scholarly journals WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

2016 ◽  
Vol 23 (11) ◽  
pp. T135-T154 ◽  
Author(s):  
Marianne E Pavel ◽  
Christine Sers
Keyword(s):  
Personalized Medicine ◽  
Neuroendocrine Tumors ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Objective Response ◽  
Peptide Receptor Radionuclide Therapy ◽  
Response Duration ◽  
Somatostatin Analogues ◽  
Molecular Alterations ◽  
Therapeutic Decision Making

Neuroendocrine tumors (NETs) are a group of heterogenous neoplasms. Evidence-based treatment options for antiproliferative therapy include somatostatin analogues, the mTOR inhibitor everolimus, the multiple tyrosine kinase inhibitor sunitinib and peptide receptor radionuclide therapy with 177-Lu-octreotate. In the absence of definite predictive markers, therapeutic decision making follows clinical and pathological criteria. As objective response rates with targeted drugs are rather low, and response duration is limited in most patients, numerous combination therapies targeting multiple pathways have been explored in the field. Upfront combination of drugs, however, is associated with increasing toxicity and has shown little benefit. Major advancements in the molecular understanding of NET based on genomic, epigenomic and transcriptomic analysis have been achieved with prognostic and therapeutic impact. New insight into molecular alterations has paved the way to biomarker-driven clinical trials and may facilitate treatment stratification toward personalized medicine in the near future. However, an improved understanding of the complexity of pathway interactions is required for successful treatment. A systems biology approach is one of the tools that may help to achieve this endeavor.

scholarly journals GEP–NETs UPDATE: Radionuclide therapy in neuroendocrine tumors

2015 ◽  
Vol 172 (1) ◽  
pp. R1-R8 ◽  
Author(s):  
Wouter A van der Zwan ◽  
Lisa Bodei ◽  
Jan Mueller-Brand ◽  
Wouter W de Herder ◽  
Larry K Kvols ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Targeted Therapies ◽  
Radionuclide Therapy ◽  
Randomized Clinical Trials ◽  
Treatment Options ◽  
Objective Response ◽  
Somatostatin Analogs ◽  
Peptide Receptor Radionuclide Therapy ◽  
Treatment Modalities ◽  
Gastroenteropancreatic Neuroendocrine Tumors

Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors (GEPNETs) patients. Most studies report objective response rates in 15–35% of patients. Also, outcome in terms of progression free survival (PFS) and overall survival compares very favorably with that for somatostatin analogs, chemotherapy, or new, ‘targeted’ therapies. They also compare favorably to PFS data for liver-directed therapies. Two decades after the introduction of PRRT, there is a growing need for randomized controlled trials comparing PRRT to ‘standard’ treatment, that is treatment with agents that have proven benefit when tested in randomized trials. Combining PRRT with liver-directed therapies or with targeted therapies could improve treatment results. The question to be answered, however, is whether a combination of therapies performed within a limited time-span from one another results in a better PFS than a strategy in which other therapies are reserved until after (renewed) tumor progression. Randomized clinical trials comparing PRRT with other treatment modalities should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs.

scholarly journals The state of PRRT and its sequencing amongst current therapeutic options for gastroenteropancreatic neuroendocrine tumors

2021 ◽  
Author(s):  
Lauren M Raymond ◽  
Tetiana Korzun ◽  
Adel Kardosh ◽  
Kenneth J. Kolbeck ◽  
Rodney Pommier ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Standard Dose ◽  
Peptide Receptor Radionuclide Therapy ◽  
Somatostatin Analogues ◽  
Tumor Burden ◽  
Treatment Modalities ◽  
Its Sequencing ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Reduce Tumor Burden ◽  
Spectrum Of Patients

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs, however, this may change with emerging data to suggest PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogues, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.

scholarly journals Targeting Angiogenesis in Pancreatic Neuroendocrine Tumors: Resistance Mechanisms

2019 ◽  
Vol 20 (19) ◽  
pp. 4949 ◽  
Author(s):  
Pozas ◽  
San Román ◽  
Alonso-Gordoa ◽  
Pozas ◽  
Caracuel ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Neuroendocrine Tumors ◽  
Peptide Receptor Radionuclide Therapy ◽  
Standard Of Care ◽  
Initial Response ◽  
Somatostatin Analogues ◽  
Resistance Mechanisms ◽  
Phase Iii ◽  
Pancreatic Neuroendocrine Tumors ◽  
Optimal Sequence

Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.

Neuroradiological and Neuropathological Changes After 177Lu-Octreotate Peptide Receptor Radionuclide Therapy of Refractory Esthesioneuroblastoma

2018 ◽  
Vol 15 (6) ◽  
pp. 100-109 ◽  
Author(s):  
Julia R Schneider ◽  
Deborah R Shatzkes ◽  
Stephen C Scharf ◽  
Tristan M Tham ◽  
Kay O Kulason ◽  
...  
Keyword(s):  
Radionuclide Therapy ◽  
Therapeutic Option ◽  
Somatostatin Receptor ◽  
Malignant Neoplasm ◽  
Peptide Receptor Radionuclide Therapy ◽  
Olfactory Neuroblastoma ◽  
Somatostatin Analogues ◽  
Symptomatic Improvement ◽  
Peptide Receptor ◽  
Molecular Alterations

Abstract BACKGROUND AND IMPORTANCE Olfactory neuroblastoma, also known as esthesioneuroblastoma (ENB), is a malignant neoplasm with an unpredictable behavior. Currently, the widely accepted treatment is inductive chemotherapy, with or without surgery, followed by radiotherapy. Since data on genetics and molecular alterations of ENB are lacking, there is no standard molecularly targeted therapy. However, ENB commonly expresses the somatostatin receptor (SSTR) that is also expressed by neuroendocrine tumors. Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogues, such as 177Lu-octreotate, is an effective treatment for the latter. We present the complex neuroradiological and neuropathological changes associated with 177Lu-octreotate treatment of a patient with a highly treatment-resistant ENB. CLINICAL PRESENTATION A 60-yr-old male presented with an ENB that recurred after chemotherapy, surgery, stereotactic radiosurgery, and immunotherapy. Pathology revealed a Hyams grade 3 ENB and the tumor had metastasized to lymph nodes. Tumor SSTR expression was seen on 68Ga-octreotate positron emission tomography (PET)/computed tomography (CT), suggesting that PRRT may be an option. He received 4 cycles of 177Lu-octreotate over 6 mo, with a partial response of all lesions and symptomatic improvement. Four months after the last PRRT cycle, 2 of the lesions rapidly relapsed and were successfully resected. Three months later, 68Ga-octreotate PET/CT and magnetic resonance imaging indicate no progression of the disease. CONCLUSION We describe imaging changes associated with 177Lu-octreotate PRRT of relapsing ENB. To our knowledge, this is the first report describing neuropathological changes associated with this treatment. PRRT is a promising therapeutic option to improve the disease control, and potentially, the survival of patients with refractory ENB.

FIDES-01, a phase II study of derazantinib in patients with unresectable intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions and mutations or amplifications (M/A).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS597-TPS597
Author(s):  
Milind M. Javle ◽  
Walid Labib Shaib ◽  
Stephan Braun ◽  
Marc Engelhardt ◽  
Mitesh J. Borad ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Current Status ◽  
Open Label ◽  
Open Label Phase ◽  
Duration Of Response ◽  
Symptom Response

TPS597 Background: Deregulation of the FGFR signaling pathway is implicated in various cancers. In iCCA, FGFR genetic aberrations include FGFR2 fusions and, less commonly, FGFR2 M/A. iCCA prognosis is poor, and chemotherapeutic and targeted treatment options are limited. While FGFR2 fusions are acknowledged oncogenic drivers, the oncogenic potential of FGFR2 M/A is less well defined. Derazantinib (DZB) is an investigational, oral small-molecule kinase inhibitor with activity against FGFR1, 2 and 3, which demonstrated antitumor activity in patients with unresectable iCCA with FGFR2 fusions. Based on preliminary efficacy data demonstrating durable responses of > 6 months and a clinically meaningful progression-free survival in a subset of iCCA patients harboring FGFR2 M/A (NCT01752920), the multicenter, multicohort open-label phase 2 study FIDES-01 is evaluating the effect of DZB in separate cohorts of iCCA patients with FGFR2 fusions or FGFR2 M/A. Methods: The new cohort evaluates 300 mg once daily dosing of DZB in patients with unresectable iCCA with FGFR2 M/A per liquid or tissue biopsy-based next generation sequencing and at least one previous systemic therapy. Treatment will continue until progressive disease, intolerance, withdrawal of informed consent, or death. Using a Simon’s two-stage design, the primary endpoint to assess the antitumor activity of DZB is the proportion of patients with PFS at 3 months (PFS3; per RECIST 1.1 central review). Secondary objectives are evaluation of median PFS, objective response rate, duration of response, safety profile, quality of life (incl., QLQ-C30, QLQ-BIL21, EQ-5D), and symptom response from baseline. Current status: The study was initiated in July 2019 with planned enrollment of 43 patients with confirmed FGFR2 M/A. Clinical trial information: NCT03230318.

scholarly journals Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5117
Author(s):  
Chandra K. Maharjan ◽  
Po Hien Ear ◽  
Catherine G. Tran ◽  
James R. Howe ◽  
Chandrikha Chandrasekharan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Neuroendocrine Tumors ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Somatostatin Receptor ◽  
Therapeutic Targets ◽  
Model Systems ◽  
Pancreatic Neuroendocrine Tumors ◽  
Acquired Drug Resistance ◽  
Molecular Alterations

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

scholarly journals Achieving objective response in treatment of non-resectable neuroendocrine tumors does not predict longer time to progression compared to achieving stable disease

2020 ◽  
Author(s):  
Espen Thiis-Evensen ◽  
Amalie Christine Poole ◽  
Hong-Thien Thi Nguyen ◽  
Jon Sponheim
Keyword(s):  
Neuroendocrine Tumors ◽  
Stable Disease ◽  
Radionuclide Therapy ◽  
Objective Response ◽  
Peptide Receptor Radionuclide Therapy ◽  
Treatment Modalities ◽  
Time To Progression ◽  
Who Grade ◽  
Peptide Receptor ◽  
Tumor Load

Abstract Background: There are several treatment modalities for unresectable neuroendocrine tumors. Traditionally, the aim of these treatments has been to reduce the tumor load; referred to as objective response (OR). Less emphasis has been put on inducing the tumors to stop growing without a reduction in total tumor load; termed as stable disease (SD). We wanted to investigate whether achieving OR compared to obtaining SD predicted a longer time to progression (TTP) in patients with neuroendocrine tumors (WHO Grade 1 and 2) treated with peptide receptor radionuclide therapy, chemotherapy or molecular targeted therapy. Methods : Patients treated with either peptide receptor radionuclide therapy (PRRT) with 177 Lutetium-DOTA-octreotate, the chemotherapy combination streptozotocin/5-fluorouracil or everolimus were retrospectively assessed to evaluate the effect of the treatments on disease progression. We analyzed the TTP for patients for each treatment modality and compared the TTP between those who achieved OR and those who achieved SD. Results: Altogether 56 patients treated with PRRT, 32 treated with streptozotocin/5-fluorouracil and 52 treated with everolimus were included in the analyses. The median TTP for those treated with PRRT and achieving OR was 31 months, the TTP for those achieving SD was 43 months (p=0,2). For patients treated with streptozotocin/5-fluorouracil the results were: OR: 18 months, SD: 23 months (p=0,9) and for those treated with everolimus; OR: 9 months, SD: 20 months (p=0,5), respectively. We found no differences between patients achieving OR compared to SD regarding age, sex, stage, primary tumor location, Ki-67% or ongoing treatment with somatostatinanalogues. Conclusions: We found no treatment benefit with regard to TTP for our patients that experienced OR compared to those who achieved SD, but a trend toward longer TTP among patients with SD.

Brigatinib in Japanese patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC): First results from the J-ALTA tyrosine kinase inhibitor (TKI)-naive expansion cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9042-9042
Author(s):  
Masashi Kondo ◽  
Shunichi Sugawara ◽  
Toshihide Yokoyama ◽  
Toru Kumagai ◽  
Makoto Nishio ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Primary Analysis ◽  
Total Study Population ◽  
Anaplastic Lymphoma ◽  
Alk Positive ◽  
Expansion Cohort

9042 Background: Brigatinib is a next-generation ALK inhibitor with demonstrated activity against ALK mutations. We report primary analysis results with brigatinib in Japanese patients with ALK-positive NSCLC who have not previously been treated with an ALK TKI in the phase 2 J-ALTA study (NCT03410108). Methods: J-ALTA, a multi-cohort study, included a TKI-naive expansion cohort. Patients in the TKI-naive cohort received brigatinib 180 mg qd with 7-day lead-in at 90 mg. Primary endpoint was 12-month progression-free survival (PFS) as assessed by an independent-review committee (IRC). Secondary endpoints included confirmed objective response rate (ORR; IRC- and investigator-assessed); IRC-assessed PFS and duration of response (DoR); overall survival (OS); intracranial PFS (iPFS by IRC); and safety. Results: A total of 104 patients were enrolled in the whole study; of these, 32 patients had TKI-naive NSCLC (median age, 60.5 y; 94% had adenocarcinoma; 22% had baseline brain metastases; 25% received prior chemotherapy). As of September 29, 2020, median follow-up was 14.2 months and 27 patients remained on treatment. IRC-assessed 12-month PFS was 93% (90% CI, 79–98). Confirmed ORR was 97% (90% CI, 84–100) by IRC, with 2 complete responses and 29 partial responses. Median DoR as assessed by the IRC was not mature; median PFS, iPFS, and OS were not reached. In the TKI-naive cohort, treatment-emergent adverse events (TEAEs) were reported in all 32 patients (most common: increased creatine phosphokinase, 81%; hypertension, 59%; diarrhea, 47%). Grade ≥3 TEAEs were reported in 91% of patients in this cohort (most common: increased creatinine phosphokinase, 44%; hypertension, 34%; increased lipase, 19%) and 75% of all patients. Three cases (9.4%) of interstitial lung disease/pneumonitis were reported in the TKI-naive cohort; all were grade 1 and occurred after day 15 of brigatinib treatment. Dose discontinuations/interruptions/reductions due to AEs in the TKI-naive cohort were 0%/94%/66%, respectively, and in the total study population were 5%/72%/41%. AE frequency and profile were similar in the TKI-naive and overall cohorts. Conclusions: In the J-ALTA TKI-naive cohort, brigatinib demonstrated substantial efficacy and manageable safety in the Japanese patient population. Brigatinib remains one of the treatment options in Japanese patients. Clinical trial information: NCT03410108.

Single institution experience with peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 623-623
Author(s):  
Heying Duan ◽  
Gaia Ninatti ◽  
Bradley Girod ◽  
Valentina Ferri ◽  
Pamela L. Kunz ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Radionuclide Therapy ◽  
Objective Response ◽  
Peptide Receptor Radionuclide Therapy ◽  
Progression Free Survival ◽  
Unknown Primary ◽  
Single Institution ◽  
Free Survival ◽  
Peptide Receptor ◽  
Low Toxicity

623 Background: Neuroendocrine tumors (NETs) are rare but increasing in incidence. The only curative treatment is surgery, which in many cases is not an option due to metastatic disease at diagnosis. The NETTER-1 study showed high efficacy and low toxicity of peptide receptor radionuclide therapy (PRRT) for midgut NETs. Here, we present our initial experience with PRRT in the treatment of patients with NET. Methods: Fifty-two patients (27 males and 25 females; 37 - 81 yo, mean ± SD: 61.8 ± 10.6 years) with documented progressive NET (25 pancreas, 17 small intestine, 1 coecum, 4 unknown primary, 3 paragangliomas, and 2 pheochromocytomas) were referred to undergo PRRT at our institution from July 2018 to September 2019. Laboratory tests were obtained at baseline, 1 week before each cycle and every 3 months following treatment. Progression-free survival (PFS), objective response rate (ORR) and toxicity were assessed. An interim overall survival (OS) analysis was performed. Results, when possible, were compared with the NETTER-1 trial. Lines of therapy were documented. Results: 22/52 (42%) patients completed all 4 cycles of PRRT. 18/52 (34%) patients are currently being treated. 12/52 (23%) patients had to discontinue treatment. Hematotoxicity was the only side effect which can be related to PRRT. The 6-month and 9-month PFS rate was 82.4% and 66.8% respectively vs. 89% and 84% in the NETTER-1 trial. The ORR was 36% vs. 18% in the NETTER-1 trial. In the interim OS analysis, 6 deaths occurred. In contrast to the NETTER-1 study, PRRT in our patient cohort was performed later in the course of treatment (median lines of therapy before PRRT = 4 ±1.3 (range 1-6)). Conclusions: Our preliminary data show overall good results of PRRT in patients with NETs. However, compared to the NETTER-1 trial, PFS is shorter which is most likely due to the extensive pretreatment, but ORR was higher. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document