Making Sense of a Complex Disease: A Practical Approach to Managing Neuroendocrine Tumors

JCO Oncology Practice ◽

10.1200/op.21.00240 ◽

2021 ◽

Author(s):

Janie Y. Zhang ◽

Pamela L. Kunz

Keyword(s):

Functional Status ◽

Neuroendocrine Tumors ◽

Complex Disease ◽

Treatment Plan ◽

Performance Status ◽

Somatostatin Receptor ◽

The United States ◽

Making Sense ◽

Pathologic Classification ◽

Therapeutic Decision Making

Neuroendocrine tumors (NETs) are a heterogeneous clinical entity with a broad range of grade, pace of disease, functional status, and primary sites. Pathologic classification, diagnostic modalities, and therapeutic options for NETs have evolved considerably in the past decade. In part driven by these advances, incidence and prevalence of NETs are rising in the United States and the practicing oncologist is likely to encounter these in the clinic. However, there are no clear lines of therapy for unresectable or metastatic NETs, and sequencing of systemic therapies depends on consideration of patient and tumor characteristics including extent of disease, grade, pace of growth, functional status, primary site, somatostatin receptor status, performance status, and comorbidities. Familiarity with ongoing clinical trials will guide therapeutic decision making as well. In this review, we seek to provide a framework to formulate and tailor an individualized treatment plan for each patient with a NET.

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NETTER-1 phase III: Progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-Lu-Dotatate.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.194 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 194-194 ◽

Cited By ~ 33

Author(s):

Jonathan R. Strosberg ◽

Edward M. Wolin ◽

Beth Chasen ◽

Matthew H. Kulke ◽

David L Bushnell ◽

...

Keyword(s):

Overall Survival ◽

Neuroendocrine Tumors ◽

Controlled Trial ◽

Somatostatin Receptor ◽

Objective Response ◽

Progression Free Survival ◽

The United States ◽

Phase Iii ◽

Octreotide Lar ◽

Related Quality

194 Background: Currently, there are limited therapeutic options for patients with advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog therapy. Methods: NETTER-1 is the first Phase III multicentric, randomized, controlled trial evaluating 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) in patients with inoperable, progressive, somatostatin receptor positive midgut NETs. 230 patients with Grade 1-2 metastatic midgut NETs were randomized to receive Lutathera 7.4 GBq every 8 weeks (x4 administrations) versus Octreotide LAR 60 mg every 4-weeks. The primary endpoint was PFS per RECIST 1.1 criteria, with objective tumor assessment performed by an independent reading center every 12 weeks. Secondary objectives included objective response rate, overall survival, toxicity, and health-related quality of life. Results: Enrolment was completed in February 2015, with a target of 230 patients randomized (1:1) in 36 European and 15 sites in the United States. At the time of statistical analysis, the number of centrally confirmed disease progressions or deaths was 23 in the Lutathera group and 67 in the Octreotide LAR 60 mg group. The median PFS was not reached for Lutathera and was 8.4 months with 60 mg Octreotide LAR [95% CI: 5.8-11.0 months], p < 0.0001, with a hazard ratio of 0.21 [95% CI: 0.13-0.34]. Within the current evaluable patient dataset for tumor responses (n = 201), the number of CR+PR was 19 (18.8%) in the Lutathera group and 3 (3.0%) in the Octreotide LAR 60 mg group (p < 0.0004). Although the OS data were not mature enough for a definitive analysis, the number of deaths was 13 in the Lutathera group and 22 in the Octreotide LAR 60 mg group (p < 0.019 at interim analysis) which suggests an improvement in overall survival. Conclusions: The Phase III NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS and ORR, and also suggests a survival benefit in patients with advanced midgut NETs treated with Lutathera. Clinical trial information: NCT01578239.

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Predicting Advanced Prostate Cancer from Modeling Early Indications in Biopsy and Prostatectomy Samples via Transductive Semi-Supervised Survival Analysis

BioMed Research International ◽

10.1155/2018/2178645 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12

Author(s):

Faisal M. Khan

Keyword(s):

Prostate Cancer ◽

Survival Analysis ◽

Cancer Progression ◽

Advanced Prostate Cancer ◽

Complex Disease ◽

Treatment Plan ◽

The United States ◽

Censored Samples ◽

Psa Recurrence ◽

Regression Techniques

Prostate cancer is the most prevalent form of cancer and the second most common cause of cancer deaths among men in the United States. Accurate prognosis is important as it is the principal factor in determining the treatment plan. Prostate cancer is a complex disease which advances in stages. While clinical failure (including metastasis) is a significant endpoint following a radical prostatectomy, it can often take years to manifest, usually too late to be optimistically treated. In practice, the earlier endpoint of PSA Recurrence is frequently used as a surrogate in prognostic modeling. The central issue in these models is managing censored observations which challenge traditional regression techniques. The true target times of a majority of instances are unknown; what is known is a censored target representing some earlier indeterminate time. In this work we apply a novel transduction approach for semi-supervised survival analysis which has previously been shown to be powerful in medical prognosis. The approach considers censored samples as semi-supervised regression targets leveraging the partial nature of unsupervised information. We explore the use of this approach in building prostate cancer progression models from multimodal characteristics extracted from both biopsy and prostatectomy tissues samples. In this work, the approach leads to a significant increase in performance for predicting advanced prostate cancer from earlier endpoints and may also be useful in other diseases for predicting advanced endpoints from earlier stages of the disease.

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The Role of Wireless Capsule Endoscopy (WCE) in the Detection of Occult Primary Neuroendocrine Tumors

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.262.wce ◽

2017 ◽

Vol 26 (2) ◽

pp. 151-156

Author(s):

Manuele Furnari ◽

Andrea Buda ◽

Gabriele Delconte ◽

Davide Citterio ◽

Theodor Voiosu ◽

...

Keyword(s):

Neuroendocrine Tumor ◽

Neuroendocrine Tumors ◽

Capsule Endoscopy ◽

Primary Tumor ◽

Diagnostic Yield ◽

Somatostatin Receptor ◽

Tertiary Care ◽

Wireless Capsule Endoscopy ◽

First Line ◽

Wireless Capsule

Background & Aims: Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with unclear etiology that may show functioning or non-functioning features. Primary tumor localization often requires integrated imaging. The European Neuroendocrine Tumors Society (ENETS) guidelines proposed wireless-capsule endoscopy (WCE) as a possible diagnostic tool for NETs, if intestinal origin is suspected. However, its impact on therapeutic management is debated. We aimed to evaluate the yield of WCE in detecting intestinal primary tumor in patients showing liver NET metastases when first-line investigations are inconclusive.Method: Twenty-four patients with histological diagnosis of metastatic NET from liver biopsy and no evidence of primary lesions at first-line investigations were prospectively studied in an ENETS-certified tertiary care center. Wireless-capsule endoscopy was requested before explorative laparotomy and intra-operative ultrasound. The diagnostic yield of WCE was compared to the surgical exploration.Results: Sixteen subjects underwent surgery; 11/16 had positive WCE identifying 16 bulging lesions. Mini-laparotomy found 13 NETs in 11/16 patients (9 small bowel, 3 pancreas, 1 bile ducts). Agreement between WCE and laparotomy was recorded in 9 patients (Sensitivity=75%; Specificity=37.5%; PPV=55%; NPV=60%). Correspondence assessed per-lesions produced similar results (Sensitivity=70%; Specificity=25%; PPV=44%; NPV=50%). No capsule retentions were recorded.Conclusions: Wireless-capsule endoscopy is not indicated as second-line investigation for patients with gastro-entero-pancreatic NETs. In the setting of a referral center, it might provide additional information when conventional investigations are inconclusive about the primary site.Abbreviations: DBE: double balloon enteroscopy; GEP-NET: gastro-entero-pancreatic neuroendocrine tumor; GI: gastrointestinal; ENETS: European Neuroendocrine Tumor Society; NET: neuroendocrine tumor; SSRS: somatostatin receptor scintigraphy; WCE: wireless capsule endoscopy.

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Gender disparities in opioid treatment progress in methadone versus counseling

Substance Abuse Treatment Prevention and Policy ◽

10.1186/s13011-021-00389-4 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Erick Guerrero ◽

Hortensia Amaro ◽

Yinfei Kong ◽

Tenie Khachikian ◽

Jeanne C. Marsh

Keyword(s):

United States ◽

Treatment Outcomes ◽

Treatment Plan ◽

Dropout Rate ◽

The United States ◽

Gender Disparities ◽

Opioid Use ◽

Lower Odds ◽

Male Clients ◽

Multi Level

Abstract Background In the United States, the high dropout rate (75%) in opioid use disorder (OUD) treatment among women and racial/ethnic minorities calls for understanding factors that contribute to making progress in treatment. Whereas counseling and medication for OUD (MOUD, e.g. methadone, buprenorphine, naltrexone) is considered the gold standard of care in substance use disorder (SUD) treatment, many individuals with OUD receive either counseling or methadone-only services. This study evaluates gender disparities in treatment plan progress in methadone- compared to counseling-based programs in one of the largest SUD treatment systems in the United States. Methods Multi-year and multi-level (treatment program and client-level) data were analyzed using the Integrated Substance Abuse Treatment to Eliminate Disparities (iSATed) dataset collected in Los Angeles County, California. The sample consisted of 4 waves: 2011 (66 SUD programs, 1035 clients), 2013 (77 SUD programs, 3686 clients), 2015 (75 SUD programs, 4626 clients), and 2017 (69 SUD programs, 4106 clients). We conducted two multi-level negative binomial regressions, one per each outcome (1) making progress towards completing treatment plan, and (2) completing treatment plan. We included outpatient clients discharged on each of the years of the study (over 95% of all clients) and accounted for demographics, wave, homelessness and prior treatment episodes, as well as clients clustered within programs. Results We detected gender differences in two treatment outcomes (progress and completion) considering two outpatient program service types (MOUD-methadone vs. counseling). Clients who received methadone vs. counseling had lower odds of completing their treatment plan (OR = 0.366; 95% CI = 0.163, 0.821). Female clients receiving methadone had lower odds of both making progress (OR = 0.668; 95% CI = 0.481, 0.929) and completing their treatment plan (OR = 0.666; 95% CI = 0.485, 0.916) compared to male clients and receiving counseling. Latina clients had lower odds of completing their treatment plan (OR = 0.617; 95% CI = 0.408, 0.934) compared with non-Latina clients. Conclusions Clients receiving methadone, the most common and highly effective MOUD in reducing opioid use, were less likely to make progress towards or complete their treatment plan than those receiving counseling. Women, and in particular those identified as Latinas, were least likely to benefit from methadone-based programs. These findings have implications for health policy and program design that consider the need for comprehensive and culturally responsive services in methadone-based programs to improve outpatient treatment outcomes among women.

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Predictive and Prognostic Impact of Blood-Based Inflammatory Biomarkers in Patients with Gastroenteropancreatic Neuroendocrine Tumors Commencing Peptide Receptor Radionuclide Therapy

Diagnostics ◽

10.3390/diagnostics11030504 ◽

2021 ◽

Vol 11 (3) ◽

pp. 504

Author(s):

Fiona Ohlendorf ◽

Rudolf Werner ◽

Christoph Henkenberens ◽

Tobias Ross ◽

Hans Christiansen ◽

...

Keyword(s):

Treatment Response ◽

Neuroendocrine Tumors ◽

Radionuclide Therapy ◽

Somatostatin Receptor ◽

Peptide Receptor Radionuclide Therapy ◽

Tumor Burden ◽

Inflammatory Biomarkers ◽

Whole Body ◽

Prognostic Impact ◽

Peptide Receptor

Tumor microenvironment inflammation contributes to the proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, and reduced treatment response. We aimed to evaluate the early predictive and prognostic significance of markers of systemic inflammation in patients receiving somatostatin-receptor targeted peptide receptor radionuclide therapy (PRRT). This retrospective observational cohort study included 33 patients with advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) treated with PRRT. Pretreatment blood-based inflammatory biomarkers, e.g., Creactive protein levels (CRP), white blood cell count (WBC), and absolute neutrophil count (ANC), were documented and inflammation indexes, e.g., neutrophil-lymphocyte ratio (NLR) and Platelet × CRP multiplier (PCM), were calculated. Tumor burden was determined using [68Ga]GaDOTATATE PET/CT before enrollment and every 2 cycles thereafter until progression. Therapy response was assessed using RECIST 1.1, including its volumetric modification. Inflammatory biomarkers and inflammatory indexes demonstrated marked heterogeneity among patients, and were significantly higher in non-responders (e.g., CRP (P < 0.001), ANC (P = 0.002), and PCM (P < 0.001)). Change in whole-body tumor burden after two cycles of PRRT was significantly associated with CRP (P = 0.0157) and NLR (P = 0.0040) in multivariate regression analysis. A cut-off of 2.5 mg/L for CRP (AUC = 0.84, P = 0.001) revealed a significant outcome difference between patients with adversely high vs. low CRP (median PFS 508 days vs. not yet reached (HR = 4.52; 95% CI, 1.27 to 16.18; P = 0.02)). Tumor-driven systemic inflammatory networks may be associated with treatment response, change in tumor burden, and prognosis in patients with GEPNETs receiving PRRT.

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Surgical Indication Optimization of Brain Metastases Based on the Evolutionary Analysis of Karnofsky Performance Status

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0040-1714410 ◽

2021 ◽

Author(s):

Jorge Rasmussen ◽

Pablo Ajler ◽

Daniela Massa ◽

Pedro Plou ◽

Matteo Baccanelli ◽

...

Keyword(s):

Brain Metastases ◽

Functional Status ◽

Surgical Resection ◽

Pharmacological Treatment ◽

Karnofsky Performance Status ◽

Performance Status ◽

Cohort Analysis ◽

Surgical Indication ◽

Evolutionary Analysis ◽

Survival Curves

Abstract Background and Objective Surgical resection of brain metastases (BM) offers the highest rates of local control and survival; however, it is reserved for patients with good functional status. In particular, the presence of BM tends to oversize the detriment of the overall functional status, causing neurologic deterioration, potentially reversible following symptomatic pharmacological treatment. Thus, a timely indication of surgical resection may be dismissed. We propose to identify and quantify these variations in the functional status of patients with symptomatic BM to optimize the indication of surgical resection. Patients and Methods Historic, retrospective cohort analysis of adult patients undergoing BM microsurgical resection, consecutively from January 2012 to May 2016, was conducted. The Karnofsky performance status (KPS) variation was recorded according to the symptomatic evolution of each patient at specific moments of the diagnostic–therapeutic algorithm. Finally, survival curves were delineated for the main identified factors. Results One hundred and nineteen resection surgeries were performed. The median overall survival was 243 days, while on average it was 305.7 (95% confidence interval [CI]: 250.6–360.9) days. The indication of surgical resection of 10% of the symptomatic patients in our series (7.5% of overall) could have been initially rejected due to pharmacologically reversible neurologic impairment. Survival curves showed statistically significant differences when KPS was stratified following pharmacological symptomatic treatment (p < 0.0001), unlike when they were estimated at the time of BM diagnosis (p = 0.1128). Conclusion The preoperative determination of the functional status by KPS as an evolutive parameter after the nononcologic symptomatic pharmacological treatment allowed us to optimize the surgical indication of patients with symptomatic BM.

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Cutaneous Metastasis of Prostate Adenocarcinoma: A Rare Presentation of a Common Disease

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/2324709621990769 ◽

2021 ◽

Vol 9 ◽

pp. 232470962199076

Author(s):

Alexander Dills ◽

Okechukwu Obi ◽

Kevin Bustos ◽

Jesse Jiang ◽

Shweta Gupta

Keyword(s):

Prostate Cancer ◽

Serine Proteases ◽

Cancer Genetics ◽

Performance Status ◽

Distant Metastases ◽

The United States ◽

Cutaneous Metastasis ◽

Common Disease ◽

Cutaneous Metastases ◽

Rare Presentation

Prostate cancer is the most common cancer affecting men in the United States and the second greatest cause of cancer-related death. Metastases usually occur to bone followed by distant lymph nodes and then viscera. Cutaneous metastases are extremely rare. Their presence indicates advanced disease and a poor prognosis. As they are highly variable in appearance and may mimic a more benign process, biopsy is essential for identification. Serine proteases, particularly human tissue kallikreins, may play an important role in promoting metastasis and facilitate infiltration of the skin. Individual cancer genetics may predispose to more aggressive cancer and thus earlier and more distant metastases. In this article, we report our case of a 67-year-old man with a 4-year history of castrate-resistant prostate cancer with cutaneous metastases confirmed by histology. Despite multiple lines of systemic therapy, the patient suffered progressive disease with worsening performance status and was enrolled in hospice.

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Assessment of γ-H2AX and 53BP1 Foci in Peripheral Blood Lymphocytes to Predict Subclinical Hematotoxicity and Response in Somatostatin Receptor-Targeted Radionuclide Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumors

Cancers ◽

10.3390/cancers13071516 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1516

Author(s):

Thorsten Derlin ◽

Natalia Bogdanova ◽

Fiona Ohlendorf ◽

Dhanya Ramachandran ◽

Rudolf A. Werner ◽

...

Keyword(s):

Treatment Response ◽

Neuroendocrine Tumors ◽

Peripheral Blood ◽

Somatostatin Receptor ◽

Therapy Response ◽

Strand Break ◽

Peripheral Blood Lymphocytes ◽

Radioligand Therapy ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Blood Lymphocytes

Background: We aimed to characterize γ-H2AX and 53BP1 foci formation in patients receiving somatostatin receptor-targeted radioligand therapy, and explored its role for predicting treatment-related hematotoxicity, and treatment response. Methods: A prospective analysis of double-strand break (DSB) markers was performed in 21 patients with advanced gastroenteropancreatic neuroendocrine tumors. γ-H2AX and 53BP1 foci formation were evaluated in peripheral blood lymphocytes (PBLs) at baseline, +1 h and +24 h after administration of 7.4 GBq (177Lu)Lu-DOTA-TATE. Hematotoxicity was evaluated using standard hematology. Therapy response was assessed using (68Ga)Ga-DOTA-TATE PET/CT before enrollment and after 2 cycles of PRRT according to the volumetric modification of RECIST 1.1. Results: DSB marker kinetics were heterogeneous among patients. Subclinical hematotoxicity was associated with γ-H2AX and 53BP1 foci formation (e.g., change in platelet count vs change in γ-H2AX+ cells between baseline and +1 h (r = −0.6080; p = 0.0045). Patients showing early development of new metastases had less γ-H2AX (p = 0.0125) and less 53BP1 foci per cell at +1 h (p = 0.0289), and demonstrated a distinct kinetic pattern with an absence of DSB marker decrease at +24 h (γ-H2AX: p = 0.0025; 53BP1: p = 0.0008). Conclusions: Assessment of γ-H2AX and 53BP1 foci formation in PBLs of patients receiving radioligand therapy may hold promise for predicting subclinical hematotoxicity and early treatment response.

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