Publications by authors named "Pamela Kunz"

79 Publications

Rapid Progression After 177Lu-DOTATATE in Patients With Neuroendocrine Tumors.

Pancreas 2021 Jul;50(6):890-894

Section of Medical Oncology, Department of Medicine, Yale Cancer Center, Yale School of Medicine, New Haven, CT.

Abstract: Peptide receptor radionuclide therapy (PRRT) is a treatment option for somatostatin receptor-positive, unresectable or metastatic neuroendocrine tumors (NETs). Despite high disease control rates seen with PRRT, a subset of the NET population seems to have a short progression-free interval. We hypothesize that patients with NETs with rapid progression post-PRRT may have mixed low- and high-grade cell populations, and PRRT treats the lower-grade component, allowing the more aggressive high-grade component to progress.We report 7 patients with biopsy-proven NET who received PRRT with 177Lu-DOTATATE at the Stanford Cancer Center who had evidence of progressive disease (PD) on or within 6 months of therapy.All patients had primary pancreatic, metastatic, well-differentiated NET on diagnosis and were heavily pretreated before receiving PRRT. Two patients had PD while on PRRT; 5 had PD within 6 months of completing PRRT. The median time from the last cycle to PD was 3.2 months (range, 1.1-4.6 months). The median progression-free survival was 7.7 months (95% confidence interval, 5.7-9.8 months). Three patients had a repeat biopsy post-PRRT, 2 of which demonstrated higher disease grade compared with their initial pathology. Further evaluation in larger patient cohorts is warranted to elucidate predictive factors of PRRT response/nonresponse to enable better patient selection.
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http://dx.doi.org/10.1097/MPA.0000000000001841DOI Listing
July 2021

Temozolomide in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Retrospective Review.

Oncologist 2021 Aug 3. Epub 2021 Aug 3.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada.

Background: Grade 3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEPNENs) are often aggressive, and the optimal treatment is unclear for this subgroup of neuroendocrine neoplasms (NENs). Temozolomide (TEM)-based regimens have been increasingly used to treat grade 1-2 NENs, but their efficacy in G3 NENs remains undetermined. We aimed to assess the clinical efficacy of TEM-containing regimens in advanced grade 3 GEPNENs.

Materials And Methods: A multicenter retrospective review (2008-2018) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen was undertaken within a North American partnership to pool data. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports.

Results: One hundred and thirty patients in six high-volume NEN centers were included (median age 55, 64% male, 18% functional, 67% pancreatic NEN). Forty-nine percent were well-differentiated, 35% poorly differentiated, and 15% unknown based on local pathology reports. The regimen used was capecitabine and temozolomide (CAPTEM) in 92% and TEM alone in 8%. Radiological response by local assessment was seen in 36% of patients. Median TTF was 3.6 months and median overall survival (OS) 19.2 months. Six percent of patients required discontinuation of therapy due to adverse events. TTF was longer in first-line treatment (7.8 months vs. 2.9 months; hazard ratio, 1.62; 95% confidence interval, 1.11-2.36; p = .015) and in patients with pancreatic NENs (panNENs) compared with gastrointestinal NENs (5.8 months vs 1.8 months; p = .04). The overall response rate was higher in the first-line setting (51% vs 29%; p = .02) and in panNEN (41% vs 23%; p = .04).

Conclusion: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NEN centers as a partnership. Thirty-six percent of patients showed some degree of radiographic response, and treatment was generally well tolerated, although the median duration of response was short. Response rates and time to treatment failure were superior in the first-line setting. CAPTEM should be considered a viable treatment option in this setting. Further randomized trials are warranted.

Implications For Practice: Neuroendocrine neoplasms (NENs) are heterogeneous, and optimal treatment for aggressive grade 3 (G3) NENs remains undetermined. The capecitabine and temozolomide (CAPTEM) regimen has been used in low-grade pancreas NENs but there are few data for its safety and efficacy in the G3 setting. This article reports on the efficacy of temozolomide-containing regimens, particularly CAPTEM, in management of G3 NENs. The good tolerance and response rate show that CAPTEM should be considered a viable regimen in treatment of G3 NENs pending confirmatory prospective studies.
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http://dx.doi.org/10.1002/onco.13923DOI Listing
August 2021

Analysis of Survival Among Adults With Early-Onset Colorectal Cancer in the National Cancer Database.

JAMA Netw Open 2021 Jun 1;4(6):e2112539. Epub 2021 Jun 1.

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.

Importance: While increased adherence to colorectal cancer (CRC) screening guidelines in the US has been associated with significant reductions in cancer incidence in US individuals aged 50 years and older, the incidence of CRC among those aged younger than 50 years has been steadily increasing. Understanding the survival among individuals with early-onset CRC compared with those aged 50 years and older is fundamental to informing treatment approaches and understanding the unique biological distinctiveness within early-onset CRC.

Objective: To characterize the overall survival for individuals with early-onset CRC.

Design, Setting, And Participants: This cohort study used data from the National Cancer Database. Included individuals were ages 0 to 90 years and diagnosed with primary CRC from January 1, 2004, through December 31, 2015. Individuals diagnosed at ages 51 through 55 years were selected as the reference group and defined as later-onset CRC for this study. Individuals diagnosed at age 50 years were excluded to minimize an apparent screening detection bias at that age in our population, given that these individuals disproportionately presented with earlier stage. All statistical analyses were conducted from January 4, 2020, through December 26, 2020.

Exposures: Early-onset CRC was defined as age younger than 50 years at diagnosis.

Main Outcomes And Measures: Overall survival was assessed by Kaplan-Meier analysis and Cox proportional hazards regression.

Results: Among 769 871 individuals with CRC (377 890 [49.1%] women; 636 791 White individuals [82.7%]), 353 989 individuals (46.0%) died (median [range] follow-up: 2.9 [0-14.0] years), 102 168 individuals (13.3%) had early-onset CRC, and 78 812 individuals (10.2%) had later-onset CRC. Individuals with early-onset CRC, compared with those diagnosed with CRC at ages 51 through 55 years, had a lower 10-year survival rate (53.6% [95% CI, 53.2%-54.0%] vs 54.3% [95% CI, 53.8%-54.8%]; P < .001) in unadjusted analysis. However, after adjustment for other factors associated with mortality, most notably stage, individuals with early-onset CRC had a lower risk of death compared with individuals diagnosed from ages 51 through 55 years (adjusted hazard ratio [HR], 0.95 [95% CI, 0.93-0.96]; P < .001). In the model adjusted for stage, the HR for individuals with early-onset CRC was 0.89 (95% CI, 0.88-0.90; P < .001). The survival advantage was greatest for individuals diagnosed at ages 35 through 39 years (adjusted HR, 0.88 [95% CI, 0.84-0.92]; P < .001) and stages I (adjusted HR, 0.87 [95% CI, 0.81-0.93]; P < .001) and II (adjusted HR, 0.86 [95% CI, 0.82-0.90]; P < .001) and was absent among those diagnosed at ages 25 years or younger and stages III through IV.

Conclusions And Relevance: These findings suggest that there is a survival benefit for individuals with early-onset CRC compared with those diagnosed with CRC at later ages. Further study is needed to understand the underlying heterogeneity of survival among individuals with early-onset CRC by age and stage.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.12539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209612PMC
June 2021

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.

Pancreas 2021 04;50(4):469-493

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract: This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma held on October 2 and 3, 2019. The panelists consisted of endocrinologists, medical oncologists, surgeons, radiologists/nuclear medicine physicians, nephrologists, pathologists, and radiation oncologists. The panelists performed a literature review on a series of questions regarding the medical management of metastatic and unresectable pheochromocytoma and paraganglioma as well as questions regarding surveillance after resection. The panelists voted on controversial topics, and final recommendations were sent to all panel members for final approval.
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http://dx.doi.org/10.1097/MPA.0000000000001792DOI Listing
April 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

Examination of factors associated with lymph node metastases in lung carcinoids: Results from a single institution retrospective cohort study.

Lung Cancer 2021 04 23;154:186-194. Epub 2021 Jan 23.

Stanford University School of Medicine, Stanford Cancer Institute, Department of Medicine, Division of Oncology, 875 Blake Wilbur, Stanford, CA, 94305, USA. Electronic address:

Background: Well-differentiated lung neuroendocrine tumors (NETs), also known as typical and atypical carcinoids, have a decreased incidence of lymph node (LN) and distant metastases compared to poorly differentiated lung NETs. We aimed to (i) examine the clinicopathologic features associated with LN involvement in lung carcinoids and (ii) describe the postoperative management of patients with LN metastases.

Methods: We identified 98 patients who underwent surgical resection and lymph node sampling at Stanford University. We assessed the following and used AJCC staging version 7: clinical features (age, sex, race, prior malignancy, smoking history), tumor features (functional syndrome, histology, size, location, laterality), pre-operative workup performed (imaging and suspicion of LN metastases), surgery (nodes and stations sampled, margin status, surgical approach, and type of surgery), and recurrence outcome. These features were examined between patients with and without LN metastases using the Wilcoxon test (continuous variables) and Fisher's exact test (categorical variables).

Results: 87 patients (89%) had typical carcinoid and 11 patients (11%) had atypical carcinoid. 17 patients were found to have at least one positive lymph node, with 11 having N1 disease and 6 having N2 disease. In the univariable analysis, patients with lymph node disease were more likely to have recurrence of lung carcinoid (29% vs. 6%, p=0.01). In the multivariable logistic regression, there was a trend towards performance of preoperative SSTR imaging and lymph node involvement (OR = 3.06, p=0.07). No patients received adjuvant therapy.

Conclusion: We found a trend for the performance of SSTR imaging and association of lymph node metastases in both univariable and multivariable analysis. A large proportion (41%) of patients with lymph node positive disease had < 2 cm tumors. This suggests the potential importance of incorporating SSTR imaging into routine practice and not restricting the use of this staging modality in patients with small tumors.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026717PMC
April 2021

Angiogenesis inhibitors in neuroendocrine tumours: finally coming of age.

Authors:
Pamela L Kunz

Lancet Oncol 2020 11;21(11):1395-1397

Department of Medicine, Division of Oncology, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30560-XDOI Listing
November 2020

Cost-Effectiveness of Initial Versus Delayed Lanreotide for Treatment of Metastatic Enteropancreatic Neuroendocrine Tumors.

J Natl Compr Canc Netw 2020 09;18(9):1200-1209

Department of Medical Oncology, Yale School of Medicine, New Haven, Connecticut.

Background: The Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET) trial showed prolonged progression-free survival in patients initially treated with lanreotide versus placebo. We evaluated the cost-effectiveness of upfront lanreotide versus active surveillance with lanreotide administered after progression in patients with metastatic enteropancreatic neuroendocrine tumors (NETs), both of which are treatment options recommended in NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine and Adrenal Tumors.

Methods: We developed a Markov model calibrated to the CLARINET trial and its extension. We based the active surveillance strategy on the CLARINET placebo arm. We calculated incremental cost-effectiveness ratios (ICERs) in dollars per quality-adjusted life-year (QALY). We modeled lanreotide's cost at $7,638 per 120 mg (average sales price plus 6%), used published utilities (stable disease, 0.77; progressed disease, 0.61), adopted a healthcare sector perspective and lifetime time horizon, and discounted costs and benefits at 3% annually. We examined sensitivity to survival extrapolation and modeled octreotide long-acting release (LAR) ($6,183 per 30 mg). We conducted one-way, multiway, and probabilistic sensitivity analyses.

Results: Upfront lanreotide led to 5.21 QALYs and a cost of $804,600. Active surveillance followed by lanreotide after progression led to 4.84 QALYs and a cost of $590,200, giving an ICER of $578,500/QALY gained. Reducing lanreotide's price by 95% (to $370) or 85% (to $1,128) per 120 mg would allow upfront lanreotide to reach ICERs of $100,000/QALY or $150,000/QALY. Across a range of survival curve extrapolation scenarios, pricing lanreotide at $370 to $4,000 or $1,130 to $5,600 per 120 mg would reach ICERs of $100,000/QALY or $150,000/QALY, respectively. Our findings were robust to extensive sensitivity analyses. The ICER modeling octreotide LAR is $482,700/QALY gained.

Conclusions: At its current price, lanreotide is not cost-effective as initial therapy for patients with metastatic enteropancreatic NETs and should be reserved for postprogression treatment. To be cost-effective as initial therapy, the price of lanreotide would need to be lowered by 48% to 95% or 27% to 86% to reach ICERs of $100,000/QALY or $150,00/QALY, respectively.
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http://dx.doi.org/10.6004/jnccn.2020.7563DOI Listing
September 2020

Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines.

J Thorac Oncol 2020 10 11;15(10):1577-1598. Epub 2020 Jul 11.

Department of Oncology, Monash Health, Monash University, Melbourne, Victoria, Australia.

Lung neuroendocrine tumors (LNETs) are uncommon cancers, and there is a paucity of randomized evidence to guide practice. As a result, current guidelines from different neuroendocrine tumor societies vary considerably. There is a need to update and harmonize global consensus guidelines. This article reports the best practice guidelines produced by a collaboration between the Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society. We performed a formal endorsement and updating process of the 2015 European Neuroendocrine Tumor Society expert consensus article on LNET. A systematic review from January 2013 to October 2017 was conducted to procure the most recent evidence. The stepwise endorsement process involved experts from all major subspecialties, patients, and advocates. Guided by discussion of the most recent evidence, each statement from the European Neuroendocrine Tumor Society was either endorsed, modified, or removed. New consensus statements were added if appropriate. The search yielded 1109 new publications, of which 230 met the inclusion criteria. A total of 12 statements were endorsed, 22 statements were modified or updated, one was removed, and two were added. Critical answered questions for each topic in LNET were identified. Through the consensus process, guidelines for the management of patients with local and metastatic neuroendocrine tumors have been updated to include both recent evidence and practice changes relating to technological and definitional advances. The guidelines provide clear, evidence-based statements aimed at harmonizing the global approach to patients with LNETs, on the basis of the principles of person-centered and LNET-specific care. The importance of LNET-directed research and person-centered care throughout the diagnosis, treatment, and follow-up journey is emphasized along with directions for future collaborative research.
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http://dx.doi.org/10.1016/j.jtho.2020.06.021DOI Listing
October 2020

PAM staining intensity of primary neuroendocrine neoplasms is a potential prognostic biomarker.

Sci Rep 2020 07 2;10(1):10943. Epub 2020 Jul 2.

Chemistry, Engineering and Medicine for Human Health (ChEM-H) Institute, Stanford University, Stanford, CA, USA.

Neuroendocrine neoplasms (NENs) are rare epithelial tumors with heterogeneous and frequently unpredictable clinical behavior. Available biomarkers are insufficient to guide individual patient prognosis or therapy selection. Peptidylglycine α-amidating monooxygenase (PAM) is an enzyme expressed by neuroendocrine cells that participates in hormone maturation. The objective of this study was to assess the distribution, clinical associations and survival implications of PAM immunoreactivity in primary NENs. Of 109 primary NENs, 7% were PAM-negative, 25% were PAM-low and 68% were PAM-high. Staining intensity was high in small bowel (p = 0.04) and low in stomach (p = 0.004) NENs. PAM staining was lower in higher grade tumors (p < 0.001) and patients who died (p < 0.001) but did not vary by tumor size or stage at surgery. In patients who died, time to death was shorter in patients with reduced PAM immunoreactivity: median times to death were 11.3 (PAM-negative), 29.4 (PAM-low) and 61.7 (PAM-high) months. Lower PAM staining was associated with increased risk of death after adjusting for disease stage [PAM negative, HR = 13.8 (CI: 4.2-45.5)]. PAM immunoreactivity in primary NENs is readily assessable and a potentially useful stage-independent predictor of survival.
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http://dx.doi.org/10.1038/s41598-020-68071-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331689PMC
July 2020

A PHASE IIA STUDY REPOSITIONING DESIPRAMINE IN SMALL CELL LUNG CANCER AND OTHER HIGH-GRADE NEUROENDOCRINE TUMORS.

Cancer Treat Res Commun 2020 Apr 20;23:100174. Epub 2020 Apr 20.

Stanford University School of Medicine, Department of Internal Medicine, Division of Oncology, Stanford Cancer Institute.

Background: A bioinformatics approach identified antitumor effects of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinomas) (G3NEC) that was subsequently validated in preclinical models with a putative mechanism of action via inhibition of neuroendocrine signaling pathways. This study was undertaken to reposition the candidate TCA desipramine in a clinical trial in SCLC and G3NEC.

Methods: In this prospective, phase IIa intrapatient dose escalation clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC. Treatment with desipramine began at 75 mg nightly with escalation in increments of 75 mg weekly to a maximum of 450 mg daily.

Results: Six patients were enrolled, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreas). Tolerability of desipramine was worse than predicted. Of the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 neurocognitive adverse events. Median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6).

Conclusions: No clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated. Intolerable low and medium grade neurocognitive side effects led to intermittent treatment and early discontinuation in most patients; given this limitation, doses achieved may be inadequate compared to the preclinical studies.

Microabstract: A bioinformatics approach previously identified a potential antitumor effect of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinoma) (G3NEC), which was validated in preclinical models. In this prospective, phase IIa clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC (Ki-67 ≥ 20% or ≥ 20 mitoses/10 HPF). Treatment with desipramine began at 75 mg nightly with escalation by 75 mg weekly to a maximum dose of 450 mg daily. Six patients were enrolled on this clinical trial, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreatic). Tolerability of desipramine was worse than predicted. In the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 drug related dizziness, confusion, and somnolence. Though numbers are small, median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). Although preclinical evidence was promising, no clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated.
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http://dx.doi.org/10.1016/j.ctarc.2020.100174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572629PMC
April 2020

Patient Selection and Toxicities of PRRT for Metastatic Neuroendocrine Tumors and Research Opportunities.

Curr Treat Options Oncol 2020 03 14;21(4):25. Epub 2020 Mar 14.

Department of Medicine, Division of Oncology, Stanford University, School of Medicine, Stanford, CA, 94305, USA.

Opinion Statement: Neuroendocrine tumors (NETs) are a heterogenous group of neoplasms characterized by varied biological hallmarks and behavior, ranging from indolent to aggressive. For many decades, somatostatin analogues and few targeted therapies were available for NETs and these therapies had minimal response rates. However, there have been a number of recent treatment advances. Peptide receptor radionuclide therapy (PRRT) is a novel approach to treatment of NETs and has changed the landscape of treatment for NETs. It is a form of targeted therapy in which a radiolabeled somatostatin analogue delivers radiation specifically to tumor cells expressing the somatostatin receptor.
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http://dx.doi.org/10.1007/s11864-020-0711-9DOI Listing
March 2020

Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome.

J Gastrointest Cancer 2021 Mar;52(1):212-221

Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin, Berlin, Germany.

Background: Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods.

Methods: First occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial.

Results: In TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3-4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2-3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6-11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7-11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR.

Conclusion: The time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency.

Trial Registration: ClinicalTrials.gov Identifiers: NCT01677910, NCT02063659.
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http://dx.doi.org/10.1007/s12029-020-00375-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714089PMC
March 2021

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with Lu-Dotatate: an analysis of the NETTER-1 study.

Eur J Nucl Med Mol Imaging 2020 09 2;47(10):2372-2382. Epub 2020 Mar 2.

Department of Nuclear Medicine, Hôpital de la Timone, Marseille, France.

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with Lu-Dotatate.

Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression.

Results: Significantly prolonged median PFS occurred with Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden.

Conclusions: Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.
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http://dx.doi.org/10.1007/s00259-020-04709-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396396PMC
September 2020

Surgery Versus Surveillance for Well-Differentiated, Nonfunctional Pancreatic Neuroendocrine Tumors: An 11-Year Analysis of the National Cancer Database.

Oncologist 2020 02 2;25(2):e276-e283. Epub 2019 Oct 2.

Department of Hematology/Oncology, Stephenson Cancer Center, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Background: Pancreatic neuroendocrine tumors (panNETs) are a rare group of tumors that make up 2%-3% of pancreatic tumors. Recommended treatment for panNETs generally consists of resection for symptomatic or large asymptomatic tumors; however, optimal management for localized disease is still controversial, with conflicting recommendations in established guidelines. Our study aim is to compare surgical intervention versus active surveillance in nonmetastatic panNETs by size of primary tumor.

Materials And Methods: Using the National Cancer Database, we identified 2,004 patients diagnosed with localized well-differentiated, nonfunctional panNETs (NF-panNETs) between 2004 and 2015. Patients' clinicopathologic characteristics, treatment modalities, and overall survival (OS) were analyzed using frequency statistics, chi-square, and Kaplan-Meier curves. The objective of the study is to assess the outcome of surgical resection versus nonoperative management in patients with panNETs with different tumor sizes.

Results: Tumor sizes were divided into three categories: <1 cm, 1-2 cm, and >2 cm. The number of patients with tumor size <1 cm, 1-2 cm, and >2 cm was 220 (11%), 794 (39.6%), and 990 (49.4%), respectively. Overall, 1,781 underwent surgical resection, whereas 223 patients did not. Median follow-up was 25.9 months. After adjusting for covariates, surgical resection was associated with improved OS in patients with tumor size 1-2 cm (hazard ratio [HR] = 0.37) and >2c m (HR = 0.30) but not <1 cm (HR = 2.81). Independent prognostic factors were age at diagnosis, Charlson-Deyo comorbidity score, stage, tumor location, and surgical resection. Higher tumor grade was not associated with worse OS.

Conclusion: Our findings suggest that active surveillance is potentially a safe approach for NF-panNETs <1 cm. Larger tumors likely need active intervention. Intermediate-grade tumors did not result in worse survival outcome compared with low-grade tumors. Future studies might consider prospective randomized clinical trials to validate our findings.

Implications For Practice: The present study seeks to address the discrepancy in treatment recommendations in the management of nonfunctional pancreatic neuroendocrine tumors (NF-panNETs) by evaluating whether surgical resection is associated with improved overall survival in different tumor size groups as well as elucidating independent prognostic factors in patients with NF-panNETs. Data from the National Cancer Database were reviewed. This study's findings suggest that active surveillance is potentially a safe approach for NF-panNETs <1 cm. Larger tumors likely need active intervention. Independent prognostic factors include age at diagnosis, Charlson-Deyo comorbidity score, stage, tumor location, and surgical resection. These findings will help guide medical and surgical oncologists when formulating treatment plans for patients with small NF-panNETs.
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http://dx.doi.org/10.1634/theoncologist.2019-0466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011621PMC
February 2020

Comparison of definitive chemoradiation with 5-fluorouracil versus capecitabine in anal cancer.

J Gastrointest Oncol 2019 Aug;10(4):605-615

Division of Medical Oncology, Department of Internal Medicine, Stanford University, Stanford, CA, USA.

Background: Capecitabine (Cap) is an established treatment alternative to 5-fluorouracil (5-FU) for chemoradiation in rectal cancer. Few studies have compared the two agents in anal cancer. We compared outcomes and toxicities using Cap versus 5-FU in non-metastatic anal cancer patients at Stanford.

Methods: All non-metastatic anal cancer patients treated with definitive chemoradiation at Stanford from 1997-2016 were included. Fisher's exact and Mann-Whitney U tests were used to compare nominal and continuous variables. Gray's test was used to compare incidence of recurrence and colostomy, and Log-rank test was used to compare survival.

Results: Sixty-eight patients were included. Thirty-six patients received Cap and 32 received 5-FU (12 received standard 5-FU and 20 received low-dose continuous 5-FU). Patient characteristics were similar between the two groups. There was no difference in the 3-year overall and disease-specific survival between Cap and 5-FU (94% 80%, P=0.197; 100% 86%, P=0.051). Overall incidence of recurrence was equivalent between Cap and 5-FU (11% 13%, P=0.703), but incidence of locoregional recurrence was higher in the 5-FU group (0% 13%, P=0.042); patients treated with Cap had longer recurrence-free intervals (18 6 months, P=0.400), and all recurrences were distant. More colostomies were needed with 5-FU (3% 13%, P=0.133). Toxicities were similar between the two groups. The most common grade ≥2 toxicities were dermatitis (77%), anal pain (78%), and diarrhea (56%).

Conclusions: Overall survival (OS), cancer-specific survival and incidence of recurrence were equivalent between Cap and 5-FU in anal cancer. Patients treated with Cap had statistically significant lower incidence of loco-regional relapses.
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http://dx.doi.org/10.21037/jgo.2019.02.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657317PMC
August 2019

Prognostic value of somatostatin receptor expressing tumor volume calculated from Ga-DOTATATE PET/CT in patients with well-differentiated neuroendocrine tumors.

Eur J Nucl Med Mol Imaging 2019 Oct 27;46(11):2244-2251. Epub 2019 Jul 27.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5281, USA.

Purpose: To evaluate the prognostic value of volumetric parameters calculated from Ga-1,4,7,10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-Thr-octreotate (Ga-DOTATATE) positron emission tomography/computed tomography (PET/CT) in patients with well-differentiated neuroendocrine tumor (WD-NET).

Methods: Ninety-two patients (44 men and 48 women, mean age of 59.5-year-old) with pathologically confirmed WD-NET (grades 1 or 2) were enrolled in a prospective expanded access protocol. Selected data was analyzed retrospectively for this project. Maximum standardized uptake value (SUV) in the lesion with the highest Ga-DOTATATE uptake was measured and recorded for each patient. In addition, two volumetric parameters, namely, somatostatin receptor expressing tumor volume (SRETV) and total lesion somatostatin receptor expression (TLSRE), were calculated in each Ga-DOTATATE-avid lesion. SRETV was defined as tumor volume with higher Ga-DOTATATE uptake than the 50% of SUV within the volume of interest (VOI) for each lesion. TLSRE was calculated by multiplying SRETV and mean SUV within the same VOI. Thereafter, the sum of SRETV (ΣSRETV) and TLSRE (ΣTLSRE) for all detected lesions per patient were calculated. Progression-free survival (PFS) was set as primary endpoint. Kaplan-Meier survival analysis, log-rank test, and Cox's proportional hazard model were used for statistical analysis.

Results: Univariate analyses revealed significant difference of PFS for WHO tumor grade and ΣSRETV (P < 0.05), while there were no significant differences in age, sex, SUV, and ΣTLSRE (P > 0.05). Multivariate analysis identified WHO tumor grade and ΣSRETV as independent predictors of PFS.

Conclusion: ΣSRETV calculated from Ga-DOTATATE PET/CT may have prognostic value of PFS in WD-NET patients.
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http://dx.doi.org/10.1007/s00259-019-04455-9DOI Listing
October 2019

Evaluating the Role of Theranostics in Grade 3 Neuroendocrine Neoplasms.

J Nucl Med 2019 07 8;60(7):882-891. Epub 2019 Mar 8.

Department of Medicine, Stanford University School of Medicine, Stanford, California

The diagnosis and subsequent therapy of neuroendocrine neoplasms (NENs) have long relied on somatostatin receptor (SSTR) expression. The field of theranostics now uses newer SSTR-based PET imaging with Ga-DOTATATE or Ga-DOTATOC as a prerequisite for the administration of peptide receptor radionuclide therapy (PRRT). In the United States, Food and Drug Administration approval of Lu-DOTATATE, a form of PRRT, in 2018 for use in gastroenteropancreatic NENs was obtained on the basis of prolonged progression-free survival versus high-dose octreotide long-acting release in a phase III clinical trial of well-differentiated midgut NENs. Well-differentiated grade 1 and grade 2 NENs have a low proliferation index (Ki-67 < 20%) and longer overall survival (>10 y), whereas higher-grade (grade 3 [G3]) NENs have a high Ki-67 (>20%) and shorter overall survival (<1 y). Here, we present a review on the role of SSTR-based imaging and PRRT in G3 NENs, including a discussion of well-differentiated G3 NENs, the newest histologic classification. Some studies suggest that G3 NENs are less likely to be positive on SSTR-based imaging (but more likely on F-FDG PET) than are well-differentiated NENs, but these data are limited. We found only 13 studies mentioning the use of PRRT in G3 NENs and a total of only 151 patients across these studies in whom radiologic response was measured. Of these 151 patients, 99 (66%) demonstrated at least stable disease or a partial response, indicating that some G3 NENs can be responsive to PRRT. We suggest that patients with G3 NENs should receive both F-FDG PET and SSTR-based imaging to aid in both diagnosis and treatment selection, as positivity on SSTR-based imaging helps with patient identification for PRRT and discordance may suggest important clues to tumor biology and prognosis. However, prospective studies are needed to fully understand the role of PRRT in G3 NENs, especially in well- versus poorly differentiated G3 disease.
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http://dx.doi.org/10.2967/jnumed.118.217851DOI Listing
July 2019

Organoid Modeling of the Tumor Immune Microenvironment.

Cell 2018 12;175(7):1972-1988.e16

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.
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http://dx.doi.org/10.1016/j.cell.2018.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656687PMC
December 2018

Surgical and molecular characterization of primary and metastatic disease in a neuroendocrine tumor arising in a tailgut cyst.

Cold Spring Harb Mol Case Stud 2018 10 1;4(5). Epub 2018 Oct 1.

Department of Bioengineering, Stanford University, Stanford, California 94305, USA.

Neuroendocrine tumors (NETs) arising from tailgut cysts are a rare but increasingly reported entity with gene expression profiles that may be indicative of the gastrointestinal cell of origin. We present a case report describing the unique pathological and genomic characteristics of a tailgut cyst NET that metastasized to liver. The histologic and immunohistochemical findings were consistent with a well-differentiated NET. Genomic testing indicates a germline frameshift in and a few somatic mutations of unknown significance. Transcriptomic analysis suggests an enteroendocrine L cell in the tailgut as a putative cell of origin. Genomic profiling of a rare NET and metastasis provides insight into its origin, development, and potential therapeutic options.
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http://dx.doi.org/10.1101/mcs.a003004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169824PMC
October 2018

Long-Term Survivors of Pancreatic Cancer: A California Population-Based Study.

Pancreas 2018 09;47(8):958-966

Greater Bay Area Cancer Registry, Cancer Prevention Institute of California, Fremont.

Objectives: Pancreatic cancer continues to carry a poor prognosis with survival rates that have had minimal improvement over the past 4 decades. We report a population-based, comprehensive analysis of long-term survivors of pancreatic adenocarcinoma diagnosed in the diverse population of California.

Methods: Data from the California Cancer Registry were used to evaluate long-term survival. A total of 70,442 patients diagnosed with pancreatic adenocarcinoma between 1988 and 2009 were identified. Logistic regression was used to identify factors associated with achieving 5-year survival.

Results: The overall 5-year survival was 2.5%, with minimal incremental improvements throughout the 3 decades. Age, stage, degree of differentiation, and surgical resection were associated with 5-year survival. Furthermore, younger age and receiving care at a National Cancer Institute-designated cancer center were similarly correlated with 5-year survival regardless of surgical intervention. In addition, we identified stage, differentiation, and adjuvant chemotherapy as significant factors for long-term survival in surgically resected patients. In the unresectable patients, Asian/Pacific islanders and Hispanics were significantly more likely to reach the 5-year milestone than non-Hispanic whites.

Conclusions: Although pancreatic cancer mortality remains high, our study highlights baseline characteristics, treatment, biological factors, and ethnicity that are associated with long-term survival. These findings may serve as a springboard for further investigation.
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http://dx.doi.org/10.1097/MPA.0000000000001133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095724PMC
September 2018

NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018.

J Natl Compr Canc Netw 2018 06;16(6):693-702

The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs.
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http://dx.doi.org/10.6004/jnccn.2018.0056DOI Listing
June 2018

Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With Lu-Dotatate in the Phase III NETTER-1 Trial.

J Clin Oncol 2018 09 7;36(25):2578-2584. Epub 2018 Jun 7.

Jonathan Strosberg, Moffitt Cancer Center, Tampa, FL; Edward Wolin, Montefiore Einstein Center for Cancer Care, Bronx, NY; Beth Chasen, University of Texas MD Anderson Cancer Center, Houston, TX; Matthew Kulke, Dana-Farber Cancer Institute, Boston, MA; David Bushnell, University of Iowa, Iowa City, IA; Martyn Caplin, Royal Free Hospital, London, United Kingdom; Richard P. Baum, Zentralklinik, Bad Berka, Germany; Pamela Kunz, Stanford University Medical Center, Stanford; Andrew Hendifar, Cedars Sinai Medical Center, Los Angeles, CA; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Kjell Oberg, University Hospital, Uppsala University, Uppsala, Sweden; Maribel Lopera Sierra, Thomas Thevenet, and Ines Margalet, Advanced Accelerator Applications, Geneva, Switzerland; Philippe Ruszniewski, Hopital Beaujon and Paris Diderot University, Clichy, France; and Eric Krenning, Erasmus Medical Center, Rotterdam, Netherlands.

Purpose Neuroendocrine tumor (NET) progression is associated with deterioration in quality of life (QoL). We assessed the impact of Lu-Dotatate treatment on time to deterioration in health-related QoL. Methods The NETTER-1 trial is an international phase III study in patients with midgut NETs. Patients were randomly assigned to treatment with Lu-Dotatate versus high-dose octreotide. European Organisation for Research and Treatment of Cancer quality-of-life questionnaires QLQ C-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on health-related QoL. Patients completed the questionnaires at baseline and every 12 weeks until tumor progression. QoL scores were converted to a 100-point scale according to European Organisation for Research and Treatment of Cancer instructions, and individual changes from baseline scores were assessed. Time to QoL deterioration (TTD) was defined as the time from random assignment to the first QoL deterioration ≥ 10 points for each patient in the corresponding domain scale. All analyses were conducted on the intention-to-treat population. Patients with no deterioration were censored at the last QoL assessment date. Results TTD was significantly longer in the Lu-Dotatate arm (n = 117) versus the control arm (n = 114) for the following domains: global health status (hazard ratio [HR], 0.406), physical functioning (HR, 0.518), role functioning (HR, 0.580), fatigue (HR, 0.621), pain (HR, 0.566), diarrhea (HR, 0.473), disease-related worries (HR, 0.572), and body image (HR, 0.425). Differences in median TTD were clinically significant in several domains: 28.8 months versus 6.1 months for global health status, and 25.2 months versus 11.5 months for physical functioning. Conclusion This analysis from the NETTER-1 phase III study demonstrates that, in addition to improving progression-free survival, Lu-Dotatate provides a significant QoL benefit for patients with progressive midgut NETs compared with high-dose octreotide.
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http://dx.doi.org/10.1200/JCO.2018.78.5865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366953PMC
September 2018

Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome.

Clin Ther 2018 06 1;40(6):952-962.e2. Epub 2018 May 1.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival.

Methods: Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan.

Findings: In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status.

Implications: Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910.
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http://dx.doi.org/10.1016/j.clinthera.2018.04.006DOI Listing
June 2018

The Power of Trust.

JAMA Oncol 2018 09;4(9):1173-1174

Division of Medical Oncology, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1001/jamaoncol.2018.0495DOI Listing
September 2018

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial.

Endocr Relat Cancer 2018 03 12;25(3):309-322. Epub 2018 Jan 12.

Oncology DepartmentHospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain.

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients ( = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges-Lehmann estimators of median treatment differences from placebo of -54.0% (95% confidence limits, -85.0%, -25.1%,  < 0.001) and -89.7% (95% confidence limits, -113.1%, -63.9%,  < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).
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http://dx.doi.org/10.1530/ERC-17-0455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811631PMC
March 2018

Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-controlled Study of Telotristat Ethyl.

Clin Ther 2017 Nov 23;39(11):2158-2168. Epub 2017 Oct 23.

RTI Health Solutions, Research Triangle Park, North Carolina.

Purpose: Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in TELESTAR, a Phase III study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview substudy was conducted to provide insight into the patient experience in TELESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful.

Methods: Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment.

Findings: All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving ≥30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoid syndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo.

Implications: Patient interviews revealed that TELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl.
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http://dx.doi.org/10.1016/j.clinthera.2017.09.013DOI Listing
November 2017

Carcinoid Syndrome Complicating a Pancreatic Neuroendocrine Tumor: A Case Report.

Pancreas 2017 Nov/Dec;46(10):1381-1385

From the *Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA; †Division of Cardiovascular Medicine, Department of Medicine; ‡Department of Radiation Oncology, Stanford University School of Medicine, Stanford; §Department of Cardiovascular Surgery, UCSF Medical Center, San Francisco; ∥Department of Radiology (Nuclear Medicine); and ¶Department of Medicine (Division of Oncology), Stanford University School of Medicine, Stanford, CA.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms. These tumors can produce a wide variety of hormones that can lead to syndromes of hormone excess, such as carcinoid syndrome. We present the case of a 47-year-old man who presented with right upper quadrant abdominal pain and emesis. He was found to have metastatic pancreatic NET and was treated with systemic chemotherapy. He subsequently developed dyspnea on exertion and was found to have severe right-sided heart disease secondary to elevated levels of serum serotonin. He was successfully treated with surgical tricuspid and pulmonic valve replacement. True carcinoid syndrome with pancreatic NETs is rare, but, as a treatable complication of the disease, is an important entity for which oncologists should be familiar.
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http://dx.doi.org/10.1097/MPA.0000000000000932DOI Listing
June 2018
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