Richard R.P. Warner

Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: Early results in 148 patients

Purpose:The use of 90Y-microspheres to treat unresectable liver metastases originating from a variety of neuroendocrine tumors was reviewed. Materials and Methods:This is a retrospective review from 10 institutions of patients given 90Y-microsphere therapy for neuroendocrine hepatic metastases. Physical, radiographic, biochemical, and clinical factors associated with treatment and response were examined. All patients were followed with laboratory and imaging studies at regular intervals until death, or censured whether other therapy was given after brachytherapy. Toxicities (acute and late) were recorded, and survival of the group determined. Results:A total of 148 patients were treated with 185 separate procedures. The median age was 58 years (26–95 years) at treatment with median performance status of Eastern Cooperative Oncology Group (0). The median activity delivered was 1.14 GBq (0.33–3.30 GBq) with a median of 99% of the planned activity able to be given (38.1%–147.4%). There were no acute or delayed toxicity of Common Terminology Criteria for Adverse Events v3.0 grade 3 in 67% of patients, with fatigue (6.5%) the most common side effect. Imaging response was stable in 22.7%, partial response in 60.5%, complete in 2.7% and progressive disease in 4.9%. No radiation liver failure occurred. The median survival is 70 months. Conclusion:Radioembolization with 90Y-microspheres to the whole liver, or lobe with single or multiple fractions are safe and produce high response rates, even with extensive tumor replacement of normal liver and/or heavy pretreatment. The acute and delayed toxicity was very low without a treatment related grade 4 acute event or radiation induced liver disease in this modest-sized cohort. The significant objective response suggests that further investigation of this approach is warranted.

Treatment Parameters and Outcome in 680 Treatments of Internal Radiation With Resin 90Y-Microspheres for Unresectable Hepatic Tumors

PURPOSE Radioembolization (RE) using (90)Y-microspheres is an effective and safe treatment for patients with unresectable liver malignancies. Radiation-induced liver disease (RILD) is rare after RE; however, greater understanding of radiation-related factors leading to serious liver toxicity is needed. METHODS AND MATERIALS Retrospective review of radiation parameters was performed. All data pertaining to demographics, tumor, radiation, and outcomes were analyzed for significance and dependencies to develop a predictive model for RILD. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria Adverse Events Version 3.0 scale. RESULTS A total of 515 patients (287 men; 228 women) from 14 US and 2 EU centers underwent 680 separate RE treatments with resin (90)Y-microspheres in 2003-2006. Multifactorial analyses identified factors related to toxicity, including activity (GBq) Selective Internal Radiation Therapy delivered (p < 0.0001), prescribed (GBq) activity (p < 0.0001), percentage of empiric activity (GBq) delivered (p < 0.0001), number of prior liver treatments (p < 0.0008), and medical center (p < 0.0001). The RILD was diagnosed in 28 of 680 treatments (4%), with 21 of 28 cases (75%) from one center, which used the empiric method. CONCLUSIONS There was an association between the empiric method, percentage of calculated activity delivered to the patient, and the most severe toxicity, RILD. A predictive model for RILD is not yet possible given the large variance in these data.

Cryoablation of unresectable malignant liver tumors

BACKGROUND Unresectable malignant liver tumors, particularly metastases of gastrointestinal origin, are rapidly lethal in a vast majority of patients, regardless of treatment. PATIENTS AND METHODS We evaluated 58 patients by laparoscopy and/or laparotomy. Thirty-nine were treated with cryoablation of liver tumors using a liquid-nitrogen cryoprobe delivering a tumoricidal temperature of -196 degrees C with intraoperative ultrasound monitoring. Histologic evaluation showed that 25 patients had colorectal metastases, 3 had gastric tumors, 4 hepatocellular carcinomas, 6 carcinoids, and 1 gastrinoma. RESULTS All patients who received complete cryoablation are alive with a mean follow-up of 14 months. Five whose treatment could not be completed died between 3 and 9 months postoperatively. Thirteen patients (28%) have recurrent disease and 20 (51%) have no evidence of disease. There were no operative mortalities. Postoperative transient elevation of liver function tests and thrombocytopenia were noted. All patients received postoperative chemotherapy. CONCLUSION Cryoablation is an active and safe treatment for advanced liver malignancies.

The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (NETs): Well-differentiated nets of the distal colon and rectum

Neuroendocrine tumors (NETs) of the distal colon and rectum are also known as hindgut carcinoids based on their common embryologic derivation. Their annual incidence in the United States is rising, primarily as a result of increased incidental detection. Symptoms of rectal NETs include hematochezia, pain, and change in bowel habits. Most rectal NETs are small, submucosal in location, and associated with a very low malignant potential. Tumors larger than 2 cm or those invading the muscularis propria are associated with a significantly higher risk of metastatic spread. Colonic NETs proximal to the rectum are rarer and tend to behave more aggressively. The incidence of rectal NETs in African Americans and Asians is substantially higher than in Caucasians. Colorectal NETs are generally not associated with a hormonal syndrome such as flushing or diarrhea. A multidisciplinary approach is recommended in diagnosing and managing hindgut NETs.

Biochemical Testing for Neuroendocrine Tumors

In this review, we focus on the use of biochemical markers for the diagnosis of neuroendocrine tumors and exclusion of conditions that masquerade as neuroendocrine tumors. In addition, we outline the use of biochemical markers for follow-up, response to intervention, and determination of prognosis. Previous publications have focused only on markers specific to certain tumor types, but the uniqueness of this chapter is that it presents a new approach ranging from biochemical markers that relate to symptoms to the use of markers that facilitate decision making with regard to optimizing the choices of therapy from the complex arrays of intervention, The sequence of presentation in this chapter is first to provide the usual view, that is, biochemical markers of each tumor type and thereafter the diagnosis of the underlying condition or exclusion thereof and finally the algorithm for their use from the clinical presentation to the suspected diagnosis and the biochemical markers to monitor progression and therapeutic choice. There is also a specific description of the properties of the most important biochemical markers and 2 complications, bone metastasis and carcinoid heart disease, from the biochemical point of view.

Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Gastroduodenal Ulceration Associated with Radioembolization for the Treatment of Hepatic Tumors: An Institutional Experience and Review of the Literature

BackgroundMicrosphere radioembolization is a method of delivering radiation therapy directly to tumors, thereby minimizing toxicity to adjacent structures. Despite the relatively high precision of this modality, numerous adverse effects have been recognized. One particularly untoward complication is the development of severe gastroduodenal ulceration.MethodsIn order to further characterize gastroduodenal ulceration associated with radioembolization, our institutional experience as well as the reported literature were reviewed.ResultsThe current evidence suggests that radioembolization-associated gastroduodenal ulceration results from inadvertent delivery of microspheres to the microvasculature of the gastrointestinal tract, leading to direct radiation toxicity. The reported incidence of this entity ranges between 2.9% and 4.8%. Most patients with this complication present with abdominal pain, often associated with nausea, vomiting, and anorexia. Symptoms can arise from hours to months after radioembolization treatment; diagnosis is made by endoscopic biopsy and histopathologic evaluation of the ulcer specimen. Radiation-induced ulcers have proven to be extremely difficult to treat. Current therapy based on acid suppression has had limited success, and the evidence for the addition of antioxidants and anti-inflammatory agents is still sparse.ConclusionsThe increasing utilization of radioembolization will lead to adverse events including gastroduodenal ulceration. This entity must be considered in any patient treated with radioactive microspheres presenting with symptoms of dyspepsia. Accurate diagnosis and aggressive treatment are necessary to improve patient outcomes.

Biochemical Assessment of Niacin Deficiency Among Carcinoid Cancer Patients

OBJECTIVE:Carcinoid cancer patients often have elevated levels of serotonin or its precursor 5-hydroxytryptophan. Normally, serotonin synthesis accounts for a small fraction of tryptophan catabolism, which should be directed along a pathway that allows partial conversion to niacin; hence, increased diversion of tryptophan toward serotonin could cause variable degrees of niacin deficiency in carcinoid patients. Therefore, the prevalence of niacin deficiency among carcinoid patients was investigated by clinical assessment of pellagra and biochemical assessment of whole blood niacin number, a ratio derived from two biologically active forms of niacin (NAD/NADP × 100).METHODS:Clinical and biochemical niacin status were assessed in a cohort of newly diagnosed carcinoid patients with carcinoid syndrome (CCS, n = 36), carcinoid patients without carcinoid syndrome (CWCS, n = 32) and noncarcinoid controls (n = 24) recruited at two primary care clinics. Other aspects of serotonin metabolism were measured by analyses of plasma serotonin and tryptophan and urinary excretion of 5-hydroxyindoleacetic acid.RESULTS:Biochemical niacin deficiency (niacin number < 130) was significantly more common in CCS patients (10 out of 36) compared to controls (p < 0.05, Fishers exact test), while CWCS patients displayed an incidence that was not significantly elevated (4 out of 32). Only one CCS patient, who was also identified biochemically as niacin deficient, was clinically diagnosed with pellagra.CONCLUSION:Biochemical niacin deficiency is more prevalent among newly diagnosed CCS patients than in controls. Manifestation of pellagra is a less sensitive indicator, and dependence on this endpoint could lead to a lack of appropriate nutritional support for this group of patients.

Early and late results of valvular surgery for carcinoid heart disease.

To the Editor: Carcinoid tumors are rare, arising in 3 to 4 per 100,000 people per year ([1][1]). These tumors derive from enterochromaffin cells, particularly those located in the gastrointestinal tract and the bronchopulmonary system. At diagnosis, 20% to 30% of patients present with disseminated

Clinical and Prognostic Features of Rectal Neuroendocrine Tumors

Background: Rectal neuroendocrine tumors (NETs) are among the most common NETs. The aim was to validate European Neuroendocrine Tumor Society (ENETS)/North American Neuroendocrine Tumor Society (NANETS) staging and grading systems with regard to clinical outcomes. Methods: A comprehensive database was constructed from existing databases of the Mount Sinai Division of Gastrointestinal Pathology and the Carcinoid Cancer Foundation. Analysis was performed on 141 patients identified with rectal NETs seen at Mount Sinai Hospital between 1972 and 2011. Results: The median age was 52.7 years; 43% were males. Average tumor size was 0.88 cm. NETs <1 cm accounted for 75.6% of the tumors. Stage I, II, III and IV accounted for 79.4, 2.8, 5.0 and 12.8% of the tumors, respectively. G1 tumors accounted for 88.1%, G2 8.3% and G3 3.6%. Of G1 tumors, 94.6% were stage I and 5.4% were stage IV. The median survival time for all 141 patients was 6.8 years (range, 0.8-34.7 years). The overall 5-year survival rate was 84.4%. The 5-year survival rates for patients in stages I-IV were 92.7, 75.0, 42.9 and 33.2%, respectively. The 5-year survival rates for patients with G1-G3 tumors were 87.7, 47.6 and 33.3%, respectively. Univariate analysis of increased survival showed significance for lower stage, lower grade, smaller size, absence of symptoms and endoscopically treated tumors. Multivariate analysis showed that stage alone was statistically significant as the strongest predictor of survival. Conclusion: The results of our study validated ENETS/NANETS guidelines for staging and grading of rectal NETs in the US setting of a tertiary referral center. Staging according to ENETS/NANETS guidelines should be used in the treatment algorithm rather than size alone.