Clinical Hematology
`and Oncology
`P•esentatian, Diagnosis,
`and T•eatn1ent
`
`Bruce Furie; MO
`Professor of Medicine
`Harvard Medical School
`Chief, Division of Hemostasis and Thrombosis
`Department of Medicine
`Beth Israel Deaconess Medical Center
`Boston, Massachusetts
`Peter A. cassileth, MD
`Professor of Medicine
`Division of Hematology and Oncology
`Department of Medicine
`University of Miami School of Medicine
`Miami, Florida
`Michael B. Atkins, MD
`Professor of Medicine
`Harvard Medical School
`Deputy Director, Division of Hematology/Oncology
`Department of Medicine
`Beth Israel Deaconess Medical Center
`Boston, Massachusetts
`Robert J. Mayer, MD
`Professor of Medicine
`Harvard Medical School
`Vice Chair for Academic Affairs
`Department of Medical Oncology
`Dana-Farber Cancer Institute
`Boston, Massachusetts
`
`......... CHURCHILL LIVINGSTONE
`
`A)
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`An Imprint of Elsevier
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`
`~ CHURCHILL lMNCSTONE
`An Imprint of Elsevier
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`
`CLINICAL HEMATOLOGY AND ONCOLOGY
`Copyright © 2003, Elsevier Inc. (USA). All rights reserved.
`
`ISBN 0-443-06556-X
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`Library of Congress Cataloging-in-Publication Data
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`Clinical hematology and oncology: presentation, diagnosis, and treatment /
`Bruce Furie ... [et al.].-1" ed.
`p.; cm.
`Includes bibliographical references
`ISBN 0-443-06556-X
`I. Cancer-Handbooks. manuals, etc. 2. Blood-Diseases-Handbooks, manuals, etc.
`I. Furie, Bruce.
`[DNLM:
`I. Hematologic Diseases-diagnosis. 2. Hematologic Diseases-therapy.
`3. Hematology-methods. 4. Medical Oncology-methods. 5. Neoplasms-diagnosis.
`6. Neoplasms-therapy. WH 120 C6416 2003]
`RC262.5.C557 2003
`6I6.99'4-dc21
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`2003043470
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`International Standard Book Number 0-443-06556-X
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`
`Chapter 110
`Neuroendocrine Cancer
`
`Matthew H. Kulke
`
`tumors are generally classified
`Neuroendocrine
`into two groups: carcinoid tumors and pancreatic
`endocrine tumors. Both tumor types arc thought to
`arise from neurocndocrine cells. and they are often
`tumors are
`histologically
`indistinguishable. These
`typically composed of small cells containing regular,
`well-rounded nuclei. The cytoplasm of these cells
`contains numerous membrane-bound neurosecretory
`granules, which contain a variety of hormones and
`biogenic amines. The release of these substances into
`the systemic circulation results in the unique systemic
`syndromes associated with neurocndocrine tumors.
`Differences in these systemic syndromes, as well as
`dif!ercnces in the location of the primary tumor,
`account for
`the diverse clinical presentations of
`patients with carcinoid and pancreatic endocrine
`tumors.
`
`carcinoid rumors
`Carcinoid tumors occur in one to two individuals per
`l 00,000 per year. They may originate anywhere in the
`body but most commonly develop in the bronchi,
`stomach, small intestine, appendix, or rectum. The
`clinical and biologic characteristics of the tumors may
`vary considerably depending on their site of origin. A
`commonly used classification scheme groups carcinoid
`tumors according to their presumed embryonic site of
`origin: foregut (bronchial and gastric carcinoids),
`midgut (small intestine and appendiceal carcinoids),
`and hindgut (rectal carcinoids) (Table 110-1 ).
`
`aronchlal carclnold TUmors
`Bronchial carcinoids comprise approximately 2% of
`primary lung tumors and most commonly occur in
`individuals in the fifth decade of life. They often arise
`in the proximal bronchi and consequently may be
`associated with symptoms of cough, hemoptysis, or
`recurrent pneumonia. Neuroendocrinc manifestations
`are relatively uncommon. When present, these man-
`
`ifestations may include ectopic secretion of corti(cid:173)
`cotropin, resulting in Cushing's syndrome. Bronchial
`carcinoid tumors can usually be successfully treated
`with conservative procedures such as wedge or seg(cid:173)
`mental resection. These procedures arc associated
`with low rates of local recurrence and excC'llent long(cid:173)
`term survival rates.
`Approximately one third of bronC'hial carcinoid
`tumors have atypical histologic features. In compari(cid:173)
`son to typical carcinoid tumors, these tumors have
`increased nuclear pleomorphism and higher mitotic
`activity and may contain areas of necrosis. More
`aggressive surgical procedures have been advocated for
`such atypical tumors. Despite such procedures, distant
`recurrence is common, and the live-year survival rate
`following resection is only approximately 50%.
`
`Gastric carclnold rumors
`Gastric carcinoid tumors make up fewer than l % of
`gastric neoplasms. They can be classified into three
`distinct groups: those associated with chronic atrophic
`gastritis
`type A (CAG-A),
`those associated with
`Zollinger-Ellison syndrome, and sporadic gastric carci(cid:173)
`noids. Both type I (chronic atrophic gastritis type
`A-associated gastric carcinoids) and type II (Zollinger(cid:173)
`Ellison syndrome-associated gastric carcinoids) are
`associated with hypergastrinemia. High
`levels of
`gastrin are thought to re~ult in hyperplasia of ente(cid:173)
`rochromaffinlike cells in the gastric mucosa; these
`areas of hyperplasia may ultimately develop into
`carcinoid tumors. Both type l and type II gastric
`carcinoids are often small and multifocal. Lesions
`measuring less than I cm in diameter can be treated
`with endoscopic resection followed by close endo(cid:173)
`scopic surveillance. Gastric carcinoids associated with
`hypergastrinemia tend to follow an indolent course,
`and metastatic spread of disease is extremely rare. For
`larger lesions, antrectomy and treatment with somato(cid:173)
`statin analogs results in tumor regression in selected
`cases.
`
`1133
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`1134
`
`section Ill: Evaluation and Treatment Of Hematologic and oncologlc Disease• Endocrine cancer
`
`r
`
`Table 110-1 • Neuroendocrine Tumors:
`Clinical Presentation
`
`carclnold rumors
`Foregut
`Bronchial carcinoids
`
`Gastric carcinoids
`
`Midgut
`Small intestine
`carcinoids
`
`Appendiceal
`carcinoids
`Hindgut
`Rectal carcinoids
`
`cough, hemoptvsis, postobstructive
`pneumonia. Cushing·s syndrome.
`Carcinoid syndrome rare.
`usually asymptomatic and found
`incidentally.
`
`Intermittent bowel obstruction or
`mesenteric ischemia. carcinoid
`syndrome common when metastatic.
`Usually found incidentally. May cause
`carcinoid syndrome when metastatic.
`
`Figure 110-1 • Heal carcinoid. Enteroclvsls shows lumlnal
`narrowing and marked distortion of the bowel contour (open
`arrow>. A carclnold tumor is depicted as a circular mass defect
`larrowl. !From Lappas JC, Magllnte DDT: smau bowel cancer.
`In Bragg DG, Rubin P, Hrlcak H 1eds1: onco1og1c Imaging, 2nd
`ed. Philadelphia: WB Saunders, 2002. pp 419-433.l
`
`tomography (CT) scan, endoscopy, and small bowel
`follow-through often fail
`to detect these lesions
`(Figure 110-1 ). At the time they are detected, they are
`frequently associated with extensive mesenteric fibro(cid:173)
`sis and metastases to local lymph nodes or liver
`(Figure 110-2). Small bowel resection is usually
`
`Either found incidentally or discovered
`due to bleeding, pain, and
`constipation. Rarely cause hormonal
`symptoms. even when metastatic.
`Pancreatic Endocrine rumors
`Symptoms of hypoglycemia:
`lnsulinoma
`intermittent confusion, sweating,
`weakness. nausea.
`Necrotizing migratory ervthema.
`cachexia. diabetes.
`Secretory diarrhea. electrolyte
`disturbances.
`Acid hypersecretion: peptic ulcer
`disease, esophageal reflux. diarrhea.
`Diabetes, diarrhea, cholelithiasis.
`"Nonfunctioning·; may be first
`diagnosed owing to mass effect.
`
`Glucagonoma
`
`VIPoma
`
`Gastrinoma
`
`somatostatinoma
`PPoma
`
`In contrast to type I and type II gastric carcinoids,
`sporadic (type III) gastric carcinoids develop in the
`absence of hypergastrinemia and tend to pursue an
`aggressive clinical course. These lesions are usually
`solitary and often measure more than 1 cm in diame(cid:173)
`ter. The majority of these tumors are metastatic at the
`time of presentation. Those that remain localized
`should be treated with radical gastrectomy.
`
`carclnold TUmors of the small Intestine
`
`Small bowel carcinoid tumors make up approximately
`one third of all small bowel tumors. They are classi(cid:173)
`cally multicentric and located in the distal ileum.
`Patients with small bowel carcinoids may present with
`a long history of abdominal pain or intermittent small
`bowel obstruction, often initially attributed to irritable
`bowel syndrome. Because of their submucosal loca(cid:173)
`tion, standard imaging techniques such as computed
`
`Figure 110-2 • Metastatic carclnold. computed tomography
`shows a mesenterlc mass <arrow> with flbrotlc strands
`extending from the mass that represent the typical desmo(cid:173)
`plastlc response. !From Lappas JC. Magllnte DDT: small bowel
`cancer. In Bragg DG. Rubin P, Hricak H Cedsll: oncologlc
`Imaging, 2nd ed. Philadelphia: WB Saunders, 2002. pp 419-433.1
`
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`
`1134 Section Ill: Evaluation and Treatment of Hematologic ard oncologic Disease• Endocrine Cancer
`
`Table 110-1 • Neuroendocrine Tumors:
`Clinical Presentation
`
`carclnoid Tumors
`Foregut
`Bronchial carcinoids
`
`Gastric carcinoids
`
`Midgut
`Small intestine
`carcinrnds
`
`Append1ceal
`carcinoids
`H1ndgut
`Rectal carcinoids
`
`Cough, hemoptysis, postobstructive
`pneumonia. Cushlng's syndrome.
`Carcinoid syndrome rare.
`usually asympromatic and found
`incidentally
`
`Intermittent bowel obstruction or
`mesenteric lschem1a. Carc11101d
`syndrome common when metastatic
`Usually found incidentally. May cause
`carc1noid syndrome when metastatic.
`
`Either found incidentally or discovered
`due to bleeding, pain, and
`constipation. Rarely cause hormonal
`symptoms, even when metastatic.
`
`Glucagonoma
`
`Pancreatic Endocrine Tumors
`lnsulinoma
`Symptoms of hypoglycemia
`intermittent confusion, sweating,
`weakness, nausea.
`Necrotlzing migratory ervthema,
`cacl~ex1a. diabetes
`secretory diarrhea. electrolyte
`disturbances.
`Acid hypersecretion: peptic ulcer
`disease. esophageal reflux, diarrhea
`Diabetes, diarrhea, cholelithiasis.
`"Nonfunccioning": may be first
`diagnosed owing to mass effect
`
`VIPoma
`
`Gastrinoma
`
`somatostatinoma
`PPoma
`
`Figure 110-1 • 11eal carcinoid. Enteroclysis shows luminal
`narrowing and marked distortion of the bowel contour (open
`arrow). A carcinold tumor is depicted as a circular mass defect
`tarrowl. (From Lappas JC, Magllnte DDT: small bowel cancer.
`In Bragg DG, Rubin P, Hricak H ledsl: Oncologlc Imaging, 2nd
`ed. Philadelphia: WB Saunders, 2002, pp 419-433.J
`
`tomography (CT) scan, encl ~copy, and small bowel
`follow-through oflen
`fail
`the~e
`lesions
`to detect
`(Figure 110-1). AL rhe time they are detected, they are
`lrequcntl) associ,Hed with extensive mesenteric fibro(cid:173)
`l)'mpb nodes or liver
`sis and metastases to local
`(Figure
`l l0-2) , S111i1ll bowel resection is usually
`
`[n contrn~l to 1ypc T and type Tl gastric carcinoids,
`sporadic (type II[) gastric carcinoicls develop in the
`absence of hyprrgas1rinemia and tend Lo pursue an
`aggressive clinical course. The~c lesions are usually
`solitary and often measure more than I cm in diame(cid:173)
`ter. The majority o[ these 1umors arc metastatic at the
`1ime of presentation. Them: that remain localized
`should l>e tn·ated with radical gasrrectomy.
`
`carcinoid tumors of the Small Intestine
`
`Small bowel carcinoid tumors make up appro:ximm ,1y
`one third oI all small bowel tumors. The are classi (cid:173)
`cally nrnlticemri and located in the di~tal ileum.
`Patients with sn all bowel carcinoids may presenr wirh
`a long history of abdominal pain or intcrminent small
`t owe] ob truction, often initially auributed to irritable
`bowel syndrome. Because of their submucosa l loca(cid:173)
`tion, standard imaging technique~ such as compu ted
`
`Figure 110-2 • Metastatic carcinoid. computed tomography
`shows a mesenterlc mass (arrowl With fibrotic strands
`extending from the mass that represent the typical desmo(cid:173)
`plastic response. (From Lappas JC, Maglinte DDT: small bowel
`cancer. In Bragg DG, Rubin P, Hricak H ledsll: oncologic
`Imaging, 2nd ed. Philadelphia: WB Saunders, 2002, pp 419-433.l
`
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`
`undertaken, even in the presence of metastatic
`disease, for palliative purposes.
`
`Appendlceal carclnold TUmors
`Carcinoid tumors are the most common cancers of
`the appendix. They are often diagnosed in younger
`individuals, in the fourth or fifth decade of life, and
`are usually found incidentally during appendectomy
`for other reasons. Tumor size is the best predictor of
`prognosis in patients with appendiceal carcinoid
`tumors. The vast majority of appendiceal carcinoid
`tumors measure less than 2 cm in diameter. Metas(cid:173)
`tases arc extraordinarily uncommon in such tumors,
`and simple appendectomy is nearly always curative.
`In contrast, approximately one third of patients with
`appendiceal carcinoids greater than 2 cm in diameter
`have nodal or even distant metastases. Most patients
`with tumors measuring more than 2 cm are treated
`with right hemicolectomy.
`
`Rectal carclnold TUmors
`Rectal carcinoid tumors make up 1 % to 2% of all
`rectal tumors. Approximately 50% are asymptomatic
`and are found during routine endosocopy; patients
`who have symptoms usually experience rectal bleed(cid:173)
`ing, pain, or constipation. As with appendiceal carci(cid:173)
`noids, size is an accurate predictor of prognosis in
`patients with rectal carcinoids. Patients with tumors
`measuring less than 2 cm in diameter can be success(cid:173)
`fully treated with local excision, which is nearly
`always curative. Tumors measuring more than 2 cm in
`diameter are generally treated with either low ante(cid:173)
`rior resection or abdominoperineal resection. Despite
`the use of radical resection in such cases, distant
`metastases occur in the majority of patients, and the
`prognosis for such patients is poor.
`
`Pancreatic Endocrine rumors
`Pancreatic endocrine tumors occur in three to four
`individuals per million per year. These tumors may
`arise sporadically or, less commonly, in patients with
`multiple endocrine neoplasia type I (MEN I). This
`autosomal-dominant inherited syndrome is associated
`with loss of chromosome llql3 and is characterized
`by a high incidence of pancreatic endocrine tumors,
`as well as tumors involving the pituitary and parathy(cid:173)
`roid gland~. The clinical presentations of pancreatic
`endocrine tumors are diverse and most often related
`to symptoms of hormonal hypersecretion (Table 110-
`2). The best-characterized of these syndromes are
`insulinoma, glucagonoma,
`those associated with
`VIPoma, and gastrinoma.
`
`Chapter 110: Neuroendocrlne cancer
`
`1135
`
`Table 110-2 • Hormone Levels
`in Neuroendocrine rumors
`
`TUmor
`Carcinoid tumor
`lnsulinoma
`Glucagonoma
`VIPoma
`Gastrinoma
`Somatostatinoma
`
`1YPlcal HOrmone Level
`24-hour urinary SHIAA > 24 mg/dl •
`Fasting insulin ~ 6 µU/mL
`Fasting glucagon ~ 50 pmol/l
`Fasting VIP > 200 pg/ml
`Fasting gastrin > 100 pg/ml
`Somatostatin > 100 pg/ml
`
`*24-hour urinarv SHIAA Is most commonly elevated In patients with
`metastatic small bowel or appendiceal carcinoids and only rarely elevated
`in patients with bronchial, gastric, or rectal carcinoids.
`
`One of the first described patients with insulinoma
`is said to have ·resembled an acute alcoholic-great
`motor activity, dancing and talking, squinting and
`frowning, apparently having hallucinations of sight
`and hearing, negativistic, and difficult to control."
`These symptoms are the classic manifestations of
`hypoglycemia, which typically can cause not only
`central nervous system dysfunction but also auto(cid:173)
`nomic symptoms such as sweating, weakness, and
`nausea. The combination of symptoms of hypo(cid:173)
`glycemia, a documented blood glucose level of less
`than 50 mg/dL, and relief of symptoms with adminis(cid:173)
`tration of glucose constitutes Whipple's triad, first
`described in 1935 and still useful in the diagnosis of
`insulinoma.
`Although glucagonomas may be associated with
`diabetes mellitus, clinically significant hyperglycemia
`occurs in just over half of such patients. Patients with
`glucagonomas are in fact most frequently diagnosed
`by a dermatologist after presenting with necrolytic
`migratory erythcma. This rash, characterized by raised
`erythematous patches beginning in the perineum and
`subsequently involving the trunk and extremities,
`is found in nearly 75% of all patients. Patients with
`the glucagonoma syndrome may also experience
`profound cachexia. A tendency for patients with
`glucagonoma to develop venous thrombosis makes
`perioperativc anticoagulation mandatory.
`Pancreatic tumors that secrete vasoactive intesti(cid:173)
`nal peptide (VIPomas) classically cause a syndrome
`characterized by watery diarrhea, hypokalemia,
`hypochlorhydria, and acidosis, hence the occasionally
`used acronym WDHA syndrome. Others have referred
`to this syndrome as pancreatic cholera. Like the cholera
`toxin, VIP causes intracellular elevation of cyclic AMP,
`resulting in inhibition of electrolyte absorption and
`profound secretory diarrhea.
`The gastrinoma syndrome is characterized by
`gastric hypersecretion. Gastrin, which is normally
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`
`1136
`
`section Ill: Evaluation and Treatment of Hematologic emu unco1og1c u1sease • Endocrine cancer
`
`secreted by the G cells in the gastric antrum, not only
`stimulates acid secretion in parietal cells, but also acts
`as a trophic factor, causing parietal cell hyperplasia.
`The net effect is an increase in both basal and maximal
`acid output. The profound acid hypersecretion associ(cid:173)
`ated with gastrinomas typically causes abdominal pain
`due to peptic ulcer disease or reflux esophagitis. Diar(cid:173)
`rhea also occurs in more than half of patients.
`In contrast to other pancreatic endocrine tumors,
`gastrinomas occur more commonly outside the pan(cid:173)
`creas than within it. The overwhelming majority of
`gastrinomas are found in the gastrinoma triangle, an
`area bounded by the cystic and common bile ducts,
`the duodenum, and the pancreas. Recent surgical
`series have found that within this area, over half of
`gastrinomas are found in the duodenum.
`Two other types of pancreatic endocrine tumor
`have been somewhat less well characterized. The first
`of these, somatostatinomas, may be associated with
`diabetes, hypochlorhydria, and diarrhea. PPomas are
`pancreatic neuroendocrine tumors associated with
`high serum levels of pancreatic polypeptide. Secretion
`of pancreatic polypeptide is not associated with any
`clinical syndrome; these tumors are therefore gener(cid:173)
`ally classified as nonfunctioning pancreatic endocrine
`tumors. They are usually first diagnosed when they
`grow large enough to cause symptoms from tumor
`bulk.
`The initial medical management of pancreatic
`endocrine tumors centers on control of the symptoms
`of hormonal hypersecretion (Table 110-3). Adminis(cid:173)
`tration of somatostatin analogs such as octreotide is
`often highly effective in controlling the symptoms of
`VIPoma as well as glucagonoma. Its efficacy is some(cid:173)
`what less predictable in the treatment of patients with
`insulinomas and gastrinomas. Patients with insulino(cid:173)
`mas more reliably benefit from administration of car-
`
`Table 110-3 • Medical Management
`of Hormonal Symptoms in Patients
`with Neuroendocrine Tumors
`
`Symptom
`carcinoid syndrome
`lnsulinoma
`
`Glucagonoma
`VIPoma
`
`Gastrinoma
`
`Somatostatinoma
`
`Treatment
`somatostatin analogs, interferon-alpha
`Diazoxide, administration of
`carbohydrates, somatostatin analogs
`(benefit less predictable)
`SOmatostatin analogs, amino acid infusion
`somatostatin analogs, administration of
`IV fluids
`Proton pump inhibitors, somatostatin
`analogs (benefit less predictable)
`Not available
`
`bohydratcs and the use of diazoxide, which directly
`inhibits the release of insulin from insulinoma cells.
`Patients with gastrinomas often achieve excellent
`symptomatic relief simply with the use of proton
`pump inhibitors.
`The localization of pancreatic endocrine tumors
`often presents a clinical challenge, since these tumors
`may be physically small yet still cause profound hor(cid:173)
`monal symptoms. Invasive studies such a~ angiogra(cid:173)
`phy and portal venous sampling are highly sensitive
`but have more recently been largely replaced with
`other, less invasive imaging techniques. In cases in
`which conventional modalities such as computed
`tomography scan and magnetic resonance imaging
`(MRI) fail, endosoipic ultrasound, with a reported
`sensitivity in excess of 80%, may be useful. Somato(cid:173)
`statin scintigraphy detects 70% of pancreatic rndo(cid:173)
`crine tumors and may detect not only occult primary
`tumors, bm also previously unsuspected metastatic
`disease. Once
`localized,
`pancreatic
`endocrine
`tumors arc usually successfully treated with either
`enucleation (in the case of smaller tumors), pancre(cid:173)
`aticoduodenectomy (for tumors in the pancreatic
`head), or distal pancreatectomy (for tumors in the tail
`of the pancreas).
`
`Metastatic Neuroendocrine Tumors
`The clinical course of patients with metastatic neu(cid:173)
`roendocrine tumors is highly variable, and some
`patients with indolent tumors may remain free of
`symptoms for years. Asymptomatic patients with
`metastatic neuroendocrine tumors can occasionally he
`followed for years without treatment. In most cases,
`metastatic lesions can easily be followed by conven(cid:173)
`tional computed tomography scan. In patients with
`metastatic carcinoid tumors, measurements of the
`serotonin metabolite 5-HIAA in 24-hour urine collec(cid:173)
`tions may also be useful in confirming the diagnosis
`and in the subsequent monitoring of patients.
`It is not uncommon for patients with metastatic
`disease to first become symptomatic from symptoms
`of hormonal hypcrsecretion rather than from symp(cid:173)
`toms related to tumor bulk. This is especially true for
`patients with small bowel or appendiceal carcinoid
`tumors, who generally do not experience systemic
`symptoms unless metastases to the liver arc present,
`In these patients, the secretion of serotonin and other
`vasoactive substances into the systemic circulation
`results in the carcinoid syndrome, which is manifested
`by episodic flushing, wheezing, and diarrhea and the
`eventual development of carcinoid heart disease.
`The carcinoid syndrome can often be well con(cid:173)
`trolled with somatostatin analogs. In an initial study,
`subcutaneous administration ol octreotide at a dosage
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`
`of 150 µg three times a day improved symptoms of the
`carcinoid syndrome in 88%, of patients. A long-acting
`depot form of octreotide, which can be administered
`on a monthly basis, is now commonly used to manage
`symptoms of hormonal secretion associated with both
`carcinoid and pancreatic endocrine tumors.
`The successful use of somatostatin analogs to
`control the carcinoid syndrome has led to increased
`interest in the management of carcinoid heart disease.
`Carcinoid heart disease occurs in two thirds of patients
`with the carcinoid syndrome and is characterized by
`the development of plaquelike endocardial thickening
`involving the right side of the heart. Tricuspid regur(cid:173)
`gitation is a nearly universal finding and, when severe,
`111c1y lead to right-sided heart failure. Valvular replace(cid:173)
`ment should be considered in patients who have sig(cid:173)
`nificant symptoms from their valvular disease and in
`whom the other manifestations of hormonal hyper(cid:173)
`secretion are well controlled.
`Interferon-alpha (IFN-a) has been reported to
`result in improved symptoms of hormonal hyper(cid:173)
`secretion in 40% to 50% of patients with the carci(cid:173)
`syndrome
`and
`in
`tumor
`regression
`in
`noid
`approximately I 5% of patients. The addition of IFN(cid:173)
`a to therapy with somatostatin analogs has also been
`effective in controlling the symptoms of patients
`whose symptoms are
`resistant
`to somatostatin
`analogs. A high rate of side effects, which may include
`fever, fatigue, anorexia, weight loss, and depression,
`has limited the routine use of lFN-a in this setting.
`The surgical resection of liver metastases may be
`of benefit to patients with limited hepatic metastases
`from either carcinoid or pancreatic endocrine tumors.
`Such surgl'ry has resulted in the long-term relief of
`symptoms and prolonged survival in highly selected
`patients. Hepatic arterial embolization is an alternative
`for patients who are not candidates for hepatic resec(cid:173)
`tion. Unfortunately, the duration of response follow(cid:173)
`ing hepatic artery embolization is often short. ln one
`study of patients with metastatic pancreatic endocrine
`or carcinoid
`tumors, objective
`regressions were
`observed in 60% of patients, but the duration of
`response was only four months.
`Cytotoxic therapy has played only a limited rule
`in the management of patients with metastatic neu(cid:173)
`roendocrine tumors. Cytotoxic therapy appears to be
`most useful in patients with more aggressive, atypical
`neuroendocrine tumors. In one study, a combination
`of cisplatin and etoposide produced a 67% response
`rate in such patients. Cytotoxic therapy also appears
`to be beneficial
`in the
`treatment of pancreatic
`endocrine tumors. ln an initial randomized study
`involving
`patients with metastatic
`pancreatic
`endocrine tumors, the combination of strcptozotocin
`and 5-fluorouracil was shown to be superior to strep-
`
`Chapter 110: Neuroendocrine cancer
`
`1137
`
`tozotocin alone, with response rates of 36% and 33%,
`respectively. A subsequent study demonstrated that
`the combination of streptozotocin and doxorubicin
`resulted in a response rate of 69%, whereas the com(cid:173)
`bination of streptozotocin and 5-fluorouracil resulted
`in responses in only 45% of patients. An analysis of
`patients with pancreatic endocrine tumors treated
`with a combination of streptozotocin and doxorubicin
`found a true radiologic response rate of less than l 0%.
`Trials have shown only minor activity associated
`with cytotoxic chemotherapy in the treatment of
`patients with metastatic carcinoid tumors. Patients
`with metastatic carcinoid tumors assigned to receive
`either streptozotocin combined with 5-fluorouracil or
`streptozotocin combined with cyclophosphamide had
`response rates, measured by either tumor regression
`or a decrease in urinary 5-HIAA levels, of 33% for
`streptozotocin/5-fluorouracil and 26% for strepto(cid:173)
`zotocin/cyclophosphamide. There was no difference
`in survival between the two treatment groups.
`
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