J. Kirk Martin

The Management of Patients with Advanced Carcinoid Tumors and Islet Cell Carcinomas

Among the rarest of cancers, the gastrointestinal neuroendocrine tumors (islet cell carcinomas and carcinoid tumors) present difficult and complex challenges for individual patient management. When the tumors metastasize, patients have a variety of clinical presentations including manifestations of tumor bulk and bizarre syndromes resulting from massive hormone production. Table 4. SI Units When physicians analyze therapeutic options for patients with metastatic carcinoid tumors or islet cell carcinomas, they should consider the course of the patients malignant disease, the distribution of metastasis, the severity of clinical manifestations, and the relative contributions of the hormonal syndromes and tumor bulk to symptoms and disability. The oncologist must be conservative, because these diseases frequently run an indolent course, allowing years of comfortable life with no treatment whatsoever. However, aggressive approaches may be justified when the patient develops disabling symptoms because tumor debulking or correction of mechanical problems may sometimes provide the patient with additional years of comfortable life. If the patient has a clinically dominant hormonal syndrome and has no imminent threat from tumor bulk, it is frequently possible to produce substantial palliation with minimal therapeutic risk. In earlier years, only patients with gastrinoma could be helped in this manner by the use of histamine-2 blockers (for example, adequate doses of cimetidine or ranitidine or, more recently, omeprazole [Prilosec, Merck and Company, West Point, Pennsylvania]). The development and clinical application of an analog of somatostatin (octreotide; Sandostatin, Sandoz Pharmaceuticals, East Hanover, New Jersey) has provided a novel and frequently highly effective tool for control of almost all the endocrine syndromes. Striking decreases in hormonal levels and substantial or complete relief from symptoms can be achieved in approximately 80% of patients [1, 2]. Although octreotide usually produces only minimal immediate side effects, gallstones are a frequent long-term complication. However, octreotide therapy is cumbersome to the patient and is costly. Further, most patients become resistant to this therapy; for patients with carcinoid tumor, the median interval is about 1 year and for patients with islet cell carcinomas, only a few months. For these reasons, octreotide therapy for the carcinoid syndrome should be reserved for patients with severe flushing or diarrhea. In those with islet cell carcinomas, it should be used primarily to restore the patient to a better general and nutritional status so that more aggressive and definitive therapy can be undertaken with an acceptable risk. Regression rates after systemic chemotherapy or immunotherapy (using either single drugs or drug combinations) for metastatic carcinoid tumors and islet cell carcinomas have been variable, as is typical for solid tumors [3]. For carcinoid tumors, regression rates (even with our most effective regimens) seldom exceed 20%, and the discouragingly short duration of these responses hardly justifies the risks and side effects of treatment. For this reason, we urge that systemic therapy for carcinoid tumors be carried out in a research setting. For islet cell carcinoma, however, treatment may be of true clinical value. Streptozocin (Zanosar, The Upjohn Company, Kalamazoo, Michigan) seems to have specific cytotoxicity for the islet cell carcinoma and produces credible tumor regressions in about 30% of patients. Because of its minimal hematologic toxicity, it is useful in drug combinations with chemotherapeutic agents that are dose limited by leukopenia and thrombocytopenia. In a randomized trial, fluorouracil plus streptozocin was found to produce a 45% regression rate and seemed to improve survival when compared with streptozocin alone [4]. In a recent randomized trial, the combination of doxorubicin and streptozocin increased the regression rate to 69% and produced a statistically significant increase in survival [5]. However, fewer than one third of patients have a substantive and prolonged response to chemotherapy, and it produces considerable toxicity. A special consideration in managing these patients is the usually dominant involvement of the liver in the metastatic process. For selected patients, the surgeon can make a major and usually long-lasting contribution by resection of large solitary tumor masses or well-localized clusters of metastatic lesions [6]. With modern surgical technology, operative morbidity and mortality have been reduced to acceptable levels. Among 40 such patients reported by McEntee and colleagues [6], only a single postoperative death occurred. Usually, however, the diffuse nature of hepatic metastasis precludes effective surgical debulking. Therefore, hepatic artery infusion of various drugs has been attempted but with little documented evidence of success. Occlusion of hepatic arterial flow is attractive, because metastatic tumor neovascularity and oxygenation derive almost entirely from the hepatic artery. In contrast, hepatocytes are resilient, and viability may be maintained through the portal vein until rearterialization occurs. Although many researchers have shown that hepatic artery occlusion effectively shrinks primary or metastatic cancer in the liver, for the more common and more aggressive malignant diseases, tumor regrowth occurs so quickly that any net gain is difficult to discern. Because carcinoid tumors and islet cell carcinomas usually grow slowly, lasting benefit may be possible using hepatic artery occlusion. This review documents our experience with hepatic arterial occlusion, by either surgical ligation or embolization, in selected patients with neuroendocrine tumors and hepatic-dominant metastatic disease. Although frequent and substantial tumor regressions were produced, the duration of these regressions, even with these indolent neoplasms, was discouragingly short. We therefore developed and tested a regimen of sequential hepatic arterial occlusion and chemotherapy with the hope that regressions could be enhanced and prolonged. For chemotherapy, we elected to give each of the drugs that have been most active for these tumors when used alone (that is, fluorouracil, streptozocin, doxorubicin, and dacarbazine [DTIC]). Methods Patient Selection All patients selected for study had histologically confirmed carcinoid tumor or islet cell carcinoma with metastasis clinically limited to or dominant in the liver. They were ambulatory and maintaining a reasonable state of oral nutrition (at least 1200 calories daily). One or more measurable parameters of malignant disease were required to serve as objective indicators of response to therapy. For liver metastasis, this required clearly demarcated lesions on liver imaging that measured at least 5 cm in greatest diameter using radioisotope scanning or at least 3 cm in diameter using computed tomography or magnetic resonance imaging. Alternatively, if the patient had malignant hepatomegaly with a distinct liver edge extended at least 5 cm below the xiphoid or costal margins on quiet respiration, this was also used as a marker for response to therapy. In the absence of measurable liver involvement, hormonal assays could be used alone as markers for response to therapy, if they were greater than twice the upper limit of normal. Contraindications to study entry were a total serum bilirubin level more than 51.3 mol/L (3 mg/dL), previous radiation therapy to the liver or hepatic arterial chemotherapy, and the standard contraindications for each of the involved cytotoxic drugs. In practice, protocol entry was limited to those patients who, in the judgment of the physician, had clinically significant symptoms related to tumor bulk or to the endocrine syndrome or had extensive metastasis associated with abnormal test results for liver function. Treatment Hepatic artery occlusion was done by surgical ligation in those patients who had other specific indications for abdominal surgery (for example, an obstructing carcinoid tumor of the small bowel) or for those patients in whom catheterization and embolization were not considered to be technically feasible. For all other patients, occlusion was done by catheterization and embolization. Before hepatic artery occlusion by either method, the anatomy of the hepatic vasculature was determined by angiography. If any evidence of portal vein occlusion or compromise of portal vein flow was noted, occlusion was not done. In patients having operative tumor devascularization, the hepatic artery was approached for ligation through the gastrohepatic ligament of the lesser omentum. The primary right and left hepatic arteries were ligated and divided individually distal to the gastroduodenal artery. Dearterialization was completed by division of the entire gastrohepatic omentum from the diaphragm to the bile duct. Any accessory or replaced hepatic arteries were also identified, ligated, and divided; lymphoareolar tissue in the hepatoduodenal ligament was also divided. Cholecystectomy was done to avoid gallbladder ischemia. For occlusion by embolization, the hepatic artery was selectively catheterized with injection of embolic material, usually gel foam or polyvinyl alcohol or both. Because of the technical difficulty encountered in the procedure, the pretreatment impairment of liver function, and the total mass and distribution of hepatic metastasis, eight patients had embolization done at two or three sittings separated by 3 to 4 work-week intervals. After hepatic artery occlusion, the patient was observed in the hospital for a minimum of 5 days to monitor complications. In some instances, prophylactic antibiotics were used. The patient was released from hospital when there was no clinical evidence of complications, definite recovery of abnormal test results for liver function, and reduction of fever. Sequential chemother

External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer

One hundred fifty‐nine patients with unresectable but localized pancreatic cancer, as defined at exploratory laparotomy, were treated at the Mayo Clinic between February 1974 to April 1985. Postoperative therapy consisted of 4000 to 6000 cGy external beam irradiation (XRT) alone in 122 patients or 4500 to 5500 cGy XRT in combination with an intraoperative electron boost in 37. In addition, 132 (both groups) received 5‐fluorouracil (5‐FU) chemotherapy. Local control (LC) at 1 year was 82% with XRT + intraoperative radiation therapy (IORT) versus 48% with XRT and 66% versus 20% at 2 years respectively (P < 0.0005). Due to the high incidence of hematogenous and/or peritoneal spread in both groups (abdominal failure in 54 and 56% of patients at risk), the decreased frequency of local progression did not translate into an improved survival. Neither median nor long‐term survival of the two treatment groups (XRT versus XRT + IORT) was statistically different (median 12.6 months versus 13.4 months, P = 0.25). With tumor arising in the head of the pancreas, survival at 2 years was 18% as opposed to 0% for other locations (P < 0.01). On the basis of a Cox multivariate analysis, no other treatment or prognostic factor significantly altered survival. Until the problem with systemic failure (usually abdominal) can be resolved, the median and long‐term survival of patients with pancreatic carcinoma is likely to remain unchanged. Since IORT appears to improve local control, we will continue to utilize IORT in phase 1,2 studies which also attempt to decrease the incidence of abdominal failures. Even with IORT + XRT combinations, the incidence of local progression is excessive and radiation dose modifiers need to be evaluated.

Peripheral nerve and ureteral tolerance to intraoperative radiation therapy: clinical and dose-response analysis

Between April 1981 and July 1984, 51 patients received intraoperative radiation therapy (IORT) as a component of therapy for the management of primary or recurrent pelvic malignancies which were initially unresectable for cure. For these patients, curative surgical alternatives did not exist, or would have involved extensive procedures such as pelvic exenteration, distal sacrectomy, hemipelvectomy, or hemicorporectomy. The primary disease was colorectal in 38 patients. Treatment consisted of external beam radiation (range 3000 to 6890 cGy, median 5040 cGy), surgical debulking when feasible, and an intraoperative electron beam boost to the gross or microscopic residual disease (dose range 1000 to 2500 cGy, median 1750 cGy) utilizing 9-18 MeV electrons. The most common IORT associated toxicities were peripheral neuropathy and ureteral obstruction. None were life-threatening or fatal in severity. Of the 50 patients evaluable for neurotoxicity analysis, 16 (32%) developed peripheral neuropathy consisting of pain in 16 patients, numbness and tingling in 11, and weakness in 8. The pain, numbness and tingling resolved in about 40% of patients, while weakness resolved in only 1 of 8. Sixteen ureters were initially unobstructed by tumor at the time of IORT. Of these, 10 (63%) subsequently showed evidence of obstruction and hydronephrosis. The development of neurotoxicity was more common at IORT doses of 1500 cGy or more versus 1000 cGy. Ureteral obstruction with hydronephrosis occurred more frequently at IORT doses of 1250 cGy or more compared to 1000 cGy. There was no relationship between the likelihood of developing complications and the total external beam dose. The observed dependence of human nerve toxicity primarily on the IORT dose is consistent with data generated from animal experiments.

Fine-Needle Aspiration of the Breast

One of the numerous controversial issues related to the clinical management of breast cancer is the role of fine-needle aspiration (FNA). Despite its enthusiastic use in the diagnosis of thyroid nodules, its application to breast abnormalities has been accepted reluctantly. Breast FNA necessitates technical and interpretative skill and continual practice and is not 100% accurate. It also entails an additional, although moderate, expense. To assess the accuracy and determine the possible role of FNA at our institution, we performed both FNA and excisional biopsy in 100 unselected women with palpable breast nodules and correlated the cytologic and histologic findings. Our results were similar to those in previously published studies. FNA had a false-negative rate of 6%, no false-positive results, and an accuracy of 94%. After reviewing the potential assets and liabilities of this technique, we believe that breast FNA may add a measure of confidence in the diagnosis of benign breast lesions, provides a safeguard for preventing misdiagnosis of malignant lesions, and might expedite and reduce the cost of managing both primary and recurrent breast cancer.

High-dose preoperative external beam and intraoperative irradiation for locally advanced pancreatic cancer

PURPOSE To analyze results of high-dose preoperative external beam irradiation followed by surgical exploration and intraoperative radiation therapy in patients with unresectable pancreatic cancer. METHODS AND MATERIALS From December 1983 through December 1990, 27 patients with primary unresectable but localized pancreatic adenocarcinoma received high-dose (50 to 54 Gy) external beam irradiation with or without concomitant bolus 5-fluorouracil followed by surgical exploration and intraoperative electron beam irradiation (20 Gy) at the Mayo Clinic. RESULTS Local control was achieved in 21 of 27 (78%) patients. Actuarial local control at 1, 2, and 5 years was 86%, 68%, and 45%, respectively. In 19 (70%) of the 27 patients, distant metastasis developed, and peritoneal or liver progression (or both) was found in 14 (52%). The actuarial distant metastasis rate at 2 and 5 years was 69% and 83%, respectively. Median survival from the date of diagnosis was 14.9 months. Actuarial 2- and 5-year overall survival was 27% and 7%, respectively. These survival rates are higher (p = 0.001) than the 6% and 0% actuarial 2- and 5-year survival observed in 56 patients who underwent intraoperative radiation therapy followed by postoperative high-dose external beam treatment at our institution. CONCLUSION Administering the full component of external beam irradiation before exploration and intraoperative radiation therapy may be more appropriate because it allows better patient selection. Unfortunately, altered patient selection was not effective in decreasing the relative risk of abdominal failure. Because effective systemic chemotherapy does not currently exist, whole abdominal irradiation alone or in combination with chemotherapy warrants evaluation.

Analysis of failure following curative irradiation of gallbladder and extrahepatic bile duct carcinoma

Twenty patients with carcinoma of the gallbladder (GB-4 patients) or extrahepatic bile ducts (EHBD-16 patients) received radiation therapy with curative intent between January, 1980 and December, 1982. All 20 received 4500-5000 rad in 180-200 rad fractions to the tumor and regional lymph nodes. A 1000 to 1500 rad external beam boost was delivered in 180-200 rad fractions in 10 patients who received external beam alone or concomitant 5-Fluorouracil (5-FU). Three of the four GB and 5 of the 16 EHBD patients received a transcatheter boost with 192-Iridium (192Ir) to a dose of 2000-2500 rad calculated at a 0.5-0.1 cm radius. An additional 2 patients with EHBD lesions received an intraoperative electron (IORT) boost of 1500-2000 rad in one fraction calculated to the 90% isodose. Survival and patterns of failure were analyzed by site and treatment method. All four patients with GB carcinoma are dead of disease at 5 1/2, 6, 9 and 10 months from the date of diagnosis respectively. Three of the four developed diffuse peritoneal carcinomatosis. Five of the 16 patients with EHBD carcinoma are alive with a median follow-up of 18 months (range 6-23 months). Four of the 5 patients received a transcatheter 192Ir or IORT boost and all are without evidence of disease. Four of 9 patients who had a subtotal resection with transection of tumor, dilatation of the bile ducts with probes or curettement of the bile ducts developed either diffuse peritoneal carcinomatosis (3 patients) or a recurrence in the surgical scar (2 patients). Local failure was documented in 3 of the nine patients treated with external beam alone +/- 5-FU, and has been documented in one of the seven patients who received an IORT or transcatheter 192Ir boost. Further experience is necessary to determine whether this aggressive treatment will result in long-term disease-free survival in these patients.

Vascular Resection and Reconstruction for Pancreatic Malignancy: A Single Center Survival Study

IntroductionPancreatic cancer is one of the leading causes of cancer-related death in the USA. Recently, several centers have introduced portal and superior mesenteric vein resection and reconstruction during extended pancreatectomy, rendering the previously inoperable cases resectable.AimThe aim of this study is to confirm whether patients with locally advanced pancreatic cancer and mesenteric vascular invasion can be cured with extended pancreatectomy with vascular reconstruction (VR) and to compare their survival to patients treated with pancreatectomy without VR and those treated without resection (palliation).MethodsSurvival of 22 patients who underwent pancreatectomy with VR was compared with two control groups: 54 patients who underwent pancreatectomy without the need for VR and 28 patients whose pre-operative imaging suggested resectability but whose laparotomy indicated inoperability.ResultsA slight survival benefit was noted in patients who did not require VR (33.5%) compared to those who did require VR [20%, p = 0.18], although not reaching statistical significance. Despite a low 15% three-year survival in patients treated palliatively, this was not statistically different compared to survival after resection with VR (P = 0.23). The presence of nodal metastasis was associated with worse survival (p = 0.006), and the use of adjuvant therapy was associated with better survival (p = 0.001).ConclusionPancreatic cancers that require VR to completely resect the tumor have a similar survival to those not requiring VR. Long-term survival was achievable in approximately 1 out 5 patients requiring VR, although we were not able to demonstrate statistically improved survival compared to palliative care.

Analysis of failure after curative irradiation of extrahepatic bile duct carcinoma

Thirty-four patients with subtotally resected or unresectable carcinoma of the extrahepatic bile ducts received radiation therapy; a minimum of 45 Gy (external beam) to the tumor and regional lymph nodes ± 5-fluorouracil (5-FU). Seventeen patients received an external beam boost of 5 to 15 Gy to the tumor, and a specialized boost was used in the remaining 17 patients (iridium-192 transcatheter seeds in 10 and intraoperative radiation therapy [IORTJ with electrons in seven). The median time to death in all 34 patients was 12 months (range, 4 to 98 months). The only patients who survived longer than 18 months were those either with gross total or subtotal resection before external irradiation (2 of 6) or who received specialized boosts (192Ir, 3 of 10; IORT, 3 of 7). Local failure was documented in 9 of 17 patients who received external beam irradiation alone ± 5-FU, 3 of 10 patients who received an 192Ir boost, and 2 of 6 patients who received an IORT boost with curative intent.

Patient outcomes after total pancreatectomy: a single centre contemporary experience

INTRODUCTION Total pancreatectomy (TP) is associated with significant metabolic abnormalities leading to considerable morbidity. With the availability of modern pancreatic enzyme formulations and improvements in control of diabetes mellitus, the metabolic drawbacks of TP have diminished. As indications for TP have expanded, we examine our results in patients undergoing TP. MATERIALS AND METHODS Retrospective study of 47 patients undergoing TP from January 2002 to January 2008 was performed. Patient data and clinical outcomes were collected and entered into a database. Disease-free survival and overall survival were estimated using the Kaplan-Meier method. RESULTS Fifteen males and 32 females with a median age of 70 years underwent TP for non-invasive intraductal papillary mucinous neoplasms (IPMN) (21), pancreatic adenocarcinoma (20), other neoplasm (3), chronic pancreatitis (2) and trauma (1). Median hospital stay and intensive care stay were 11 days and 1 day, respectively. Thirty-day major morbidity and mortality was 19% and 2%, respectively. With a median follow-up length of 23 months, 33 patients were alive at last follow-up. Estimated overall survival at 1, 2 and 3 years for the entire cohort was 80%, 72% and 65%, and for those with pancreatic adenocarcinoma was 63%, 43% and 34%, respectively. Median weight loss at 3, 6 and 12 months after surgery was 6.8 kg, 8.5 kg and 8.8 kg, respectively. Median HbA1c values at 6, 12 and 24 months after surgery were 7.3, 7.5 and 7.7, respectively. Over one-half of the patients required re-hospitalization within 12 months post-operatively. CONCLUSION TP results in significant metabolic derangements and exocrine insufficiency, diabetic control and weight maintenance remain a challenge and readmission rates are high. Survival in those with malignant disease remains poor. However, the mortality appears to be decreasing and the morbidities associated with TP appear acceptable compared with the benefits of resection in selected patients.

Splenectomy for hairy cell leukemia: A clinical review of 63 patients†

To further define the role of splenectomy in hairy cell leukemia (HCL), 63 patients who underwent splenectomy for symptomatic cytopenias or splenomegaly associated with HCL were reviewed. Hematologic response to splenectomy was assessed 6 months postsplenectomy by a modification of Catovskys criteria. The prognostic value of individual clinical findings, hematologic parameters, spleen size, and Jansen stage were examined by the Cox proportional hazards model. Twenty‐one patients were excluded from hematologic response analysis for the following reasons: eight patients died between 1 and 6 months after splenectomy was performed; in seven patients hematologic data were unavailable; and six patients did not have significant preoperative cytopenias. Of 42 remaining patients, hematologic response was complete in 67%, partial in 19%, and there was no response in 14%. Overall, 44% of patients had disease progression within 5 years of splenectomy. Thirteen patients had a leukemic progression 1 year after splenectomy was performed. Overall 5‐year survival was 61%. There was no operative mortality (30–day), and only 9% of patients had complications. Survival rates after complete, partial, and no response were 62%, 57%, and 75%, respectively at 5 years. Preoperative clinical findings, hematologic data, spleen size, or Jansen stage were not predictive of survival. Despite the absence of identifiable prognostic criteria, splenectomy continues to be advocated for symptomatic cytopenias and splenomegaly of hairy cell leukemia because of its safety and efficacy.