Jarosław B. Ćwikła

Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors

BACKGROUND Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study

BACKGROUND To evaluate the clinical and radiological effectiveness of [DOTA(0), D-Phe(1), Tyr(3)]-octreotate (DOTATATE) Y-90 in patients with extensive progressive gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs). MATERIALS AND METHODS Sixty patients with histologically proven GEP-NETs were treated with DOTATATE Y-90. Clinical responses were assessed 6 weeks after completing therapy and then after each of the 3- to 6-month intervals. The radiological response was classified according to RECIST criteria. RESULTS At 6 months after final treatment, radiological partial response (PR; at least a 30% decrease in the sum of the longest diameter of target lesions) was observed in 13 patients (23%), and the remaining patients had stable disease (SD; less than 30% decrease in the sum of the longest diameter of target lesions or less than 20% increase in the sum of the longest diameter of target lesions) (77%). Clinical PR at 6 months was in 43 patients (72%), nine patients had SD and progressive disease (PD) was noted in eight patients. Median progression-free survival (PFS) was 17 months, while the median overall survival (OS) was 22 months. In eight patients with early PD, the PFS was 4.5 and OS 9.5 months, while in those with SD or PR, PFS and OS were 19.5 and 23.5 months, respectively. After 12 months of follow-up, five patients had World Health Organization (WHO) grade 2 or 3 renal toxicity. Haematological toxicity (WHO grade 3 and 4) was noted during therapy in 10% of patients and persisted in 5%. CONCLUSIONS DOTATATE Y-90 therapy is effective and relatively safe in patients with GEP-NET. Standard doses of DOTATATE Y-90 result in a relatively low risk of myelotoxicity. However, due to ongoing risk of renal toxicity, careful monitoring of the kidney is recommended.

ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas

a Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid , Spain; b Department of Oncology, Haukeland University Hospital, Bergen , Norway; c Institut Gustave Roussy, Villejuif , and d Oncologie Médicale, Hôpitaux Universitaires Paris Nord Val de Seine, Paris , France; e Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin , Germany; f Department of Surgery, Medical University of Vienna, Vienna , Austria; g Department of Oncology, First Faculty of Medicine and General Teaching Hospital, Prague , Czech Republic; h Neuroendocrine Tumour Unit, Royal Free Hospital, London , UK; i Institut für Pathologie und Zytologie, St. Vincenz Krankenhaus, Limburg , Germany; j Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn , Poland; k Neuroendocrine Tumour Unit, Royal Free Hospital, London , UK; l NET Centre, St. Vincent’s University and Department of Clinical Medicine, St. James Hospital and Trinity College, Dublin , Ireland; m Institute of Pathology, University of Bern, Bern , Switzerland

Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study

In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

Efficacy and Safety of Cyclophosphamide, Azathioprine, and Cyclosporine (Ciclosporin) as Adjuvant Drugs in Pemphigus Vulgaris

AbstractBackground:Pemphigus vulgaris is a potentially life-threatening, autoimmune bullous disease of the skin and mucous membranes. Most commonly, the disease is treated with prednisone in combination with an immunosuppressant agent, frequently referred to as adjuvant drug. However, there is no consensus regarding the first-choice adjuvant drug for the treatment of pemphigus vulgaris or the recommended dosage. Objective:To evaluate the efficacy and safety of prednisone as monotherapy and in combination with the three most popular adjuvant agents — azathioprine, cyclosporine (ciclosporin), and cyclophosphamide in the treatment of pemphigus vulgaris time to immunologic remission (non-detectable circulating pemphigus vulgaris antibodies), proportion of patients who remained free of clinical relapse within 5 years after discontinuation of therapy, time from treatment discontinuation until first relapse, and incidence of adverse effects. Results:The average (± SD) time to clinical remission was 7.2 ± 13.1 months in patients who received prednisone monotherapy, 6.8 ± 10.5 months in patients receiving additional azathioprine, 8.1 ± 11.8 months in the cyclosporine group, and 4.9 ± 6.9 months (which was significantly shorter than all other treatment groups, p < 0.05) in patients receiving cyclophosphamide. The average (± SD) times to immunologic remission were 33 ± 27 months, 28 ± 24 months, 30 ± 21 months, and 23 ± 17 months for prednisone monotherapy, azathioprine, cyclosporine, and cyclophosphamide, respectively. The proportions of patients who remained free of clinical relapse within 5 years after discontinuation of therapy were 55%, 50%, 43%, and 69% for prednisone monotherapy, azathioprine, cyclosporine, and cyclophosphamide, respectively. In patents who experienced relapse, the average (± SD) time from treatment discontinuation to clinical relapse was 10.50 ± 6.86 months in patients receiving prednisone monotherapy, 16.40 ± 17.36 months in the azathioprine group, 12.44 ± 6.48 months in the cyclosporine group, and 21.16 ± 20.13 months in the cyclophosphamide group. The safety profiles of all treatment regimens were comparable. Conclusion:Oral prednisone with cyclophosphamide is the most effective treatment for pemphigus vulgaris. All therapy regimens had a similar safety profile. In our opinion, cyclophosphamide at a dose of 1.1–1.5 mg/kg/day should be the adjuvant drug of choice in the treatment of moderate-to-severe pemphigus vulgaris.

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine and Hybrid Imaging

Contrast-enhanced computed tomography (CT) of the neck-thorax-abdomen and pelvis, including 3-phase examination of the liver, constitutes the basic imaging for primary neuroendocrine tumor (NET) diagnosis, staging, surveillance, and therapy monitoring. CT characterization of lymph nodes is difficult because of inadequate size criteria (short axis diameter), and bone metastases are often missed. Contrast-enhanced magnetic resonance imaging (MRI) including diffusion-weighted imaging is preferred for the examination of the liver, pancreas, brain and bone. MRI may miss small lung metastases. MRI is less well suited than CT for the examination of extended body areas because of the longer examination procedure. Ultrasonography (US) frequently provides the initial diagnosis of liver metastases and contrast-enhanced US is excellent to characterize liver lesions that remain equivocal on CT/MRI. US is the method of choice to guide the biopsy needle for the histopathological NET diagnosis. US cannot visualize thoracic NET lesions for which CT-guided biopsy therefore is used. Endocopic US is the most sensitive method to diagnose pancreatic NETs, and additionally allows for biopsy. Intraoperative US facilitates lesion detection in the pancreas and liver. Somatostatin receptor imaging should be a part of the tumor staging, preoperative imaging and restaging, for which 68Ga-DOTA-somatostatin analog PET/CT is recommended, which is vastly superior to somatostatin receptor scintigraphy, and facilitates the diagnosis of most types of NET lesions, for example lymph node metastases, bone metastases, liver metastases, peritoneal lesions, and primary small intestinal NETs. 18FDG-PET/CT is better suited for G3 and high G2 NETs, which generally have higher glucose metabolism and less somatostatin receptor expression than low-grade NETs, and additionally provides prognostic information.

Initial Direct Comparison of 99mTc-TOC and 99mTc-TATE in Identifying Sites of Disease in Patients with Proven GEP NETs

The imaging of neuroendocrine tumors has become one of the most significant areas in nuclear oncology. In an attempt to provide high-quality imaging and possible sensitivity at a reduced cost, time, and radiation dose, several 99mTc agents have been proposed. The aim of this initial study was to compare the tumor uptake and biodistribution of 2 new 6-hydrazinopyridine-3-carboxylic acid (HYNIC)–derivatized Tyr3-octreotide analogs, 99mTc-[HYNIC,Tyr3]octreotide (99mTc-TOC) and 99mTc-[HYNIC,Tyr3,Thr8]octreotide (99mTc-TATE), in patients with somatostatin receptor–expressing tumors. Methods: Each of 12 patients with proven gastrointestinal pancreatic neuroendocrine tumors received a mean activity of 520 MBq of 99mTc-TOC and 99mTc-TATE. Scintigraphy with both tracers was performed 3–4 h after their injection using standard whole-body and SPECT imaging. The images were reviewed subjectively by 2 readers, who reported tumor uptake lesion by lesion. Results: Both radiotracers demonstrated concordance between the results in 7 patients (58%). In total, 110 sites of disease were identified with 99mTc-TOC, compared with 115 with 99mTc-TATE. There was 1 case in which 99mTc-TOC identified sites of disease not seen on 99mTc-TATE imaging but 4 cases in which some sites of disease were seen with 99mTc-TATE and not 99mTc-TOC. Conclusion: In this initial study, both tracers seem to show similar sites of tumor, with 99mTc-TATE having a slight edge in the total number of lesions seen, especially in lymph node metastases.

Circulating Transcript Analysis (NETest) in GEP-NETs Treated With Somatostatin Analogs Defines Therapy

CONTEXT Early and precise delineation of therapeutic responses are key issues in neuroendocrine neoplasm/tumor management. Imaging is currently used but exhibits limitations in sensitivity and specificity. The utility of biomarkers is unclear. objective, setting, and design: This prospective cohort study (11 mo) sought to determine whether measurements of circulating neuroendocrine tumor transcripts (NETest) predict responses to somatostatin analogs (SSAs). PATIENTS The test set consisted of 35 SSA-treated gastroenteropancreatic-NETs (RECISTevaluated). The prospective set consisted of 28 SSA-treated Grade 1-Grade 2 GEP-NETs. INTERVENTION(S) Whole blood for transcript analysis (NETest) and plasma for Chromogranin A (CgA) (baseline), were collected every 4 weeks (prior to SSA injection). Morphologic (multidetector computed tomography/MRI) and functional imaging ((99m)Tc-[HYNIC, Tyr(3)]-Octreotide) was undertaken at entry and 6-month intervals until progression (RECIST 1.0). MAIN OUTCOME MEASURE(S) Treatment response. RESULTS Test set: NETest (≥80%; scale, 0-100%) differentiated stable (SD) and progressive (PD) disease (P < .0001). Prospective set: 28 patients (26/28 SD) undergoing standard SSA. Grading: 12 G1, 16 G2. SSA Response: progression-free survival: 315 days: 14 (50%) SD, 14 (50%) PD. NETest: Twenty had elevated (≥80%) values; 14 developed PD; six, SD. CgA: Twelve of 28 exhibited elevated baseline values and/or subsequent >25% increase; eight developed PD; four, SD. NETest (P = .002) and grade (P = .054) were the only factors associated with treatment response. Multiple regression analysis established that the NETest could predict disease progression (P = .0002). NETest changes occurred significantly earlier (146 d prior to progression vs 56 d CgA; P < .0001; χ(2) = 19) and in more patients (100 vs 57%; P < .02). CONCLUSIONS NETest values (80-100%) were more accurate and occurred at a significantly earlier time point than CgA and predicted SSA treatment response.

Can scintimammography with 99mTc-MIBI identify multifocal and multicentric primary breast cancer?

Scintimammography with 99mTc-MIBI has been shown to be an effective adjunct to imaging of the breast with mammography. Uptake of 99mTc-MIBI is particularly high in sites of non-calcified cancer and ductal carcinoma in situ (DCIS), and as a consequence it may be possible to use this method of imaging in identifying multifocal or multicentric disease. The aim of this study was to evaluate the efficacy of preoperative scintimammography in the detection of multifocal and multicentric breast cancer and compare these results with mammography. A retrospective review was performed of 353 women imaged with 99mTc-MIBI as part of the clinical assessment of their suspected primary breast cancer. The results of the scintimammography and mammography were then compared with the final pathological diagnosis obtained after mastectomy in all patients. Histopathological assessments of breast tissue from mastectomy confirmed 40 women (12%) had multifocal (34) or multicentric (six) breast cancer. Scintimammography correctly identified 39 of these cancers and the multifocal or multicentric character of the cancer was identified in 22 (52%) of these patients. Anatomical imaging performed in all 40 patients including 25 with mammography alone, mammography and ultrasound in 11 cases and ultrasound alone in four patients. Anatomical imaging identified cancer to be present in 28 patients (70%) and the combination of mammography and ultrasound identified correctly that the cancer was multifocal or multicentric in eight patients (22%). In this study scintimammography was able to identify more cases of multifocal and multicentric cancer than mammography and/or ultrasound. In patients where pre-operative identification of multicentric or multifocal disease can alter treatment scintimammography may be a useful investigative tool.

Impact of Screening Kindreds for SDHD p.Cys11X as a Common Mutation Associated with Paraganglioma Syndrome Type 1

CONTEXT AND OBJECTIVE Germline mutations of the genes SDHB, SDHC, and SDHD predispose to paraganglioma syndromes. Mutation-specific counseling, risk assessment, and management recommendations ideally should be performed. Here, we provide data for a single common mutation of the SDHD gene. METHODS The European-American Pheochromocytoma-Paraganglioma Registry served as the source for unrelated index cases affected by pheochromocytoma or paraganglioma. Patients with the SDHD c.33 C-->A (p.Cys11X) germline mutations were reinvestigated by whole-body magnetic resonance imaging and 24-h urinary catecholamine assay. First-degree relatives underwent genetic testing and those testing positive had same clinical investigations. Microsatellite analyses were used to test the hypothesis that all index cases were related and the mutation is a founding one. RESULTS Sixteen index cases with the mutation SDHD p.Cys11X are registered. After testing their relatives, there were a total of 25 mutation carriers. We excluded seven subjects who inherited the mutation from the mother because of maternal imprinting. Thus, 18 mutation carriers were clinically affected. Among these 16 (89%) had head and neck paragangliomas, six (33%) thoracic tumors, six (33%) extraadrenal retroperitoneal, and five (28%) intraadrenal. Of note, 16 (89%) had multiple tumors at first diagnosis, and one (5%) had signs of malignancy during follow-up. Overall penetrance was 100% at age 54. Haplotype analyses revealed evidence for a founder effect. CONCLUSIONS The SDHD p.Cys11X mutation is a founding mutation associated with a high penetrance for paraganglial tumors of the skull base, neck, thorax, and retroperitoneum in the first four decades of life and, rarely, with malignancy.