Recent progress in the understanding, diagnosis, and treatment of gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare tumors that arise from the diffuse neuroendocrine system. This heterogeneous group of tumors was often considered a single entity. This belied their biological diversity, and the biggest advance in understanding these tumors over the past decades has been in understanding this diversity. Diagnosis of these tumors has been aided by advances in pathological diagnosis and classification and tumor imaging with endoscopic ultrasound and somatostatin receptor fusion imaging. Genetic and molecular advances have identified molecular targets in the treatment of these tumors. Surgery remains the mainstay of treatment, amply supported by interventional radiological techniques, including embolization. Treatment of metastatic disease has improved significantly with the addition of several new agents, including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and yttrium-90-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and lutetium-177-DOTA octreotate. Despite significant advances in the understanding and management of GEP-NETs, the survival of patients remains largely unchanged and there remains a need for the development of national and international research collaborations to spearhead future efforts.

Multimodality Management of "Borderline Resectable" Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) constitute approximately 3% of pancreatic neoplasms. Like patients with pancreatic ductal adenocarcinoma (PDAC), some of these patients present with "borderline resectable disease." For these patients, an optimal treatment approach is lacking. We report our institution's experience with borderline resectable PanNETs using multimodality treatment. METHODS: We identified patients with borderline resectable PanNETs who had received neoadjuvant therapy at our institution between 2000 and 2013. The definition of borderline resectability was based on National Comprehensive Cancer Network criteria for PDAC. Neoadjuvant regimen, radiographic response, pathologic response, surgical margins, nodal retrieval, number of positive nodes, and recurrence were documented. Statistics were descriptive. RESULTS: Of 112 patients who underwent surgical resection for PanNETs during the study period, 23 received neoadjuvant therapy, 6 of whom met all inclusion criteria and had borderline resectable disease. These 6 patients received at least 1 cycle of temozolomide and capecitabine, with 3 also receiving radiation. All had radiographic evidence of treatment response. Four (67%) had negative-margin resections. Four patients had histologic evidence of a moderate response. Follow-up (3.0-4.3 years) indicated that all patients were alive, with 5/6 free of disease (1 patient with metastatic disease still on treatment without progression). CONCLUSIONS: A multimodality treatment strategy (neoadjuvant temozolomide and capecitabine ± radiation) can be successfully applied to patients with PanNETs who meet NCCN borderline resectable criteria for PDAC. To our knowledge, this is the first report of the use of a multimodality protocol in the treatment of patients with borderline resectable PanNETs.

Impact of Previous Somatostatin Analogue Use on the Activity of Everolimus in Patients with Advanced Neuroendocrine Tumors: Analysis from the Phase III RADIANT-2 Trial.

BACKGROUND/AIMS: The phase III placebo-controlled RADIANT-2 trial investigated the efficacy of everolimus plus octreotide long-acting repeatable (LAR) in patients with advanced neuroendocrine tumors (NET) associated with carcinoid syndrome. Here we report a secondary analysis based on the previous somatostatin analogue (SSA) exposure status of patients enrolled in RADIANT-2. METHODS: Patients were randomly assigned to receive oral everolimus 10 mg/day plus octreotide LAR 30 mg intramuscularly (i.m.) or to receive matching placebo plus octreotide LAR 30 mg i.m. every 28 days. SSA treatment before study enrollment was permitted. Patient characteristics and progression-free survival (PFS) were analyzed by treatment arm and previous SSA exposure status. RESULTS: Of the 429 patients enrolled in RADIANT-2, 339 were previously exposed to SSA (95% received octreotide); 173 of 339 patients were in the everolimus plus octreotide LAR arm. All patients had a protocol-specified history of secretory symptoms, but analysis by type showed that more patients who previously received SSA therapy had a history of flushing symptoms (77%), diarrhea (86%), or both (63%) compared with SSA-naive patients (62, 62, and 24%, respectively). Patients who received everolimus plus octreotide LAR had longer median PFS regardless of previous SSA exposure (with: PFS 14.3 months, 95% confidence interval, CI, 12.0-20.1; without: 25.2 months, 95% CI, 12.0-not reached) compared with patients who received placebo plus octreotide LAR (with: 11.1 months, 95% CI, 8.4-14.6; without: 13.6 months, 95% CI, 8.2-22.7). CONCLUSION: Everolimus in combination with octreotide improves PFS in patients with advanced NET associated with carcinoid syndrome, regardless of previous SSA exposure.

Treatment of metastatic neuroendocrine tumors of the thymus with capecitabine and temozolomide: a case series.

BACKGROUND: Metastatic neuroendocrine tumors of the thymus are exceedingly rare with an annual incidence of approximately 0.2 per 1,000,000. They are highly resistant to therapy and there have been no reports of an objective radiographic response to treatment. MATERIALS AND METHODS: The authors retrospectively evaluated 3 patients with progressive, metastatic neuroendocrine tumors of the thymus who were treated with a combination of capecitabine and temozolomide. Radiographic scans were evaluated and response assessed using RECIST criteria. RESULTS: One patient experienced a partial radiographic response, another patient experienced a minor response and the third patient experienced stable disease as the best response to treatment. CONCLUSION: The combination of capecitabine and temozolomide appears to be active in a rare neuroendocrine malignancy that is generally refractory to systemic therapy. Prospective multicenter trials are needed to validate this strategy.

Relapse-free survival in patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors: an analysis of the AJCC and ENETS staging classifications.

BACKGROUND: The risk of metastatic spread among patients with early-stage pancreatic neuroendocrine tumors has not been well established. The authors sought to evaluate whether the new TNM staging systems proposed by the American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumor Society (ENETS) are prognostic for relapse-free survival (RFS) after surgical resection. METHODS: Patients with surgically resected localized or locally advanced pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I-III) based on the AJCC and ENETS classifications. RFS and overall survival were measured using Kaplan-Meier methodology, with log-rank testing for evaluation of the 2 tumor staging systems. Multivariate analysis was performed controlling for tumor grade, location, surgery type, functional hormonal status, and incidental diagnosis. RESULTS: The authors identified 123 patients with nonmetastatic, surgically resected pancreatic NETs. When using the AJCC classification, 5-year RFS rates for stages I through III were 78%, 53%, and 33%, respectively (P < 0.01). Using the ENETS classification, 5-year RFS rates for stages I to III were 100%, 70%, and 53% (P < 0.18). When excluding patients who were referred after their metastatic recurrence, the 5-year RFS rates for stages I to III were 90%, 73%, and 66% according to the AJCC classification, and 100%, 84%, and 75% according to the ENETS classification. Recurrence rates peaked at approximately 2 years after surgery. CONCLUSIONS: The AJCC and ENETS TNM classifications for pancreatic NETs are prognostic for recurrence-free survival and can be adopted in clinical practice.

A review of systemic and liver-directed therapies for metastatic neuroendocrine tumors of the gastroenteropancreatic tract.

BACKGROUND: Treatment options for metastatic gastroenteropancreatic neuroendocrine tumors (NETs) have evolved in recent years. The somatostatin analogs octreotide and lanreotide have long been used for management of symptoms such as flushing and diarrhea associated with hormonally active NETs. New evidence demonstrates that these agents can also inhibit tumor growth. Other novel agents targeting the VEGF and mTOR pathways have recently been investigated in multicenter phase III studies. METHODS: The authors review the recent literature on treatments for metastatic gastroenteropancreatic NETs and summarize new therapeutic developments. RESULTS: Novel agents targeting somatostatin receptors and the VEGF and mTOR pathways are capable of significantly prolonging progression-free survival in certain NET subtypes. New temozolomide-based chemotherapy regimens have demonstrated considerable activity in pancreatic NETs. Liver-targeted therapies, including surgical resection, radiofrequency ablation, and hepatic artery embolization, are effective options for patients whose metastases are predominantly confined to the liver. Embolization of (90)Y-embedded spheres (radioembolization) represents a novel approach to managing liver metastases. CONCLUSIONS: Treatment options are expanding rapidly for patients with metastatic gastroenteropancreatic NETs, driven largely by randomized, collaborative clinical trials. Future clinical trials should compare the efficacy of emerging therapies and evaluate combination vs sequential approaches.

Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut.

BACKGROUND: Gastrointestinal neuroendocrine tumors (NETs) are heterogeneous neoplasms that vary in mortality according to location of primary tumor and stage of disease. Past analyses of survival suggest a trend towards improving longevity among patients with metastatic mid-gut NETs. METHODS: We evaluated all cases of metastatic NETs of the mid-gut seen in our institution between 1999 and 2003, measuring survival from time of diagnosis of distant metastatic disease. Median and 5-year survival rates were estimated using Kaplan-Meier methodology. We assessed the impact of various prognostic factors including age, gender, hepatic cytoreductive surgery, and operative resection of the primary tumor. RESULTS: 146 cases of metastatic mid-gut NETs were identified. The median overall survival was 103 months and the 5-year survival rate was 75%. Most patients (91%) received octreotide therapy. Other medical treatments included hepatic artery embolization, chemotherapy, and peptide receptor radiotherapy. Primary tumor resection was performed in 69% of cases, and hepatic cytoreductive surgery in 22% of cases. A median survival of 95 months was observed among patients who did not undergo cytoreductive surgery. Operative resection of the primary tumor was not associated with a significant survival advantage. CONCLUSIONS: Median overall survival is 103 months (8.5 years) in patients with metastatic mid-gut NETs. Among patients who are not candidates for hepatic cytoreductive surgery, median survival is 95 months (7.9 years). Resection of the primary tumor does not appear to be associated with a survival benefit in the metastatic setting.

Aggressive surgical resection in the management of pancreatic neuroendocrine tumors: when is it indicated?

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) comprise a heterogeneous group of neoplasms for which treatment is variable, depending on the clinical stage. Despite this diversity, surgery remains the gold standard in the management of PNETs. This paper discusses whether aggressive surgical intervention is indicated for PNETs and investigates what prognostic factors may assist in predicting which patients with invasive disease will benefit most from surgical intervention. METHODS: A review was conducted of large surgical series reported in the English literature over the last 10 years as they pertain to current surgical intervention in PNETs and of prognostic factors related to surgical outcome and survival. RESULTS: Improved survival can be achieved with aggressive surgical management of PNETs. The presence of hepatic metastases is not a contraindication to surgical resection of the primary PNET. Results of series that reported prognostic factors are heterogeneous. CONCLUSIONS: Aggressive surgical resection for selected individuals with PNETs can be performed safely and may improve both symptomatic disease and overall survival. Consideration for resection of primary PNETs should be given to patients with treatable hepatic metastases. Prognostic indices such as tumor differentiation and ability to achieve R0/R1 resection have been linked to survival outcome in PNETs and should be considered when planning aggressive surgical management for this disease.

Outcomes following resection of pancreatic adenocarcinoma: 20-year experience at a single institution.

BACKGROUND: Pancreatectomy for ductal adenocarcinoma has been performed with increasing frequency since the late 1980s as postoperative mortality decreased and long-term survival became more common. However, the belief persists among some clinicians that pancreatectomy offers little survival benefit. This report reviews our institutional experience with pancreatectomy for pancreatic adenocarcinoma and provides a critical overview of the controversies regarding the benefits of surgical intervention for patients who are candidates for curative resection. METHODS: We determined the survival of 142 patients who underwent pancreatectomy for ductal adenocarcinoma with curative intent (stage IA-IIB) at Moffitt Cancer Center during the last two decades by using data obtained from review of the medical record, the Moffitt Cancer Registry, and the Social Security Death Index. Histologic diagnosis was confirmed by expert review of stained sections cut from fixed surgical specimens. RESULTS: In the 137 patients who survived at least 30 days after surgery, the median survival was 21.2 months after resection, with Kaplan-Meier 3- and 5-year disease-specific survival rates of 36% and 32%, respectively. One patient has survived without evidence of recurrent disease for more than 15 years after pancreatectomy. Survival for patients greater than 75 year of age did not differ from that of younger patients. The postoperative mortality rate was 1.5% during the most recent years of highest operative volume (2003 to 2006) and 3.5% for the entire patient cohort. CONCLUSIONS: Review of our 20-year experience with resection of pancreatic adenocarcinoma indicates that pancreatectomy with curative intent offers a real chance of long-term survival to patients with this highly lethal disease for which there is no other curative modality.

Therapy using labelled somatostatin analogues: comparison of the absorbed doses with 111In-DTPA-D-Phe1-octreotide and yttrium-labelled DOTA-D-Phe1-Tyr3-octreotide.

OBJECTIVE: We estimated the absorbed doses for (111)In-DTPA-D-Phe(1)-octreotide and (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide in the same patients in order to compare the potential effectiveness (tumour dose) and safety (kidney and red marrow dose) of these drugs for peptide-targeted radiotherapy of somatostatin receptor positive tumours. METHODS: Six patients with neuroendocrine tumours underwent quantitative (111)In-DTPA-D-Phe(1)-octreotide SPECT and (86)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide PET scan at intervals of 1 week. All studies were performed with a co-infusion of amino acids for renal protection. PET and SPECT were reconstructed using iterative algorithms, incorporating attenuation and scatter corrections. Tissue uptakes (IA%) were measured and used to calculate residence times. Absorbed doses to tissues were estimated and the maximal allowed activity, defined as either the activity delivering 23 Gy to the kidneys (MAA(K)) or 2 Gy to the red marrow (MAA(RM)), was calculated and the resulting tumour absorbed doses were computed. RESULTS: For the MAA(K) the mean absorbed dose to the red marrow was lower for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide than for (111)In-DTPA-D-Phe(1)-octreotide (1.8+/-0.9 Gy vs. 6.4+/-1.6 Gy; P<0.001). The median absorbed dose to tumours for the MAA(K) was two-fold higher for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide as compared to (111)In-DTPA-D-Phe(1)-octreotide (30.1 vs. 12.6 Gy; P<0.05). The median absorbed dose to tumours estimated for the MAA(RM) was 10-fold higher for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide than for (111)In-DTPA-D-Phe(1)-octreotide (35.1 Gy vs. 3.9 Gy; P<0.05). CONCLUSIONS: This direct intra-patient comparison confirms that the use of (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide is more appropriate for therapy of somatostatin receptor bearing tumours. When using (111)In-DTPA-D-Phe(1)-octreotide, the red marrow represents the major critical organ; this can result in significant toxicity if high activities have to be administered to obtain efficient tumour irradiation.

213Bi-[DOTA0, Tyr3]octreotide peptide receptor radionuclide therapy of pancreatic tumors in a preclinical animal model.

PURPOSE: The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) beta-emitters, such as 177Lu or 90Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET alpha-emitter, 213Bi, was evaluated. EXPERIMENTAL DESIGN: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of 213Bi-DOTATOC (specific activity 7.4 MBq/microg) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq 213Bi-DOTATOC was determined in a rat pancreatic carcinoma model. RESULTS: Radiolabeling of the 213Bi-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield > or = 99.9%. Biodistribution data showed specific binding to somatostatin receptor-expressing tissues. Administration of free 213Bi, compared with 213Bi-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 +/- 1.40% injected dose/g (ID/g) tissue versus 11.15 +/- 0.46%, P < 0.0001] and bone marrow (0.31 +/- 0.01% ID/g versus 0.06 +/- 0.02%, P < 0.0324). A significant decrease in tumor growth rate was observed in rats treated with >11 MBq of 213Bi-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of 213Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11 MBq (P < 0.02). CONCLUSIONS: 213Bi-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.

Intermittent bowel obstruction due to a retained wireless capsule endoscope in a patient with a small bowel carcinoid tumour.

A 43-year-old man with a history of metastatic carcinoid disease is presented. The patient had symptoms of chronic intermittent abdominal pain two years after undergoing a wireless capsule endoscopy procedure. Radiological examinations revealed a retained capsule endoscope, and the patient underwent exploratory laparotomy with capsule retrieval. To the authors' knowledge, this is the first case presentation of chronic, partial small bowel obstruction caused by unrecognized retention of a capsule endoscope.

Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0,Tyr3]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.

Radiation sensitizers: a selective review of molecules targeting DNA and non-DNA targets.

The ideal radiation sensitizer would reach the tumor in adequate concentrations and act selectively in the tumor compared with normal tissue. It would have predictable pharmacokinetics for timing with radiation treatment and could be administered with every radiation treatment. The ideal radiation sensitizer would have minimal toxicity itself and minimal or manageable enhancement of radiation toxicity. The ideal radiation sensitizer does not exist today. This review outlines the concept of combining 2 modalities of cancer treatment, radiation and drug therapy, to provide enhanced tumor cell kill in the treatment of human malignancies and discusses molecules that target DNA and non-DNA targets. Combining drugs that have unique mechanisms of action and absence of overlapping toxicities with systemically administered radiotherapy should be exploited in future clinical trials. This is an exciting time in clinical oncology research, because we have a plethora of new molecules to evaluate.

Practical dosimetry of peptide receptor radionuclide therapy with (90)Y-labeled somatostatin analogs.

The challenge for internal therapy is to deliver the highest possible dose to the tumor while sparing normal organs from damage. Currently, the potential risk of kidney and red marrow toxicity limits the amount of radioactivity that may be administered. An accurate dosimetry method that would provide reliable dose estimates to these critical organs and to tumors before therapy would allow the clinician to plan a specific therapeutic regimen and also select those patients who would benefit the most from treatment. The dosimetry for (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide is usually based on quantitative imaging at different time points that provides information on activity retention in organs over time and on stylized models representing average individuals. Because the therapeutic agent labeled with (90)Y is not suitable for quantitative imaging, the peptide surrogate labeled with the positron emitter (86)Y can be considered the most appropriate tracer for measuring distribution and retention of the radiopharmaceutical over time. Dose calculations in target organs are generally performed using the MIRDOSE program, in which S values from source to target are integrated. Significant improvement of dose estimates may be achieved by introducing patient-specific adjustments to the standard models. The use of individual kidney volumes assessed by CT instead of the use of a fixed volume for males and females may significantly improve the determination of kidney radiation doses. The use of actual CT-derived tumor volumes has also shown a dose-efficacy relationship. Additional improvements in this field include the validation and use of an (111)In surrogate to avoid the complexity of (86)Y use and the consideration of radiobiologic parameters, such as fractionation effects and the specific biologic efficacy of internally deposited radiation, which are probably underestimated using currently available methods.

Patient-specific dosimetry in predicting renal toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect relationship.

UNLABELLED: Nephrotoxicity is the major limiting factor during therapy with the radiolabeled somatostatin analog (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). Pretherapeutic assessment of kidney absorbed dose could help to minimize the risk of renal toxicity. The aim of this study was to evaluate the contribution of patient-specific adjustments to the standard dosimetric models, such as the renal volume and dose rate, for estimating renal absorbed dose during therapy with (90)Y-DOTATOC. In particular, we investigated the correlation between dose estimates and effect on renal function after therapy. METHODS: Eighteen patients with neuroendocrine tumors (9 men and 9 women; median age, 59 y) underwent treatment with (90)Y-DOTATOC (8.1-22.9 GBq) after pretherapeutic biodistribution study with (86)Y-DOTATOC. Kidney uptake and residence times were measured and the absorbed dose (KAD) was computed using either the MIRDOSE3.1 software assuming a standard kidney volume (KAD(StdVol)) or the MIRD Pamphlet 19 values and the actual kidney cortex volume determined by pretherapeutic CT (KAD(CTVol)). For each patient, the biologic effective dose (BED) was calculated according to the linear quadratic model to take into account the effect of dose rate and fractionation. Renal function was evaluated every 6 mo by serum creatinine and creatinine clearance (CLR) during a median follow-up of 35.5 mo (range, 18-65 mo). The individual rate of decline of renal function was expressed as CLR loss per year. RESULTS: KAD(CTVol) ranged between 19.4 and 39.6 Gy (mean, 28.9 +/- 5.34 Gy). BED, obtained from KAD(CTVol), ranged between 27.7 and 59.3 Gy (mean, 40.4 +/- 10.6 Gy). The CLR loss per year ranged from 0% to 56.4%. In 12 of 18 patients, CLR loss per year was <20%. No correlation was observed between CLR loss per year and the KAD(StdVol) or the KAD(CTVol). In contrast, BED strongly correlated with CLR loss per year (r = 0.93; P < 0.0001). All 5 patients with CLR loss per year >20% received a BED >45 Gy. Patients who were treated with low fractionation were those with the highest rate of renal function impairment. CONCLUSION: Radiation nephrotoxicity after (90)Y-DOTATOC therapy is dose dependent. Individual renal volume, dose rate, and fractionation play important roles in an accurate dosimetry estimation that enables prediction of risk of renal function impairment.

Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs.

A new treatment modality for inoperable or metastasized gastroenteropancreatic tumors is the use of radiolabeled somatostatin analogs. Initial studies with high doses of [(111)In-diethylenetriaminepentaacetic acid (DTPA)(0)]octreotide in patients with metastasized neuroendocrine tumors were encouraging, although partial remissions were uncommon. Another radiolabeled somatostatin analog that is used for peptide receptor radionuclide therapy (PRRT) is [(90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)(0),Tyr(3)]octreotide. Various phase 1 and phase 2 PRRT trials have been performed with this compound. Despite differences in the protocols used, complete and partial remissions in most of the studies with [(90)Y-DOTA(0),Tyr(3)]octreotide were in the same ranges, 10%-30%; these ranges were higher than those obtained with [(111)In-DTPA(0)]octreotide. Treatment with the newest radiolabeled somatostatin analog, [(177)Lu-DOTA(0),Tyr(3)]octreotate, which has a higher affinity for the subtype 2 somatostatin receptor, resulted in complete or partial remissions in 30% of 76 patients. Tumor regression was positively correlated with a high level of uptake on OctreoScan imaging, a limited hepatic tumor mass, and a high Karnofsky performance score. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all (111)In-, (90)Y-, or (177)Lu-labeled somatostatin analogs that have been used for PRRT. The results obtained with [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the duration of the therapy response for both radiopharmaceuticals is more than 2 y. These data compare favorably with those for the limited number of alternative treatment approaches.

Long-term follow-up of renal function after peptide receptor radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0), Tyr(3)-octreotate.

UNLABELLED: The kidneys are critical organs in peptide receptor radiation therapy (PRRT). Renal function loss may become apparent many years after PRRT. We analyzed the time course of decline in creatinine clearance (CLR) in patients during a follow-up of at least 18 mo after the start of PRRT with (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA),Tyr(3)-octreotide ((90)Y-DOTATOC) or (177)Lu-DOTA(0),Tyr(3)-octreotate ((177)Lu-DOTATATE). METHODS: Twenty-eight patients with metastasized neuroendocrine tumors received 1-5 cycles of (90)Y-DOTATOC, leading to renal radiation doses of 5.9-26.9 Gy per cycle and a total of 18.3-38.7 Gy. Median follow-up was 2.9 y (range, 1.5-5.4 y), with a median of 16 measurements (range, 5-53) per patient. Thirty-seven patients with metastasized neuroendocrine tumors received 3-7 cycles of (177)Lu-DOTATATE, leading to renal radiation doses of 1.8-7.8 Gy per cycle and a total of 7.3-26.7 Gy. Median follow-up was 2.4 y (range, 1.7-4.0 y), with a median of 10 (range, 6-27) measurements per patient. All renal dose estimates were calculated with the MIRDOSE3 model. All patients were infused with renoprotective amino acids during the administration of the radioactive peptides. The time trend of CLR was determined by fitting a monoexponential function through the data of individual patients, yielding the decline in CLR in terms of percentage change per year. RESULTS: The median decline in CLR was 7.3% per y in patients treated with (90)Y-DOTATOC and 3.8% per y in patients treated with (177)Lu-DOTATATE (P = 0.06). The time trend of decline in CLR was sustained during the follow-up period. Eleven patients had a >15% per y decline in CLR. Cumulative renal radiation dose, per-cycle renal radiation dose, age, hypertension, and diabetes are probable contributing factors to the rate of decline in CLR after PRRT. CONCLUSION: This study showed that the time course of CLR after PRRT was compatible with the pattern of sustained CLR loss in progressive chronic kidney disease.

GEPNETs update: Radionuclide therapy in 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.

Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings.

In preclinical studies in rats we evaluated biodistribution and therapeutic effects of different somatostatin analogs, [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide and [(177)Lu-DOTA,Tyr(3)]octreotate, currently also being applied in clinical radionuclide therapy studies. [Tyr(3)]octreotide and [Tyr(3)]octreotate, chelated with DTPA or DOTA, both showed high affinity binding to somatostatin receptor subtype 2 (sst(2)) in vitro. The radiolabelled compounds all showed high tumor uptake in sst(2)-positive tumors in vivo in rats, the highest uptake being reached with [(177)Lu-DOTA,Tyr(3)]octreotate. In preclinical therapy studies in vivo in rats, excellent, dose dependent, tumor size responses were found, responses appeared to be dependent on tumor size at therapy start. These preclinical data showed the great promise of radionuclide therapy with radiolabelled somatostatin analogues. They emphasised the concept that especially the combination of somatostatin analogs radiolabeled with different radionuclides, like (90)Y and (177)Lu, is most promising to reach a wider tumor size region of high curability. Furthermore, different phase I clinical studies, using [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide or [(177)Lu-DOTA, Tyr(3)]octreotate are described. Fifty patients with somatostatin receptor-positive tumors were treated with multiple doses of [(111)In-DTPA(0)]octreotide. Forty patients were evaluable after cumulative doses of at least 20 GBq up to 160 GBq. Therapeutic effects were seen in 21 patients: partial remission in 1 patient, minor remissions in 6 patients, and stabilization of previously progressive tumors in 14 patients. The toxicity was generally mild bone marrow toxicity, but 3 of the 6 patients who received more than 100 GBq developed a myelodysplastic syndrome or leukemia. Radionuclide therapy with [(90)Y-DOTA,Tyr(3)]octreotide started in 3 different phase I trials. Overall, antimitotic effects have been observed: about 20% partial response and 60% stable disease (N = 92) along with complete symptomatic cure of several malignant insulinoma and gastrinoma patients. Maximum cumulative [(90)Y-DOTA,Tyr(3)]octreotide dose was about 26 GBq, without reaching the maximum tolerable dose. New is the use of [(177)Lu-DOTA,Tyr(3)]octreotate, which shows the highest tumor uptake of all tested octreotide analogs so far, with excellent tumor-to-kidney ratios. Radionuclide therapy with this analog in a phase 1 trial started recently in our center in 63 patients (238 administrations), Interim analysis of 18 patients with neuroendocrine tumors was performed very recently. According to the WHO, toxicity criteria no dose limiting toxicity was observed. Minor CT-assessed tumor shrinkage (25% - 50% reduction) was noticed in 6% of 18 patients and partial remission (50% - 100% reduction, SWOG criteria) in 39%. Eleven percent of patients had tumor progression and in 44% no changes were seen. These data show that radionuclide therapy with radiolabelled somatostatin analogs, like [DOTA, Tyr(3)]octreotide and [DOTA, Tyr(3)octreotate is a most promising new treatment modality for patients who have sst(2)-positive tumors.