Advanced Gastroenteropancreatic Research Articles

Tyrosine kinase inhibitors in patients with neuroendocrine neoplasms: a systematic literature review.

Several tyrosine kinase receptors inhibitors (TKIs) have demonstrated antiproliferative effects in well-differentiated neuroendocrine tumors (NETs). We aimed to summarize and appraise the current evidence of the efficacy of TKIs in patients with different types of NETs. We performed a systematic review of clinical trials of TKIs in patients with advanced gastroenteropancreatic or lung NETs (PROSPERO registration number: CRD42024507379). Population characteristics, efficacy, and safety results were summarized by type of NET. Twenty-eight studies were eligible, totaling 2284 patients. While sunitinib remains the only Food and Drug Administration-approved TKI in patients with NETs (for patients with pancreatic well-differentiated NETs), recent placebo-controlled randomized trials have demonstrated improved response rates and progression-free survival for patients with progressive and pre-treated well-differentiated pancreatic (cabozantinib or surufatinib) or gastrointestinal (GI) NETs (pazopanib, cabozantinib, or surufatinib). There is limited evidence to support the use of a TKI in patients with lung or grade 3 NETs. The toxicity associated with TKIs follows a class effect, with a significant proportion of patients experiencing fatigue, hypertension, and hand-foot skin reactions. TKIs are effective therapies in patients with pancreatic or GI well-differentiated NETs and should be part of the therapeutical sequencing of these patients.

Nutritional status of patients with advanced gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENS) in Spain: Nutrigetne study

Nutritional status of patients with advanced gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENS) in Spain: Nutrigetne study

92: [177Lu]Lu-Dota-Tate as First-Line Therapy for Patients with Grade 2 and 3 Advanced Gastroenteropancreatic Neuroendocrine Tumours (GEP-NETS): The NETTER-2 Study

92: [177Lu]Lu-Dota-Tate as First-Line Therapy for Patients with Grade 2 and 3 Advanced Gastroenteropancreatic Neuroendocrine Tumours (GEP-NETS): The NETTER-2 Study

Platinum-doublet chemotherapy for advanced gastroenteropancreatic neuroendocrine carcinoma: a systematic review and meta-analysis

BackgroundPlatinum-doublet chemotherapy has been conventionally used for patients with advanced gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) but evidence of chemotherapy is based on studies with small sample sizes and remains scarce. Thus, we conducted a systematic review and meta-analysis to elucidate the efficacy of platinum-doublet chemotherapy for advanced GEP-NEC.MethodsWe performed a database search in PubMed/MEDLINE and EMBASE. Eligible studies were prospective and retrospective studies documenting the efficacy of platinum plus etoposide (EP) and platinum plus irinotecan (IP) for advanced GEP-NEC. Overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were pooled and weighted using generic inverse variance in a random-effects meta-analysis model.ResultsNineteen studies including 1157 patients were identified. The ORR of the platinum-doublet regimen, EP, and IP was 49.1% (95% confidence interval [CI], 41.8–56.5), 44.4% (95% CI: 35.9–53.0), and 59.4% (95% CI: 48.0–70.8). The pooled median OS of the platinum-doublet regimen, EP, and IP was 12.9 months (95% CI:10.9–15.3), 12.9 months (95% CI: 10.8–15.4), and 12.9 months (95% CI: 6.0–27.8), and the pooled median PFS of the platinum-doublet regimen, EP, and IP was 5.4 months (95% CI: 4.5–6.4), 5.4 months (95% CI 4.5–6.5), and 4.0 months (95% CI: 1.4–11.7), respectively.ConclusionConsiderable response rate and survival time of the platinum-doublet regimen for advanced GEP-NEC were observed. IP and EP regimens can be reasonably applicable and these results provide a reference for oncologists in deciding the suitable regimen for patients with advanced GEP-NEC.

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.

Simple SummaryAssessment of the radiation-induced alterations in peripheral blood lymphocytes is a validated strategy for biological dosimetry and assessment of individual radiosensitivity. However, its clinical significance as a liquid biopsy for predicting hematotoxicity and treatment response when targeting tumor cells with ionizing radiation from a systemically administered radioligand is unexplored. The results from this study revealed that the analysis of radiation-induced foci in peripheral blood lymphocytes may hold potential for predicting both individual subclinical hematotoxicity and tumor response to somatostatin-receptor targeted radioligand therapy in patients with advanced gastroenteropancreatic neuroendocrine tumors. These preliminary data provide the rationale for further studies evaluating analyses-guided treatment intensification in patients at high risk of early progression.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.

Long-Term Survival and Value of 18F-FDG PET/CT in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with Second Peptide Receptor Radionuclide Therapy Course with 177Lu-DOTATATE.

Peptide receptor radionuclide therapy (PRRT) has been recognized as a promising therapy against neuroendocrine tumors (NETs). The use of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in NETs has been a matter of controversy. The purpose of this study was to evaluate the long-term survival and efficacy of a second PRRT course with 177Lu-DOTATE in patients with advanced gastroenteropancreatic (GEP) NETs. Furthermore, the value of 18F-FDG PET/CT in these patients was evaluated. 40 patients with GEP NETs who underwent two PRRT courses with 177Lu-DOTATATE and combined examinations with 68Ga-DOTA-TOC and 18F-FDG PET/CT were evaluated. After the second PRRT course, two patients (5.0%) were in partial remission, 21 patients (52.5%) in stable disease and 17 patients (42.5%) had progressive disease. The median overall survival was 122.10 months. After the second PRRT course, the median overall survival was significantly higher (p = 0.033) in the 18F-FDG-negative group compared to the 18F-FDG-positive group (145.50 versus 95.06 months, respectively). The median time to progression was 19.37 months. In conclusion, a second PRRT course with 177Lu-DOTATE is an effective treatment approach for GEP NET patients with disease progression. A change in 18F-FDG status after PRRT may predict the disease course and survival. Patients who are 18F-FDG-negative have a significantly longer overall survival than those who are 18F-FDG-positive.

Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors in Korea: Literature Review and Expert Opinion.

Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed.

Metformin and everolimus in neuroendocrine tumours: A synergic effect?

To explore potential synergy in effectiveness between metformin and everolimus, 2 inhibitors of the mTOR pathway, for neuroendocrine tumours (NET). A cohort of patients with advanced gastroenteropancreatic or lung NETs treated by everolimus were stratified in to those without diabetes, those with diabetes and without metformin, and those with diabetes with metformin. The primary endpoint was the median progression-free survival (PFS). A total of 213 patients were included, 165 of which were non-diabetic; among diabetic patients, 19 were treated with metformin and 29 with others anti-diabetic drugs. No significant difference in median PFS [95%CI] was found between the three groups: 10.05 months [8.27;11.83] for non-diabetic patients, 15.24 [19.88;49.43] for diabetic w/metformin, and 9.03 months [4.01;14.06] for diabetic w/o metformin group. In univariate analysis, factors significantly associated with longer PFS was a functioning NET, a number of metastatic sites<3, the absence of lung metastasis, and an uptake on Octreoscan®, but not the absence of metformin use; only uptake on Octreoscan® remained significant in multivariate analysis. In contrast with the literature, we did not find a synergy between everolimus and metformin in NET. Prospective studies are underway to improve the comprehension of the potential synergy regarding population and tumour type.

Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/folinic acid (FA) in refractory advanced high-grade neuroendocrine cancer (HG-NEC) of gastroenteropancreatic (GEP) or unknown origin.

TPS636 Background: The incidence of GEP HG-NEC is increasing and the prognosis is poor. Etoposide–platinum (EP) combination is considered the standard (std) therapy (Rx), but survival is less than 1 year. There is an unmet need for an optimal 2nd line Rx in these patients (pts). Nal-IRI has shown efficacy in small cell lung cancer (pathologically similar to HG-NEC) and in 2nd line pancreatic adenocarcinoma. In a retrospective study, HG-NEC pts with progression on 1st line EP when treated with 2nd line FOLFIRI (FA+5-FU+ IRI) had a good response and a tolerable safety profile (Hentic et al, 2012). Based on this data and the fact that no std 2nd line Rx option exists in HG-NEC, we are evaluating the efficacy of nal-IRI+ 5-FU/FA in a prospective single-arm multicenter study. Methods: Advanced GEP or unknown origin HG-NEC pts with progressive disease/intolerance to 1st line Rx with EP or temozolomide/capecitabine; ECOG PS 0-2 would receive nal-IRI 70 mg/m2, FA 400 mg/m2 followed by 5-FU 2400 mg/m2 on D1 &amp; 15 of 28-days cycle. Rx to continue till disease progression or unacceptable toxicity. Tumor assessment by CT/MRI per RECIST 1.1 q6 wks. Primary end point is to measure ORR (CR+PR). Secondary endpoints include PFS, TTP, OS, safety and QOL changes. Assuming a historic ORR of 15% with std Rx, 37 pts (upto 41 pts considering non-evaluable pts) are required to show an ORR of 30% at a power of 80% at 1-sided significance of α = 0.1. In stage 1, n1= 18 pts will be enrolled. If 3 or more responses are seen, an additional n2= 19 pts to be enrolled. If 8 or more responses are observed of the n = 37 evaluable pts, the Rx would be considered promising for further study. Genomic mutational profiling to be conducted on pre-study tumor samples and correlated with circulating tumor DNA (CT DNA). CT DNA level, assessed serially, will be correlated with Rx response and disease recurrence. We plan to accrue over 3 years at 3 sites. As of August 2019, 1-patient has been enrolled. The trial is funded by Ipsen Pharmaceuticals and the North American Neuroendocrine Tumor Society through the Clinical Investigator Scholarship. Clinical trial information: NCT03736720.

1387P - Differences in multikinase inhibitors (MKI) toxicity profile according to gender. A pooled analysis of three phase II trials with lenvatinib, pazopanib and sorafenib in patients (pts) with advanced gastroenteropancreatic (GEP) neuroendocrine tumours (NETs)

BackgroundThere is a dearth of understanding of gender influence in targeted therapies toxicity. Increasing evidence suggests a possible different toxicity profile according to gender, but mostly retrospective studies in common tumors. Currently, data from prospective studies are minimal. In the present study, we will review MKI toxicity profiles according to gender in pts with NETs in three clinical trials. MethodsMulticenter open-label phase II studies TALENT, PAZONET and GETNE0801 included pts with advanced GEP NETs treated with lenvatinib, pazopanib, and sorafenib-bevacizumab respectively. All studies were performed by the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). All pts were included in the review, considering all toxicity grades with an incidence higher than 5% for the univariate analysis. Bevacizumab specific toxicities were excluded in patients from GETNE0801 trial. Additionally, all grade 3-4 toxicities were analyzed separately. Results199 pts (46.23% female) with 1349 adverse events (AEs) (12.23% G3-4) divided into 125 categories were included. In female patients, nausea/vomiting, skin disorders (excluding palmar-plantar erythrodysesthesia), liver alterations (including transaminase and bilirubin), headache, pyrexia, hair disorders and dizziness were significantly more common (Table). The only toxicity with a higher incidence in men was dysphonia (OR 0.42, 95% CI 0.2-0.9, p0.02). The only G3-4 toxicity significantly more frequent in women was liver toxicity (20.65% vs. 7.55%, OR 3.18, p0.009).Table: 1387PTable: 1387PToxicity (all grades)Women (%)Men (%)Difference (%)Odds Ratio (95% CI)pNausea/Vomiting63.0444.86182.090.01Skin disorders60.8745.79151.840.03Liver toxicity57.6130.84263.040.0002Headache28.2612.15162.840.005Pyrexia17.395.61113.440.01Hair disorders20.658.41122.830.01Dizziness17.396.54103.000.02Dysphonia16.3037.38210.320.001 ConclusionsIn our study, we observed significant differences in toxicity AEs by gender, especially in women with seven increased toxicities. A different approach in toxicity management should be adopted based on gender in pts with GEP NETs treated with MKI. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureJ. Hernando Cubero: Speaker Bureau / Expert testimony: Eisai, Ipsen, Roche, Angelini, ; Travel / Accommodation / Expenses: Ipsen, Novartis, AAA, Roche, AstraZeneca, Eisai. E. Grande: Speaker Bureau / Expert testimony: Pfizer, Ipsen, BMS, Eisai, Roche, MSD, Sanofi, Adacap, Novartis, EUSA Pharma, Pierre Fabre, Lexicon, Celgene; Research grant / Funding (institution): MSD, Roche. T. Ibrahim: Advisory / Consultancy: Eisai; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Ipsen, PharmaMar, Novartis. J.W. Valle: Advisory / Consultancy: Abbott, Agios, AstraZeneca, Baxalta, Bioven, Celgene, Delcath, Genoscience Pharma, Incyte, Ipsen, Keocyt, Lilly, Merck, MidaTech, Mundipharma, Novartis, NuCana, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED Pharmaceuticals; Speaker Bureau / Expert testimony: Abbott, Celgene, Ipsen, Novartis, Pfizer, Sirtex; Travel / Accommodation / Expenses: Celgene, Ipsen, Novartis, NuCana. V. Alonso: Advisory / Consultancy: Amgen, Roche, Merck, Servier, Sanofi, Ipsen, Bayer, Novartis. R. Manneh Kopp: Speaker Bureau / Expert testimony: Pfizer, Ipsen, BMS, Roche, MSD, Sanofi, Novartis; Research grant / Funding (institution): MSD, Roche, BMS. R. Salazar: Advisory / Consultancy: VCN-BCN, Agendia, Guardant Health, Roche Diagnostics, Ferrer, Pfizer, Novartis, Ipsen, Amgen, Merck, Roche Farma, Lylli, MSD; Speaker Bureau / Expert testimony: Pfizer, Amgen, Novartis, Merck, MSD, AZD, Celgene,. J. Capdevila: Honoraria (self): Novartis, Pfier, Ipsen, Exelixis, Bayer, Eisai, AAA, Amgen, Sanofi, Merck; Research grant / Funding (institution): Eisai, Novartis, Ipsen, AstraZeneca, Pfier, AAA. All other authors have declared no conflicts of interest.

Neuroendocrine Tumor Therapy with Lutetium-177: A Literature Review.

The worldwide incidence of neuroendocrine tumors (NETs) has been increasing. They are a very diverse group of tumors which are commonly found in the gastrointestinal and bronchopulmonary tracts. These tumors usually express somatostatin receptors. Therefore, somatostatin analogs are used for symptom relief as well as treatment. Of the many therapeutic options available, peptide receptor radionuclide therapy (PRRT) has been shown to be very promising. In January 2018, the Food Drug and Authority (FDA) approved 177Lu-Dotatate for use in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Lutetium is a lower energy beta-emitting radionuclide. The therapeutic use of lutetium-177 (177Lu) has shown better results in advanced gastroenteropancreatic and bronchial neuroendocrine tumors when compared with other therapies available. Adverse effects associated with this therapy include myelotoxicity and nephrotoxicity as the radiopeptides are reabsorbed and accumulate in the renal interstitium. Everolimus is a good and safe option in patients pretreated with 177Lu-Dotatate. Lutetium, in combination with somatostatin analogs, has proven efficacy to treat gastroenteropancreatic neuroendocrine tumors in candidates with somatostatin receptor-positive advanced tumors and normal renal function. This therapy has great potential as it decreases tumor size, improves symptoms, and improves quality of life.

Improved survival with higher doses of octreotide long-acting release in gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) represent a heterogeneous group of tumors that is associated with an indolent course. Octreotide has a positive effect on disease stabilization in well-differentiated midgut NETs, but a meaningful survival analysis was not possible due to insufficient events. Higher doses of octreotide long-acting release (LAR) are often used in clinical practice for control of carcinoid symptoms and our objective was to determine if dose of octreotide correlates with survival. We reviewed all patients with advanced GEP NETs who initiated treatment with octreotide LAR between 2000 and 2013 in a large, representative Canadian province. We compared overall survival in patients who received low (< 30mg) compared to high (≥ 30mg) doses of octreotide. A total of 170 patients were identified. Baseline characteristics in the low- and high-dose groups were similar: median age 62/63years, 50/58% were male, 46/48% originated from the small bowel, and 74/66% had liver metastases at diagnosis. The median time from diagnosis to treatment initiation was 5.5 and 6.0months. Octreotide LAR was initiated with the intent of symptom management (71%), disease stabilization (23%), or biomarker control (6%). Median overall survival (OS) was better in the high-dose group, 66months compared to 22months (multivariate HR 0.5, p < 0.01). Age ≥ 65 (HR 1.9, p < 0.01), ECOG ≥ 2 (HR 2.7, p < 0.01), and pancreatic NETs (HR 1.7, p = 0.03) were all predictors of worse survival. Our findings suggest that octreotide may confer survival benefits in GEP NETs. Further prospective studies are warranted to validate the impact of high-dose octreotide on outcomes.

Biology and Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors.

In recent years, there have been important scientific advances in the biologic characterization of neuroendocrine neoplasms and in their treatment. This review will describe these scientific advances, the evolving systemic treatment approaches, and important topics to be addressed in future research.

1030 - Predictors of Antiproliferative Effect of Lanreotide Autogel as First-Line Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumours (GEP Net)

1030 - Predictors of Antiproliferative Effect of Lanreotide Autogel as First-Line Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumours (GEP Net)

Circulating Chromogranin A as A Marker for Monitoring Clinical Response in Advanced Gastroenteropancreatic Neuroendocrine Tumors.

Chromogranin A (CgA), present in the chromaffin granules of neuroendocrine cells, is a useful biomarker for the diagnosis of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This study was conducted to investigate the potential role of circulating CgA in monitoring clinical response in Chinese patients with advanced GEP-NETs. Eighty patients with advanced GEP-NETs treated in Peking University Cancer Hospital from September 2011 to May 2014 and 65 healthy individuals were included in this study. Serum CgA levels were analyzed for relationship with patient’s baseline characteristics and clinical outcome. Median CgA levels were significantly higher in patients with advanced GEP-NETs than in healthy individuals (93.8 ng/mL vs. 37.1 ng/mL; P<0.01), as well as significantly higher in patients with carcinoid syndrome or liver metastasis than in those without carcinoid syndrome (298.8 ng/mL vs. 82.9 ng/mL; P = 0.011) or liver metastasis (137.0 ng/mL vs. 64.4 ng/mL; P = 0.023). A CgA cutoff value of 46.2 ng/mL was used in this study with a sensitivity of 78.8% and specificity of 73.8%. Patients with CgA levels higher than 46.2 ng/mL had a worse prognosis than patients with CgA levels lower than 46.2 ng/mL (P = 0.045). Notably, a weak correlation was observed between changes in serum CgA levels and clinical response to the IP regimen as well as SSAs. Our data also indicate that serum CgA could be a useful indicator of patient prognosis though there is more research required in order to validate such claims.

Symptomatic presentation as a predictor of recurrence in gastroenteropancreatic neuroendocrine tumors: A single institution experience over 15 years.

228 Background: The prognostic implications on outcomes of symptomatic presentation of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) remains unclear. Methods: Patients who underwent curative-intent resection of nonfunctional, well-differentiated GEP NETs from 2000-2014 at a single institution were analyzed. Patients were classified as symptomatic if clinical symptoms were present at diagnosis. Primary end points were distant recurrence-free survival (DRFS) and overall survival (OS). Results: A total of 339pts were identified, of which 208pts (61%) were symptomatic at presentation. Symptomatic presentation was associated with younger age at presentation (55vs59yrs, p = 0.001), higher tumor grade (38vs21%, p = 0.027), LVI (58vs33%, p &lt; 0.001), PNI (53vs30%, p = 0.002), and advanced disease (T3/T4/N1/M1 63vs44%, p = 0.002), but not tumor size (2.6vs2.5cm, p = 0.74). Symptomatic presentation was associated with decreased DRFS but not OS. When accounting for race, tumor size, positive resection margins, presence of metastatic disease, and positive lymph nodes on multivariate analysis (MVA), symptomatic presentation remained independently associated with reduced DRFS (HR 3.51, p = 0.007). On subgroup analysis of patients only with advanced disease (T3/T4/N1/M1), symptomatic presentation was still associated with decreased 3-yr DRFS (67vs79%, p = 0.012), but not OS. On MVA, symptomatic presentation persisted as an independent factor associated with decreased DRFS in patients with advanced disease (HR 2.89, p = 0.014). Conclusions: Symptomatic presentation of GEP NETs is associated with more aggressive pathologic features and worse DRFS than incidentally diagnosed NETs irrespective of tumor size. As our armamentarium of therapeutic agents for NETs expands and improves, trials assessing the value of adjuvant therapy for advanced GEP NETs are needed, and symptomatic presentation may be considered as one inclusion criterion. Following resection, symptomatic presentation should be taken into account when planning follow-up strategies, as these patients may require closer surveillance than their incidentally diagnosed counterparts.

Survival and Response After Peptide Receptor Radionuclide Therapy With [ 90Y-DOTA 0,Tyr 3]Octreotide in Patients With Advanced Gastroenteropancreatic Neuroendocrine Tumors

Because the role of chemotherapy, interferon, or somatostatin analogs as antiproliferative agents is uncertain, currently few treatment options exist for patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NET). Fifty-eight patients with somatostatin receptor-positive GEP-NET were treated in a phase I dose-escalating study with cumulative doses of 47 mCi to 886 mCi of the radiolabeled somatostatin analog [(90)Y-DOTA(0),Tyr(3)]-octreotide. At baseline, 47 patients had progressive disease, and 36 were symptomatic. The extent of disease was: 4 patients without liver metastases and 52 patients with liver metastases, including 16 patients with very advanced disease, qualified as "end-stage," and 2 end-stage patients without liver metastases. The objective responses were 5 partial response (PR), 7 minor response (MR), 29 stable disease (SD), and 17 PD. Overall, 33 patients (57%) experienced some improvement in their disease status, including conversion from PD into SD and improvement from SD into MR. Accordingly, 21 of 36 patients (58%) had improvement in Karnofsky performance score or symptoms. The median overall survival (OS) was 36.7 months (95% confidence interval [CI] 19.4-54.1 months). The median progression-free survival in 41 patients who had at least stable disease at the end of the treatment period was 29.3 months (95% CI 19.3-39.3 months). Patients who had SD at baseline had a significantly better OS than patients who had PD at baseline. The extent of disease at baseline also was a significant predictive factor for OS. The OS after therapy with [(90)Y-DOTA(0),Tyr(3)]-octreotide was significantly better than in a historic control group of 32 comparable patients with GEP-NET who had been treated with another radiolabeled somatostatin analog, [(111)In-DTPA(0)]-octreotide (median OS 12.0 months, 95% CI 6.2-17.8 months). The difference in OS for both therapies remained highly significant in a multivariate Cox proportional hazard model including progression status and extent of disease at baseline as covariates. Although the objective response after therapy with [(90)Y-DOTA(0),Tyr(3)]-octreotide by standard criteria seems modest, the significantly longer OS compared with historic controls is most encouraging.