 0.04). Patients who were disease-free had a complete resection of the primary tumor and no liver involvement. CONCLUSIONS: Glucagonomas generally present with liver metastases at the time of diagnosis. Cure is only possible if the disease is localized and completely resected.

Outcome of patients with proximal gastric cancer depends on extent of resection and number of resected lymph nodes.

BACKGROUND: Studies have shown that the survival of patients with gastric adenocarcinoma is related to the number of regional lymph nodes with metastases. The probability of identifying node-positive cancers increases with the number of lymph nodes resected and examined. It has been recommended that at least 15 lymph nodes be removed and examined for adequate staging. Prospective randomized studies have shown the lymph node yield is much greater with the D2 resection than the D1. This study evaluated the relative contribution of both the number of resected lymph nodes and the extent of gastric resection (D1/D2) on the outcome of patients with proximal gastric cancer. METHODS: The medical records of 114 patients with adenocarcinoma of the proximal stomach, who underwent a curative gastric resection, were reviewed. Patients were stratified into four groups, i.e., two groups, D1/D1.5 and D2/D2.5, based on the extent of resection, and two groups based on the number of lymph nodes removed, fewer than 15 lymph nodes and 15 or more lymph nodes. Survival was determined by the method of Kaplan-Meier and differences compared by the log-rank test. Multivariate analysis was performed by using the Cox model. RESULTS: The number of resected lymph nodes had no effect on the survival of the group as a whole. A significant improvement in survival was noted for patients with a D2 or greater resection. The median survival of patients with 15 or more lymph nodes resected improved from 25 months to 42 months when treated with an extended resection, (D2 or D2.5). Resection of 15 or more lymph nodes alone, or combined with an extended resection, resulted in a statistically significant improvement in survival for patients in American Joint Committee on Cancer Staging (AJCC) stage II. CONCLUSIONS: Both resection of 15 or more lymph nodes and extended lymphadenectomy contributed to the survival advantage observed in patients with AJCC stage II gastric cancer. The D2 gastric resection prolonged the median survival time and improved the 5-year survival rate for patients with 15 or more resected lymph nodes.

Unexpected cyanosis in the surgical patient.

Benzocaine is a commonly used topical anesthetic present in many over-the-counter preparations. The development of methemoglobinemia, associated with the use of benzocaine, is potentially fatal. Methemoglobinemia remains unresponsive to the administration of oxygen alone and, in fact, results in greater tissue hypoxemia than the usual monitoring techniques indicate. We report two cases of benzocaine-induced methemoglobinemia occurring 3 months apart at the same institution. A brief discussion regarding methemoglobin is presented.

Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group.

Squamous carcinoma of the thoracic esophagus has an extremely poor prognosis. This study, EST-1282, was undertaken by the Eastern Cooperative Oncology Group (ECOG) to determine whether the combined use of 5-fluorouracil (5-FU), mitomycin C, and radiation therapy improved the disease-free survival and overall survival of patients with carcinoma of the esophagus, compared to those who received radiation therapy alone. Two- and 5-year survivals were 12% and 7% in the radiation alone arm and 27% and 9% in the chemoradiation arm. Patients treated with chemoradiation had a longer median survival (14.8 months), compared to patients receiving radiation therapy alone (9.2 months). This difference was statistically significant. The same pattern of survival was noted in almost all subgroups independent of whether surgical resection was performed.

Management of the incidentally discovered adrenal mass or "incidentaloma".

The prevalence of an incidentally discovered adrenal mass or "incidentaloma" by abdominal computerized tomography (CT) scan is 1% to 2%. The majority of patients with incidentalomas do not have clinical manifestations nor require further treatments of their incidentalomas. Thus the goal for their management is two-fold: 1) To identify and treat the hormonally hyperactive adrenal adenoma and the rare adrenal carcinoma, and 2) To avoid creating an iatrogenic disease of medical progress. An adrenal mass > or = 6 cm, excluding metastatic malignant disease, needs to be surgically resected due to the risk for carcinoma. The risk of primary adrenal cancer for a hormonally inactive lesion < or = 3 cm is extremely low and can be safely observed. Treatment for the hormonally inactive lesion between 3 and 6 cm must be individualized, based on age, specific scan characteristics (irregular border, local invasion, metastasis), and clinical status of the patient. All hormonally active adrenal adenomas should be surgically resected. In this article, we review the data to support the above recommendations.

A phase II study of 5-fluorouracil, leucovorin, adriamycin, and cisplatin (FLAP) for metastatic gastric and gastroesophageal junction adenocarcinoma. A Penn Cancer Clinical Trial Group and Roswell Park Cancer Institute Community Oncology Research Program Trial.

A Phase II study was performed to evaluate the activity and toxicity of 5-fluorouracil, leucovorin, Adriamycin, and cisplatin combination chemotherapy (FLAP) in patients with previously untreated advanced gastric and gastroesophageal (GE) junction adenocarcinoma. Forty-two consecutive patients were enrolled to received FLAP in this multi-institutional trial. Response, toxicity, and survival data were noted. Fifteen of 42 (36%) patients demonstrated objective responses, with two complete responses (5%) and 13 partial responses (31%). The median time to disease progression was 17 weeks, and the overall survival duration was 30 weeks. Myelosuppression was significant, requiring dose modifications, but there were no treatment-related deaths. FLAP is an active regimen in the treatment of advanced gastric and GE junction adenocarcinoma. We are presently using this regimen in the neoadjuvant setting in patients with gastric and GE junction cancers.

Survival benefit of extended D2 resection for proximal gastric cancer.

BACKGROUND: The long-term survival of patients with adenocarcinoma of the proximal stomach remains dismal. Despite its increasing frequency and poor prognosis, a general consensus has not been reached on the extent of surgical resection. The significance of extended lymph node dissection (D2 gastrectomy) for the surgical treatment of patients with proximal gastric cancer was evaluated. METHODS: Sixty-two patients who underwent a potentially curative total or proximal gastric resection were retrospectively divided by extent of lymphadenectomy into two groups: the extended resection group (D2,D2.5) and limited resection group (D1,D1.5). Survival rates were estimated by the method of Kaplan and Meier [J Am Stat Assoc 53:457-486, 1958] and the differences compared by the log rank test. Multivariate analysis of prognostic parameters was performed using the Cox proportional hazard model. RESULTS: The median overall survival time for the extended resection group (D2,D2.5) was 34 months compared to 18 months for patients treated by a more limited resection (D1,D1.5). Patients treated with extended resection had an estimated 5-year overall survival rate of 37% compared to 21% for patients treated with limited resection. This difference was statistically significant with a P value of 0.04. The median disease-free interval for the extended resection group was 31 months compared to 17.6 months for patients in the limited resection group. The 5 year disease-free survival rate for both groups was 37% and 17%, respectively (P = 0.09). Extent of lymphadenectomy and stage of disease were found to be independent predictors of overall and cancer-free survival. CONCLUSIONS: Patients treated with an extended lymph node dissection (D2 gastrectomy) were more likely to survive 5 years, had longer disease-free intervals, and prolonged median survival times (particularly patients with T1-3,N0-1,M0 cancers) as compared to those patients treated with a more limited lymph node dissection (D1,D1.5). These differences reached or approached statistical significance.

D2 dissection for gastric cancer.

Theodore Billroth successfully performed the first gastrectomy for cancer in Vienna in 1881. This was the beginning of modern gastric cancer surgery and provided the first real hope for cure from this form of cancer. Gastric cancer is a leading cause of cancer related mortality world wide, particularly in Central and South America, Japan and Korea, and in the Baltic Sea countries. In the United States, the incidence of gastric cancer has been on the decline since the 1930s. In 1996, it was estimated that there were 24,000 new cases of gastric cancer with 80-90% expected to die of their disease. The Japanese Research Society for Gastric Cancer has classified the draining lymph nodes of the stomach and assigned 16 different lymphatic stations. The nodes were then assigned to one of four echelons (N1-N4). Different locations of the cancer within the stomach require different forms of gastric resections. The Japanese have defined four levels of lymph node dissections (D1-D4), where specified lymph nodes from assigned lymphatic stations are dissected for a given type of resection. This was defined by the General Rules for the Gastric Cancer Study in Surgery and Pathology by the Japanese Research Society for Gastric Cancer in 1962 and revised in 1994. When a tumor has progressed to the muscularis propria or subserosa (T2), 8-31% of the second echelon lymph nodes (N2) will contain metastases. When a tumor has penetrated the serosa (T3), more than 40% of the second echelon lymph nodes will have metastases. Therefore, less than a D2 dissection will inadequately stage a significant population of patients. When retrospective series are reviewed at institutions committed to performing D2 dissections, the overall survival repeatedly shows improved results for patients undergoing D2 dissections when compared to D1 dissections. Moreover, there have been several large trials from all areas of the world which have shown similar morbidity and mortality results when D1 and D2 dissections have been compared. To date, there have been no trials which have been reproducible that have shown an improved survival in patients receiving adjuvant chemotherapy. Intergroup 0116 is currently studying the use of adjuvant radiation therapy in gastric cancer. We have not come far from the days of Theodore Billroth in the treatment modalities for gastric cancer. As surgical expertise and technology have improved, and the field of anesthesia has developed, survival of patients has improved. Only the extent of lymphatic dissection (D2 dissection) has proven beneficial to the outcomes of patients with this disease.

Phase II study of ZD1694 in patients with advanced gastric cancer.

ZD1694 (Tomudex), a quinazoline folate analogue, is a potent and selective thymidylate synthase inhibitor. A phase II trial was undertaken to determine the efficacy and toxicity of ZD1694 in patients with advanced, measurable gastric adenocarcinoma. ZD1694, 3.0 mg/m2, was administered as a 15 min intravenous infusion every three weeks. Tumor measurements were obtained for response assessment every six weeks. Clinical examinations, adverse event assessments, and clinical laboratory tests were performed every three weeks. Thirty-three patients were enrolled. There were no objective responses to ZD1694. In general, treatment was well-tolerated. Grade 3 and 4 toxicities were infrequent, and included mucositis, nausea and vomiting, leukopenia, thrombocytopenia, and elevations of liver enzymes. Mild to moderate asthenia was common. Toxicities with ZD1694 were reversible and manageable. In conclusion, ZD1694 has an acceptable toxicity profile but shows no antitumor activity in patients with advanced gastric cancer.

Granulocyte-macrophage colony-stimulating factor as infection prophylaxis in high-risk oncologic surgery.

BACKGROUND: A method of augmenting host defenses against bacterial pathogens could result in a decrease in postoperative infections. Given its effects on leukocyte proliferation and function, it is possible that prophylactic granulocyte-macrophage colony-stimulating factor (GM-CSF) could reduce the incidence and severity of infections in high-risk surgical patients. The current study was undertaken to determine the safety and hematologic effects of perioperative GM-CSF. METHODS: Cancer patients undergoing operations with a high risk of postoperative infection were treated perioperatively for 10 days with subcutaneous GM-CSF. Cohorts were treated with GM-CSF at 125 micrograms/m2/day (12 patients) and 250 micrograms/m2/day (11 patients). RESULTS: There were no severe or life-threatening toxicities associated with GM-CSF. Mean maximum neutrophil counts during the first 5 postoperative days were 16.3 +/- 9.14 and 24.5 +/- 7.60 at 125 and 250 micrograms/m2, respectively (P = 0.04). Only one wound infection was diagnosed during this study. CONCLUSIONS: GM-CSF may be safely administered perioperatively at doses that augment neutrophil number and function. An ongoing randomized clinical trial will determine the impact of GM-CSF on postoperative infection.

Phase II trial of ZD1694 (Tomudex) in patients with advanced pancreatic cancer.

BACKGROUND: Currently available therapies for advanced pancreatic cancer offer only palliative benefits, and patients with this disease have a poor prognosis. We undertook a phase II trial of ZD1694 (Tomudex), a quinazoline folate analogue that is a potent and selective thymidylate synthase inhibitor, to determine this analogue's efficacy and safety in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: ZD1694, 3.0 mg/m2, was administered to 42 adult patients with pancreatic adenocarcinoma as a 15-minute intravenous infusion every 3 weeks for up to 6 doses. Objective tumor response was assessed every 6 weeks; clinical examinations, adverse event assessments, and clinical laboratory tests were performed every 3 weeks. RESULTS: ZD1694 produced an overall response rate of 5% (95% confidence limits [CI], 1% to 16%) in the study group. Of 42 patients, 2 (5%) had a partial response, 12 (29%) had stable disease, 21 (50%) had disease progression, and 5 (11%) could not be evaluated for response. Grade 3 vomiting, grades 3 and 4 fever, grade 3 leukopenia, grade 4 thrombocytopenia, and grades 3 and 4 liver function elevations were reported. Toxic effects with ZD1694 were reversible and manageable. CONCLUSIONS: ZD1694 has an acceptable safety profile but limited activity in patients with advanced pancreatic cancer.

Phase II trial of etoposide, doxorubicin, and cisplatin combination in advanced measurable gastric cancer. An Eastern Cooperative Oncology Group study.

A phase II study was performed to determine the efficacy and toxicity of the etoposide, doxorubicin, cisplatin (EAP) regimen in the treatment of patients with advanced measurable gastric cancer in a multi-institutional cooperative group setting. Thirty-one evaluable patients with advanced measurable gastric adenocarcinoma were treated with etoposide 120 mg/m2 on days 3, 4, and 5, doxorubicin 20 mg/m2 on days 1 and 8, and cisplatin 40 mg/m2 on days 2 and 9. The treatment was repeated every 28 days. Objective responses were seen in 7 (23%) patients, all achieving partial remissions. Median survival was 9 months for the entire group. Toxicity was mostly hematologic, with grade 3 leukopenia in 26% and grade 4 leukopenia in 55% of the patients. There were 4 treatment-related deaths that were attributable to severe leukopenia and sepsis. Because of the high toxicity and moderate response rate, this regimen is not superior to other less toxic regimens and cannot be recommended for the treatment of advanced gastric cancer outside of an investigational protocol.

The effect of extended lymphadenectomy on survival in patients with gastric adenocarcinoma.

BACKGROUND: In the United States of America, the five-year survival rate among patients surviving curative resection for gastric carcinoma will range between 20 and 25 percent. In Japan, early diagnosis and an aggressive surgical approach including planned lymph node dissection has resulted in the five-year survival rate exceeding 50 percent for all patients with newly diagnosed gastric carcinoma. This report is a retrospective review evaluating the effect of extended lymph node dissection (D2) on overall survival in 101 patients with gastric adenocarcinoma who underwent a potentially curative gastric resection from 1975 to 1990 at Roswell Park Cancer Institute. STUDY DESIGN: Gastric carcinomas were staged according to the revised 1987 TNM classification. Lymph node dissections were defined according to the General Rules of the Japanese Research Society for Gastric Cancer. Gastric resections in this study were classified as D2.5, D2, D1.5, and D1 and divided into two groups, the extended resection group (D2, D2.5) and the limited resection group (D1, D1.5). RESULTS: The median follow-up period was 33 months. The entire group (n = 101) had an estimated five-year survival rate of 36 percent with a median survival rate of 33 months. The estimated five-year survival rate for the extended resection group (n = 46) was 49 percent with a median of 50 months compared with 27 percent and 25.7 months, respectively, for the limited resection group (n = 55, p = 0.01). Following extended resection, 74 percent of patients with stage I gastric carcinoma survived five years, 75 percent of patients with stage II carcinoma were alive at five years as were 13 percent with stage IIIA, and 30 percent with stage IIIB. Patients whose tumors fell into the classifications of T2-4, N0-1, M0 and required a total or proximal gastrectomy enjoyed a significant survival advantage undergoing an extended resection, with 44 percent surviving five years with a median of 43 months compared with 16 percent and 25 months, respectively, for patients undergoing a limited resection (p = 0.05). Of 13 patients treated with a D2 or greater resection whose gastric carcinomas metastasized to N2 lymph nodes, four patients (31 percent) survived at least five years. Only the extent of lymph node dissection and type of gastric resection proved to be significant independent predictors of overall survival. CONCLUSIONS: Patients treated by extended resection (D2, D2.5) were more likely to survive five years and had prolonged median survival times when compared with patients treated with limited resection (D1, D1.5). For patients with T2-4, N0-1, M0 gastric carcinomas treated with extended resection, their differences reached levels at or approaching statistical significance.