Carcinoid Heart Disease: Prognostic Value of 5-Hydroxyindoleacetic Acid Levels and Impact on Survival: A Systematic Literature Review.

BACKGROUND: Carcinoid heart disease (CHD) can develop in patients with carcinoid syndrome (CS), itself caused by overproduction of hormones and other products from some neuroendocrine tumours. The most common hormone is serotonin, detected as high 5-hydroxyindoleacetic acid (5-HIAA). This systematic literature review summarises current literature on the impact of CHD on survival, and the relationship between 5-HIAA levels and CHD development, progression, and mortality. METHODS: MEDLINE, Embase, Cochrane databases, and grey literature were searched using terms for CHD, 5-HIAA, disease progression, and mortality/survival. Eligible articles were non-interventional and included patients with CS and predefined CHD and 5-HIAA outcomes. RESULTS: Publications reporting on 31 studies were included. The number and disease states of patients varied between studies. Estimates of CHD prevalence and incidence among patients with a diagnosis/symptoms indicative of CS were 3-65% and 3-42%, respectively. Most studies evaluating survival found significantly higher mortality rates among patients with versus without CHD. Patients with CHD reportedly had higher 5-HIAA levels; median urinary levels in patients with versus without CHD were 266-1,381 versus 67.5-575 µmol/24 h. Higher 5-HIAA levels were also found to correlate with disease progression (median progression/worsening-associated levels: 791-2,247 µmol/24 h) and increased odds of death (7% with every 100 nmol/L increase). CONCLUSIONS: Despite the heterogeneity of studies, the data indicate that CHD reduces survival, and higher 5-HIAA levels are associated with CHD development, disease progression, and increased risk of mortality; 5-HIAA levels should be carefully managed in these patients.

Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study.

Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated. Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm. Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov.

The Influence of Preoperative Symptoms on the Death of Patients with Small Intestinal Neuroendocrine Tumors.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are uncommon tumors with an annual incidence of about 1 per 100,000. Usually, SI-NETs have a slow progression, and patients often present with generalized disease. Many patients do well, and the disease has a relatively favorable 5-year survival rate. Some SI-NETs, however, have a more negative prognosis. This study aimed to establish prognostic factors for death identifiable at primary surgery. METHODS: A nested case-control study investigated 1150 patients from the cohort of all patients with a diagnosis of SI-NETs in Sweden between 1961 and 2001. The study cases consisted of all patients who died of SI-NETs during the study period. Each case was assigned a control subject matched by age at diagnosis and calendar period. Possible prognostic factors [gender, degree of symptoms, indication for surgery, World Health Organization (WHO) stage] were evaluated in uni- and multivariable analyses. RESULTS: The patients with symptomatic disease had an increased risk of dying. The indication for primary surgery influenced survival, showing a more negative prognosis for elective surgery. The WHO stage influenced survival, and stage 4 patients had an almost threefold risk of dying compared with stages 1 to 3b patients. CONCLUSIONS: This study showed that preoperative symptoms are important in prognostication for SI-NETs. Hormonal symptoms generally signify a patient with a more advanced disease stage and a worse prognosis. Including symptomatic disease together with the WHO stage and grade could possibly increase the accuracy of prognostication.

Octreotide long-acting repeatable among elderly patients with neuroendocrine tumors: a survival analysis of SEER-Medicare data.

BACKGROUND: Octreotide long-acting repeatable (LAR) is approved in the United States for the management of carcinoid syndromes among patients with neuroendocrine tumors (NET). The objective of our study is to evaluate the impact of octreotide LAR on overall survival (OS), as it has not been established. METHODS: NET patients of 65 years and older diagnosed between January 1999 and December 2009 were identified from the SEER-Medicare database. We compared the OS of NET patients who started octreotide LAR within 12 months of diagnosis with those who did not receive it during the same period. We conducted Kaplan-Meier estimations and Cox proportional hazard models to examine the association between octreotide LAR and OS. RESULTS: Among 1,176 distant stage patients, 233 (20%) received octreotide LAR within 12 months of diagnosis, compared with 2% (96 in 5,764) of local/regional stage patients. Median OS for patients who started octreotide LAR within 12 months was 35.22 months [95% confidence interval (CI), 27.96-47.77], longer than those who did not receive it (19.15 months; 95% CI, 16.36-22.80; P < 0.0001). Multivariate analysis showed that octreotide LAR was associated with significant survival improvement for distant stage patients (HR, 0.68; P < 0.001) and in the subgroups with (HR, 0.65; P, 0.003) and without (HR, 0.55; P, 0.002) carcinoid syndrome. No survival benefit was found among local/regional stage patients. CONCLUSION: This population-based study suggests potential survival benefits of octreotide LAR among elderly distant stage NET patients, both with or without carcinoid syndrome. IMPACT: The study provides population-based evidence of a positive association between octreotide LAR and overall survival among elderly distant stage NET patients.

Octreotide long-acting repeatable use among elderly patients with carcinoid syndrome and survival outcomes: a population-based analysis.

BACKGROUND: Octreotide long-acting repeatable (LAR) is indicated for the treatment of carcinoid syndrome and diarrhea related to VIPoma, and may delay tumor growth in patients with neuroendocrine tumors (NETs). To the authors' knowledge, the pattern of octreotide LAR use in clinical practice and its impact on survival outcomes has not been well documented. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the authors identified patients with NET aged ≥ 65 years who were diagnosed between July 1999 and December 2007. Patients with US Food and Drug Administration-approved indications for octreotide LAR were identified from Medicare claims. Multivariate logistic regression was performed to ascertain factors associated with octreotide LAR use, whereas the Cox proportional hazards model was used to evaluate the impact of octreotide LAR on survival. RESULTS: Among those with Food and Drug Administration-approved indications, 245 of 4848 patients with distant-stage disease (51%) and 81 of 807 patients with local/regional disease (10%) initiated treatment with octreotide LAR within 6 months of diagnosis. Multivariate logistic regression indicated that among those with distant-stage disease, older age (≥ 80 years vs 65-69 years) (odds ratio [OR], 0.43; 95% confidence interval [95% CI], 0.23-0.81), female sex (OR, 0.62; 95% CI, 0.40-0.97), and living in the South (vs Northeast) (OR, 0.36; 95% CI, 0.18-0.72) were associated with a lower likelihood of using octreotide LAR. The multivariate proportional hazards model showed that octreotide LAR provided a significant 5-year survival benefit for patients with distant-stage disease (hazards ratio, 0.61; P ≤ .001), whereas this survival benefit was not shown for the patients with local/regional stage (hazards ratio, 0.88; P = .563). CONCLUSIONS: The results of this retrospective study suggest a possible survival benefit for the use of octreotide LAR in elderly patients with distant-stage NET with carcinoid syndrome. The results of the current study also suggest that octreotide LAR is underused in this population despite recommended guidelines.

[Surgical treatment of pulmonary carcinoids - ten-year results]. / Chirurgische Behandlung von Lungenkarzinoiden - Zehnjahresergebnisse.

INTRODUCTION: Carcinoids are malignant neuro-endocrine tumours occurring in the bronchopulmonary location in about 25 %, and accounting for approximately 2 % of all pulmonary tumours. MATERIAL AND METHODS: Our retrospective analysis included 27  patients, 14  men and 13  women, mean age 58.4  years, treated from 2000 to 2009 for carcinoids in bronchopulmonary locations. The tumour manifested clinically in 52 % of the cases, the most common symptom being cough; one tumour manifested as carcinoid syndrome. All patients underwent fibrobronchoscopy that was positive in 20  cases (74.1 %). Pre-surgery histological diagnoses were made in 13  patients (48.1 %). Chest CT scans were carried out in 26  patients, and the investigation failed to detect the expected pathological process in 2  of the patients. Octreoscans were carried out in 12  patients, and were successful in identifying a primary neuroendocrine tumour in 75 %. RESULTS: All patients in the sample underwent rad-ical surgical therapy; the most common surgical procedure was lobectomy (70.4 %). Perioperative morbidity and mortality were zero. Typical carcinoids were found in 20  cases while 7  cases were atypical carcinoids, 20  tumours were located centrally. 74 % of the tumours were consistent with stage  I A disease. Mean follow-up period was 47 (range: 6-134)  months. Local recurrences were observed in 2  patients (7.4 %), but the tumour disseminated in 4  patients (14.8 %). Two patients (7.4 %) died during the follow-up period. Overall five-year survival in the sample was 92.3 %, 90.9 % in the typical carcinoid group and 100 % for atypical carcinoids. We found a statistically significant association between disease-free interval and histological type of the tumour; the risk of progression was 8  times higher in -patients with atypical carcinoids compared to patients with typical carcinoids (Log-Rank-Test: p-value = 0.0049). CONCLUSION: Radical surgical treatment of bronchopulmonary carcinoids is the optimum therapeutic approach that results in the best results both regarding perioperative morbidity and mortality and regarding long-term survival of the patients.

Comparison of prognostic value of tissue Doppler imaging in carcinoid heart disease versus the value in patients with the carcinoid syndrome but without carcinoid heart disease.

The aim of this study was to evaluate the prognostic value of tissue Doppler imaging (TDI) in carcinoid heart disease (CHD). We prospectively enrolled 56 consecutive patients with proved digestive endocrine tumor and carcinoid syndrome. All patients underwent serial conventional, contrast, and TDI echocardiographic studies. The end point was all-cause mortality. Mean follow-up was 34 +/- 21 months. At the end of follow-up, 30 patients (54%) presented right CHD and 13 patients (23%) left CHD. A progression of CHD was documented in 23 patients (41%). Twenty-two patients (39%) died during follow-up. According to mortality receiver operating characteristic curves, ratio of early transmitral flow velocity to early diastolic mitral annulus velocity (E/e' ratio) associated with an optimal sensitivity of 80% and specificity of 90% was 8. Mortality rate was significantly higher when the E/e' ratio was >or=8 (94% vs 10% when E/e' ratio was <8, p <0.0001). Using univariate analysis, the following factors were associated with death: left-sided CHD (p = 0.07) and E/e' ratio >or=8 (p <0.0001). The only independent marker of death detected by multivariate analysis was an E/e' ratio >or=8 (odds ratio 6.2, 95% confidence interval 1.95 to 19.7, p = 0.002). In conclusion, TDI used during routine transthoracic echocardiography can be helpful to identify high-risk patients with CHD.

Long-term results of patients with malignant carcinoid syndrome receiving octreotide LAR.

BACKGROUND: Octreotide LAR is an established treatment for malignant carcinoid syndrome. However, studies with large number of patients and long follow-up are lacking. AIM: To present long-terms results with octreotide LAR, assessing duration of clinical and objective response and treatment tolerance, in a large, homogeneous cohort of patients with malignant carcinoid syndrome. METHODS: A total of 108 patients with metastatic midgut neuroendocrine tumours were included in this 8-year study. Clinical evaluation was based on a symptom score. Radiological assessment was based on RECIST (Response Evaluation Criteria In Solid Tumours) criteria. RESULTS: Of the 108 patients, 24% had a sustained symptomatic response. In the remaining patients, loss of symptomatic response with the initial dose was noted within 3-60 months. In 17% of them, symptoms were controlled by just an increase of octreotide LAR dose, whilst the other patients required additional treatment. Overall, in 45.3% of patients, symptoms were well controlled during the study period with only octreotide LAR, and no additional treatment was required. No significant adverse effects were noted. CONCLUSIONS: Octreotide LAR treatment provides a sustained symptomatic response in about half of the patients with malignant carcinoid syndrome and contributes to disease stabilization for a longer period than previously described.

The palliative benefit of aggressive surgical intervention for both hepatic and mesenteric metastases from neuroendocrine tumors.

BACKGROUND: Metastatic neuroendocrine tumors (NETs) can present with complications of gastrointestinal tract obstruction or ischemia and carcinoid syndrome (CS). The purpose of this study was to assess whether aggressive surgical intervention of metastatic NETs provides effective palliation from these symptoms. METHODS: Sixty-six patients with metastatic gastrointestinal tract NETs that presented with either CS and/or obstructive symptoms were retrospectively reviewed. All patients were managed according to a standardized protocol that involved initial surgical resection of regional and/or hepatic disease followed by appropriate medical therapy. RESULTS: Symptoms of obstruction or ischemia were present in 24 patients (36%) and CS in 56 (85%). All patients with obstructive symptoms undergoing operative therapy had complete symptomatic relief. Hepatic cytoreduction was performed in 30 (45%). Overall symptoms of CS improved in 42 patients (75%); 86% of patients that underwent hepatic cytoreduction and 64% of those receiving medical therapy alone (P = .064). Postoperative morbidity was 22% with no mortality. Mean follow-up was 47 months (range, 6-156). Overall 5-year survival rate was 74%. CONCLUSIONS: Surgical resection is highly effective in relieving symptoms of intestinal obstruction and ischemia. Hepatic cytoreduction seems to enhance the ability to control the symptoms of carcinoid syndrome. A surgically aggressive approach in patients with metastatic NETs provides effective palliation in carefully selected patients.

Phase II study of interferon gamma in malignant carcinoid tumors (E9292): a trial of the Eastern Cooperative Oncology Group.

PURPOSE: To determine the safety and efficacy of treatment with gamma interferon (IFNgamma) in patients with metastatic carcinoid tumor. PATIENTS AND METHODS: 51 patients were enrolled on this Phase II Eastern Cooperative Oncology Group (ECOG) study. Seventy five percent of them had hormonally active tumors. Treatment consisted of IFNgamma subcutaneously at a daily dose of 0.1 mg/m(2). Patents were evaluated for toxicity weekly for the first month and monthly thereafter; response was determined radiologically every 8 weeks. RESULTS: Patients received treatment with IFNgamma for a median of 17.9 weeks (range 2-175). Toxicity was generally mild and expected: 61% experienced noninfected fever and 21% developed granulocytopenia. Three patients (6%) had a partial response; there were no complete responses. Median time to progression was 5.5 months (95% confidence interval 3.9-11.1). The 1-year progression free rate was 28% (13.4-43.4%). Median survival was 42 months, with a 1-year survival rate of 67% (53.3-80%). DISCUSSION: This Phase II study demonstrated that therapy with IFNgamma in patients with metastatic carcinoid tumor was well-tolerated, but did not produce significant antitumor effects. The overall results were somewhat comparable to those previously seen with alpha interferons as well as cytotoxic drugs.

Duodenal carcinoid tumors: how aggressive should we be?

Duodenal carcinoid tumors are uncommon. It is not known whether they behave more like carcinoid tumors in the appendix (indolent course) or those in the ileum (often virulent)-crucial information for determining the need for radical resection. A retrospective review at our tertiary referral center (from 1976 to 1999) identified 27 patients with primary duodenal carcinoid lesions, excluding functional islet cell tumors. Endoscopic biopsy provided the diagnosis in 78% of patients. Treatment was by endoscopic excision (n = 11), transduodenal excision (n = 8), pancreaticoduodenectomy (n = 3), segmental distal duodenectomy (n = 2), or palliative operation (n = 2). One patient did not undergo operation because of comorbidity. Eighteen of 19 patients with tumors smaller than 2 cm remained disease free after local (endoscopic or transduodenal) excision. The exception was a patient with a small periampullary carcinoid lesion. In contrast, all four patients with carcinoid tumors 2 cm or larger who were resected for cure developed a recurrence (2 to 9 years postoperatively). We conclude that duodenal carcinoid tumors smaller than 2 cm may be excised locally; to ensure complete resection we recommend open transduodenal excision for tumors between 1 and 2 cm. Endoscopic follow-up is indicated. It is unclear whether patients with larger tumors benefit from more aggressive locoregional resection. Ampullary/periampullary carcinoid tumors should be considered separately, as their behavior is unpredictable.

Atypical bronchial carcinoids. Review of 46 patients.

BACKGROUND: The purpose of this study was to assess the behaviour of atypical carcinoids operated at our Department in the period 1977-1998 and to review the last 19 cases according to Capella's classification (1994), indicating the most adequate surgical approach. METHODS: On the basis of anatomo-pathological characteristics, we have reviewed surgical treatment and outcome in 46 patients, submitted in the last 22 years to surgical resection for neuroendocrine neoplasms. RESULTS: 5-year survival is 77.2%; 10-year survival is 53.2%. Lymph node metastases are also important for survival, but less than the histotype. The review of our last six years' series, according to Capella's classification, of 19 patients affected by so-called atypical carcinoids revealed that: 5 were well differentiated neuroendocrine tumors (WDNT), 12 were well differentiated neuroendocrine carcinomas (WDNC), 2 were small cell neuroendocrine carcinomas (SCLC). The 5-year overall survival of our cases is 78%, for the WDNT 100%, for WDNC 81.2%. Of the 2 patients with SCLC, one survived 2 months; the other is still alive 5 months after surgery. CONCLUSIONS: The authors conclude that 5-year and 10-year survival are strongly related to the histological type of neuroendocrine neoplasm and to the presence of lymph node metastases. Capella's anatomo-pathological classification helps to give a more accurate prognosis for survival in so-called "atypical carcinoids". If the neoplasm is malignant, the authors recommend radical resection, if possible.

Carcinoid syndrome: a statistical evaluation of 748 reported cases.

No statistical evaluation of patients with carcinoid syndrome in a reliable number of cases has been available in the past 35 years. To update our knowledge about the syndrome, we have evaluated from various clinicopathologic viewpoints a large series of patients with the syndrome reported up to date. The data of 748 patients with the syndrome were collected from 8876 carcinoid patients reported in the literature and analyzed by the Gut-Pancreatic Endocrinoma Analyzing System (the Niigata Registry). The results are summarized as follows. 1) The patients with the syndrome had a tendency to be older than those without it. 2) The incidence of the syndrome was 8.4% of 8876 carcinoid patients. 3) Serotonin activities were extremely high in patients with the syndrome as compared to those without it (91.7% versus 26.6%). 4) The rate of metastases was higher in patients with the syndrome than in those without it (84.8% versus 29.2%), and higher in the liver than in lymph nodes among patients with the syndrome (73.4% versus 37.4%). 5) Flushing and carcinoid heart as most specific clinical manifestations of the syndrome were recorded at 78.3% and 17.4%, respectively. 6) The 5-year survival rate after resection of primary lesions was 76.0% of 304 patients with the syndrome, lower in patients with digestive carcinoids than in those with extradigestive lesions (67.2% versus 88.7%). It is expected that the results obtained in the present evaluation on patients with carcinoid syndrome will provide investigators active in this specialized field with useful and extensive information for their future activities.

Manejo del tumor carcinoide del aparato digestivo y del síndrome carcinoide / Management of gastrointestinal carcinoid tumors and carcinoid syndrome

Introducción. Los tumores carcinoides son raros, la mayoría de las publicaciones informan casos clínicos aislados y la descripción de series clínicas es limitada. La calidad de vida y el tiempo de supervivencia de los pacientes dependen del control del crecimiento tumoral y de la paliación adecuada de sus síntomas. Objetivo. Informar datos epidemiológicos y formas de manejo de esta tumoración así como del síndrome carcinoide en el Instituto Nacional de Cancerología, (INCan) de México durante los últimos 15 años. Métodos. Se revisaron los expedientes clíncos de pacientes diagnosticados y tratados de tumores carcinoides en el INCan de 1982 a 1997. Resultados. El sitio primario más frecuente de localización fue el aparato digestivo (61 por ciento) seguido del árbol broncopulmonar (23 por ciento). De los del aparato digestivo, la mayoría se localiza en el colon derecho y el apéndice cecal. La supervivencia mayor fue en los de origen apendicular, menores de 2 cm y/o localizados. Al momento del diagnóstico 47 por ciento tenían enfermedad metastásica siendo también factor de mal pronóstico. En nuestro medio, el interferón solo o en combinación con octreotida o cirugía citorreductora ofrecen las mejores formas de paliación para el síndrome carcinoide. Conclusiones. Los carcinoides son raros, en general tienen un mejor comportamiento biológico que otros tumores. El tratamiento está encaminado a resecar las lesiones localizadas lo que incrementa la supervivencia o a paliar a aquellos pacientes sintomáticos cuyas lesiones no son resecables

Cryotherapy of metastatic carcinoid tumors.

BACKGROUND: To describe the use of hepatic cryotherapy to treat patients with symptomatic carcinoid metastates. METHODS: Hepatic cryotherapy was performed on five patients with carcinoid syndrome resulting from metastatic carcinoid tumors. Intraoperative ultrasound was used to guide the cryotherapy and to assess the adequacy of freezing. RESULTS: All five patients had relief of the carcinoid syndrome after treatment. In four of the five patients, the relief was prolonged (>3 months); in one patient, the relief of symptoms was transient (2 months). Four of five patients had a transient reduction in hormonal tumor markers (the fifth patient did not have hormonal-level follow-up). During a follow-up period of 2.5 years, four of the five patients died. The 6-month survival rate was 80%, the 1-year survival rate was 60%, the 2-year survival rate was 40%, and the 2.5-year survival was 20%. One patient is alive 30 months after treatment. CONCLUSION: Hepatic cryotherapy can provide symptomatic relief for patients with hepatic metastates producing the carcinoid syndrome.

[Management of digestive system carcinoid tumors and carcinoid syndrome]. / Manejo del tumor carcinoide del aparato digestivo y del síndrome carcinoide.

INTRODUCTION: Carcinoid tumors are rare, most of the publications are case reports and the clinical series are uncommon. The quality of life and survival time of these patients depend on the adequate control of tumor growth and good palliation of their symptoms. AIMS: The purpose of this study is to inform epidemiological data and forms of management for these tumors and the Carcinoid Syndrome at the National Institute of Cancerology (INCan) at Mexico City in the last 15 years. METHODS: A retrospective review of the clinical records of patients diagnosed and treated at the INCan with carcinoid tumors from 1982 to 1997 was performed. RESULTS: The most common origin place was the gastrointestinal tract (GI), and the majority involved the right colon and the appendix. The longest survivors were patients with tumors originated in the appendix, tumors smaller than 2 cm or localized. At the time of diagnosis 47% of patients had metastatic disease that was also a poor prognostic factor. The experience in our hospital seem to support the use of interferon alone or in combination with octreotide or debulking surgery for the palliation of carcinoid syndrome. CONCLUSIONS: Carcinoid tumors are rare, and have a slow growth and less aggressive biological nature than noncarcinoid tumors. Treatment should be focused on trying to cure the small or localized lesions or to find the best palliative method for those symptomatic advanced lesions.

Gastroenteropancreatic endocrine tumors: effect of Sandostatin on tumor growth. The German Sandostatin Study Group.

One hundred fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumors entered a prospective multicenter trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumors, and five with other endocrine GEP tumors) to determine the efficacy of 200 micrograms Sandostatin three times a day in the control of tumor growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a "negative" selection of patients included in the trial and suggesting that Sandostatin cannot prevent disease progress when it is far advanced. In the evaluation of 68 patients monitored for at least 3 months, partial regression was observed in 4.4%, stable disease in 50%, and tumor progression in 45%. However, an initially favorable response frequently occurred with a decrease in response later: 54.4% at 3 months to 38% at 12 months for the whole group of patients. Proven inhibition of tumor growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatin exerts a beneficial effect on tumor growth in patients with metastatic endocrine GEP tumors. This beneficial effect decreases with time and is as yet unpredictable in the individual patient.

Octreotide and interferon alfa: a new combination for the treatment of malignant carcinoid tumours.

24 patients with malignant carcinoid tumours received octreotide and interferon alfa (IFN-alpha). All the patients initially received octreotide 50-100 micrograms, twice daily. When progressive symptoms or increasing biochemical markers were observed, the daily dose was raised to a median 300 micrograms. If the initial dose proved ineffective or if no improvement was seen after escalation, IFN-alpha was added (median 9 MU subcutaneously per week). After the addition of IFN-alpha, 17 of the 22 patients (77%) with elevated urinary 5-hydroxyindoleacetic acid showed a significant (> 50%) reduction. Only 1 patient progressed and 4 had continuously stable biochemical disease. No significant reduction in tumour size was noted; in 5 patients, the tumour continued to grow despite decreasing hormone levels. 18 patients had carcinoid syndrome when IFN-alpha was added in 10 (56%) symptoms ameliorated. Thus, the addition of IFN-alpha is beneficial for patients with malignant carcinoid tumours that progress and/or who do not respond to octreotide.

The role of interferons in the management of carcinoid tumours.

Malignant carcinoid tumours with the carcinoid syndrome has over the years presented a therapeutic challenge. The patients might not only die from tumour progression but also from symptoms relating to hormone overproduction and the specific cardiac disease, e.g. right heart fibrosis and failure. Surgery has been the treatment of choice in local disease, but when liver metastases have developed other treatment procedures must be considered. Conventional chemotherapy has been of little beneficial value, with response rates of only 10-30%, whereas a new somatostatin analogue, octreotid, is effective in controlling clinical symptoms but not tumour progression. Interferon treatment was introduced in 1982 by our group, and we are now presenting treatment results of 130 patients with histologically verified malignant carcinoid tumours and liver metastases. One hundred and eleven patients were treated with a median dose of 6 mega units (MU) of interferon alpha, five times weekly (dose range 3-9 MU), whereas 29 patients received conventional chemotherapy. Forty-seven out of 111 patients (42%) treated with interferon alpha demonstrated a significant biochemical response and 15% demonstrated more than 50% reduction in tumour size. In another 43 (39%) patients stabilization of the carcinoid disease have been noted, whereas 21 (19%) showed progressive disease. The median duration of response was 34 months. Subjective responses with improvement of diarrhoea, flush and/or bronchoconstriction were noticed in 76 patients (68%). The 19 patients treated with chemotherapy demonstrated only 10% biochemical response, lasting for only 3-5 months. The survival analysis demonstrates a median survival of only 8 months in the group of patients treated with chemotherapy, compared to 80+ months (P less than 0.001) in the groups treated with interferon alpha. Interferon adverse reactions of fatigue, weight loss and anaemia were manageable. Neutralizing interferon antibodies were documented in 5-15% of the patients. Interferon alphas are active in patients with malignant carcinoid tumours. Clinical symptoms are significantly reduced following reduction of circulating hormones. Interferon might also have an impact on survival in this group of patients. The side-effects are moderate and managed by dose adjustments.