REVIEW ARTICLE Treatment of the Carcinoid Tumor and the Malignant Carcinoid Syndrome By Charles G. Moertel T an uncommon TUMOR, CARCINOID HE not but rare neoplasm, offers an exciting and multifaceted challenge for oncologic management-a challenge that demands informed multidisciplinary interaction of surgical and medical oncologists as well as diagnostic radiologists and laboratory scientists. It is a disease that presents many paradoxes-among the rarest sites for malignant disease the carcinoid is the most common of tumors-for example, the appendix, Meckel's diverticulum, and the small bowel; whereas among the most common sites for neoplasia the carcinoid is among the most rare of tumors-for example, the lung, colon, breast, and stomach. In surgical management only the most conservative of procedures is indicated for the early and most curable disease whereas very aggressive surgical treatment may be indicated in the patient who already has distant metastasis. In medical management frequently no treatment is the best treatment. The carcinoid tumor is a member of that fascinating family of neuroendocrine or APUD (amine precursor uptake and decarboxylation) tumors. Although it has been reported in essentially all tissues taking origin from the primitive entoderm, the overwhelming majority of these neoplasms begin in only three sites: the small intestine (usually in the terminal ileum), the appendix (usually in the tip), and the rectum (usually in a small area from 4-13 cm above the dentate line). In the latter two sites tumors are generally incidental findings and most require only local treatment. Carcinoids of truly malignant behavior most commonly originate in the small bowel and well over 90% of patients with the malignant carcinoid syndrome will have tumors primary to this origin. From the standpoint of histopathology, it is important to note that the pathologist cannot distinguish between benign and malignant forms of this disease by microscopy nor can he distinguish in ordinary hemotoxylin and eosin-stained preparations between the carcinoid and the other common gastrointestinal Journal of Clinical Oncology, Vol. 1, No. 11 (November) 1983 APUD tumor, the islet-cell carcinoma. Histochemical and immune staining may provide assistance but an overlap in polypeptide hormone production between these two neoplasms will still frequently blur distinction. In this regard it is noteworthy that rectal carcinoids seldom contain serotonin and are seldom, if ever, associated with the carcinoid or other endocrine syndromes even in the presence of massive metastasis. In a discussion of management of carcinoid tumors, the disease can for practical purposes be divided into three stages: localized, regional, and distant metastasis. MANAGEMENT OF LOCALIZED CARCINOID TUMORS The great majority of localized carcinoid tumors are encountered as interesting curios at the time of appendectomy or proctoscopic examination that was performed for other reasons. Treatment strategy and prognosis are determined by the size of the tumor. From 70%-90% of these lesions will be very small, one centimeter or less in diameter. ,2The only real threat that tumors of this size present to the patient with an appendiceal or rectal primary is when he is treated by an overzealous and injudicious physician. Very conservative local removal is all that is required, that is, simply appendectomy or fulguration of rectal lesions (Table 1). Cure rates of essentially 100% may be anticipated. Any risk of late metastasis is miniscule and greatly exceeded by the risk of radical surgery. The patient should be firmly reassured and there should be no subsequent periodic determinations of urine 5hydroxyindoleacetic acid (5HIAA) or other follow-up procedures. From the Mayo Clinic and Mayo Medical School, Rochester, Minn. Submitted July 22, 1983; accepted July 29, 1983. Address reprint requests to CharlesG. Moertel, MD, Comprehensive CancerCenter,Mayo Clinic,Rochester, MN 55905. © 1983 by American Society of Clinical Oncology. 0732-183X/83/0111-0010$2.00/0 727 Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. CHARLES G. MOERTEL 728 Table 1. Results of Local Therapy For Rectal 2 and Appendiceal Carcinoid Tumors"' Recurrence Rate* Primary Site Rectum Appendix Therapy Fulguration or local excision Simple appendectomy At 5 Years At 10 Years 0/85 0/41 0/108 0/83 NOTE. All tumors in the rectum were * 1 cm in diameter; 72% of the tumors in the appendix were < 1.0 cm, 22% were 1.0-1.4 cm, and 6% were 1.5-1.9 cm in diameter. *Data are no. patients who recurred/no. patients followed. In contrast, primary tumors measuring 2 cm or larger have a strong propensity to metastasis (80% or more) and these lesions should be treated by aggressive cancer operations, that is, right hemicolectomy for appendiceal lesions and anterior or AP-resection for rectal tumors. A disturbing gray zone is presented by those tumors measuring 1-2 cm in diameter where approximately half of the patients will have either regional, nodal, or distant metastasis. In many of these patients, the presence of metastasis will be apparent at the time of clinical or surgical examination. For those with apparently localized disease, clinical judgment must be applied based on actual size of the tumor (closer to 1 cm, closer to 2), degree of local invasion, necessity for AP versus anterior resection for rectal lesions, age of the patient, and estimated operative risk. Rectal lesions should be removed, at minimum, by wide local excision; if patients are so managed they should be carefully followed. Appendiceal lesions from 1-1.4 cm in diameter can probably be safely treated by simple appendectomy since we have observed no metastases among 24 such patients followed from five to more than 10 years. If only appendectomy is elected for appendiceal lesions 1.5-2.0 cm, such patients may represent one of the rare indications for a later planned second-look operation. Since the primary tumor for small intestinal carcinoids is usually small in size and arises in the deep mucosa, it rarely disturbs the physiology of the host sufficiently to cause clinical symptoms. A symptomatic tumor almost always has invaded the mesentery and usually has metastasized at least to regional nodes. Localized disease, therefore, is usually an incidental find- ing at necropsy or, less commonly, at surgery performed for other purposes. Similar to rectal and appendiceal tumors, these localized tumors are usually less than one centimeter in diameter. Metastasis may occur from such diminutive small bowel primaries but this is uncommon, there were only two of 104 patients with lesions less than one centimeter in diameter in our study. 3 Conservative local resection would seem adequate for such lesions, whereas wider segmental resection with dissection of the mesentery should be accomplished for lesions one centimeter or greater in diameter. A problem peculiar to carcinoids of the small bowel and stomach is a marked tendency to multicentricity. In our study of small bowel carcinoids, 29% of 207 patients presented with more than one primary lesion,3 and in a review of the literature 7% of 90 gastric carcinoids had multicentric primaries.' Frequently these are only two or three closely approximated lesions and require little or no extension of the usual surgical resection. Much more challenging is the patient who has many lesions extending over the entire stomach or throughout the entire small bowel where the surgical procedure required for complete removal would either be incompatible with life or could produce serious nutritional disability. Here the most appropriate surgery would seem to be subtotal gastrectomy or segmental small bowel resection encompassing the larger tumors or those producing or threatening small bowel obstruction, but leaving in place the smaller tumors (< 1 cm in diameter) unless they are easily accessible to limited local excisions. A reasonable hope can be entertained that these smaller lesions will never metastasize or will require many years to do so. Periodic endoscopic examination can be used to monitor unresected gastric lesions. For small bowel tumors a case could again be made for a planned second-look operation. MANAGEMENT OF CARCINOID TUMORS WITH REGIONAL SPREAD All patients with carcinoid tumors and metastasis confined to regional nodes should be treated with aggressive cancer surgery. Resection of more remote nodal involvement or extensive regional invasion, which might seem to be useless and excessive surgery for gastric or colorectal adenocarcinomas, will produce a high frequency Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. CARCINOID TUMOR AND SYNDROME of apparent cures or very long-term survival in patients with carcinoid tumors. Among 17 patients with peritoneal and nodal metastases where all visible malignant disease could be resected, we recorded a 71% five-year survival rate.3 It must be remembered, however, that in this indolent disease five-year survival does not necessarily indicate cure. Among 10 such patients who developed recurrence after initial resection we found the median interval to recurrence was seven years and nine months with a range to 20 years. It is also of interest that among eight patients we found to have disease confined to regional nodes or peritoneum which was unresectable, 38% survived five years. There is no surgical adjuvant treatment that should be applied to patients with resected carcinoid tumor since none is known to be effective and none has been tested. If regional disease cannot be resected, heroic efforts at partial resection or "debulking" are probably not justified. Certainly, however, every attempt should be made to bypass existing or impending areas of small bowel obstruction. Radiation therapy has occasionally been attempted for locally unresectable carcinoid tumor with reports of regression seen on second-look operation;' but there is no evidence that such treatment contributes to patient survival, which will generally be very long with no treatment at all. MANAGEMENT OF MALIGNANT CARCINOID TUMORS WITH DISTANT METASTASIS AND WITH THE MALIGNANT CARCINOID SYNDROME Most patients with distant metastasis of carcinoid tumor will have a small-bowel primary and the great majority will have liver involvement which will usually be the clinically dominant site of disease. Osseous metastasis may occasionally be troublesome. Metastatic carcinoid tumor has an unusual predilection for the eye and the orbital region, and a surprising 21 such cases have been recorded in the literature. 6 Other metastatic sites are rare and usually are seen only as the patient approaches terminal status. The clinical presentation of metastasis often will be complicated by the malignant carcinoid syndrome which will most frequently consist of flushing and/or diarrhea of varying severity. Approximately 20% of such patients will develop carcinoid heart disease detectable by usual clinical 729 means, 7 although it appears that a substantially larger proportion may have subclinical valvular involvement detectable by echocardiography or discovered at necropsy. Tricuspid regurgitation and/or stenosis and pulmonary stenosis are the most common lesions. In our experience less than 10% of carcinoid syndrome patients will develop symptomatic cardiac disease and only about 5% will die a cardiac death. Other manifestations such as asthmatic attacks, osteoarthropathy, or pellagra are still less common. Although in general the frequency and severity of symptoms of the syndrome are related to serotonin production as reflected by urine 5HIAA excretion, there are frequent exceptions with florid syndromes in patients with minimal 5HIAA excretion as well as marked elevation of 5HIAA to 500 or more mg per 24 hours with no manifestations of the syndrome at all. For the syndrome to occur it seems necessary that tumor products have direct access to the systemic circulation with no intervening hepatic detoxification. Usually (>95%) this implies metastasis to the liver although pelvic metastasis or local tumor invading the right peritoneal gutter can also provide the required systemic access. Very rarely the syndrome may occur without metastasis in patients with carcinoids in ovarian or testicular teratomas where, in contrast to other carcinoids, the primary tumor may be quite bulky. As a dogma it can be stated that if the patient has clinically detectable hepatic metastasis and no elevation of urine 5HIAA, he does not have the carcinoid tumor. Certainly there have been reported cases of patients only excreting 5-hydroxytryptophane or other substances but such patients are exceedingly rare. It is far more likely that the patient without 5HIAA elevation has an islet-cell carcinoma or other neuroendocrine tumor that has been misinterpreted by the pathologist as carcinoid. A second dogma is that if the patient flushes and does not have either an elevated 5HIAA or liver metastasis detectable by usual diagnostic studies, he does not have the carcinoid syndrome. Again, exceptions can be quoted but they are so exceedingly rare that patients would probably be better off if physicians forgot they existed. A unique feature of carcinoid tumor metastatic to liver, shared with islet-cell carcinoma, is that the patient may have extensive involvement and Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. CHARLES G. MOERTEL 730 considerable hepatomegaly but little or no impairment of nutrition or activity level or other associated symptoms. Liver function tests will characteristically show disproportionately little impairment when compared to those in patients with a comparable extent of liver involvement by other carcinomas. Another unique feature of metastatic carcinoid tumor which contrasts with other malignant diseases is a characteristically indolent clinical course. Among 60 patients with the malignant carcinoid syndrome we found the median survival from first flush to be 38 months and from first determination of an elevated 5HIAA to be 23 months.7 The range extended to 17 years. In an Eastern Cooperative Oncology Group (ECOG) study the median survival of 76 such patients chosen for chemotherapy was 22 months from the diagnosis of unresectable malignant disease. 8 It is not uncommon for patients with metastatic carcinoid tumor to live many years with no treatment and eventually die of unassociated cause with their malignant disease having no apparent influence on their longevity. SURGICAL TREATMENT Even if the patient initially presents with established hepatic metastasis, high levels of 5HIAA, and a clinically manifest carcinoid syndrome, the first therapeutic option to be considered should be surgical. The symptoms of diarrhea, abdominal pain, and weight loss are more likely to be due to a partially obstructing small bowel lesion than to circulating hormones. The simple expedient of bypassing the site of obstrucTable 2. tion may provide years of comforable life in spite of advanced malignant disease. It should be emphasized that with partial obstruction due to carcinoid tumor a small bowel roentgenogram will usually be negative. For carefully selected patients, the most successful and reliable means of treating the syndrome itself is resection of hepatic metastasis.9 Patients selected for this procedure should have an isolated metastatic mass or cluster of masses confined to a single surgically accessible area of the liver and obviously they should be good operative risks. We have employed hepatic lobectomy or wedge resection in five patients with a symptomatic carcinoid syndrome who appeared preoperatively to have solitary metastatic masses (Table 2). At surgery, however, two of these patients had unsuspected smaller lesions; and in one of these, small nodules were palpated that could not be resected. All five of these patients had striking relief of their carcinoid syndrome with a complete biochemical response and these responses were of long duration. Two additional patients without a symptomatic syndrome had resection of hepatic metastasis which was found incidentally at the time of small bowel surgery. One of these patients developed recurrence after nine years and died of disease at 12 years. The other remains alive without recurrence at 11 years. Certainly for appropriate patients such treatment can be of substantive value, but this endorsement should not be extended to simply whittling away at areas of a diffusely involved liver for the sake of producing a partial reduction of 5HIAA. The operative risk is not justified Treatment of Carcinoid Tumor by Resection of Hepatic Metastasis Greatest Diameter Sex/Age (Years) ofSexAge Resecteddof Lesion(s) Urine 5HIAA (mg/24 hr) Preoperative Postoperative F/52 14 cm 81 <6 M/59 15 cm 219 <6 5.5 cm 26 <6 3 and 10 cm 56 <6 0.5 (3 lesions), 1, and 10 cm 0.7 and 1.3 cm 2.5 and 3.5 cm 94 <6 19 <6 <6 <6 F/72 M/60 F/69 M/68 F/57 End Result Complete relief of syndrome; recurrence at 27 mo; living 3 years Complete relief of syndrome; osseous metastasis 4.5 yrs; death 5 yrs Complete relief of syndrome; living, no recurrence at 16.5 mo Complete relief of syndrome; mediastinal metastasis at 7 mo; death 26 mo Complete relief of syndrome; death with heart disease at 3 yrs, 11 mo No syndrome preoperatively; living, no recurrence 11 years No syndrome preoperatively; recurrence 8 yrs; death 11 yrs Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. 731 CARCINOID TUMOR AND SYNDROME under such circumstances and hepatic artery occlusion probably provides a safer and equally effective means of accomplishing this purpose (vide infra). A third possible area of surgical intervention would be valve replacement for severe and disabling carcinoid heart disease. Although the technology is available for such a procedure, it would seem obvious that cardiac surgery of such magnitude should only rarely be considered in a patient who has known advanced cancer. We have found that most of our patients with carcinoid heart disease die of cancer rather than cardiac failure. Nevertheless there will be the exceptional patient who has shown an extraordinarily indolent course of his malignant disease and who is otherwise in excellent general condition where the possibility of surgical correction of a cardiac disability could be entertained. In reviewing 13 such valve replacements recorded in the literature prior to 1980, Strickman et al found one operative death, six deaths at periods ranging from one month to six years after surgery, and six patients alive at from four months to eight years.1 o The mean and median survival for all of these patients will probably exceed two years. Two other indications of a less common nature for possible surgical intervention should also be considered. The first is mesenteric arterial occlusion. We have observed this on several occasions as a catastrophic cause of death and we have also seen several instances of impending mesenteric thrombosis in patients operated on for presumed mechanical obstruction. This is a unique complication of mesenteric abdominal carcinoid tumor presumably because of the often associated marked fibrotic reaction. The diagnosis should be considered in patients who seem to have abdominal pain problems disproportionate to the effects of tumor per se and certainly in any patients who have signs of peritoneal irritation. Resection of the involved bowel segment can be lifesaving. Another rare complication of metastatic carcinoid tumor requiring surgical correction is extrinsic obstruction of the low sigmoid colon by a mass of carcinoid tumor with associated fibrosis localized to the pelvis. Radiologically the patient will have a smooth concentric napkinring type narrowing of the low sigmoid but no evidence of any mucosal involvement. Under these circumstances a colostomy will be required. CHEMOTHERAPY Because the patient with metastatic carcinoid tumor may frequently have a very long and comfortable life expectancy without treatment, and because of the very limited and transient accomplishments of currently available chemotherapy, it would seem appropriate for the oncologist to restrain any urge to offer cytotoxic drugs to the patient with early stage disease who has either minor or no symptoms of tumor or syndrome. Such therapy should be reserved until symptoms are significantly interfering with the patient's activities or until poor prognostic signs develop such as clinical evidence of carcinoid heart disease (median survival, 14 months) or urine 5HIAA excretion in excess of 150 mgs per 24 hours (median survival, 11 months). 7 In selecting carcinoid tumor patients for chemotherapy it is important to be certain that one is indeed treating carcinoid tumor. There would seem to be little doubt when dealing with the patient who has previously had a small bowel primary identified surgically, who has high level of 5HIAA in the urine, and who has a liver biopsy histologically consistent with a neuroendocrine tumor. The problem arises in patients who have liver metastasis but no elevation in 5HIAA or who have liver metastasis and an elevated 5HIAA but no identified primary. In the former instance one must be very suspicious that the tumor has been misdiagnosed by light microscopy examination of a liver biopsy core that was perhaps inadequate for confident interpretation. In the latter instance one must raise the question of a noncarcinoid tumor that may be more responsive to other specific treatment approaches. Under these circumstances the pathologist can frequently be very helpful through electron microscopy which can be diagnostic for at least a neuroendocrine tumor. Silver staining and immunohistologic techniques can be helpful in identifying the presence of serotonin or other hormonal substances. A computerized tomographic scan of the pancreatic area can also be a very useful investment. In this further study one is specifically pursuing evidence for islet-cell carcinoma, which may be either nonfunctioning or serotonin producing, and where streptozoto- Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. 732 CHARLES G. MOERTEL cin-based regimens may be of much more substantial benefit. In ECOG studies for example, the combination of 5-fluorouracil (5-FU) and streptozotocin produced a 63% response rate in islet-cell carcinoma with a median response duration of 17 months whereas this same regimen produced only a 33% response rate in carcinoids with a median duration of only seven months. 8"' Small-cell carcinoma of the lung may also be confused with carcinoid and demands an entirely different treatment approach. One is also trying to avoid subjecting patients with drug resistant noncarcinoid tumors to essentially useless therapy. In the ECOG study mentioned above, response rates were substantially reduced in patients with no known site of primary and with no 5HIAA elevation. 8 Chemotherapy of the carcinoid tumor has frequently been reported in a rather sketchy fashion with the usual study involving only a handful of patients on any given regimen. Criteria for response have varied and are often not clearly stated. This discussion will center on our Mayo Clinic experience as well as a few other reports with adequate patient numbers to provide a reasonable therapeutic perspective. In all of our studies we have required tissue confirmation of metastatic carcinoid tumor and a measurable indicator of response to theapy. Acceptable indicator lesions included a tumor mass measurable in two dimensions, malignant hepatomegaly if the liver contains proven metastasis and measures at least 5 cm below the costal margin or xyphoid on quiet respiration, or a urine 5HIAA excretion on two consecutive occasions of at least 25 mg per 24 hours (normal to 6 mg). To declare an objective response we have required a 50% reduction in the product of perpendicular diameters of a mass lesion, a 30% reduction in the sum of liver measurement below the costal margins and xyphoid, or a 50% reduction in 24-hour urine 5HIAA excretion. An ECOG evaluation has shown that 5HIAA excretion is a Table 3. Correlation of Measured Tumor Response and Urine 5HIAA Responses Tumor Measurement Response 5HIAA Response Improved Stable Progression Improved Stable Progression 8 5 ... 4 14 2 ... 2 2 useful marker for therapeutic effect that corresponds very closely to measured change in tumor mass (Table 3). Our own experience as well as that of Feldmanl2 has shown that the blood serotonin level is not a useful marker since it may fluctuate widely from time to time in any given patient and has reduced sensitivity for diagnosis of metastatic carcinoid when compared to 24hour urine 5HIAA. The obvious limitation of urine 5HIAA is the reliability of compliance whenever patients are entrusted with specimen collection. Our Mayo Clinic experience, encompassing more than 200 individual patient treatment studies, is displayed in Table 4. All patients had advanced and symptomatic disease and all had at least biochemical evidence of the carcinoid syndrome. All patients, however, were ambulatory and maintained a good state of nutrition. Single drug treatment was administered in standard dosTable 4. Chemotherapy of the Malignant Carcinoid Tumor (Mayo Clinic Experience) Regimen Single agents Adriamycin 5-Fluorouracil Actinomycin D DTIC Tamoxifen Cisplatinum Melphalan Streptozotocin (STZ) Fluorometholone Mitomycin C BCNU Cyclophosphamide (CTX) Hydroxyurea Other (1 each) Drug combinations STZ + 5-FU Methotrexate + CTX STZ + CTX 5-FU + BCNU 5-FU + Methyl CCNU + Adriamycin Other (1 each) Response Objective Duration No. of Response Median (Mo) Patients (%) 33 19 17 15 11 10 7 6 5 4 3 2 2 6 43 12 7 5 1 2 (21) (26) (6) (13) 3.5 3 ... 4.5 1 (10) 1 1 ... 14 (33) ... 12 3 2 1 4 3* ... 7 *STZ + BCNU, 5-FU + mitomycin C, 5-FU + CTX + prednisone. Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. CARCINOID TUMOR AND SYNDROME age regimens. Drug combinations were either administered in dosage schedules recommended by others or established by us as producing definite but clinically tolerable toxicity. Because our early experience as well as the experience of others had indicated that chemotherapy may occasionally trigger off a potentially lethal carcinoid crisis, patients with a clinically florid carcinoid syndrome or with a 24-hour 5HIAA excretion exceeding 150 mg were administered first courses of therapy at 50% of the planned total dosage. If this is well tolerated we have then escalated later courses to full dose. Adriamycin Our largest single agent experience has been with Adriamycin (60 mg/m 2 every three weeks) and 21% of our patients responded for a median time of three months. The ECOG reported an identical 21% response rate among 81 patients. Workers at M.D. Anderson Hospital and Tumor Institute, Houston, reported frequent responses among patients treated with a variety of Adriamycin-containing combinations as well as with Adriamycin-DNA complex.14 5-FU Our experience with 5-FU given by rapid IV injection in an intensive course (500 mg/m 2 per day for five days every five weeks) showed a rate and duration of response comparable to that we have observed with Adriamycin. The ECOG has also recorded an 18% response rate with the same regimen of 5-FU among 11 patients. 8 Rochlin et al reported three responses among seven patients.'5 The M.D. Anderson group, however, reported no responses among 12 patients treated with systemic 5-FU by various dosages and schedules.'14 Dacarbazine (DTIC) DTIC also appears to have some activity as demonstrated by our results'6 as well as those of Kissinger et al who treated two patients and reported objective improvement in one and subjective improvement in the other." The ECOG is currently evaluating this agent in a larger patient group to put its activity into perspective. Actinomycin D In 1967 Dolinger and Golbey reported, in abstract form, three responses among five carci- 733 noid tumor patients treated with actinomycin D.'8 Our experience is less favorable with only one partial response among 17 patients.' 6 This single patient, however, has had striking clinical improvement maintained over eight years of continuous therapy. Alkylating Agents Although the alkylating agents melphalan and cyclophosphamide had been reported in years past to show activity,'9 our results among nine patients treated with these agents were entirely negative as were the results with cyclophosphamide among eight patients treated by the ECOG,8 six patients treated by Melia et al, 20 and three by Legha et al. 14Rochlin et al reported no response in three patients treated with melphalan.'5 It seems doubtful that alkylating agents have an important role in the management of the carcinoid tumor. Streptozotocin Since streptozotocin has considerable activity in a related gastrointestinal neuroendocrine tumor, the islet-cell carcinoma, it was our hope that activity might be shared with the carcinoid. Although we demonstrated only one clear-cut response out of six patients treated, two additional patients had interesting mixed responses with definite regression of some lesions and progression of others. Stolinsky et al reported one response among four patients treated with streptozotocin, 2' and activity was also recorded by Feldman et al. 22 Schein et al, however, reported no responses among eight patients.23 Whereas streptozotocin may have some activity in carcinoid tumor, it would seem evident that this in no way matches the therapeutic effect of this agent in islet-cell carcinoma. Tamoxifen We evaluated tamoxifen because of scattered reports of estrogen receptor (ER) positivity of carcinoid tumors and because of two very favorable single case reports. The first involved symptomatic improvement but no objective benefit was documented. 24 The second case report, however, also reported clear evidence of tumor regression plus reduction of urine 5HIAA from 174 to 15 mg per 24 hours. 25 Although we have also observed occasional borderline or slightly elevat- Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. 734 ed ER titers in carcinoid tumors, we did not observe any evidence of antineoplastic activity among 11 patients treated with tamoxifen at a dosage of 40 mg daily. Only one of nine patients with clinically evident carcinoid syndromes had substantive symptomatic improvement. Other Single Agent Approaches Because of the relative rarity of metastatic carcinoid tumor a number of important antineoplastic agents have yet to have an adequate phase II study in this disease. Experience with cisplatinum has not, as yet, been reported. We have observed one definite objective response among 10 patients treated with a dosage of 90 mg/m2 and our studies of this agent are still in process. VP16 (Etoposide) has considerable activity in the related small-cell carcinoma of the lung and the ECOG group is currently conducting a phase II trial of this agent. Certainly the four patients we have treated with mitomycin C represent an inadequate evaluation but even in this small number we have observed one response. Another interesting and, as yet, unpursued report from the Royal Marsden Hospital, London, involved the striking response of a single patient to cyprohepatadine treatment.26 There was marked regression of hepatic metastasis and a grossly elevated urine 5HIAA reduced to undetectable levels. They also reported a second objective response in a nonfunctioning APUD tumor metastatic to liver. Another interesting report from the University of Uppsala, Uppsala, Sweden, has indicated possible activity of human leukocyte interferon. 27 These investigators observed marked symptomatic relief with modest but consistent reductions in 5HIAA excretion among six patients with the malignant carcinoid syndrome. These patients did not meet the criteria for objective response stated above, but on the other hand they were treated with very low doses of interferon. Higher dose treatment is now possible using recombinant DNA-produced interferon and a study of this approach is currently ongoing at the Mayo Clinic. Since metastatic carcinoid tumor tends to be strongly dominant in the liver, hepatic arterial administration of cytotoxic drugs is attractive in theory and there have been scattered case reports claiming success. Perhaps the most definitive re- CHARLES G. MOERTEL port to date is that of Melia et al who treated 12 patients with 5-FU by hepatic artery infusion and three by portal vein infusion. 20 Only one (7%) of these 15 patients experienced symptomatic relief and only two (13%) showed some evidence of partial objective response. As with hepatic artery infusion of cytotoxic drugs for other tumors, it would appear that no advantage has been clearly demonstrated when compared to much simpler and less costly systemic administration. Drug Combinations Combination chemotherapy of metastatic carcinoid tumor was first reported by Mengel and Shaffer who used methotrexate plus cyclophosphamide and reported a 55% response rate in 11 patients. 19 Since this is the most favorable response rate reported in a major oncology test, CancerMedicine, this regimen has been accepted by many as standard therapy for this disease. Regrettably, according to the criteria for response stated above, our group did not observe a single response among 16 patients and only one of these patients could conceivably be credited with minor and transient symptomatic improvement. 28 Our later experience centered around streptozotocin combinations because this agent seems to have some activity and has minimal bone marrow toxicity. It, therefore, can be combined with essentially full doses of other cytotoxic drugs. Based on our initial favorable experience with streptozotocin plus 5-FU, this combination together with the streptozotocin plus cyclophosphamide combination was brought into phase III study by the ECOG. 8 The latter combination was studied because Mengel and Shaffer had reported activity with cyclophosphamide as a single agent."' Streptozotocin was given in a five day course of 500 mg/m 2 per day every five weeks. 5FU also was given in five day courses at 400 mg/ m2 per day by rapid intravenous injection concomitant with courses of streptozotocin. Cyclophosphamide was given IV at 1,000 mg/m 2 on days 1 and 22 of each cycle. Although a somewhat more favorable response rate was achieved with the 5-FU and streptozotocin combination, this difference was not statistically significant nor were differences in duration of response, interval to progression, or survival. Response rates were more favorable in patients with good per- Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. CARCINOID TUMOR AND SYNDROME 735 formance status, in those with a documented carcinoid syndrome, and in those with small bowel primaries versus pulmonary or unknown primaries. Response durations were disappointing with a median of only seven months in both the ECOG study overall and in our Mayo Clinic experience with streptozotocin and 5-FU. Because treatment with the streptozotocin regimens were characterized by substantial nausea, vomiting, and anorexia that seemed to counterbalance any favorable antineoplastic effects, a more recent ECOG study evaluated giving the five day courses of streptozotocin at a longer 10-week interval with courses of 5-FU repeated every five weeks. 3 Regrettably nausea and vomiting remained a significant problem and the response rate was 23% in comparison to 33% with the initial study regimen. The studies done by other groups have primarily involved combinations including 5-FU, Adriamycin, cyclophosphamide, and streptozotocin. 29-31 Response rates have been in the 20%-40% range, and although case numbers are small, none of these combinations appear to be outstanding in therapeutic effectiveness (Table 5). HEPATIC ARTERY OCCLUSION The facts that metastatic carcinoid tumor is so often clinically limited to the liver, that the carcinoid is a very vascular tumor, and that metastatic carcinoid tumor to the liver seldom produces significant impairment of liver function until very late stage disease combine to make hepatic artery occlusion an attractive treatment consideration. This is a rational approach because it will take away approximately 90% of oxygenation from the tumor causing cell death Table 5. Recent Studies of Combination Chemotherapy For Metastatic Carcinoid Tumor Reporting Group Eastern Cooperative Oncology Group 8 Eastern Cooperative Oncology Group 12 M.D. Anderson 29 Southwest Oncology Group 30 New York Memorial 31 whereas normal liver will lose only 50%. The remaining oxygenation for normal liver comes from portal vein flow and this is usually sufficient to sustain viability until rearterialization occurs. Hepatic artery ligation for most cancers has not been notably successful since by the time the patient with hepatoma or metastatic colon cancer or metastatic pancreatic carcinoma recovers from the operation, the cancer has usually grown right back. The carcinoid, however, takes a long time to grow back. In a review of the literature through 1982 we found 32 reasonably well-documented experiences with surgical ligation of the hepatic artery for treatment of the carcinoid syndrome. 20 ,32 It is obvious that this is not an innocuous procedure. There have been a number of significant complications including acute hepatic necrosis, liver abscess, carcinoid crisis or acute cardiovascular collapse, and an instance of perforated gallbladder in a patient who did not have a concomitant cholecystectomy. Seven patients died in the postoperative period for an operative mortality of 22%. Among the 25 patients surviving surgery, however, 18 were reported to have shown either striking improvement or a complete clinical response. In eight patients these results have apparently been maintained for in excess of one year. It is difficult to know how much validity to accord such a cumulative review of the literature since the largest single series is only four patients who survived surgery; it is unlikely that anyone would report just one, two, or three cases of treatment failure or that any journal would accept such a report. We felt that a larger consecutive series would provide a more representative picture. We therefore studied a total of 11 patients all of whom had significant symptoms of the Regimen Streptozotocin (STZ)* + 5-FU STZ + cyclophosphamide (CTX) STZ** + 5-FU 5-FU + Adriamycin + CTX 5-FU + Adriamycin + methyl CCNU; + mitomycin C 5-FU + Adriamycin + CTX + STZ 5-FU + CTX + STZ STZ (weekly) + Adriamycin Objective Response Rate (%) 14/42 (33) 12/47 (26) 18/80 (23) 3/8 2/9 7/20 (35) 2/5 4/10 (40) *Streptozotocin in five-day courses repeated every six weeks. **Streptozotocin in five-day courses repeated every 10 weeks. Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. 736 CHARLES G. MOERTEL carcinoid syndrome with a median preoperative 5HIAA level of 207 mg per 24 hours (range, 64438 mg) (Table 6).9 One patient did not have the planned ligation because portal vein flow was not demonstrated in preoperative angiogram. Surgery for the remaining 10 patients was relatively standard involving ligation of the hepatic artery just distal to the gastroduodenal as well as vessels in the hepatic round and triangular ligaments. Cholecystectomy was performed because of the possible threat of an infarcted gallbladder with perforation. Although we did not cover our patients with antiserotonin agents they tolerated anesthesia very well and there were no carcinoid crises. One patient died six days postoperatively with a hepatorenal syndrome. In all surviving patients there was a prompt and striking increase of a serum glutamic oxaloacetic transaminase reaching as high as several thousand units as well Table 6. Treatment of Malignant Carcinoid Syndrome by Hepatic Artery Ligation (Mayo Clinic Experience) Urine 5HIAA (mg/24 hr) Sex/Age Preop- Postop(Years) erative erative F/45 245 23 F/66 64 35 M/53 107 34 M/51 112 19 M/59 215 40 F/51 369 78 M/53 361 138 M/40 438 138 F/48 109 103 M/72 198 ... End Result Complete relief of syndrome; progressive disease at 10 mo; death at 11 mo Complete relief of syndrome; osseous metastasis at 4 mo; living at 30 mo Complete relief of syndrome; progressive disease at 5 mo; living at 32 mo Complete relief of syndrome; progressive disease at 16.5 mo; living at 36 mo Complete relief of syndrome; progressive disease at 4.5 mo; living at 31 mo Complete relief of syndrome; progressive disease at 2 mo; living at 26 mo Complete relief of syndrome; progressive disease at 5 mo; death at 12 mo Marked relief of syndrome; pulmonary metastasis at 3.5 mo; death at 10.5 mo No relief of syndrome; living at 13 mo Death postoperatively day 6 of hepatorenal syndrome as less dramatic increases in the alkaline phosphatase and occasional slight increases in serum bilirubin. Within seven days these values had returned to normal. Fever in these patients was universal and lasted for a week or more but there were no episodes of abscess or sepsis. A single patient had a transient renal shutdown. Eight of the nine surviving patients showed a rapid decrease in urine 5HIAA to less than 50% of pretreatment levels. This was associated with prompt and usually complete relief of symptoms of the syndrome. Whereas these responses were clinically impressive, in no instance did the urine 5HIAA return completely to normal. The median 5HIAA level at the time of best response for all patients was 40 mg per 24 hours. Two of our patients have shown evidence of metastasis to other sites after just a few months and the remainder have had slow regrowth of their hepatic metastasis with increasing levels of urine 5HIAA and recurrence of flushing. The median duration of response in our entire group was only five months. More recently we have been evaluating hepatic artery occlusion accomplished by percutaneous catheterization and plugging with either gel foam or Ivalon (Unipoint Industries, High Point, NC). Our early results would indicate that dearterialization can be accomplished and clinical results are probably comparable to those achieved with the open surgical procedure. Nevertheless, it seems evident that although hepatic artery occlusion will produce a high frequency of objective responses and relief of the carcinoid syndrome, it does not provide long-term control of the disease. TREATMENT OF THE CARCINOID SYNDROME Symptomatic therapy of the malignant carcinoid syndrome at present is in a fascinating state of confusion reflecting a parallel state of confusion regarding the pathophysiologic mechanisms involved in generating the flush, the diarrhea, the pulmonary symptoms, and the cardiac lesions. Attempts have been made to classify varieties of flushing according to primary tumor site and presumed site-specific hormonal excesses. Intense persistent flushing with cyanosis, conjunctival injection, and facial edema has been classified as "foregut" and has been related to a higher 5hydroxytryptophan production in tumors primary to the lung, stomach, or thymus. The more Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. 737 CARCINOID TUMOR AND SYNDROME commonly observed transient erythema of the face and upper trunk has been classified as "midgut" and related to bradykinin and/or serotonin release in association with primary tumors of the ileum or cecum. Although there may be some trend towards site-specific flushing characteristics, practical experience indicates there are broad overlaps. The very rare "histamine" flush with generalized patchy, spreading, intensely pruritic areas of cutaneous erythema and edema does seem to be characteristic of gastric carcinoids and clearly associated with excessive circulating histamine. What is essentially today's state of the art knowledge of pharmacology of the carcinoid syndrome was thoroughly and lucidly summarized by Sandler in 1968.33 The carcinoid flush may be stimulated by exertion, emotional stress, food intake, alcohol intake, calcium infusion, epinephrine, norepinephrine, pentagastrin, or dopamine. Much of this spectrum suggests the possibility of an adrenergic trigger mechanism. Although serotonin may be the primary mediator of the flush and diarrhea for most patients, this concept has been challenged because flushes are not usually accompanied by increases in circulating serotonin. Since carcinoids have also been found to produce kallikrein, it has been hypothesized that adrenergic stimuli mediated through catecholamines lead to kallikrein release which in turn acts on a serum globulin, kininogen, to release and activate bradykinin. Bradykinin is thought by some to be the ultimate mediator of the flush by its induction of dilatation of small blood vessels. Increases in bradykinin, however, have also not been consistently associated with flushing so alternative mediators have been suggested such as prostaglandins or other substances yet to be identified. An attractive hypothesis is that flushing may represent a synergistic interaction of bradykinin and serotonin. This lack of clear definition of mechanisms involved in the production of the carcinoid syndrome is reflected by a lack of clear definition of effective treatment methods. The many and varied pharmacologic approaches suggested for therapy are listed in Table 7, classified according to possible mechanisms of action. Each of these agents have been claimed effective either alone or in combinations. These therapeutic claims, however, have almost always been anecdotal in Table 7. Agents Reported To Produce Symptomatic Relief of Carcinoid Syndrome According To Suggested Mechanism of Action Adrenergic blocking agents Clonidine34 3 5 36 Phenoxybenzamine , 36 Phentolamine 37 Propranolo1 Kinin antagonist 38 Chlorpromazine synthesis of serotonin Inhibition 38 a-methyl dopa 40 5-Fluorotryptophan 41 Parachlorophenylalanine (PCPA) Peripheral serotonin antagonists 42 Cyproheptadine 43 Methysergide H1 histamine receptor antagonist Cyproheptadine42 H2 histamine receptor antagonist Cimetidine"44 Unknown mechanisms of action Corticosteroids45 Somatostatin46 nature based on experience with very few patients, sometimes only one. Quantitation of therapeutic effect has often been imprecise and controls have usually been lacking. It is evident that none of the listed agents are reliably effective in palliating all symptoms of the syndrome in all patients. It is also apparent that for occasional patients some of these agents may be quite helpful. The adrenergic blocking agents presumably exert their effect by inhibiting catecholamine triggering of the kallikrein-bradykinin sequence. These agents as well as the histamine antagonists have seemed, by casual review of the literature, to have their greatest frequency of favorable therapeutic effects in patients with pulmonary or gastric primary tumors or in patients with the "foregut" type flush. Phentolamine is the least desirable of these agents because of a high incidence of intolerable side effects at therapeutic doses. Chlorpromazine is presumed to act as a kinin antagonist but may simply exert its effect (it is not often effective) by blocking the emotional stimulus to flushing. Among the inhibitors of serotonin synthesis, alpha methyldopa has been disappointing and any useful effects have really only been shown at very high doses (4-6 g per day) which would not Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. 738 be tolerable in clinical practice. 5-Fluorotryptophan is not currently available and its documented credentials probably do not justifty availability. Parachlorophenylalanine will reduce 5HIAA excretion, will frequently help diarrhea, and will rarely help flushing. These gains are minor and more than counterbalanced by the side effects of the drug which include psychiatric and hypersensitivity reactions, both of which preclude longterm management. The peripheral serotonin antagonists, cyproheptadine and methysergide, presumably block serotonin receptors. They will occasionally relieve diarrhea but seldom effect flushing. Although other antihistamines such as chlorpheniramine or diphenylhydramine have occasionally been tried, their effectiveness has not been well documented. Among drugs of this class, cyproheptadine is recommended because of its activity as a serotonin antagonist as well as a histamine antagonist. Evidence for useful therapeutic activity of cimetidine, an H2 antagonist, is still fragmentary. Among those agents with an unknown mechanism of action, corticosteroids have occasionally shown some benefit, particularly in patients with bronchial primaries, but unless the gain is striking it will be outweighed by the side effects of long-term administration. Somatostatin at present can only be given by parenteral route and therefore would be unsuitable for chronic therapy. It could play some role in the management of a carcinoid crisis, but effectiveness under these circumstances has not, as yet, been reported. An interesting recent study has documented that fenfluramine caused reproducible decreases in 5HIAA excretion, in a patient with a symptomatic syndrome, presumably by causing serotonin depletion.47 From a practical clinical standpoint for most patients with the carcinoid syndrome, a strong case can be made for therapeutic nihilism. Flushing is usually only a minor nuisance that is easily managed by a word of reassurance. Diarrhea is usually mild and frequently responsive to timehonored bowel-slowing nostrums, for example, codeine, tincture of opium, diphenoxylate, or loperamide. A vigorous and costly pharmacologic assault on such minor symptoms holds a greater risk of producing disability than the symptoms themselves. For those patients who are experi- CHARLES G. MOERTEL encing major discomfort or disability, a trial and error approach may be used perhaps first attempting the adrenergic and histamine antagonists or corticosteroids for patients with "foregut" syndromes and first attempting the peripheral serotonin antagonists for patients with the more common "mid-gut" syndromes. Failure, particularly in reducing flushing, must be anticipated. Clearly in the symptomatic management of the carcinoid syndrome there is need for well controlled clinical trials involving adequate numbers of patients so that a reasonable perspective can be obtained regarding rational and effective pharmacologic therapy. SUMMARY Certainly in treatment of the carcinoid tumor surgery has a well-established curative and palliative potential. The primary challenge is a knowledgable marriage between stage of disease and aggressiveness of operative procedure. Nonsurgical treatment of the malignant disease per se has thus far not produced optimum results and, in the opinion of this author, should still be confined to a clinical research setting. It would seem very doubtful, however, that the more mundane types of trials, empirically testing drug after drug and arbitrarily concocted drug combinations, is the most productive road to follow. There is an evident need for more sophisticated approaches to this tumor, which has unique metabolic characteristics that should be pharmacologically exploitable. Past experience has indicated that such a setting may permit dramatic therapeutic accomplishment. There is a strong need for animal models or established cell lines which would facilitate preclinical therapeutic exploration. The carcinoid syndrome presents an unparalleled opportunity for fundamental physiologic observations and for experimental therapeutic study that can have applicability not only in palliating the syndrome itself but also in the management of other pathophysiologic states that may involve more subtle abnormalities of the same hormonal mechanisms. The patient with the carcinoid tumor should not just be a fascinating curio for grand rounds exhibition. He should be a focal point for research involving an experienced, multidiscipli- Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. CARCINOID TUMOR AND SYNDROME nary clinical team supported by devoted basic scientists. If our patient resources and efforts can be concentrated in this manner, the carcinoid should be a strong candidate for the next medically curable human cancer. REFERENCES 1. Caldarola VT, Jackman RJ, Moertel CG, et al: Carcinoid tumor of the rectum. Am J Surg 107:844-849, 1964 2. Moertel CG, Dockerty MB, Judd ES: Carcinoid tumors of the vermiform appendix. Cancer 21:270-278, 1968 3. Moertel CG, Sauer WG, Dockerty MB, et al: Life history of the carcinoid tumor of the small intestine. Cancer 14:901912, 1961 4. Pestana C, Beahrs OH, Woolner LB: Multiple (seven) carcinoids of the stomach. Mayo Clin Proc 38:453-456, 1963 5. Kean TJ, Rider WD, Harwood AR, et al: Whole abdominal radiation in the management of gastrointestinal carcinoid tumor. Int J Radiat Oncol Biol Phys 7:1519-1521, 1981 6. Riddle PJ, Font RL, Zimmerman LE: Carcinoid tumors of the eye and orbit. Human Pathol 13:459-469, 1982 7. Davis Z, Moertel CG, McIllrath DC: The malignant carcinoid syndrome. Surg Gynecol Obstet 137:637-644, 1973 8. Moertel CG, Hanley JA: Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Clin Cancer Trials 2:327-334, 1979 9. Martin JK, Moertel CG, Adson MA, et al: Surgical treatment of functioning metastatic carcinoid tumors. Arch Surg 118:537-542, 1983 10. Strickman NE, Rossi PA, Massum Kharis GA, et al: Carcinoid heart disease. Curr Prob Cardiol 6:1-41, 1982 II. Moertel CG, Hanley JA, Johnson LA: Streptozotocin alone compared with streptozotocin plus fluorouracil in the treatment of advanced islet cell carcinoma. N Engl J Med 303:1189-1195, 1980 12. Feldman JA: Serotonin metabolism in patients with carcinoid tumors. Gastroenterology 75:1109-1114, 1978 13. Engstrom P, Lavin P, Folsch E, et al: Streptozotocin plus fluorouracil vs. Adriamycin for metastatic carcinoid tumor. Proceedings of the American Association of Cancer Research 24:139, 1983 (Abstr) 14. Legha SS, Valdivieso M, Nelson RS, et al: Chemotherapy for metastatic carcinoid tumors. Cancer Treat Rep 61:16991703, 1981 15. Rochlin DB, Smart CR, Silva A: Chemotherapy of malignancies of the gastrointestinal tract. Am J Surg 109:43-46, 1965 16. VanHazel GA, Rubin J, Moertel CG: Treatment of metastatic carcinoid tumor and dactinomycin or dacarbazine. Cancer Treat Rep 67:577-579, 1983 17. Kessinger A, Foley FJ, Lemon HJ: Use of DTIC (Dacarbazine) in the malignant carcinoid syndrome. Cancer Treat Rep 61:101-102, 1977 18. Dolinger M, Golbey R: Actinomycin D in the treatment of the carcinoid tumors. Clin Res 15:335, 1967 (Abstr) 19. Mengel CE, Shaffer RD: The carcinoid syndrome, in Holland JF, Frei E: Cancer Medicine. Philadelphia, Lea & Febiger, 1973, p 1584-1593 20. Melia WM, Nummerley HB, Johnson PJ, et al: Use of arterial devascularization and cytotoxic drugs in 30 patients with the carcinoid syndrome. Br J Cancer 46:331-339, 1982 739 21. Stolinsky DC, Sadoff L, Braunwald J, et al: Streptozotoc in in the treatment of cancer: Phase 11study. Cancer 30:61-67, 1972 22. Feldman JM, Quickel RE Jr, Muracek RL, et al: Streptozotocin treatment of metastatic carcinoid tumors. South Med J 65:1325-1327, 1972 23. Schein PS, O'Connell MJ, Blom J, et al: Clinical antitumor activity and toxicity of streptozotocin. Cancer 34:9931000, 1974 24. Stathopoulos GP, Karvoantzis GG, Yiotis J: Tamoxifen in carcinoid syndrome. N Engl J Med 305:52, 1981 25. Myers CF, Ershler WB, Tannenbaum MA, et al: Tamoxifen and carcinoid tumor. Ann Intern Med 96:383, 1982 26. Harris AL, Smith IE: Regression in carcinoid tumour with cyproheptadine. Br Med J 285:475, 1982 27. Oberg K, Funs K, Aim G, et al: Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumor. N Engl J Med 309:129-132, 1983 28. Moertel CG, O'Connell MG, Reitemeier RJ, et al: An evaluation of combined cyclophosphamide and methotrexate therapy in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Treat Rep (in press) 29. Ajani JA, Legha SS, Karlin JA, et al: Combination chemotherapy of metastatic carcinoid tumors with 5-FU, Adriamycin, and Cytoxan and 5-FU, Adriamycin, Mitomycin, and Methyl CCNU. Proceedings of the American Association of Cancer Research 2:124, 1983 (Abstr) 30. Bukowski RM, Stephens R, Oishi N, et al: Phase II trial of 5-FU, Adriamycin, cyclophosphamide, and streptozotocin (FAC-S) in metastatic carcinoid. Proceedings of the American Society of Clinical Oncology 2:130, 1983 (Abstr) 31. Kelsen DP, Cheng E, Kemeny N, et al: Streptozotocin and Adriamycin in the treatment of APUD tumors. Proceedings of the American Association of Cancer Research 23:433, 1982 (Abstr) 32. Metz SA, Haller JR, Porte D, et al: Suppression of plasma catecholamines and flushing by clonidine in man. J Clin Endocrinol Metab 46:83-90, 1978 33. Sandler M: The role of 5-hydroxyindoles in the carcinoid syndrome. Adv Pharmacol 6:127-142, 1968 34. Arnold AC, Leichter SB: Use of novel pharmacologic agents in carcinoid syndrome. Milit Med 142:949-950, 1977 35. Levine RJ, Sjoerdsma A: Pressor amines and the carcinoid flush. Ann Intern Med 58:818-828, 1963 36. Ludwig GD, Cushard W, Bartuska D, et al: Effects of beta-adrenergic blockade in the carcinoid syndrome. Ann Intern Med 68:1188, 1968 37. Sjoerdsma A, Weissbach H, Terry LL, et al: Further observations on patients with malignant carcinoid. Am J Med 23:5-15, 1957 38. Sjoerdsma A, Oates JA, Zaltzman P, et al: Serotonin synthesis in carcinoid patients; its inhibition by alpha-methylDOPA, with measurement of associated increases in urinary 5hydroxytrytophan. N Engl J Med 263:585-588, 1960 39. Costello C: Carcinoid tumor metastases. Am J Surg 130:756-759, 1975 40. Sjoerdsma A, Lovenberg W, Engelman K: Serotonin now: Clinical implications of inhibiting its synthesis with parachlorophenylalamine. Ann Intern Med 73:607-629, 1970 41. Vroom FQ, Brown RE, Demsey H, et al: Studies on Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. 740 several possible antiserotonin compounds in a patient with the functioning carcinoid syndrome. Ann Intern Med 56:941-945, 1962 42. Melmon KL, Sjoerdsma A, Oates JA, et al: Treatment of malabsorption and diarrhea of the carcinoid syndrome with methysergide. Gastroenterology 48:18-24, 1965 43. Wilkin JE, Rountree CB: Blockade of carcinoid flush with cimetidine and clonidine. Arch Dermatol 118:109-111, 1982 CHARLES G. MOERTEL 44. Sjoerdsma A, Melmon KL: Severe flushing reactions responsive to steroids in patients with bronchial carcinoid. Lancet 2:791-792, 1964 45. Frohlic JC, Bloomgarden ZI, Oates JA, et al: The carcinoid flush: Provocation by pentagastrin and inhibition by somatostatin. N Engl J Med 299:1055-1057, 1978 46. Stahl SM, Levin B: Serotonin depletion by fenfluramine in the carcinoid syndrome. N Engl J Med 306:429, 1982 Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved.
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