Seminars in Surgical Oncology 9453-458 (1993)

Palliative Treatment of Neu roendocrine Tumors

J. GREGORY McKINNON, MD

From the Department of Surgery, University of Calgary, Calgary, Alberta, Canada

Effective palliation of patients with incurable neuroendocrine tumors requires both control of hormonal overproduction symptoms as well as control of tumor growth. Several important advances have been made in recent years toward these two goals. Octreotide and ome- prazole have both been extremely effective in ameliorating hormonal symptoms of carcinoids, islet cell tumors and medullary thyroid carci- noma. Newer cytotoxic chemotherapy regimens and interferon have increased response rates over traditional therapy. More aggressive surgical extirpation of metastatic disease has also been beneficial. @ 1993 Wiley-Liss, Inc.

KEY WORDS: APUDoma, carcinoid, islet cell tumor, pheochromocytoma, thyroid neoplasm

INTRODUCTION Although neuroendocrine tumors present a myriad

of different and challenging clinical problems, they tend to share a number of common characteristics. The natural history of these tumors is usually one of slow growth over a period of 10- 15 years, which may be marked by dramatic clinical syndromes of hormone overproduction [l]. Once it has been determined that a tumor cannot be resected for cure, the treating physi- cian is faced with two tasks. The first is to control symptoms produced by hormone over production, which may be immediately life-threatening. The sec- ond is to attempt prolongation of survival by limiting the growth or ablating metastatic tumor tissue. Occa- sionally the same therapeutic maneuver may accom- plish these two goals. This review attempts to outline remarkable advances made in the last decade toward these two goals.

CONTROL OF HORMONAL SYMPTOMS Carcinoid Tumors

The natural history of carcinoid tumors is quite variable depending on their site of origin. Metastatic rate is proportional to size and averages 70% for tu- mors of the small intestine that are 1-2 cm, and higher for tumors larger than 2 cm [2]. Colorectal carcinoids seem to have a more aggressive course, with the meta- static rate of tumors greater than 2 cm being 74% with

an overall 5-year survival of 37% [3]. Once hepatic metastases have developed, outlook is dismal with a five year survival ranging from zero to 47% [4-61.

Virtually all neuroendocrine tumors contain secre- tory granules, but most are not functionally significant [7]. Carcinoid tumors occasionally secrete a number of hormonally active peptides that are thought to medi- ate carcinoid syndrome, a constellation of symptoms including diarrhea, flushing, bronchoconstriction and tissue fibrosis. Although the mechanism of these symptoms is poorly understood, it is mediated at least in part by histamine, serotonin, prostaglandin E and F, and tachykinins [8]. Fortunately, the treatment is broadly effective and does not depend on complete delineation of hormonal effects. Estimates of inci- dence of carcinoid syndrome have varied widely de- pending on the location of the primary and how dili- gently it is searched for. Feldman suggested that 84% of all patients with carcinoids had elevated levels of serotonin, although not all were clinically significant [9]. Norheim reported carcinoid syndrome in 67% of patients with metastatic tumor at time of presentation [ 101. Small intestine carcinoids produce the syndrome only when metastasized to the liver. Foregut carcin- oids have been known to produce systemic symptoms

Address reprint requests to Dr. J.G. McKinnon, 3330 Hospital Dr. N.W., Calgary, Alberta T2N 4N1, Canada.

0 1993 Wiley-Liss, Inc.

454 McKinnon

in the absence of metastases, although this is unusual [lo].

The most important advance made in the treatment of carcinoid syndrome in recent years has been the development of octreotide, the long-acting synthetic analogue of somatostatin [ 1 11. Since the introduction of this drug, numerous trials have assessed its efficacy in virtually all neuroendocrine tumors, both for symp- tom reduction and for antitumor toxicity. In carcinoid syndrome, octreotide has been extremely successful in ameliorating or abolishing flushing and diarrhea with an 80- 100% complete response. This has been accom- panied by a concomitant reduction in urine SHIAA [12-141. Octreotide is given as a chronic subcutaneous injection of 50-100 pg three times daily. Side effects have been minimal except for pain at the injection site and the development of gallstones [ 151. Recently, somatostatin receptors have been identified in carci- noid liver metastases by needle biopsy. Their presence may prove predictive of response to somatostatin treatment [16].

Anecdotal reports have suggested that carcinoid syndrome refractory to octreotide alone may be re- sponsive to a combination of Interferon-a and octreo- tide [ 171. Recently, cyproheptadine, a serotonin inhibi- tor, was shown to be successful in alleviating flushing and diarrhea although it was not tolerated in all pa- tients [18].

Gastrinoma The Zollinger-Ellison syndrome is the result of un-

controlled tumor production of gastrin from islet cell tumors. The syndrome is characterized by peptic ul- ceration and diarrhea with their associated complica- tions. It has been estimated that with an aggressive approach to localization and resection, at least 20% of patients with sporadic disease should be cured by sur- gical exploration [19]. Gastrinoma in multiple endo- crine neoplasia-type I (MEN-I) syndrome tends to be multicentric and is difficult or impossible to cure with resection [20]. These patients tend to become chronic management problems. Fortunately, malignancy rate in MEN associated tumors tends to be less than in the sporadic form, and survival with metastatic disease somewhat longer [20,21]. In those patients who are noncurable by surgical means, success in controlling gastrin induced acid hypersecretion has led to long- term survival. Ultimate mortality is usually due to malignant tumor progression. In a study of noncura- ble islet-cell tumors, Thompson reported a 3-year sur- vival of 56% [22]. Gastrinomas had a significantly bet- ter prognosis than nonfunctioning islet cell tumors [221.

Complete control of acid secretion is now possible

with the introduction of the H + K + ATPase inhibi- tor, omeprazole [23]. This drug has proved extraor- dinarily effective for long-term control of hypergas- trinemia and has largely supplanted the role of H-2 blockers and gastrectomy. Although initial animal studies suggested that long term use might result in the formation of gastric enterochromaffin-like tumors (ECL), omeprazole has been proved safe in long-term human trials [24-271.

Octreotide has been assessed for its effect on gas- trinoma and been found to control symptoms in the majority of patients [28]. However it was not effective in those patients with metastatic tumor with high lev- els of gastrin production [28]. Its role in gastrinoma therefore, is restricted to those patients who cannot tolerate omeprazole or high dose H-2 blockers. It should also be remembered that in patients with MEN-I syndrome, control of acid hypersecretion can sometimes be greatly facilitated by control of any pre- existing hyperparathyroidism [20,21].

Insulinoma Insulin secreting islet cell tumors are quite rare. Of

those that occur, the majority are benign, that is, no metastases are detected at time of surgical exploration and resection of tumor results in long-term cure in approximately 90% of cases [29]. In patients with metastasized or unresectable disease, control of severe hypoglycemia is problematic. Traditional methods of hypoglycemia control include diet and use of diazox- ide. The mechanism of diazoxide is unknown and its efficacy somewhat unpredictable [30]. Nevertheless it controls symptoms in approximately 60% of patients [31]. As with other islet cell tumors, octreotide has been reported to have a beneficial effect in patients with unresectable insulinoma [32], although resistance to therapy eventually develops with progression of disease [33]. Other therapies necessitate cytoreduction, as discussed later.

Other Islet Cell Tumors VIPoma, previously known as Verner-Morrison

syndrome, is characterized by uncontrolled release of vasoactive intestinal peptide. This results in a severe form of diarrhea with dehydration, hypokalemia and acidosis, aptly described as pancreatic cholera [34]. Glucagonoma is a rare tumor where high levels of glucagon lead to a syndrome of migratory necrolytic rash, mild diabetes and severe muscle wasting [31]. If followed long enough, both of these islet cell tumors are usually found to be malignant, unlike insulinomas. Both syndromes are responsive to octreotide, particu- larly VIPomas [34-371. Treatment of glucagonoma with octreotide has been less well documented but

Neuroendocrine Tumors 455

appears to be effective in controlling all the syn- drome’s symptoms [38,39]. The extremely rare somatostatinoma is characterized by diarrhea, stea- torrhea, cholelithiasis, and weight loss. The majority are reported to be malignant and treatment of meta- static disease is cytoreductive [40]. Not surprisingly, octreotide has been tried without success [41].

Medullary Carcinoma of the Thyroid This disease may be indolent, with the tumor dor-

mant for many years [42]. However, overall 10-year survival is only 50% [43]. Unresectable metastatic tumor may be nonfunctional or may result in uncon- trollable watery diarrhea. As with other neuroendo- crine tumors, these symptoms may be controlled with octreotide [44]. However results have not been consist- ent [45].

Pheochromocytoma Malignant pheochromocytoma is a rare disease. In

a large series of pheochromocytomas unrelated to MEN syndromes, 13% were eventually found to be malignant [46]. Metastases may occur in bone, lung, mediastinum or liver and are characterized by local symptoms and excess catecholamine release [47]. Con- trol of tumor-induced catecholamine effects are possi- ble with standard a- and P-adrenergic blockade with agents such as phenoxybenzamine and propranolol. Overall long term survival once metastases are present is 44% [48].

CYTOTOXIC THERAPY The alternative strategy for palliation of incurable

neuroendocrine tumors, which may be complemen- tary to hormone blockade, is reduction or elimination of tumor burden. The usual anticancer strategies of surgery, radiation and cytotoxic chemotherapy can all be effective in the proper circumstances. In addition to these more traditional forms of treatment, there are more specific strategies that may be useful, such as radioisotope therapy.

Chemotherapy Treatment of disseminated neuroendocrine car-

cinomas with cytotoxic chemotherapy has not been very encouraging, with poor response rates and seri- ous toxicity [49]. For carcinoids and islet cell tumors, streptozotocin has been long used with varying suc- cess. More recently this drug has been used in combi- nation with other cytotoxic and biological agents. A multicenter trial demonstrated streptozotocin + dox- orubicin to result in 69% tumor response rate [50]. A new derivative of streptozotocin, chlorozotocin was as effective in combination with doxorubicin but with

fewer side effects [SO]. However, another recent trial showed a modest response in only 19% of patients with advanced neuroendocrine tumors with combined streptozotocin and doxorubicin [5 11. A combination of etoposide and cisplatin has been reported to result in 67% response rate in tumors classified as anaplastic [52]. Although side effects were severe, duration of response ranged from 8-24 months. Continuous infu- sion of 5FU has resulted in complete response of islet cell tumors but these reports are anecdotal [53].

Cytotoxic chemotherapy for metastatic pheo- chromocytoma has had limited success with a different group of agents [54,55]. Averbruch et al. reported a complete and partial response rate of 57% with a com- bination of cyclophosphamide, vincristine, and dacar- bazine, a regimen originally used for pediatric neuro- blastoma [56].

Radiation Therapy External beam radiotherapy is rarely indicated in

neuroendocrine tumors, except for palliation of bone metastases. However there has been some success with specific isotope therapy, particularly in metastatic pheochromocytoma. * 311-MIBG accumulates in cate- cholamine storage granules and is selectively taken up in pheochromocytoma tumor tissue in a manner simi- lar to l3II in thyroid carcinoma. Recent reports sug- gest a 60% response rate [57,58]. There is some hope of using the same strategy in other tumors that take up I-MIBG such as medullary thyroid carcinoma, but no clinical trials have been reported yet.

Interferon Interferon has been investigated as a new and excit-

ing agent for treating neuroendocrine tumors. Early results reported by Oberg were extremely encourag- ing, with objective tumor response and amelioration of symptoms seen in the majority of patients [59-611. A prospective randomized trial of 20 patients showed human leukocyte interferon to be superior to strep- tozotocin and 5FU with 10 out of 10 patients treated with interferon showing regression or stable disease [62]. However, other investigators using recombinant interferon-a have been less successful. An ameliora- tion in hormonal symptoms is sometimes seen, al- though not as complete as with octreotide, but with little or no objective tumor response [63-651. Efficacy may be limited by the formation of neutralizing anti- bodies in patients as early as 3 months into treatment [66]. These antibodies have been reported to occur more often, with interferona2b than with interferon-a 2a [67]. Side effects such as fever, anorexia, and weight loss have also been serious [68,69], and there has been

456 McKinnon

one reported case of induction of a systemic lupus erythematosus (SLE)-like syndrome with human leu- kocyte-derived interferon [70].

In experimental human xenografts, interferon plus dimethylfluorornithine was superior to IFN alone. This has not reached human trials as yet [71].

Octreotide Octreotide's remarkable success in symptom con-

trol of neuroendocrine tumors led researchers to in- vestigate its possible role as a cytoreductive agent [72,- 731. Unfortunately, an observed effect in animal models and anecdotal reports has not been borne out in rigorous trials [13,15,74]. It has been tested in meta- static medullary carcinoma of the thyroid, with some fall in calcitonin levels seen but no measurable tumor response [45].

SURGICAL THERAPY Liver Metastasis Resection

Unlike most other visceral cancers, neuroendocrine malignancies tend to be slow growing, with much of their morbidity caused by autonomous hormone pro- duction. For these two reasons, cytoreductive surgery, that is resection or debulking of metastatic disease, is often beneficial and sometimes curative. Norton re- ported a series of five patients with metastatic gas- trinoma who had resection of all gross disease, includ- ing both liver and pancreas and followed by postoperative chemotherapy [75]. Four of five patients had all gross disease resected and subsequently re- quired decreased dosage of antisecretory medication. Two remained free of disease at 14 and 32 months. McEntee et al. recommended palliative resective sur- gery for islet cell tumors, even if some gross disease was left behind [76]. Eight of 16 patients with sympto- matic endocrinopathies obtained complete relief after incomplete resection of disease. Six of seven under- going curative resection obtained relief [76].

Insulinoma is slow growing with symptoms that are difficult to control medically. It is therefore particu- larly attractive to attempt ablation of gross metastatic disease. Danforth et al. reported a small series of met- astatic insulinomas which were treated with curative resection [77]. The median disease-free survival after curative resection was 5 years. The recurrence rate was 63%, with the median interval to recurrence being 2.8 years, and the median survival with recurrent tumor 19 months. Palliative resection was associated with a median survival of 4 years, and biopsy only, 11 months.

The traditional criteria and technical limitations of resective surgery of the liver have been expanded by new techniques. Ravikumar et al. reported a small series of cryosurgical ablation of metastatic neuroendocrine tu- mors [78]. Information on follow-up is limited.

Recently, a number of groups have begun using liver transplantation as a therapeutic modality for pa- tients with unresectable metastatic disease [79]. Starzl reported a series of five patients who underwent resec- tion of the primary along with liver transplantation, for metastatic disease from neuroendocrine tumors of gut origin, two of which were functional [80]. Three of five are alive and free of disease at a median of 12 months follow-up. Other reports are anecdotal but are encouraging, at least in the short term [81,82].

Hepatic Artery Embolization When other surgical and medical treatments prove

to be ineffective and metastases are limited to the liver, which is usually the case with carcinoids and islet cell tumors, hepatic arterial embolization may provide useful palliation. Because liver tumors are preferen- tially supplied by the hepatic artery and the normal liver parenchyma survives with portal circulation alone, interruption of the arterial supply can lead to ischemia and infarction of the metastases. Maton re- ported a series of 13 patients with carcinoid liver metastases treated with hepatic artery embolization, with reduction in tumor bulk and a decrease in hor- monal production [83]. Side effects, however, were se- rious with one mortality and major morbidity in the majority of patients. Other investigators have re- ported similar results in other islet cell tumors [84,85]. Selective embolization appears to be more effective than hepatic artery interruption.

Combination Therapy In view of the many different categories of therapy

available for neuroendocrine tumors, several groups have advocated an organized combination of thera- pies for patients with disseminated disease using surgi- cal, hormonal and cytotoxic therapy. It is difficult to evaluate the relative merit of these regimens because of the rarity of the disease and the lack of randomized trials. However some have reported improved survival compared to historical controls [86-881.

CONCLUSIONS The goals of therapeutic intervention for palliative

care of patients with incurable neuroendocrine tumors must be clear before embarking on potentially toxic therapy. Control of hormonal mediated symptoms and secondly, inhibition of growth or ablation of tumor are the common endpoints. The means to achieve these ends and the price to be paid by the patient must be individualized according to the type and behavior of the tumor and the overall status of the patient. Several important strides have been made in recent years in therapy for these tumors. The develop- ment of octreotide and l3*I-MIBG, the more effective use of cytotoxic chemotherapy and the more aggres-

Neuroendocrine Tumors 457

sive use of cytoreductive surgery have all been of bene- fit. It seems clear that most of these patients have relatively indolent tumors with a long natural history, and that an aggressive approach to treatment with all available means will continue to improve the length and quality of their lives.

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