A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors.

The IGF pathway has been implicated in the regulation of neuroendocrine tumor (NET) growth, and preliminary studies suggested that ganitumab (AMG 479), a human MAB against IGF1R, may have antitumor activity in this setting. We performed a two-cohort phase II study of ganitumab in patients with metastatic progressive carcinoid or pancreatic NETs (pNETs). This open-label study enrolled patients (≥18 years) with metastatic low- and intermediate-grade carcinoid or pNETs. Inclusion criteria included evidence of progressive disease (by Response Evaluation Criteria in Solid Tumors (RECIST)) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160  mg/dl. Prior treatments were allowed and concurrent somatostatin analog therapy was permitted. The primary endpoint was objective response. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Sixty patients (30 carcinoid and 30 pNETs) were treated with ganitumab 18  mg/kg every 3 weeks, among whom 54 patients were evaluable for survival and 53 patients for response. There were no objective responders by RECIST. The median PFS duration was 6.3 months (95% CI, 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients, and 4.2 months for pNET patients. The OS rate at 12 months was 66% (95% CI, 52-77%) for the entire cohort. The median OS has not been reached. Grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%), and infusion reaction (1%). Although well tolerated, treatment with single-agent ganitumab failed to result in significant tumor responses among patients with metastatic well-differentiated carcinoid or pNET.

A phase II clinical trial of sunitinib following hepatic transarterial embolization for metastatic neuroendocrine tumors.

BACKGROUND: The liver is the predominant site of metastases among patients with advanced neuroendocrine tumors (NETs). Prior retrospective studies have reported high response rates in patients treated with transarterial embolization (TAE). NETs are highly vascular and are known to express vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR). We hypothesized that administration of sunitinib, a VEGFR inhibitor, following TAE would extend progression-free survival (PFS). PATIENTS AND METHODS: Patients with metastatic NETs to the liver underwent a series of selective TAEs followed by sunitinib (until disease progression or maximum of 12 months). Radiographic response (by RECIST), survival, and safety parameters were monitored. RESULTS: Thirty-nine patients were enrolled. The overall response rate was 72% [95% confidence interval (CI), 0.58-0.86]. Median PFS was 15.2 months. Rates of overall survival (OS) at 1 and 4 years were 95% (95% CI, 0.88-1.00) and 59% (95% CI, 0.38-0.80), respectively. A significant 34% rise in serum VEGF was observed following the initial TAE (P = 0.03). CONCLUSIONS: Hepatic TAE is a highly active treatment option for patients with metastatic NETs to the liver. Embolization stimulates release of VEGF into the circulation. Sunitinib, an oral VEGFR inhibitor, can be safely administered following embolization. The high rates of PFS and OS associated with this sequence of therapies are encouraging.

A Phase II study of high-dose paclitaxel in patients with advanced neuroendocrine tumors.

BACKGROUND: New agents with antitumor activity in patients with neuroendocrine tumors are sorely needed. A Phase II study of high-dose paclitaxel in patients with metastatic carcinoid and islet cell tumors was performed at the Mayo Clinic. Granulocyte-colony-stimulating factor (GCSF) also was administered to ameliorate neutropenia. METHODS: Twenty-four patients (14 with carcinoid tumors, 9 with islet cell tumors, and 1 with an anaplastic tumor) were enrolled on this Phase II study of paclitaxel given as a 24-hour continuous infusion at a dose of 250 mg/m(2) every 3 weeks plus GCSF at a dose of 5 microg/kg/day subcutaneously, beginning 24 hours after the completion of the paclitaxel dose and continuing until the absolute neutrophil count was > 10,000/microL. RESULTS: All 24 patients were evaluable for analysis. The overall response rate was 8% (95% confidence interval [95% CI], 0-0.11). At last follow-up all patients except 1 had developed disease progression, with an estimated median time to disease progression of 3.2 months (95% CI, 1.6-6.0 months). The estimated median survival was 1.5 years (95% CI, 1.0-1.8 years). Hematologic toxicity was significant with 12 of 24 patients developing Grade 4 (according to the National Cancer Institute Common Toxicity Criteria scale) neutropenia; however, there were no septic deaths reported. There were 17 episodes of Grade 4 neutropenia in these 12 patients and the duration of these events ranged from 2-5 days. More common nonhematologic toxicities included arthralgia (21 patients), anorexia (15 patients), nausea (15 patients), diarrhea (12 patients), and allergic reactions (2 patients). CONCLUSIONS: Given the lack of antitumor activity of paclitaxel and the significant hematologic toxicity observed despite the use of GCSF support in the current study cohort of patients with neuroendocrine tumors, further studies of this combination in this particular patient population are not recommended.

Reduced uncertainty as a diagnostic benefit: an initial assessment of somatostatic receptor scintigraphy's value in detecting distant metastases of carcinoid liver tumours.

This paper employs classical concepts of diminishing marginal utility to demonstrate that risk-aversion can increase the perceived value of diagnostic procedures and thus raise optimum diagnostic expenditures. The theory is applied to a model in the spirit of Phelps and Mushlin's initial technology assessments. The specific evaluation is the cost-effectiveness of somatostatin receptor scintigraphy used to detect distant metastases of carcinoid liver tumours in a patient otherwise eligible for surgical resection of the liver. Data for the model are taken from published sources and financial databases, when available, and otherwise from a senior clinician's experience (LKK). The quantitative results indicate that receptor scintigraphy may have two beneficial impacts to risk-neutral individuals. First, it may reduce the combined costs of therapy and treatment because the diagnostic procedure costs less than the expected savings generated by avoiding inappropriate surgeries. Second, it may improve the patient's expected health-status-adjusted life years (HSALY) because the information allows physicians to better match treatment to the cancer's stage. Finally the paper demonstrates that risk aversion, as embodied in classical diminishing marginal utility applied to health status, can increase the value of the diagnostic tests and can lead the patient to choose a less beneficial treatment. An illustrative risk-averse utility function changed the optimum treatment from surgery to chemotherapy and increased scintigraphy's benefit by 500%.

Increased parathyroid hormone-related peptide in patients with hypercalcemia associated with islet cell carcinoma.

OBJECTIVE: To report the high prevalence of increased parathyroid hormone-related peptide (PTHrP) in patients with islet cell carcinoma and associated hypercalcemia. DESIGN: We conducted a retrospective study of PTHrP levels in patients with hypercalcemia and eucalcemia associated with islet cell carcinoma and compared these findings with those in healthy subjects. MATERIAL AND METHODS: Using a sensitive PTHrP immunochemiluminometric assay, we measured PTHrP levels in 17 patients with islet cell carcinoma and 110 healthy subjects. The differences between PTHrP levels in patients with normal and those with high serum calcium concentrations were analyzed statistically. RESULTS: PTHrP levels were significantly higher (P < 0.01) in 10 patients with hypercalcemia and islet cell carcinoma (median, 14.0 pmol/L; range, undetectable to 40.1) than in 7 patients with eucalcemia and islet cell carcinoma (median, undetectable; range, undetectable to 1.3 pmol/L) or in the 110 healthy subjects (median, undetectable; range, undetectable to 4.2 pmol/L). The range of increased PTHrP levels in hypercalcemic islet cell carcinoma was 2 to 20 times the upper normal limit (2.0 pmol/L). Decreased PTHrP and serum calcium and increased parathyroid hormone levels were demonstrated in two patients after effective therapy. For all seven eucalcemic patients with islet cell carcinoma, PTHrP levels did not differ significantly from those in healthy subjects. CONCLUSION: PTHrP levels are increased in a substantial proportion of patients with hypercalcemia and islet cell carcinoma and seem to decrease after treatment of the underlying tumor. Measurement of PTHrP levels may be useful for confirming the diagnosis of hypercalcemia associated with malignant disease and for monitoring of therapy.

Can molgramostim enhance the antitumor effects of cytotoxic drugs in patients with advanced sarcomas?

BACKGROUND: A phase I study was designed for the amalgamation of two previously studied antisarcoma regimens (ifosfamide+doxorubicin and mitomycin+doxorubicin+cisplatin) supported by molgramostim. Thus, we hoped to develop a better regimen for the treatment of advanced sarcomas. PATIENTS AND METHODS: Fifteen adult advanced sarcoma patients and six other patients were registered and sequentially assigned to receive three progressively more myelosuppressive levels of chemotherapy: level I-ifosfamide 2500 mg/m2 + doxorubicin 40 mg/m2 + cisplatin 60 mg/m2 all given on day 0, followed by molgramostim 5 micrograms/kg every 12 hours for 14 days; level II-exactly the same chemotherapy from level I given on day 1 preceded on day 0 by ifosfamide 2500 mg/m2 and an additional four days of molgramostim given on days-6 through-3; level III-same as level II except for the addition of mitomycin 4 mg/m2 immediately prior to cisplatin on day 1. MENSA 500 mg/m2 was given five times on each day that involved ifosfamide treatment. For all levels, treatment was repeated at four-week intervals. RESULTS: Preliminary results and toxicity were reported three years ago (J Natl Cancer Inst 86: 312-4, 1994). Mature results confirm these unexpectedly favorable results with five advanced sarcoma patients still surviving after more than three years (four more than four years). HYPOTHESIS: Molgramostim given subcutaneously in a relatively intensive schedule might enhance the antitumor effects initiated by cytotoxic drugs in patients with advanced sarcomas. This idea should be tested formally in phase III studies.

Incidence and morbidity of cholelithiasis in patients receiving chronic octreotide for metastatic carcinoid and malignant islet cell tumors.

BACKGROUND: Octreotide, a long-acting somatostatin analogue, has demonstrated clinical utility in patients with carcinoid syndrome and malignant islet cell tumors of the pancreas. Prior studies have reported a greater than expected incidence of cholelithiasis in patients treated with octreotide for acromegaly. This study attempted to determine the incidence and morbidity of cholelithiasis in a group of patients with metastatic carcinoid or malignant pancreatic islet cell tumors who were receiving chronic therapy with octreotide. METHODS: Forty-four of 55 patients on investigational protocols with octreotide were eligible for chart review; 10 patients were excluded due to prior cholecystectomy and 1 patient due to asymptomatic cholelithiasis at presentation. Patients fell into three treatment groups. The low dose (LD) group was comprised of 17 patients receiving 150 microg of subcutaneous octreotide 3 times a day. Twenty-one patients received high dose (HD) therapy comprised of 500 microg given 3 times a day. The low dose-high dose (LD-HD) group was comprised of 6 patients who had their dose escalated from 150 microg to 225-500 microg of octreotide 3 times a day. RESULTS: The overall incidence of cholelithiasis and/or gallbladder sludge was found to be 52.3% in all 3 treatment groups. Three of the 44 patients (6.8%) had symptomatic disease requiring emergency cholecystectomy. Five other patients underwent elective or incidental gallbladder surgery. The incidence of cholelithiasis in the LD, LD-HD, and HD groups was 35.3%, 66.6%, and 61.9%, respectively. The incidence of acute cholecystitis in the three groups was 11.8%, 0%, and 4.8%, respectively. CONCLUSIONS: Although greater than 50% of patients receiving octreotide developed cholelithiasis, a much smaller percentage of patients had symptomatic gallbladder disease. Patients receiving chronic octreotide treatment require monitoring for the development of gallstones. However, prophylactic cholecystectomy is not indicated, unless it is performed in conjunction with bowel resection or cytoreductive hepatic surgery.

Regression of metastatic carcinoid tumor after valvular surgery for carcinoid heart disease.

BACKGROUND: The carcinoid syndrome is a common sequela in patients with carcinoid tumor metastatic to the liver. Cardiac involvement occurs in 19-56% of patients with symptomatic carcinoid syndrome and, in some patients, leads to valvular surgery to relieve symptoms due to progressive right-sided heart failure. Reports of these patients have emphasized amelioration of cardiac symptoms, but postoperative tumor status rarely has been discussed. METHODS: This report describes four patients who underwent valvular heart surgery for severe carcinoid heart disease and had regression of their metastatic carcinoid tumor postoperatively. RESULTS: All four patients had definite clinical improvement in cardiac function and relief of symptoms related to congestive heart failure postoperatively. Unexpectedly, they also had regression of their metastatic disease, as reflected in decreased levels of urinary 5-hydroxyindoleacetic acid, and objective evidence of a reduction in the size of hepatic metastases. CONCLUSIONS: To the authors' knowledge, these four patients represent the first reported cases of metastatic disease regression after valvular surgery for carcinoid heart disease. Further descriptions of tumor status in patients having undergone a heart operation for this disease would be valuable in determining the clinical significance of this finding.

Clinical spectrum of hyperglucagonemia associated with malignant neuroendocrine tumors.

OBJECTIVE: To review the clinical features associated with hyperglucagonemia in malignant neuroendocrine tumors. MATERIAL AND METHODS: We retrospectively reviewed the medical records of patients with hyperglucagonemia encountered at our institution from Oct. 17, 1988, through February 1993 who had a fasting serum glucagon level of at least 120 pg/mL (twice the normal value). The 71 study patients also had no evidence of a secondary cause of hyperglucagonemia and had pathologic confirmation of a neuroendocrine tumor. RESULTS: The study group consisted of 46 men and 25 women with a median age of 57 years. Two patients had multiple endocrine neoplasia. Forty-nine patients had biochemically polyfunctional tumors, and 22 had hyperglucagonemia only. The most common initial symptoms were weight loss, abdominal pain, diarrhea, nausea, peptic ulcer disease, diabetes, and necrolytic migratory erythema (NME). Diabetes eventually developed in 25 patients and was associated with NME in 11. The highest median serum glucagon values occurred in patients with the glucagonoma syndrome or insulinomas, and the lowest median values were in those with carcinoid syndrome, Zollinger-Ellison syndrome, or diabetes without NME. Fasting glucagon and glucose measurements were not correlated. The most common hormonal syndromes were the Zollinger-Ellison syndrome and the glucagonoma syndrome. All the neuroendocrine tumors were malignant. Several methods of treatment, including surgical debulking, chemotherapy, somatostatin, and hepatic artery embolization, were used. Death occurred in 29 patients at a median of 2.79 years after diagnosis; 42 patients were alive at a median of 2.86 years after diagnosis. CONCLUSION: A mild degree of hyperglucagonemia can commonly be associated with multifunctional neuroendocrine tumors. The glucagonoma syndrome occurs in a few patients with malignant neuroendocrine tumors and hyperglucagonemia and is associated with very high serum glucagon levels. The correlation between serum glucagon levels and the development of diabetes is limited, and other factors such as insulin may be more important than hyperglucagonemia in the development of diabetes.

The glucagonoma syndrome. Clinical and pathologic features in 21 patients.

The glucagonoma syndrome is a rare disorder characterized by weight loss, necrolytic migratory erythema (NME), diabetes, stomatitis, and diarrhea. We identified 21 patients with the glucagonoma syndrome evaluated at the Mayo Clinic from 1975 to 1991. Although NME and diabetes help identify patients with glucagonomas, other manifestations of malignant disease often lead to the diagnosis. If the diagnosis is made after the tumor is metastatic, the potential for cure is limited. The most common presenting symptoms of the glucagonoma syndrome were weight loss (71%), NME (67%), diabetes mellitus (38%), cheilosis or stomatitis (29%), and diarrhea (29%). Although only 8 of the 21 patients had diabetes at presentation, diabetes eventually developed in 16 patients, 75% of whom required insulin therapy. Symptoms other than NME or diabetes mellitus led to the diagnosis of an islet cell tumor in 7 patients. The combination of NME and diabetes mellitus led to a more rapid diagnosis (7 months) than either symptom alone (4 years). Ten patients had diabetes mellitus before the onset of NME. No patients had NME clearly preceding diabetes mellitus. Increased levels of secondary hormones, such as gastrin (4 patients), vasoactive intestinal peptide (1 patient), serotonin (5 patients), insulin (6 patients, clinically significant in 1 only), human pancreatic polypeptide (2 patients), calcitonin (2 patients) and adrenocorticotropic hormone (2 patients), contributed to clinical symptoms leading to the diagnosis of an islet cell tumor before the onset of the full glucagonoma syndrome in 2 patients. All patients had metastatic disease at presentation. Surgical debulking, chemotherapy, somatostatin, and hepatic artery embolization offered palliation of NME, diabetes, weight loss, and diarrhea. Despite the malignant potential of the glucagonomas, only 9 of 21 patients had tumor-related deaths, occurring an average of 4.91 years after diagnosis. Twelve patients were still alive, with an average age follow-up of 3.67 years.

Rothmund-Thomson syndrome in siblings: evidence for acquired in vivo mosaicism.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder characterized by skin abnormalities that appear in infancy, skeletal abnormalities, juvenile cataracts and other manifestations of premature aging, and a predisposition to malignancy. The diagnosis is made on clinical grounds as no consistent laboratory test has been identified. Chromosome studies have been reported for only three patients with RTS and in two of these three, trisomy 8 mosaicism was found. We performed a variety of cytogenetic and molecular genetic studies on two siblings with RTS and on their phenotypically normal parents. Two chromosomally abnormal clones involving either trisomy 8 or i(8q) were found in both patients with RTS. These clones were present in vivo, as they were seen in interphase buccal smears and lymphocytes from unstimulated preparations using both conventional cytogenetic studies and fluorescence in situ hybridization (FISH) with a centromere probe for chromosome 8. These results suggest that RTS is associated with in vivo clonal chromosomal rearrangements causing an acquired somatic mosaicism.

Expression of somatostatin receptor subtypes in breast carcinoma, carcinoid tumor, and renal cell carcinoma.

The presence of transcripts for somatostatin receptor (SSTR) subtypes 1, 2, 3, and 4 was probed by reverse transcription and polymerase chain reaction in ribonucleic acid isolated from 46 malignant and 9 nonmalignant breast tissues, 15 carcinoid tumor tissues, and 13 renal cell carcinoma tissues. The transcripts for SSTR2 were amplified in all but 2 tissue samples, whereas transcripts for SSTR1, SSTR3, and SSTR4 were detected sporadically. In renal cell tumors, SSTR3 transcripts were completely absent. In breast cancer tissue, SSTR subtypes were transcribed independently of patient age, menstrual status, diagnosis, histological grade, and levels of estrogen receptor and progesterone receptor. The probability of finding transcripts for SSTR subtypes, P, was ranked differently for the three types of tumor tissues. For breast cancer, P2 > P3 = P1 > P4; for carcinoid tumors, P2 > P1 > P3 = P4; and for renal cell tumors, P2 > P1 > P4 > P3.

Therapy of neuroendocrine tumors with radiolabeled MIBG and somatostatin analogues.

The increased understanding of the neuroendocrine tumors at a cellular and molecular level has led to the development of new radiopharmaceuticals for imaging. Two of the imaging agents include 131I metaiodobenzylguanidine (131I-MIBG) and 111In-DTPA-D-Phe1-octreotide (111In-pentetreotide) each having specific localization in certain neuroendocrine tumors. The selective uptake of these radiopharmaceuticals by the tumor cells has generated interest in potential use for targeted radiotherapy for neuroendocrine tumors. 131I-MIBG has been used to treat patients with pheochromocytoma, neuroblastoma, carcinoid tumors, medullary thyroid carcinoma, and paragangliomas. The tumor responses have been variable with the most encouraging results being in patients with pheochromocytoma. The dose-limiting toxicity has been thrombocytopenia or granulocytopenia. 111In-pentetreotide has been used as therapy in only a few patients and has resulted in objective evidence of tumor responses. A therapeutic agent using a somatostatin analogue will most likely require radiolabeling with a beta- or possibly an alpha-emitting radionuclide to achieve significant and durable tumor responses.

Outcome of cardiac surgery for carcinoid heart disease.

OBJECTIVES: The hypothesis was that cardiac surgery for symptomatic carcinoid heart disease in conjunction with adjunctive therapy could improve the long-term outlook of patients with carcinoid heart disease. BACKGROUND: Patients with carcinoid heart disease have a dismal prognosis; most die of progressive right heart failure within 1 year after onset of symptoms. Improved therapies for the systemic manifestations of the carcinoid syndrome have resulted in symptomatic improvement and prolonged survival in patients without heart disease. METHODS: Twenty-six patients with symptomatic carcinoid heart disease underwent valvular surgery. Preoperative clinical, laboratory, Doppler echocardiographic and hemodynamic factors were evaluated. The survival of the surgical group was compared with that of a control group of 40 medically treated patients. RESULTS: There were nine perioperative deaths (35%), primarily from postoperative bleeding and right ventricular failure. Of the 17 surgical survivors, 8 were alive at a mean of 28 months of follow-up. The postoperative functional class of the eight surviving patients was substantially improved. Late deaths were primarily due to hepatic dysfunction caused by metastatic disease. The only predictor of operative mortality (p = 0.03) was low voltage on preoperative electrocardiography (limb lead voltage < or = 5 mm). Predictors of late survival included a lower preoperative somatostatin requirement and a lower preoperative urinary 5-hydroxy-indoleacetic acid level. There was a trend toward increased survival for the surgical group compared with the control group. CONCLUSIONS: Because new therapies have improved survival in patients with the malignant carcinoid syndrome, cardiac involvement has become a major cause of morbidity and mortality. Valve surgery is the only definitive treatment. Although cardiac surgery carries a high perioperative mortality, marked symptomatic improvement occurs in survivors. Surgical intervention should therefore be considered when cardiac symptoms become severe.

Hepatic resection for metastatic neuroendocrine carcinomas.

BACKGROUND: Metastatic neuroendocrine malignancies frequently cause incapacitating endocrinopathies, and metastases predominant in the liver. Hepatic resection of metastases from such tumors is attractive because the natural history of neuroendocrine tumors is protracted, clinical severity of the endocrinopathy correlates with tumor volume, and local and intrahepatic growth characteristics often allow complete resection. PATIENTS AND METHODS: To define the role of hepatic resection for metastatic neuroendocrine tumors, the records of 74 patients who underwent hepatic resection for such tumors between 1984 and 1992 were reviewed. Neuroendocrine tumors were classified by site of origin and clinical endocrinopathy. Survival, and type and duration of symptomatic response, were assessed as the major outcomes of this study. RESULTS: There were 50 carcinoid, 23 islet-cell, and 1 atypical neuroendocrine tumors. Resections included 36 hemihepatectomies or extended hepatectomies and 38 nonanatomic resections. Thirty-eight primary tumors were resected concomitantly. Perioperative mortality was 2.7% and morbidity was 24%. Four-year survival was 73%. Overall postoperative symptomatic response rate was 90% with a mean duration of response of 19.3 months. CONCLUSIONS: Hepatic resection for metastatic neuroendocrine malignancies is safe, provides effective palliation, and probably prolongs survival.

Expression of somatostatin receptors in childhood neuroblastoma.

Somatostatin receptors are expressed on certain neural crest-derived tumors, including pancreatic islet cell and carcinoid tumors, medullary thyroid carcinomas, pheochromocytomas, and paragangliomas. The authors evaluated the expression of high affinity somatostatin receptors in childhood neuroblastoma using autoradiography techniques with the somatostatin analogue 125I-octreotide or 125I-[Leu8,D-Trp22,Tyr25]-SS-28 as the radioligand. Thirty tumors from 30 children with neuroblastoma were analyzed. Twenty-three of 30 tumors that were tested expressed somatostatin receptors. Correlation of somatostatin receptor expression with survival was statistically significant. The survival of those patients whose tumors expressed somatostatin receptors was of longer duration than that of patients whose tumors did not. This was an independent prognostic factor. Somatostatin receptors were expressed more frequently in tumor tissue from patients with lower stages of disease and in those with no evidence of N-myc amplification. Tumoral somatostatin receptors are expressed in a subgroup of patients with childhood neuroblastoma. Survival analysis in this group of patients indicates that somatostatin receptor expression is a favorable prognostic factor. This finding may have important implications for the therapy of children with this malignancy.