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Metastatic carcinoid tumors and the carcinoid syndrome: A selective review of chemotherapy and hormonal therapy
Metastatic Carcinoid Tumors and the Carcinoid Syndrome A Selective Review of Chemotherapy and Hormonal Therapy
Malignant carcinoid tumors are remarkably varied in their biologic behavior. The disease may be indolent for years with minimal or no symptoms. On the other hand, an acute carcinoid crisis with severe diarrhea, dehydration, and hypotension may develop in the patient. Patients with flushing and/or diarrhea, not responsive to standard symptomatic measures, may benefit from chemotherapy or hormonal therapy. Chemotherapy with single agents or combination chemotherapy may be associated with response rates ranging from 20 to 40 percent. Hepatic de-arterialization by ligation or occlusion is an effective means of inducing rapid tumor shrinkage for patients who have carcinoid tumors and hepatic dominant metastases. The addition of chemotherapy after induction of a partial remigsion with hepatic de-arterialization may prolong the duration of response, but this remains to be proven in prospective clinical trials. Hormonal therapy with the antiestrogen tamoxifen has been unsuccessful, but treatment of the carcinoid syndrome with a long-acting analogue of somatostatin has been strikingly effective.
LARRY K. KVOLS, M.D. Rochester,
Minnesota
From the Division of Medical Oncology, Department of Oncology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Supported in part by a grant (CA-31224) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Requests for reprints should be addressed to Dr. Larry K. Kvols, Division of Medical Oncology, Mayo Clinic, 200 First Street, SW., Rochester, Minnesota 55905. Sandostatin (octreotide) is a registered trademark of Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey. Sandostatin is also known as SMS 201-995, SMS, and somatostatin analogue.
December
Carcinoid means “carcinoma-like” and when this neoplasm arises in the appendix or rectum and is resected in its early stages, the tumor represents a minor problem for the patient. Appendiceal carcinoids less than 1.5 cm in diameter virtually never metastasize. On the other hand, metastases will subsequently develop in the majority of patients with small bowel carcinoids greater than 1.5 cm in diameter. It should be emphasized, however, that the average duration of disease from onset of symptoms to death with metastasis is 8.6 years, with a range of six months to 29 years [I]. The indolent and varied biologic behavior of carcinoid tumors, coupled with the limited efficacy of currently available anti-neoplastic drugs, demands careful selection of patients for chemotherapy trials. Aggressive treatment should not be used in patients in the early stages of metastatic disease if they have no tumor symptoms or only minor symptoms from the syndrome. Symptoms that significantly interfere with daily activities and are not amenable to therapy with ordinary measures represent one indication for chemotherapy. The development of one of the poor prognostic signs would be another indication. Although the median survival time with the malignant carcinoid syndrome is 38 months from the occurrence of the first flush, this decreases to 14 months if the level of 5hydroxyindoleacetic acid is greater than 150 mg per 24 hours, and to only 11 months if there is clinical evidence of carcinoid heart disease [2]. Much of the medical literature in previous years has been anecdotal and response criteria were not always well defined. In the last decade,
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TABLE I
Single Agent Chemotherapy-Mayo Experience
Clinic
Objective Response Number oi
Patients
Agent Doxorubicin SFluorouracil Dacarbazine Dactinomycin cis-Platinum
33 19 18 17 15
Number of Patients
Rate (percent)
7 5 3 1 1
21 26 17 6 7
there have been a number of studies that help to provide a more solid scientific basis for making rational treatment decisions. This selective review focuses primarily on treatment alternatives available to the medical oncologist for patients with tietastatjc carcinoid tumors and the carcinoid syndrome whp 9re not show)ng a response to standard symptomatic approaches. CHEMOTHERAPY The National Cancer Institute screens thousands of comRounds every year for avti-tumor activity [3]. The decision to initiate clinical trials is made when anti-tumor effect is demonstrated in a drug screening panel of biologic or biochemical systems. Potentially useful new anti-cancer drugs then go through several stages of clinical testing. Phase I studies are des/gned to determine the proper schedule, the maximally tolerated dose, the dose-limiting toxicity, and the reversibility of this toxicity. Phase II studies are designed to determine the effectiveness of an agent in a specific human tumor, assess dose-response relationships, an! further delineate toxicity in relationship to therapeuti? effect. Phase ill studies compare experimental therapy to existing standard therapy with respect to both therapeutic effect and patterns of toxicity. Finally, phase IV studies may be done with particularly promising agents in order to investigate their role in multimodality approaches. For example, phase IV studies migh! address the therapeutic efficacy of combining a new drug with a primary modality of treatment Such as surgery or radiotherapy. Eligibility for Phase II Protocols. Eligibility for Mayo Clinic phase II protocols required histologic confirmation of metastatic carcinoid tumor, measureable disease, and symptomatic or progressive malignant carcinoid syndrome. Acceptable indicator lesions included a tumor mass measureable in two dimensions, malignant hepatomegaly if the liver contained proven metastases and measured at least 5 cm below the xiphoid or costal margins on quiet inspiration, or a urinary Shydroxyindoleacetic acid excretion rate of at least 25 mg per 24 hours (upper limit of normal, 6 mg per 24 hours).
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Dosage Scheme. Drugs were administered either in dosage schedules recommended by others or established by us as producing definite but clinically tolerable toxicity. In the early clinical trials, dosages were reduced by 50 percent with the first courses in order to prevent precipitation of carcinoid crises and then subsequently elevated if no undue toxicity was seen (Table I). SINGLE AGENT CHEMOTHERAPY 5-Fiuorouracii. Moertel used 5-fluorouracil 500 mg/m* per day in five-day courses given every five weeks and observed objective responses in five of 19 patients. Using the same dose and schedule, an identical response rate of 18 percent was observed in 11 patients in a multi-institutional trial done by the Eastern Cooperative Oncology Group [4]. Doxorubicin. Two separate trials of the anthracycline antibiotic doxorubicin, given at a dose of 60 mg/m* every three to four weeks, have reported objective responses in 21 percent of patients [2,5]. The Mayo Clinic experience encompassed 33 patients and the report of the Eastern Cooperative Oncology Group showing the same response rate included 81 patients. Dacarbazine. Kessinger et al [6] reported objective improvement lasting for a year in one patient and subjective improvement in another patient, both of whom were treated with dacarbazine. The Mayo Clinic trial observed two of 15 partial responses [7]. An Eastern Cooperative Oncology Group trial is currently evaluating this drug in greater detail. Actinomycin D. Nearly two decades ago, actinomycin D was reported to have caused responses in three of five patients with carcinoid tumors [8]. The report of Van Hazel et al [7] was less encouraging with only one of 17 patients showing a response but, interestingly, this patient has had remarkable clinical improvement lasting more than eight years. Cis-Platinum. Fifteen patients with metastatic carcinoid tumor were treated with cisplatin at doses of 45 to 90 mg/m* by rapid intravenous infusion and this was repeated every three to four weeks. In only one patient (7 percent) was any evidence of tumor regression evident, but it was partial and lasted only 3.5 months. It is unlikely that cisplatin given in this dose and schedule as a single agent has any therapeutic potential in this disease [9]. Streptozotocin. The nitrosurea antibiotic streptozotocin was observed to induce diabetes meilitus in preclinical toxicology studies [lo]. This translated into significant activity against islet cell carcinomas and led to trials in other neuroendocrine tumors. in six carcinoid patients treated with streptozotocin, Moet-lel [2] reported one objective regression and two mixed responses with regression of some lesions and progression of others. Two other reports also identified anti-tumor activity for this agent [ll ,121, but
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Schein and O’Connell [13] found no responses among eight patients. Not long after it was introduced for clinical trials, it appeared that this drug had some degree of activity in carcinoid tumors, and it was soon utilized in combination chemotherapy trials. COMBINATION CHEMOTHERAPY Mengel and Shaffer [14] reported responses in six of 11 patients treated with the combination of cyclophosphamide plus methotrexate. This was one of the early reports of enhanced activity with combination drug therapy in carcinoids and was accepted as standard therapy for this disease for several years [14]. Using eligibility and treatment response criteria delineated earlier, the Mayo group failed to observe a single response in 16 patients reported in 1984 [15]. In 1975, Moertel [16] first reported responses in six of nine patients with carcinoid tumors using the combination of 5-fluorouracil plus streptozotocin. Later in that decade, Chernicoff et al [17] reported responses in four of 10 carcinoid patients treated with the same regimen. The combination of 5fluorouracil plus streptozotocin was one of the treatment arms in a randomized multi-institutional trial performed by investigators in the Eastern Cooperative Oncology Group [18]. That randomized trial compared 5fluorouracil plus streptozotocin with cyclophosphamide plus streptozotocin. The objective response rates were 33 percent and 26 percent, respectively (Table II). The trial comprised more than 80 patients in the two arms and some interesting analyses were thus possible. Although a somewhat more favorable response rate was seen with the 5fluorouracil 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 a documented carcinoid syndrome and those with a better performance status. It was interesting that with both regimens the response rate was significantly greater for small bowel carcinoids than for carcinoids of pulmonary or unknown origin. The next protocol that the Eastern Cooperative Oncology Group undertook used the best arm of their first protocol, but streptozotocin was only given every 10 weeks rather than every five weeks in an attempt to decrease anorexia, nausea, and vomiting [19]. 5-Fluorouracil was still given daily for five days every five weeks. The study was again randomized with the second treatment arm being the single agent doxorubicin, 60 mg/m2, given intravenously on a monthly basis provided the patient did not have heart disease. Engstrom et al [19] reported the analysis of this study for the Eastern Cooperative Oncology Group in 1984. Unfortunately, nausea and vomiting secondary to streptozotocin therapy were not attenuated but the response rate seemed to be, with only 18 of 80 (23
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TABLE II
Streptozocin-Based Combination Regimens
Reference 1181 1181 v91
WI PO1
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Regimen STi!* STZ STZ+ 5-FU STZ
Patients
+ 5-FU + CTX + 5-FU + DOX + CTX + STZ (weekly) + DOX
STZ = streptozotocin; 5-FU = 5-fluorouracil; CTX = cyclophosphamide. “Streptozotocin in five-day courses repeated %treptozotocin in five-day courses repeated
43 47 80 20 10 DOX every every
Objective Resoonse (peicent) 14 12 18 7 4
(33) (26) (23) (35) (40)
= doxorubicin; six weeks. 10 weeks.
percent) fulfilling the criteria for response. The response rate with doxorubicin in this protocol was 17 of 81 (23 percent). The median duration of response was 26 weeks for doxorubicin and 31 weeks for the combination. In contrast to the preceding study, the location of the primary tumor did not correlate with survival prognosis. Neither the amount of 5-hydroxyindoleacetic acid in the urine at study entry nor the histologic classification of the tumor was prognostic for survival. A weekly schedule of streptozotocin given with doxorubicin in a single institution has been reported to cause regressions in four of 10 carcinoid tumors [20]. A four-drug regimen of 5-fluorouracil, streptozotocin, doxorubicin, and cyclophosphamide does not appear to offer any clear-cut therapeutic advantage with seven of 20 (35 percent) patients showing a response [21]. OTHER TREATMENT APPROACHES Parachlorophenylalanine. Parachlorophenylalanine has been shown to relieve diarrhea and to reduce urinary 5-hydroxyindoleacetic acid excretion, but flushing is rarely helped. The side effects of this agent, predominantly hypersensitivity reactions and psychiatric disturbances, make it intolerable for long-term clinical use (221. Cyproheptadine. Harris and Smith [23] reported regression of a carcinoid tumor and a nonfunctioning apudoma in two of 12 patients treated with cyproheptadine. They postulated that this agent might possibly affect tumor growth by blocking the effects of amine hormones. The Mayo Clinic has a phase II study under way to asses the true anti-tumor effect of this drug in patients with measurable disease. Tamoxifen. Investigators from Greece reported that the synthetic anti-estrogen tamoxifen caused symptomatic improvement in a patient with the carcinoid syndrome [24]. A second report using tamoxifen also indicated objective tumor regression and biochemical improvement (5-hydroxyindoleacetic acid excretion decreased from 174 to 15 mg per 24 hours) [25]. In a collaborative trial from the
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Natural somatostatin
SMS 201-995
Figure 1. Schematic of the amino acid sequence of native somatostatin compared with a long-acting analogue of somatostatin (SMS 207-995).
Mayo Clinic and the American Oncologic Hospital, 16 patients with metastatic carcinoid tumor were treated with tamoxifen; none showed any evidence of objective improvement in malignant disease as measured by reduced tumor size or sustained reduction in levels of Fj-hydroxyindoleacetic acid. All patients were treated for a minimum of eight weeks with divided daily doses of 20 to 40 mg. The median time to progression was 10 weeks and the disease had progressed in all patients by 24 weeks [26]. Interferon. A report by Oberg and associates [27] at the University of Upsala has sparked interest in using interferon for treatment of the carcinoid syndrome. Their six patients had significant symptomatic improvement and some reduction in 5-hydroxyindoleacetic acid excretion but these would not qualify as ‘objective responses using the criteria delineated earlier. A study of higher doses of interferon using recombinant DNA-produced alpha-interferon is now under way at the Mayo Clinic. Hepatic Artery Ligation. Martin and colleagues [28] have reported on eight patients with the carcinoid syndrome in our institution who underwent hepatic artery ligation at the time of laparotomy. The advantage of the surgical approach is that it permits resection of the frequently obstructive ileal primary lesions; this was necessary in five of their six patients with small-bowel primary tumors. Facial flushing ceased in all patients and diarrhea was uniformly reduced at the time of hospital discharge. All patients became febrile and had striking increases in the serum glutamic oxaloacetic transaminase values during the first postoperative week, but they recovered quickly thereafter. The duration of response ranged from three to 10 months (median, five months). Other investigators have confirmed that hepatic artery occlusion alone is an effective means of inducing tumor debulking for this disease [29-311. Because ligation-induced hepatic dysfunc-
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tion is transient, ligation does not preclude future chemotherapy. Hepatic Artery Occlusion Plus Sequential Chemotherapy. The early results of the Mayo Clinic trial of sequential hepatic artery occlusion and chemotherapy for metastatic carcinoid tumor have been previously reported [32]. Ten symptomatic patients with measureable hormonal and/or tumor parameters and proven hepatic dominant metastasis have been treated with hepatic artery occlusion either by surgical ligation or percutaneous embolization. Three weeks later, therapy was begun with dacarbazine, 250 mg/m2, for five days plus doxorubicin, 60 mg/m2 intravenously, alternating every four weeks with 5-fluorouracil, 400 mg/m2, for five days plus streptozotocin, 500 mg/m2, for five days. Nine of the 10 patients have had striking or complete relief of the carcinoid syndrome with urinary 5-hydroxyindoleacetic acid elevations reduced from 63 to 100 percent. The other patient had minor improvement for 12 months. Hepatic artery occlusion had side effects as noted previously in the earlier study. Chemotherapy produced its anticipated side effects, primarily vomiting and leukopenia. The early results with this program appear to show more frequent, more complete, and more lasting responses than in our prior experience with either hepatic artery occlusion or chemotherapy used alone. Somatostatin Analogue. Somatostatin is a ubiquitous hormone that inhibits the release of numerous peptides such as growth hormone, insulin, glucagon, and gut peptides [33]. Native somatostatin has been reported to be effective in blocking the carcinoid flush induced by pentagastrin and in controlling other symptoms associated with the carcinoid syndrome [34,35]. These initial observations had limited therapeutic application because the short halflife of the native compound required continuous intravenous infusion. An analogue of somatostatin with eight amino acids rather than 14 was synthesized and reported to be more specific, potent, and longer acting in its inhibitory effects [36]. The presumed essential biologically active moiety of somatostatin is present in the four amino acids shown in boldface type in Figure 1. Our initial experience with this longer-acting analogue of somatostatin (SMS 201-995, Sandoz) was very favorable in terms of ameliorating symptoms related to neuroendocrine tumors [37]. We have now studied the long-term administration of this analogue in 21 patients with histologically proven metastatic carcinoid tumor and the carcinoid syndrome. The drug was self-administered by subcutaneous injections at a dose of 150 pg three times daily. Flushing and diarrhea associated with the syndrome were promptly relieved. All 21 patients had elevated 24-hour urine 5-hydroxyindoleacetic acid excretions to serve as an objective indicator of disease activity (mean, 242 mg per 24 hour; range, 14 to 1,079 mg per 24 hours). Fifteen of the 21 patients (71 percent) have had a 50 percent or
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greater decrease in their 5-hydroxyindoleacetic acid level compared with their pretreatment level. The median duration of this biochemical response is more than nine months (range, one to more than 15 months). There has been no evidence of renal, hepatic, neurologic, or hematologic toxicity [38]. We have previously reported one instance in which therapy with this somatostatin analogue promptly reversed a potentially lethal carcinoid crisis occurring with induction of anesthesia (Figure 2) [39]. Since this report, we have successfully treated two additional patients who had carcinoid crises. A standard subcutaneous dose of 150 to 250 pg may be effective prophylaxis and 100 to 500 pg can be safely given intravenously for rapid control of hypotension. Somatostatin analogue should be available for emergency use in patients with a florid carcinoid syndrome who are undergoing diagnostic studies, chemotherapy, or surgery. It may be life-saving in this situation.
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$ )Jpf%f;// ,:. 0
5
10
Minutes
after
15
anesthesia
induction
Vgure 2. Carcinoid crisis: response of blood pressure intravenous somatostatin analogue (SMS 201-995).
to
ventions may be rather formidable, however, because of drug toxicities and other potential complications. Somatostatin analogue seems to have minimal toxicity and therefore may be appropriate for use as early therapy in patients who have symptoms of the carcinoid syndrome without an immediate threat from advancing tumor. Furthermore, patients in very poor clinical condition with dehydration, acidosis, or hypokalemia from a severe syndrome could be treated with this analogue of somatostatin initially to improve their status, so that they could then be more safely treated with more aggressive anti-tumor approaches.
COMMENTS
Single-agent or combination chemotherapy can induce objective tumor responses in 20 to 40 percent of patients with the carcinoid syndrome. Hepatic artery occlusion alone is an effective means of inducing tumor debulking. When chemotherapy is administered following hepatic artery ligation or occlusion, the duration of response appears to be prolonged. This sequence of treatment inter-
REFERENCES
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Davis Z, Moertel CG, Mcllrath DC: The malignant carcinoid syndrome. Surg Gynec Obstet 1973; 137: 637-644. Moertel CG: Treatment of the carcinoid tumor and the malignant carcinoid syndrome. J Clin Oncol 1983; 1 (11): 727-740. DeVita VT: Principles of chemotherapy. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer, principles and practice of oncology. Philadelphia: Lippincott, 1985; 257-285. Moertel CG: Clinical management of advanced gastrointestinal malignancy. Cancer 1975; 36: 675-682. Engstrom P, Lavin P, Folsch E, Moertel CG: Streptozotocin (STZ) + fluorouracil (FU) vs. Adriamycin (AD) for metastatic carcinoid tumors. Proc Am Assoc Cancer Res 1983; 24: 551. Kessinger A, Foley JF, Lemon HM: Therapy of malignant apud cell tumors: effectiveness of DTIC. Cancer 1983; 51: 790794. van Hazel GA, Rubin J, Moertel CG: Treatment of metastatic carcinoid tumor with dactinomycin or dacarbazine. Cancer Treat Rep 1983; 67 (6): 583-585. Dollinger M, Golbey R: Actinomycin D in the treatment of the carcinoid tumors. Clin Res 1967; 15: 335. Moertel CG, Rubin J, O’Connell MJ: A phase II study of cisplatin therapy in patients with metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Treat Rep (in press). Rakieten N, Rakieten ML, Nadkani MV: Studies of the diabetogenie action of streptozotocin (NSC-37917). Cancer Chemother Rep 1963; 29: 91-98. Stolinsky DC, Sadoff L, Braunwald J, Bateman JR: Streptozotocin in the treatment of cancer. Phase II study. Cancer 1972; 30: 61-67.
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Feldman JM, Quickel RE Jr, Muracek RL, et al: Streptozotocin treatment of metastatic carcinoid tumors. South Med J 1972; 65: 1325-l 327. Schein PS, O’Connell MJ, Blom J, et al: Clinical antitumor activity and toxicity of streptozotocin. Cancer 1974; 34: 993-1000. Mengel CE, Shaffer RD: The carcinoid syndrome. In Holland JF, Frei E, eds. Cancer medicine. Philadelphia: Lea & Febiger, 1973; 1584-1593. Moertel CG, O’Connell MJ, Reitemeier RJ, Rubin J: An evaluation of combined cyclophosphamide and methotrexate therapy in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Treat Rep 1984; 68: 665-667. Moertel CG: Clinical management of advanced gastrointestinal cancer. Cancer 1975; 36: 675-682. Chernicoff D, Bukowski RM, Groppe CW, et al: Combination chemotherapy for islet carcinoma and metastatic carcinoid tumors with 5-FU and streptozotocin. Cancer Treat Rep 1979; 63: 795-796. Moertel CG, Hanley JA: Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 1979; 2: 327-334. Engstrom PF, Lavin PT, Folsch E, Moertel CG, Folsch E, Douglas HO: Streptozotocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumors. J Clin Oncol 1984; 2: 1255-1259. Kelsen DP, Cheng E, Kemeny N, Magill GB, Yagoda A: Streptozotocin and Adriamycin in the treatment of apud tumors (carcinoid, islet cell, and medullary carcinomas of the thyroid).
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Proc Am Assoc Cancer Res 1982; 23: 433. Bukowski RM, Stephens R, Oishi N, Petersen R, Chen T: Phase II trial of 5-FU, Adriamycin, cyclophosphamide, and streptozotocin (FAC-S) in metastatic carcinoid. Proc Am Sot Clin Oncol 1983; 2: 130. Sjoerdsma A, Lovenberg W, Engelman K, et al: Serotonin now; clinical implications of inhibiting its synthesis with parachlorophenylalanine. Ann Intern Med 1970; 73: 607-629. Harris AL, Smith IE: Regression of carcinoid tumor with cyproheptadine. Br Med J 1962; 265 (5340): 475. Stathopoulous GP, Karvountzis GG, Yiotis J: Tamoxifen in carcinoid syndrome. N Engl J Med 1961; 305: 52. Myers CF, Ershler WB, Tannenbaum MA, et al: Tamoxifen and carcinoid tumor. Ann Intern Med 1982; 96: 383. Moertel CG, Engstrom PF, Schutt AJ: Tamoxifen therapy for metastatic carcinoid tumor: a negative study. Ann Intern Med 1984; 100: 531-532. Oberg K, Funa K, Alm GV: Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med 1983; 309: 129-133. Martin JK, Moertel CG, Adson MA, Schutt AJ: Surgical treatment of functioning metastatic carcinoid tumors. Arch Surg 1963; 118: 537-542. Maton PN, Camilleri M, Griffin G, Hodgson H, Allison DJ, Chadwick VS: The role of hepatic arterial embolization in the carcinoid syndrome. Br Med J 1983; 287: 932-935. Martensson H, Nobin A, Bengmark S, Lunderquist A, Owman T, Sanden A: Embolization of the liver in the management of
metastatic carcinoid tumors. J Surg Oncol 1984; 27: 152158. Mitty HA, Warner RRP, Newman LH, Train JS, Parnes IH: Control of carcinoid syndrome with hepatic artery embolization. Radiology 1985; 155: 623-626. Moertel CG, May GR, Martin JK, Rubin J, Schutt AJ: Sequential hepatic artery occlusion (HAO) and chemotherapy for metastatic carcinoid tumor and islet cell carcinoma (ICC). Proc Am Sot Clin Oncol 1985; 4: 80. Reichlin S: Somatostatin. N Engl J Med 1983; 309: 1495-1501. Frolich JC, Bloomgarden ZT, Oates JA, et al: The carcinoid flush: provocation by pentagastrin and inhibition by somatostatin. N Engl J Med 1978; 299: 1055-1057. Thulin L, Samnegard H, Tyden G, Long D, and Efendic S: Efficacy of somatostatin in a patient with carcinoid syndrome. Lancet 1978; 2: 43. Bauer W, Briner U, Doepfner W, et al: SMS 201-995. A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 1982; 31: 1133-I 140. Kvols LK, Moertel CG, Schutt AJ, O’Connell MJ: A somatostatin analogue (Sandoz 201-995) in therapy of malignant carcinoid syndrome. Proc Am Sot Clin Oncol 1985; 4: 89. Kvols LK, Moettel CG, O’Connell MJ, Schutt AJ, Rubin J, Hahn RG: Treatment of the malignant carcinoid syndrome: evaluation of a long acting somatostatin analogue. N Engl J Med 1986; 315: 663-666. Kvols LK, Martin JK, Marsh HM, Moertel CG: Carcinoid crisis: rapid reversal of life threatening hypotension with a somatostatin analogue. N Engl J Med 1985; 313: 1229.
31.
32.
33. 34.
35.
36.
37.
38.
39.
Discussion Dr. lvor M. Jackson: Did you measure substance K in your patients with carcinoid syndrome? Do you believe that the degree of positivity of this tachykinin family may be diagnostic of the syndrome? Dr. Keith D. Buchanan: I would like to comment on that question. I am aware of studies from Sweden showing that the level of substance K, and particularly neuropeptide K, is elevated in some patients with carcinoid syndrome. Substance K may, in fact, cause some cases of the syndrome, whereas substance P, also in the tachykinin family, may be an independent bystander, as discussed by Dr. Feldman. Dr. Thomas M. O’Dorisio: As reported by Dr. Feldman, substance P appears to be a useful marker in some cases of the carcinoid syndrome. I agree with Dr. Buchanan that substance P may be a passive bystander whereas substance K is more active. Since the substance P radioimmunoassay is more widely available, we should continue to measure substance P. Dr. David S. Cooper: Dr. O’Dorisio, since you have had a rather long-term experience with SMS 201-995 in a group of carcinoid patients, could you comment on its possible antigenicity? Dr. O’Dorisio: We have recently established an SMS 201-995 antibody technique, and have evaluated 20 patients for antibody production. No antigenicity has been demonstrated in patients treated with SMS 201-995 for as
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long as 18 months. As the question suggests, one would expect that antibodies would develop since SMS 201-995 is a synthetic antigen and given subcutaneously. This will only be answered as patients are given longer courses of therapy with this somatostatin analogue. Dr. E. Chester Ridgway: Dr. Kvols, why did you switch from the subcutaneous to intravenous route of administration in one of your patients? Dr. Larry K. Kvols: I would like to clarify that the patient was receiving SMS 201-995 subcutaneous injections every four hours and the infusion of SMS 201-995, via a subcutaneous infusion device designed for ambulatory use, was added because the patient began to have breakthrough symptoms of both flushing and diarrhea. Dr. Ridgway: In follow-up, can you then comment on the pharmacokinetics of the analogue? Dr. O’Dorisio: I would like to add that we can detect plasma levels of SMS 201-995 within 15 minutes of a subcutaneous injection. The half-life of the somatostatin analogue is between 90 and 120 minutes. Although the clearance route is not established, the kidney is probably important. The duration of action appears to be six to eight hours after a single injection of SMS 201-995. Dr. Jerome M. Feldman: Dr. Kvols, your experience with the combination of hepatic artery ligation and multiple agent chemotherapy is exciting but, as you noted, fairly toxic. We’ve used 13’I-metaiodobenzyl quanidine scans to
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localize the carcinoid tumor. Certainly this represents another therapeutic agent that would be less toxic, particularly in patients with tumors in the mid-gut. Dr. Naguib A. Samaan: Dr. Kvols, regarding hepatic artery occlusion treatment of your carcinoid patients, is this performed under open surgery or via hepatic artery catheterization/embolization? Initially our patients were treated with open surgery hepatic artery ligation. We now perform the procedure using percutaneous embolization and the procedure is repeated frequently. Dr. Kvols: In collaboration with Dr. Tom O’Dorisio, we did measure circulating SMS 201-995 levels after various subcutaneous injections. Although therapeutic levels (500 to 700 pg/ml) were achieved in one patient who required the continuous infusion, we are not certain as to whether it was the peak level or a continuous level throughout the
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day that was associated with the control of symptoms. Dr. Hagop H. Mekhjian: Dr. Kvols, in regard to the response rate to SMS 201-995 in your patients, is there a subpopulation of responders? Further, is the response complete for both flushing and diarrhea? Dr. K\iols: All patients with reduced biochemical markers showed clinical improvement with a decrease in flushing as well as in diarrhea. I know of only two cases in which diarrhea was controlled but flushing was not. Dr. Phillip L. Rayford: Does carcinoid syndrome develop in black persons? Dr. Feldman: Yes, it does. Carcinoid syndrome occurs in both white and black patients with approximately equal frequency. Black patients wilt feel the carcinoid flushing and their skin will sometimes redden. They will perspire and their eyes will tear.
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Malignant carcinoid tumors are remarkably varied in their biologic behavior. The disease may be indolent for years with minimal or no symptoms. On the other hand, an acute carcinoid crisis with severe diarrhea, dehydration, and hypotension may develop in the patient. Patients with flushing and/or diarrhea, not responsive to standard symptomatic measures, may benefit from chemotherapy or hormonal therapy. Chemotherapy with single agents or combination chemotherapy may be associated with response rates ranging from 20 to 40 percent. Hepatic de-arterialization by ligation or occlusion is an effective means of inducing rapid tumor shrinkage for patients who have carcinoid tumors and hepatic dominant metastases. The addition of chemotherapy after induction of a partial remigsion with hepatic de-arterialization may prolong the duration of response, but this remains to be proven in prospective clinical trials. Hormonal therapy with the antiestrogen tamoxifen has been unsuccessful, but treatment of the carcinoid syndrome with a long-acting analogue of somatostatin has been strikingly effective.
LARRY K. KVOLS, M.D. Rochester,
Minnesota
From the Division of Medical Oncology, Department of Oncology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Supported in part by a grant (CA-31224) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Requests for reprints should be addressed to Dr. Larry K. Kvols, Division of Medical Oncology, Mayo Clinic, 200 First Street, SW., Rochester, Minnesota 55905. Sandostatin (octreotide) is a registered trademark of Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey. Sandostatin is also known as SMS 201-995, SMS, and somatostatin analogue.
December
Carcinoid means “carcinoma-like” and when this neoplasm arises in the appendix or rectum and is resected in its early stages, the tumor represents a minor problem for the patient. Appendiceal carcinoids less than 1.5 cm in diameter virtually never metastasize. On the other hand, metastases will subsequently develop in the majority of patients with small bowel carcinoids greater than 1.5 cm in diameter. It should be emphasized, however, that the average duration of disease from onset of symptoms to death with metastasis is 8.6 years, with a range of six months to 29 years [I]. The indolent and varied biologic behavior of carcinoid tumors, coupled with the limited efficacy of currently available anti-neoplastic drugs, demands careful selection of patients for chemotherapy trials. Aggressive treatment should not be used in patients in the early stages of metastatic disease if they have no tumor symptoms or only minor symptoms from the syndrome. Symptoms that significantly interfere with daily activities and are not amenable to therapy with ordinary measures represent one indication for chemotherapy. The development of one of the poor prognostic signs would be another indication. Although the median survival time with the malignant carcinoid syndrome is 38 months from the occurrence of the first flush, this decreases to 14 months if the level of 5hydroxyindoleacetic acid is greater than 150 mg per 24 hours, and to only 11 months if there is clinical evidence of carcinoid heart disease [2]. Much of the medical literature in previous years has been anecdotal and response criteria were not always well defined. In the last decade,
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TABLE I
Single Agent Chemotherapy-Mayo Experience
Clinic
Objective Response Number oi
Patients
Agent Doxorubicin SFluorouracil Dacarbazine Dactinomycin cis-Platinum
33 19 18 17 15
Number of Patients
Rate (percent)
7 5 3 1 1
21 26 17 6 7
there have been a number of studies that help to provide a more solid scientific basis for making rational treatment decisions. This selective review focuses primarily on treatment alternatives available to the medical oncologist for patients with tietastatjc carcinoid tumors and the carcinoid syndrome whp 9re not show)ng a response to standard symptomatic approaches. CHEMOTHERAPY The National Cancer Institute screens thousands of comRounds every year for avti-tumor activity [3]. The decision to initiate clinical trials is made when anti-tumor effect is demonstrated in a drug screening panel of biologic or biochemical systems. Potentially useful new anti-cancer drugs then go through several stages of clinical testing. Phase I studies are des/gned to determine the proper schedule, the maximally tolerated dose, the dose-limiting toxicity, and the reversibility of this toxicity. Phase II studies are designed to determine the effectiveness of an agent in a specific human tumor, assess dose-response relationships, an! further delineate toxicity in relationship to therapeuti? effect. Phase ill studies compare experimental therapy to existing standard therapy with respect to both therapeutic effect and patterns of toxicity. Finally, phase IV studies may be done with particularly promising agents in order to investigate their role in multimodality approaches. For example, phase IV studies migh! address the therapeutic efficacy of combining a new drug with a primary modality of treatment Such as surgery or radiotherapy. Eligibility for Phase II Protocols. Eligibility for Mayo Clinic phase II protocols required histologic confirmation of metastatic carcinoid tumor, measureable disease, and symptomatic or progressive malignant carcinoid syndrome. Acceptable indicator lesions included a tumor mass measureable in two dimensions, malignant hepatomegaly if the liver contained proven metastases and measured at least 5 cm below the xiphoid or costal margins on quiet inspiration, or a urinary Shydroxyindoleacetic acid excretion rate of at least 25 mg per 24 hours (upper limit of normal, 6 mg per 24 hours).
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Dosage Scheme. Drugs were administered either in dosage schedules recommended by others or established by us as producing definite but clinically tolerable toxicity. In the early clinical trials, dosages were reduced by 50 percent with the first courses in order to prevent precipitation of carcinoid crises and then subsequently elevated if no undue toxicity was seen (Table I). SINGLE AGENT CHEMOTHERAPY 5-Fiuorouracii. Moertel used 5-fluorouracil 500 mg/m* per day in five-day courses given every five weeks and observed objective responses in five of 19 patients. Using the same dose and schedule, an identical response rate of 18 percent was observed in 11 patients in a multi-institutional trial done by the Eastern Cooperative Oncology Group [4]. Doxorubicin. Two separate trials of the anthracycline antibiotic doxorubicin, given at a dose of 60 mg/m* every three to four weeks, have reported objective responses in 21 percent of patients [2,5]. The Mayo Clinic experience encompassed 33 patients and the report of the Eastern Cooperative Oncology Group showing the same response rate included 81 patients. Dacarbazine. Kessinger et al [6] reported objective improvement lasting for a year in one patient and subjective improvement in another patient, both of whom were treated with dacarbazine. The Mayo Clinic trial observed two of 15 partial responses [7]. An Eastern Cooperative Oncology Group trial is currently evaluating this drug in greater detail. Actinomycin D. Nearly two decades ago, actinomycin D was reported to have caused responses in three of five patients with carcinoid tumors [8]. The report of Van Hazel et al [7] was less encouraging with only one of 17 patients showing a response but, interestingly, this patient has had remarkable clinical improvement lasting more than eight years. Cis-Platinum. Fifteen patients with metastatic carcinoid tumor were treated with cisplatin at doses of 45 to 90 mg/m* by rapid intravenous infusion and this was repeated every three to four weeks. In only one patient (7 percent) was any evidence of tumor regression evident, but it was partial and lasted only 3.5 months. It is unlikely that cisplatin given in this dose and schedule as a single agent has any therapeutic potential in this disease [9]. Streptozotocin. The nitrosurea antibiotic streptozotocin was observed to induce diabetes meilitus in preclinical toxicology studies [lo]. This translated into significant activity against islet cell carcinomas and led to trials in other neuroendocrine tumors. in six carcinoid patients treated with streptozotocin, Moet-lel [2] reported one objective regression and two mixed responses with regression of some lesions and progression of others. Two other reports also identified anti-tumor activity for this agent [ll ,121, but
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Schein and O’Connell [13] found no responses among eight patients. Not long after it was introduced for clinical trials, it appeared that this drug had some degree of activity in carcinoid tumors, and it was soon utilized in combination chemotherapy trials. COMBINATION CHEMOTHERAPY Mengel and Shaffer [14] reported responses in six of 11 patients treated with the combination of cyclophosphamide plus methotrexate. This was one of the early reports of enhanced activity with combination drug therapy in carcinoids and was accepted as standard therapy for this disease for several years [14]. Using eligibility and treatment response criteria delineated earlier, the Mayo group failed to observe a single response in 16 patients reported in 1984 [15]. In 1975, Moertel [16] first reported responses in six of nine patients with carcinoid tumors using the combination of 5-fluorouracil plus streptozotocin. Later in that decade, Chernicoff et al [17] reported responses in four of 10 carcinoid patients treated with the same regimen. The combination of 5fluorouracil plus streptozotocin was one of the treatment arms in a randomized multi-institutional trial performed by investigators in the Eastern Cooperative Oncology Group [18]. That randomized trial compared 5fluorouracil plus streptozotocin with cyclophosphamide plus streptozotocin. The objective response rates were 33 percent and 26 percent, respectively (Table II). The trial comprised more than 80 patients in the two arms and some interesting analyses were thus possible. Although a somewhat more favorable response rate was seen with the 5fluorouracil 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 a documented carcinoid syndrome and those with a better performance status. It was interesting that with both regimens the response rate was significantly greater for small bowel carcinoids than for carcinoids of pulmonary or unknown origin. The next protocol that the Eastern Cooperative Oncology Group undertook used the best arm of their first protocol, but streptozotocin was only given every 10 weeks rather than every five weeks in an attempt to decrease anorexia, nausea, and vomiting [19]. 5-Fluorouracil was still given daily for five days every five weeks. The study was again randomized with the second treatment arm being the single agent doxorubicin, 60 mg/m2, given intravenously on a monthly basis provided the patient did not have heart disease. Engstrom et al [19] reported the analysis of this study for the Eastern Cooperative Oncology Group in 1984. Unfortunately, nausea and vomiting secondary to streptozotocin therapy were not attenuated but the response rate seemed to be, with only 18 of 80 (23
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TABLE II
Streptozocin-Based Combination Regimens
Reference 1181 1181 v91
WI PO1
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Regimen STi!* STZ STZ+ 5-FU STZ
Patients
+ 5-FU + CTX + 5-FU + DOX + CTX + STZ (weekly) + DOX
STZ = streptozotocin; 5-FU = 5-fluorouracil; CTX = cyclophosphamide. “Streptozotocin in five-day courses repeated %treptozotocin in five-day courses repeated
43 47 80 20 10 DOX every every
Objective Resoonse (peicent) 14 12 18 7 4
(33) (26) (23) (35) (40)
= doxorubicin; six weeks. 10 weeks.
percent) fulfilling the criteria for response. The response rate with doxorubicin in this protocol was 17 of 81 (23 percent). The median duration of response was 26 weeks for doxorubicin and 31 weeks for the combination. In contrast to the preceding study, the location of the primary tumor did not correlate with survival prognosis. Neither the amount of 5-hydroxyindoleacetic acid in the urine at study entry nor the histologic classification of the tumor was prognostic for survival. A weekly schedule of streptozotocin given with doxorubicin in a single institution has been reported to cause regressions in four of 10 carcinoid tumors [20]. A four-drug regimen of 5-fluorouracil, streptozotocin, doxorubicin, and cyclophosphamide does not appear to offer any clear-cut therapeutic advantage with seven of 20 (35 percent) patients showing a response [21]. OTHER TREATMENT APPROACHES Parachlorophenylalanine. Parachlorophenylalanine has been shown to relieve diarrhea and to reduce urinary 5-hydroxyindoleacetic acid excretion, but flushing is rarely helped. The side effects of this agent, predominantly hypersensitivity reactions and psychiatric disturbances, make it intolerable for long-term clinical use (221. Cyproheptadine. Harris and Smith [23] reported regression of a carcinoid tumor and a nonfunctioning apudoma in two of 12 patients treated with cyproheptadine. They postulated that this agent might possibly affect tumor growth by blocking the effects of amine hormones. The Mayo Clinic has a phase II study under way to asses the true anti-tumor effect of this drug in patients with measurable disease. Tamoxifen. Investigators from Greece reported that the synthetic anti-estrogen tamoxifen caused symptomatic improvement in a patient with the carcinoid syndrome [24]. A second report using tamoxifen also indicated objective tumor regression and biochemical improvement (5-hydroxyindoleacetic acid excretion decreased from 174 to 15 mg per 24 hours) [25]. In a collaborative trial from the
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Natural somatostatin
SMS 201-995
Figure 1. Schematic of the amino acid sequence of native somatostatin compared with a long-acting analogue of somatostatin (SMS 207-995).
Mayo Clinic and the American Oncologic Hospital, 16 patients with metastatic carcinoid tumor were treated with tamoxifen; none showed any evidence of objective improvement in malignant disease as measured by reduced tumor size or sustained reduction in levels of Fj-hydroxyindoleacetic acid. All patients were treated for a minimum of eight weeks with divided daily doses of 20 to 40 mg. The median time to progression was 10 weeks and the disease had progressed in all patients by 24 weeks [26]. Interferon. A report by Oberg and associates [27] at the University of Upsala has sparked interest in using interferon for treatment of the carcinoid syndrome. Their six patients had significant symptomatic improvement and some reduction in 5-hydroxyindoleacetic acid excretion but these would not qualify as ‘objective responses using the criteria delineated earlier. A study of higher doses of interferon using recombinant DNA-produced alpha-interferon is now under way at the Mayo Clinic. Hepatic Artery Ligation. Martin and colleagues [28] have reported on eight patients with the carcinoid syndrome in our institution who underwent hepatic artery ligation at the time of laparotomy. The advantage of the surgical approach is that it permits resection of the frequently obstructive ileal primary lesions; this was necessary in five of their six patients with small-bowel primary tumors. Facial flushing ceased in all patients and diarrhea was uniformly reduced at the time of hospital discharge. All patients became febrile and had striking increases in the serum glutamic oxaloacetic transaminase values during the first postoperative week, but they recovered quickly thereafter. The duration of response ranged from three to 10 months (median, five months). Other investigators have confirmed that hepatic artery occlusion alone is an effective means of inducing tumor debulking for this disease [29-311. Because ligation-induced hepatic dysfunc-
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tion is transient, ligation does not preclude future chemotherapy. Hepatic Artery Occlusion Plus Sequential Chemotherapy. The early results of the Mayo Clinic trial of sequential hepatic artery occlusion and chemotherapy for metastatic carcinoid tumor have been previously reported [32]. Ten symptomatic patients with measureable hormonal and/or tumor parameters and proven hepatic dominant metastasis have been treated with hepatic artery occlusion either by surgical ligation or percutaneous embolization. Three weeks later, therapy was begun with dacarbazine, 250 mg/m2, for five days plus doxorubicin, 60 mg/m2 intravenously, alternating every four weeks with 5-fluorouracil, 400 mg/m2, for five days plus streptozotocin, 500 mg/m2, for five days. Nine of the 10 patients have had striking or complete relief of the carcinoid syndrome with urinary 5-hydroxyindoleacetic acid elevations reduced from 63 to 100 percent. The other patient had minor improvement for 12 months. Hepatic artery occlusion had side effects as noted previously in the earlier study. Chemotherapy produced its anticipated side effects, primarily vomiting and leukopenia. The early results with this program appear to show more frequent, more complete, and more lasting responses than in our prior experience with either hepatic artery occlusion or chemotherapy used alone. Somatostatin Analogue. Somatostatin is a ubiquitous hormone that inhibits the release of numerous peptides such as growth hormone, insulin, glucagon, and gut peptides [33]. Native somatostatin has been reported to be effective in blocking the carcinoid flush induced by pentagastrin and in controlling other symptoms associated with the carcinoid syndrome [34,35]. These initial observations had limited therapeutic application because the short halflife of the native compound required continuous intravenous infusion. An analogue of somatostatin with eight amino acids rather than 14 was synthesized and reported to be more specific, potent, and longer acting in its inhibitory effects [36]. The presumed essential biologically active moiety of somatostatin is present in the four amino acids shown in boldface type in Figure 1. Our initial experience with this longer-acting analogue of somatostatin (SMS 201-995, Sandoz) was very favorable in terms of ameliorating symptoms related to neuroendocrine tumors [37]. We have now studied the long-term administration of this analogue in 21 patients with histologically proven metastatic carcinoid tumor and the carcinoid syndrome. The drug was self-administered by subcutaneous injections at a dose of 150 pg three times daily. Flushing and diarrhea associated with the syndrome were promptly relieved. All 21 patients had elevated 24-hour urine 5-hydroxyindoleacetic acid excretions to serve as an objective indicator of disease activity (mean, 242 mg per 24 hour; range, 14 to 1,079 mg per 24 hours). Fifteen of the 21 patients (71 percent) have had a 50 percent or
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greater decrease in their 5-hydroxyindoleacetic acid level compared with their pretreatment level. The median duration of this biochemical response is more than nine months (range, one to more than 15 months). There has been no evidence of renal, hepatic, neurologic, or hematologic toxicity [38]. We have previously reported one instance in which therapy with this somatostatin analogue promptly reversed a potentially lethal carcinoid crisis occurring with induction of anesthesia (Figure 2) [39]. Since this report, we have successfully treated two additional patients who had carcinoid crises. A standard subcutaneous dose of 150 to 250 pg may be effective prophylaxis and 100 to 500 pg can be safely given intravenously for rapid control of hypotension. Somatostatin analogue should be available for emergency use in patients with a florid carcinoid syndrome who are undergoing diagnostic studies, chemotherapy, or surgery. It may be life-saving in this situation.
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$ )Jpf%f;// ,:. 0
5
10
Minutes
after
15
anesthesia
induction
Vgure 2. Carcinoid crisis: response of blood pressure intravenous somatostatin analogue (SMS 201-995).
to
ventions may be rather formidable, however, because of drug toxicities and other potential complications. Somatostatin analogue seems to have minimal toxicity and therefore may be appropriate for use as early therapy in patients who have symptoms of the carcinoid syndrome without an immediate threat from advancing tumor. Furthermore, patients in very poor clinical condition with dehydration, acidosis, or hypokalemia from a severe syndrome could be treated with this analogue of somatostatin initially to improve their status, so that they could then be more safely treated with more aggressive anti-tumor approaches.
COMMENTS
Single-agent or combination chemotherapy can induce objective tumor responses in 20 to 40 percent of patients with the carcinoid syndrome. Hepatic artery occlusion alone is an effective means of inducing tumor debulking. When chemotherapy is administered following hepatic artery ligation or occlusion, the duration of response appears to be prolonged. This sequence of treatment inter-
REFERENCES
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4. 5.
6.
7.
8. 9.
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Davis Z, Moertel CG, Mcllrath DC: The malignant carcinoid syndrome. Surg Gynec Obstet 1973; 137: 637-644. Moertel CG: Treatment of the carcinoid tumor and the malignant carcinoid syndrome. J Clin Oncol 1983; 1 (11): 727-740. DeVita VT: Principles of chemotherapy. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer, principles and practice of oncology. Philadelphia: Lippincott, 1985; 257-285. Moertel CG: Clinical management of advanced gastrointestinal malignancy. Cancer 1975; 36: 675-682. Engstrom P, Lavin P, Folsch E, Moertel CG: Streptozotocin (STZ) + fluorouracil (FU) vs. Adriamycin (AD) for metastatic carcinoid tumors. Proc Am Assoc Cancer Res 1983; 24: 551. Kessinger A, Foley JF, Lemon HM: Therapy of malignant apud cell tumors: effectiveness of DTIC. Cancer 1983; 51: 790794. van Hazel GA, Rubin J, Moertel CG: Treatment of metastatic carcinoid tumor with dactinomycin or dacarbazine. Cancer Treat Rep 1983; 67 (6): 583-585. Dollinger M, Golbey R: Actinomycin D in the treatment of the carcinoid tumors. Clin Res 1967; 15: 335. Moertel CG, Rubin J, O’Connell MJ: A phase II study of cisplatin therapy in patients with metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Treat Rep (in press). Rakieten N, Rakieten ML, Nadkani MV: Studies of the diabetogenie action of streptozotocin (NSC-37917). Cancer Chemother Rep 1963; 29: 91-98. Stolinsky DC, Sadoff L, Braunwald J, Bateman JR: Streptozotocin in the treatment of cancer. Phase II study. Cancer 1972; 30: 61-67.
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Feldman JM, Quickel RE Jr, Muracek RL, et al: Streptozotocin treatment of metastatic carcinoid tumors. South Med J 1972; 65: 1325-l 327. Schein PS, O’Connell MJ, Blom J, et al: Clinical antitumor activity and toxicity of streptozotocin. Cancer 1974; 34: 993-1000. Mengel CE, Shaffer RD: The carcinoid syndrome. In Holland JF, Frei E, eds. Cancer medicine. Philadelphia: Lea & Febiger, 1973; 1584-1593. Moertel CG, O’Connell MJ, Reitemeier RJ, Rubin J: An evaluation of combined cyclophosphamide and methotrexate therapy in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Treat Rep 1984; 68: 665-667. Moertel CG: Clinical management of advanced gastrointestinal cancer. Cancer 1975; 36: 675-682. Chernicoff D, Bukowski RM, Groppe CW, et al: Combination chemotherapy for islet carcinoma and metastatic carcinoid tumors with 5-FU and streptozotocin. Cancer Treat Rep 1979; 63: 795-796. Moertel CG, Hanley JA: Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 1979; 2: 327-334. Engstrom PF, Lavin PT, Folsch E, Moertel CG, Folsch E, Douglas HO: Streptozotocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumors. J Clin Oncol 1984; 2: 1255-1259. Kelsen DP, Cheng E, Kemeny N, Magill GB, Yagoda A: Streptozotocin and Adriamycin in the treatment of apud tumors (carcinoid, islet cell, and medullary carcinomas of the thyroid).
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Proc Am Assoc Cancer Res 1982; 23: 433. Bukowski RM, Stephens R, Oishi N, Petersen R, Chen T: Phase II trial of 5-FU, Adriamycin, cyclophosphamide, and streptozotocin (FAC-S) in metastatic carcinoid. Proc Am Sot Clin Oncol 1983; 2: 130. Sjoerdsma A, Lovenberg W, Engelman K, et al: Serotonin now; clinical implications of inhibiting its synthesis with parachlorophenylalanine. Ann Intern Med 1970; 73: 607-629. Harris AL, Smith IE: Regression of carcinoid tumor with cyproheptadine. Br Med J 1962; 265 (5340): 475. Stathopoulous GP, Karvountzis GG, Yiotis J: Tamoxifen in carcinoid syndrome. N Engl J Med 1961; 305: 52. Myers CF, Ershler WB, Tannenbaum MA, et al: Tamoxifen and carcinoid tumor. Ann Intern Med 1982; 96: 383. Moertel CG, Engstrom PF, Schutt AJ: Tamoxifen therapy for metastatic carcinoid tumor: a negative study. Ann Intern Med 1984; 100: 531-532. Oberg K, Funa K, Alm GV: Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med 1983; 309: 129-133. Martin JK, Moertel CG, Adson MA, Schutt AJ: Surgical treatment of functioning metastatic carcinoid tumors. Arch Surg 1963; 118: 537-542. Maton PN, Camilleri M, Griffin G, Hodgson H, Allison DJ, Chadwick VS: The role of hepatic arterial embolization in the carcinoid syndrome. Br Med J 1983; 287: 932-935. Martensson H, Nobin A, Bengmark S, Lunderquist A, Owman T, Sanden A: Embolization of the liver in the management of
metastatic carcinoid tumors. J Surg Oncol 1984; 27: 152158. Mitty HA, Warner RRP, Newman LH, Train JS, Parnes IH: Control of carcinoid syndrome with hepatic artery embolization. Radiology 1985; 155: 623-626. Moertel CG, May GR, Martin JK, Rubin J, Schutt AJ: Sequential hepatic artery occlusion (HAO) and chemotherapy for metastatic carcinoid tumor and islet cell carcinoma (ICC). Proc Am Sot Clin Oncol 1985; 4: 80. Reichlin S: Somatostatin. N Engl J Med 1983; 309: 1495-1501. Frolich JC, Bloomgarden ZT, Oates JA, et al: The carcinoid flush: provocation by pentagastrin and inhibition by somatostatin. N Engl J Med 1978; 299: 1055-1057. Thulin L, Samnegard H, Tyden G, Long D, and Efendic S: Efficacy of somatostatin in a patient with carcinoid syndrome. Lancet 1978; 2: 43. Bauer W, Briner U, Doepfner W, et al: SMS 201-995. A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 1982; 31: 1133-I 140. Kvols LK, Moertel CG, Schutt AJ, O’Connell MJ: A somatostatin analogue (Sandoz 201-995) in therapy of malignant carcinoid syndrome. Proc Am Sot Clin Oncol 1985; 4: 89. Kvols LK, Moettel CG, O’Connell MJ, Schutt AJ, Rubin J, Hahn RG: Treatment of the malignant carcinoid syndrome: evaluation of a long acting somatostatin analogue. N Engl J Med 1986; 315: 663-666. Kvols LK, Martin JK, Marsh HM, Moertel CG: Carcinoid crisis: rapid reversal of life threatening hypotension with a somatostatin analogue. N Engl J Med 1985; 313: 1229.
31.
32.
33. 34.
35.
36.
37.
38.
39.
Discussion Dr. lvor M. Jackson: Did you measure substance K in your patients with carcinoid syndrome? Do you believe that the degree of positivity of this tachykinin family may be diagnostic of the syndrome? Dr. Keith D. Buchanan: I would like to comment on that question. I am aware of studies from Sweden showing that the level of substance K, and particularly neuropeptide K, is elevated in some patients with carcinoid syndrome. Substance K may, in fact, cause some cases of the syndrome, whereas substance P, also in the tachykinin family, may be an independent bystander, as discussed by Dr. Feldman. Dr. Thomas M. O’Dorisio: As reported by Dr. Feldman, substance P appears to be a useful marker in some cases of the carcinoid syndrome. I agree with Dr. Buchanan that substance P may be a passive bystander whereas substance K is more active. Since the substance P radioimmunoassay is more widely available, we should continue to measure substance P. Dr. David S. Cooper: Dr. O’Dorisio, since you have had a rather long-term experience with SMS 201-995 in a group of carcinoid patients, could you comment on its possible antigenicity? Dr. O’Dorisio: We have recently established an SMS 201-995 antibody technique, and have evaluated 20 patients for antibody production. No antigenicity has been demonstrated in patients treated with SMS 201-995 for as
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long as 18 months. As the question suggests, one would expect that antibodies would develop since SMS 201-995 is a synthetic antigen and given subcutaneously. This will only be answered as patients are given longer courses of therapy with this somatostatin analogue. Dr. E. Chester Ridgway: Dr. Kvols, why did you switch from the subcutaneous to intravenous route of administration in one of your patients? Dr. Larry K. Kvols: I would like to clarify that the patient was receiving SMS 201-995 subcutaneous injections every four hours and the infusion of SMS 201-995, via a subcutaneous infusion device designed for ambulatory use, was added because the patient began to have breakthrough symptoms of both flushing and diarrhea. Dr. Ridgway: In follow-up, can you then comment on the pharmacokinetics of the analogue? Dr. O’Dorisio: I would like to add that we can detect plasma levels of SMS 201-995 within 15 minutes of a subcutaneous injection. The half-life of the somatostatin analogue is between 90 and 120 minutes. Although the clearance route is not established, the kidney is probably important. The duration of action appears to be six to eight hours after a single injection of SMS 201-995. Dr. Jerome M. Feldman: Dr. Kvols, your experience with the combination of hepatic artery ligation and multiple agent chemotherapy is exciting but, as you noted, fairly toxic. We’ve used 13’I-metaiodobenzyl quanidine scans to
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localize the carcinoid tumor. Certainly this represents another therapeutic agent that would be less toxic, particularly in patients with tumors in the mid-gut. Dr. Naguib A. Samaan: Dr. Kvols, regarding hepatic artery occlusion treatment of your carcinoid patients, is this performed under open surgery or via hepatic artery catheterization/embolization? Initially our patients were treated with open surgery hepatic artery ligation. We now perform the procedure using percutaneous embolization and the procedure is repeated frequently. Dr. Kvols: In collaboration with Dr. Tom O’Dorisio, we did measure circulating SMS 201-995 levels after various subcutaneous injections. Although therapeutic levels (500 to 700 pg/ml) were achieved in one patient who required the continuous infusion, we are not certain as to whether it was the peak level or a continuous level throughout the
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day that was associated with the control of symptoms. Dr. Hagop H. Mekhjian: Dr. Kvols, in regard to the response rate to SMS 201-995 in your patients, is there a subpopulation of responders? Further, is the response complete for both flushing and diarrhea? Dr. K\iols: All patients with reduced biochemical markers showed clinical improvement with a decrease in flushing as well as in diarrhea. I know of only two cases in which diarrhea was controlled but flushing was not. Dr. Phillip L. Rayford: Does carcinoid syndrome develop in black persons? Dr. Feldman: Yes, it does. Carcinoid syndrome occurs in both white and black patients with approximately equal frequency. Black patients wilt feel the carcinoid flushing and their skin will sometimes redden. They will perspire and their eyes will tear.
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