Medical and Pediatric Oncology 6:77-83 (1979)

Management of Carcinoid Syndrome Philip Bonomi, MD, Charlotte Hovey, MD, John R. Dainauskas, MD, Robert Slayton, MD, and Janet Wolter, MD Department of Internal Medicine (P.B., R.S., J.W.), Department of Radiology (C.H.), and Department of Pathology (J. R. D.), Rush University, Chicago

Two patients who had severe carcinoid syndrome are presented. In one patient prednisone relieved symptoms for 20 months, and in the second patient chemotherapy appears to have precipitated fatal carcinoid crisis. Changes in mentation, increased frequency and intensity of flushing, and hypotension indicate increased risk of a chemotherapy induced carcinoid crisis. Since prednisone may produce relatively long control of carcinoid syndrome, it should be tried before chemotherapy in patients who have increased risk of carcinoid crisis. If chemotherapy is given, doses should be decreased by SO%, and patients should be followed closely. Key words: carcinoid crisis, chemotherapy,prednisone

INTRODUCTION

The carcinoid tumor, which is classified as an APUDoma, is relatively rare and is frequently asymptomatic [ 1,2] . However, it can present perplexing management problems particularly when the carcinoid syndrome is present. Paroxysms of cutaneous flushing, watery diarrhea, crarnpy abdominal pain, facial edema, bronchospasm, and episodes of hypotension are manifestations of carcinoid syndrome [3,4]. Some or a l l of the symptoms occur in seven per cent of patients who have ileal carcinoid tumors, and the presence of these symptoms almost invariably indicates the presence of metastases [ 1,2] . The manifestations of the syndrome appear to be caused by substances released from the tumor. Urinary 5 hydroxyindoleacetic acid (5HIAA) is virtually always elevated in the carcinoid syndrome [5,6] ; and serotonin, the precursor of SHIAA, is one of the mediators of diarrhea [ 6 ] .Kinins appear to cause cutaneous flushing in most patients [7]. Histamine and prostaglandins have also been implicated as carcinoid syndrome

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mediators, and elevation of adrenocorticotrophic hormone and an insulin-like substance have been associated with carcinoid tumor [ 6 ] .Medications which are antagonists of the mediators of carcinoid syndrome may relieve symptoms, but their side effects may make the patient feel worse [8]. There are reports of severe, spontaneous exacerbation of carcinoid syndrome which have been referred to as “carcinoid crisis” [9]. During a crisis prolonged, intense flushing and refractory hypotension occur; and treatment with epinephrine or norepinephrine often increases the symptoms. Severe abdominal pain and respiratory distress may also occur. Spontaneous carcinoid crisis has resulted in death [9]. Exacerbations of carcinoid syndrome following chemotherapy [ 10, 1 I ] have been reported, and there is a single report of two fatalities during carcinoid crisis following chemotherapy [ 111. An additional case of fatal carcinoid crisis following chemotherapy is described in this report. A second patient with severe carcinoid syndrome that was relieved for 20 months by corticosteroids is also presented. The therapeutic and theoretical implications of these observations are discussed. CASE REPORTS

EB (RPSLH No.818084) was a 55-year-old woman who presented with small bowel obstruction in February 1967. Laparotomy revealed a tumor in the mesentery which caused the obstruction by kinking the terminal ileum. Three feet of ileum were resected, and an enterostomy was performed. No hepatic metastases were observed at this time. Histologic examination of the tumor showed features of carcinoid tumor. The patient received no additional postoperative therapy and remained asymptomatic for six months. At this time the patient noted episodes of facial flushing which lasted from 30 seconds to several minutes and which were precipitated by exertion, emotional upset, or drinking alcohol. She also experienced intermittent abdominal pain, nausea, and diarrhea. Despite these symptoms the patient did reasonably well for seven years, when bowel obstruction recurred. At laparotomy the obstruction was relieved and multiple liver metastases were found. Liver biopsy revealed carcinoid tumor. Postoperatively diphenoxylate and cyproheptadine were started; but flushing, diarrhea, and abdominal pain persisted. No specific antitumor therapy was given. From January to July 1975, the patient lost 35 pounds and began to have weekly episodes of flushing which lasted 20 to 30 minutes and which were accompanied by severe abdominal pain and weakness. In July, 1975 she was admitted to RPSLH during a severe episode. Physical examination revealed a lethargic, confused woman whose face and extremities were reddish-blue. Examination of the heart and lungs was unremarkable. Bowel sounds were hyperactive, and there was diffuse abdominal tenderness. The liver was 6 cm below the right costal margin in the mid-clavicular line and its edge was very firm and nodular. Pulse was 120/minute and regular. Blood pressure was unobtainable initially, but increased to 110/80 mm. of mercury after two units of albumin were infused. Admission laboratory data were: Hemoglobin 15.6 gmsldl, hematocrit 46.5%, leukocyte count 22,800/mm3 with 59% segmented neutrophils, 18% bands, 22% lymphocytes. Radiographs of the chest and the abdomen were normal. Electrocardiogram showed sinus tachycardia. Examination of cerebrospinal fluid revealed protein of 13 mg/dl, glucose 67 mg/dl, and no cells.

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After admission, the patient remained confused and continued to have abdominal pain. Cyproheptadine and diphenoxylate did not relieve these symptoms. Liver scan showed increase in number and single size of multiple filling defects with the largest single defect increasing from 4 to 7 cm compared to a scan done nine months previously. A liver scan done 18 months earlier had been normal. Twenty-four-hour urine determinations of SHIAA were 1,092 mg and 1,976 mg. Seven days after admission the patient had an episode of intense flushing and severe abdominal pain which persisted for one hour. Blood pressure was unobtainable for 20 minutes, but it increased to 88/70 after infusion of intravenous fluids. At this point prednisone 10 mg three times daily was started. Within four days confusion, flushing, abdominal pain, and diarrhea completely cleared. Then the patient was given 25% of the usual dose of chemotherapy because of concern about exacerbating her symptoms. She received cyclophosphamide 400 mg intravenously once and streptozotocin 200 mg intravenously daily for five days according to ECOG protocol No.3272. No side effects or exacerbations of carcinoid syndrome were observed during chemotherapy. Two days after completing chemotherapy the patient was discharged asymptomatic on prednisone 10 mg three times daily. The patient remained asymptomatic until 12 days after completion of chemotherapy when intense generalized flushing, severe abdominal pain, vomiting, and dyspnea occurred. Her blood pressure was 70/40 mm of mercury; pulse was 130/minute; and respirations were 40/minute. There was deep purple discoloration of her face, chest, and upper extremities. Heart sounds were of normal intensity with no gallop, friction rub, or murmur. Diffuse wheezes were heard over both lungs. Central venous pressure was seven cm of water. There were episodes of borborygmi, and there was diffuse abdominal tenderness without rebound tenderness. Radiographs of the chest and the abdomen were normal. Hemoglobin was 15 gms/dl, leukocyte count was 5,100 with 41% segmented neutrophils, 32% bands, 21% lymphocytes, 3 monocytes, and 3% eosinophils. Platelet count was 209,000. Arterial blood gases while the patient was breathing room air were p 0 2 - 54 mm of mercury, pC02 - 20 mm of mercury and pH - 7.45. Despite mechanical ventilation, hydrocortisone phosphate 1,000 mg intravenously, vigorous fluid replacement, and intravenous metaramine and angiotensin the patient remained hypotensive and expired 15 hours after admission. AUTOPSY REPORT

At autopsy numerous fibrous adhesions were seen in the abdomen but there was no evidence of mechanical bowel obstruction, or of residual tumor in the bowel. However, a mass of tumor 3 X 2 X 1 cm was found around the mesenteric blood vessels. The heart was not enlarged. Slight fibrous thickening of the tricuspid valve was noted but the endocardium was normal. Two metastatic tumor nodules (3 mm in diameter) were seen in the myocardium in the outflow tract of the right ventricle. The right lung weighed 700 grams and the left lung weighed 510 grams. Both contained numerous tumor nodules up to one cm in diameter, and a large bronchus was infiltrated by tumor. The tumor was also present in the perivascular and peribronchial lymphatics. Acute bronchopneumonia was also seen. The liver was enlarged and weighed 3,300 grams. Approximately 80% of the parenchyma was replaced by confluent tumor nodules. The hi$tologic appearance of the tumor at autopsy was similar to the tumor removed at laparotomy one year earlier.

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Fig. 1. This hepatic tumor nodule which was removed at autopsy shows an area of central necrosis surrounded by well preserved carcinoid cells. (Magnification X S l , hematoxylin and eosin stain).

Post mortem examination of the larger nodules revealed areas of acute necrosis. (see Fig. 1). Although tumor necrosis was not extensive, it was increased compared to that in tissue obtained at laparotomy one year earlier. SECOND CASE REPORT

BF (RPSLHNo.092020) was a 53-year old white male who noted hemoptysis in May of 1972. Chest x-ray showed a single two cm nodule in the left lower lobe, a thoracotomy was performed, and a bronchial carcinoid was resected. The patient’s postoperative course was uncomplicated. His liver scan and 24-hour urine for 5HIAA were negative. Except for occasional diarrhea the patient did well for 42 months at which time he began to experience episodes of facial flushing once or twice daily and began to have diarrhea four to five times daily. InttMarch of 1973 an episode of flushing which was accompanied by nausea, vomiting, and diarrhea resulted in dehydration requiring hospital admission for intravenous fluids. Twenty-four hours after admission, the symptoms subsided. During this admission, 24-hour urine dttTtTeterminations for 5HIAA were 1 17 and 124 mg. Liver scan showed a single lesion in the posterior aspect of the right lobe. The patient was discharged taking diphenoxylate 0.25 mg four times daily and cyproheptodine 4 mg four times daily and he was asymptomatic except for diarrhea once or twice daily.

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The patient did well until six months later when daily flushing started again, despite increasing cyproheptadine to 8 mg four times daily. In October of 1973, he was admitted to RPSLH, where liver scan showed multiple lesions compared to a single lesion detected eight months previously. The SHIAA was 489 mg/24 hours compared to 125 mg 8 months earlier. Since the patient was symptomatic and the liver scan and SHIAA indicated progression of the tumor, a partial hepatectomy was performed to reduce the tumor bulk. Four hundred and five grams of tissue were removed most of which was carcinoid tumor. During the immediate postoperative period flushing subsided but diarrhea persisted. Three weeks postoperatively he was discharged, still taking diphenoxylate and cyproheptadine. Eight weeks postoperatively, the patient was experiencing daily nausea, vomiting, and flushing. In addition, his blood pressure was lower than usual (90/60 mm of mercury). The patient’s local physician prescribed cortisone acetate 25 mg twice daily because he thought the patient might have adrenal insufficiency. Within one week flushing, nausea, and vomiting completely stopped. Cortisone was changed to prednisone 20 mg daily, and while taking steroids the patient remained asymptomatic for 20 months except for a single flare of carcinoid symptoms. When the patient began to experience regular recurrence of carcinoid symptoms 20 months after steroids were initiated, hepatic tumor was again resected. The patient’s symptoms persisted postoperatively despite his taking steroids. He expired in carcinoid crisis five months after the second hepatic resection. Autopsy was not performed. DISCUSSI ON

The management of carcinoid tumor is unique because of its slow progression and unusual clinical manifestations. The average survival from time of diagnosis of ileal carcinoid is 8.1 years [ 2 ] .Although prognosis is worse when carcinoid syndrome is present, survival is still relatively long compared to other malignant tumors [ 121 . Initial therapy is surgical excision with curative intent. Unfortunately, in the majority of cases metastatic disease is present at the time of diagnosis [2, 101 . Although incurable disease is present, resection of gross tumor is often indicated to relieve actual or impending intestinal obstruction and to decrease the tumor bulk because this can result in excellent palliation [ 1,2] . After the initial surgery chemotherapy is usually withheld, despite the presence of known metastatic disease, until there is definite evidence that tumor progression is causing disability [2, 11, 121. If carcinoid syndrome is present various pharmacologic agents can be tried to control carcinoid symptoms [8]. When there is symptomatic tumor progression, reduction of tumor mass is indicated [4, 1 1, 121. Large metastatic tumors, usually in the liver, have been resected resulting in excellent palliation lasting up to two years [4,6, 10-121 . Cyclophosphamide [ 101, methotrexate [lo], 5-fluorouracil [ 111, and streptozotocin used alone have achieved reduction of tumor and combination chemotherapy regimens are being tried [ 111 . Most single-drug-induced tumor regressions have been brief and incomplete. In addition to the usual side effects from chemotherapy, patients who have carcinoid syndrome may experience exacerbation of the syndrome after chemotherapy [ 10, 111. The increased carcinoid symptoms are presumed to be due to chemotherapy-induced tumor cells lysis causing increased release of carcinoid mediators. This hypothesis is sup-

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ported by the observations that transient elevations of urinary SHIAA occur during the carcinoid flare, and that exacerbations seem to occur more frequently during objective tumor regressions [ 121 . It appears that our first patient (EB RPSLH No.818084) died as a result of carcinoid crisis. She had prolonged flushing, severe abdominal pain, borborygmi, wheezing, facial edema, and refractory hypotension - virtually all of the manifestations of carcinoid crisis [4,9]. The autopsy findings were consistent with carcinoid crisis as the cause of death. There was no anatomic explanation for the severe abdominal pain, and no cardiac abnormalities which could explain the prolonged hypotension. From cell kinetic data for nitrosoureas and [13] from previous clinical observations for cyclophosphamide maximum tumor lysis and increased carcinoid symptoms would be expected to occur one to two weeks after therapy was given. The time interval between chemotherapy and occurrence of the carcinoid crisis in our patient was 12 days. Microscopic examination of the tumor showed some areas of necrosis which may have resulted from effective chemotherapy (See Fig. 1). Therefore, the temporal relationship between chemotherapy and carcinoid crisis and the presence of tumor necrosis support the idea that chemotherapy caused fatal carcinoid crisis in our patient. Moertel has also observed two instances of fatal carcinoid crisis which seemed to be precipitated by chemotherapy [111 . Increased frequency and intensity of flushing and changes in mentation before receiving chemotherapy appear to indicate increased risk of a chemotherapy-induced crisis. Moertel has suggested that patients who exhibit these signs should receive 50%of the usual dose of chemotherapy because of the risk of carcinoid crisis [ 111. Flushing accompanied by hypotension may also indicate risk of chemotherapy induced crisis [ 141 . All of these signs plus extremely high levels of urinary 5HIAA were present in our patient (EB RPSLH No.818084) who experienced carcinoid crisis despite receiving 25%of the usual dose of cyclophosphamide and streptozotocin. When the risk of factors are not present the change of chemoterapy caused crisis is unlikely. In a recent Eastern cooperative Oncology Group trial comparing 5-fluorouracil and streptozotocin with 5-fluorouracil and cyclophosphamide, there were two episodes of carcinoid crisis in 64 patients with carcinoid syndrome.* In our first patient all of the symptoms of carcinoid syndrome completely stopped four days after prednisone 30 mg daily was started. After resection of hepatic metastases and treatment with cyproheptadine failed to control carcinoid syndrome, our second patient (BF RPSLH N0.092020) experienced dramatic cessation of symptoms within one week of starting corticosteroids. His symptoms were controlled for 20 months. The literature contains similar reports of dramatic improvement of carcinoid symptoms during therapy with modest doses of glucocorticoids [6,8, 15-18]. Three patients remained asymptomatic for five [15], eleven [16], and eighteen months. In two patients, the symptoms recurred when steroids were withdrawn and cleared again when steroids were restarted [16, 181. In one patient necropsy revealed decrease in size of hepatic metastases compared to metastases observed at laparotomy eleven months earlier [ 161. In summary this report is not intended to discourage the use of chemotherapy in carcinoid syndrome but to draw attention to the possibility that carcinoid crisis following chemotherapy may be fatal, and second, to emphasize the potential for prolonged palliation of carcinoid syndrome with prednisone. *Personal communication from Charles Moertel MD, Mayo Clinic, Rochester, Minnesota.

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ACKNOWLEDGMENTS

We wish to thank Ms Eula Taylor for typing this manuscript and Dr. Lowell Goldberg for his cooperation in preparing the case report. REFERENCES 1. Jagar RM, Polk HC: Carcinoid APUDomas. Current Problems in Cancer. Vol 1, No.11: 3-5 1, 1977. 2. Moertel CG, Sauer WG, Dockerty MB, Bagenstoss AH: Life history of the carcinoid tumor of the small intestine. Cancer 14:901-912, 1960. 3. Throson A, Biorck G , Bjorkman G, Waldstrom J: Malignant carcinoid of the small intestine with metastases to the liver, valvular disease of the right side of the heart (pulmonary stenosis and tricuspid insufficiency without septa1 defects). Peripheral vasomotor symptoms, bronchoconstriction, and an unusual type of cyanosis; a clinical and pathological syndrome. Am Heart J 47: 795-817,1954. 4. Sjoerdsma A, Weissbach H, Undenfriend S: A clinical, physiologic and biochemical study of patients with malignant carcinoid. (Argentaffhoma) Am J Med 20:520-532, 1956. 5. Davis Z, Moertel CG, McIlrath DC: The malignant carcinoid syndrome. Surg Gynecol Obstet 137: 637-644,1973. 6. Grahame-Smith DG: Progress reports, the carcinoid syndrome.Gut 11: 189-192, 1970. 7. Adamson AR, Grahame-Smith DG, Peart WS, Starr M: Pharmacological blockade of carcinoid flushing provoked by cathecholamines and alcohol. Lancet 2:293-296. 8. Hill GJ: Carcinoid tumors. Pharmacol Therap 25:329-43, 1971. 9. Mengel CE, Weaver W,Holloway L, Anlyan WG: Adjuvant therapy of malignant carcinoid syndrome. Surgery 54: 182-190, 1963. 10. Mengel CE: Therapy of the malignant carcinoid syndrome. Ann Intl Med 62:587-599, 1965. 11. Moertel CG: Clinical Management of advanced gastrointestinal cancer. Cancer 36:675-682, 1975. 12. Martin RG: Management of carcinoid tumors. Cancer 26:547-551, 1970. 13. Tobey RA, Crissman HA: Comparative effects of three nitrosourea derivatives on mammalian cell cycle progression. Cancer Res 35:460-470, 1975. 14. Mengel CE, Kelly MG, Carbone PP. Clinical and biochemical effects of cyclophosphamide in patients with malignant carcinoid. Am J Med 38:396-404, 1965. 15. Gailitis RJ, Scheiber W: Malignant carcinoid syndrome and latest concepts in serotonin metabolism. Am J Surg 99:84-89, 1960. 16. Ureles AL, Murray M, Wolf R: Results of pharmacologic treatment in the malignant carcinoid syndrome. New England Journal Med. 267:435-438,1962. 17. Sjoerdsma A, Melmon KL: Severe flushing reactions responsive to steroids in patients with bronchial carcinoids. Lancet 2:791-792, 1964. 18. Melmon KL, Sjoerdsma A, Mason DT: Distinctive clinical and therapeutic aspects of the syndrome associated with bronchial carcinoid tumors. Am J Med 39:568-581, 1965.

Management of carcinoid syndrome.

Medical and Pediatric Oncology 6:77-83 (1979) Management of Carcinoid Syndrome Philip Bonomi, MD, Charlotte Hovey, MD, John R. Dainauskas, MD, Robert...
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