Peptide receptor radionuclide therapy (PRRT) of neuroendocrine ...

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Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors: current state and future perspectives

The heterogeneous nature of neuroendocrine tumors, their indolent course and lack of therapeutic options for the management of advanced cases – together form the Achilles heel for oncologists. Somatostatin receptor-specific imaging with Ga-68 labeled peptides has provided an opportunity for management of advanced cancers with their therapeutic radionuclide counterparts (Lu-177/Y-90 labeled peptides). Molecular imaging with positron emission tomography/computed tomography is accepted technique for treatment response assessment, since the radiolabels for imaging and therapy are same, thereby depicting accurate response. We have compiled and reviewed our experience of last 8–10 years in the use of these novel radiolabeled peptides in the treatment of neuroendocrine tumors, focusing on the survival, toxicity profiles and the recent advances and improvements.

Richard P Baum*,1, Ameya D Puranik1 & Harshad R Kulkarni1 1 THERANOSTICS Center of Molecular Radiotherapy & Molecular Imaging, Zentralklinik Bad Berka, Germany *Author for correspondence: [email protected]

Keywords: 68Ga-DOTATOC • 90Y-DOTATATE • 99mTc-DTPA • 177Lu-DOTATATE • CT • FDG PET • Ki-67 • neuroendocrine tumor • octreotide • peptide receptor radionuclide therapy • somatostatin

Neuroendocrine tumors (NETs) are relatively rare tumors originating from neuroendocrine cells, distributed ubiquitously throughout the body. The term ‘neuroendocrine’ relates to a peculiar characteristic or phenotype of these cells, namely the ability to synthesize, store and secrete neurohormones, neurotransmitters or neuromodulators, substances produced by both the endocrine and nervous systems. Gastroenteropancreatic neuroendocrine tumors (GEP-NET) constitute 75% of all NETs [1] . Current WHO classification distinguishes three groups of GEP-NET; reflecting roughly the different biology of tumors – highly differentiated neuroendocrine tumor with a proliferation rate (Ki-67) of 2% and low-differentiated neuroendocrine carcinoma with Ki-67 >20% [2] . The heterogeneous nature of neuroendocrine tumors, their indolent course and lack of therapeutic options for the management of advanced cases – together form the Achilles heel for

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oncologists. Therapeutic strategy in NETs is multidisciplinary and includes surgery, interventional radiology, medical and palliative care. Treatments such as somatostatin analogs, interferon, chemotherapy, new targeted drugs and peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs are often relied on, in advanced cases. NETs usually overexpress somatostatin receptors on their cell surface (particularly type 2), thus enabling the therapeutic use of somatostatin analogs, one of the basic tools for NETs. Octreotide therapy is most commonly used for palliative/symptomatic treatment of functional NETs; since it involves competitive blockade of somatostatin receptors (SSTR), and hence depends on the documented presence of SSTR on tumor. Likewise, the premise of PRRT using radiolabeled somatostatin analogs is overexpression of SSTR on NETs. The conventional imaging modalities like computed tomography (CT), MRI and

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Review Baum, Puranik & Kulkarni ultrasonography (USG) provide excellent morphologic information, but frequently miss the localization of the primary tumor. A recent study showed a 59% detection rate of unknown primary NET (CUP-NET) by 68 Ga DOTANOC receptor positron emission tomography/CT (PET/CT) [3] . The metabolic dimension increases the likelihood of picking up even small volume disease, often considered equivocal on anatomical imaging; this can often impact the management. It is a known fact that molecular events precede morphologic changes by days to months. The functional information provided by PET/CT along with the possibility to do semi-quantitative/semi-quantitative evaluation has resulted in the conceptualization of a ‘tailored regime.’ Also, the state of the art PET/CT scanners, apart from providing functional information about the whole body in one sitting, makes it possible to perform diagnostic CT wherever needed and give vital information regarding the morphology of NET – keeping in mind that not all the tumors are SSTR positive [4,5] . The high success of somatostatin receptor scintigraphy using 111In labeled octreotide (OctreoScan) encouraged the development of positron emitter-based SSTRspecific radiopharmaceuticals. 68Ga is a radiometal and a positron emitter with a half-life (T1/2) of 68 min and produced from a 68Ge/68Ga-generator (T1/2 = 271 day) in a convenient, fast, ‘in-house’ preparation [6] . The same peptides labeled with 68Ga for diagnosis can be labeled with 177Lu or 90Y for radionuclide therapy [7] , a form of personalized treatment which has been given the term THERANOSTICS. PRRT: basic principles

Somatostatin receptor expression on the surface of neuroendocrine tumors provided an ideal target for imaging by PET/CT. Scintigraphic localization of neuroendocrine tumors with radiolabeled somatostatin analogs further led to the development of therapeutic radiopeptides targeting the same receptor. The labeled peptide undergoes receptor-mediated internalization and intracellular retention, leading to tumor targeting at the desired site. This forms the basis of PRRT. Though still an emerging tool, clinical trials are already underway to establish its firm place in routine oncology practice all over the world [8] . PRRT can deliver radiation doses to tumors, which are adequate to achieve volume reduction or even cure. PRRT has been administered for almost two decades and is an established effective therapeutic modality in the treatment of inoperable or metastatic GastroEntero-Pancreatic, bronchopulmonary and other NETs. The two most commonly used radiopeptides, 90 Y-octreotide and 177Lu-octreotate, produce objective response rates of 15–35% [9–13] .

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Initial studies were performed with high doses of the radiopeptide [111In-DTPA0 ]-octreotide. Objective responses or ‘measurable responses,’ as seen as decrease in size and metabolic activity of tumor, were rare or questionable due to the short range (nanometers to micrometers) of the emission and therefore the short tissue penetration of the emitted Auger electrons. The radiopeptides that have been proven effective and which have been extensively studied are the 90Y labeled peptide - [DOTA0, Tyr3]-octreotide (DOTATOC) and the 177Lu labeled peptide [DOTA0, Tyr3]-octreotate (DOTATATE) [10] . Our group was the first to use also 90Y DOTATATE and in a large patient group. We also pioneered the use of 90Y and 177 Lu DOTATATE in sequence (DUO-PRRT) and the concurrent use of 90Y and 177Lu octreotide analogs (TANDEM-PRRT) as well as the intra-arterial use of 90 Y DOTATATE and DOTATOC. DOTATATE has a ninefold higher affinity for the somatostatin receptor subtype 2 compared with DOTATOC [11] . In a preliminary report, 35 patients with neuroendocrine gastroenteropancreatic tumors were treated with escalating doses of 177Lu DOTATATE, resulting in complete and partial responses in 38% of patients. No serious side effects were observed. In addition, 177Lu DOTATATE significantly improved the global health/quality of life and various function and symptom scales in patients with metastatic gastroenteropancreatic tumors [12] . Excretion of the radiopeptide through renal route makes it the critical organ during PRRT. The pathway involves proximal tubular reabsorption of the radiopeptide and the subsequent retention in the interstitium results in renal irradiation. This is overcome by the use of positively charged molecules, such as l-lysine and/or l-arginine, which competitively inhibit the proximal tubular reabsorption of the radio peptide [13] . Based on the animal experiments of the groups in Rotterdam and Amsterdam, our group has pioneered the clinical use of Gelofusine® in addition to amino acids for kidney protection. Gelofusine induces transient low molecular weight proteinuria reducing renal absorption of radiopeptides. The idea for the use of Gelofusine is based on the finding that gelatin-based plasma expanders enhance urinary excretion of specific megalin ligands, such as β-2-microglobuline. It has been shown previously by de Jong et al. [14] that megalin plays an essential role in the kidney uptake of somatostatin analogs. In rats coinjection of 80 mg/kg Gelofusine resulted in maximum reduction of renal retention of 111InDOTA,Tyr3-octreotate, which was further improved when combined with lysine [15] . Tumor uptake of radiolabeled octreotate was not affected, resulting in

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Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors

an increased tumor to kidney ratio [16] . Therefore, the use of Gelofusine for kidney protection in PRRT is logical. The factors that may result in decline or reduction in renal function in patients receiving PRRT are cumulative and per-cycle renal absorbed dose, age, hypertension and diabetes [17] . Though not a principal dose-limiting factor, bone marrow involvement must be considered as a potential source of hematotoxicity. Acute hematological toxicity is not uncommon, especially after 90Y-labeled peptide therapy, and the possibility of a mild, but progressive impoverishment in bone marrow reserves has to be considered in repeated cycles. In addition, myelodysplastic syndrome (MDS) or overt leukemia may develop in patients receiving high bone marrow doses, especially in those previously treated with alkylating agents [18–25] . The challenge for internal radiation therapy is to deliver the highest possible dose to the tumor while sparing normal organs from damage. In addition, the inter-individual differences in dose delivery should be considered, particularly on the account of varying metabolism or receptor density in organs and tumor lesions. This makes individual patient dosimetry absolutely necessary in PRRT. Personalized PRRT

Unlike conventional chemotherapy regimens wherein dosage is defined based on large patient studies, such an approach rarely benefits in NET with variable tumor phenotypes and clinical course [19] . Though the protocol for therapy administration is fixed, the therapeutic decision making process is completely individualized. The primary end point to be achieved varies with every tumor phenotype, and one should be absolutely clear of what are the goals to be achieved for every patient. Important factors which go into this are the volume of disease, prior treatment regimens received, patient’s baseline performance status, renal and hematological parameters. Within PRRT, there are multiple options including variety of isotopes, combinations with radiosensitizing therapy, using somatostatin analogs, etc. The ‘personalized’ approach involves adjusting administered activity, choice of radioisotope, sequencing and frequency of PRRT to individuals imaging phenotype and pathological grade [20] . This is to emphasize the fact that NETs are a class of tumors, with numerous subtypes of different biological behaviors, hence to have a standardized approach ‘across the board’ is disastrous. At the same time, conducting randomized control trials in these tumors is fraught with difficulty for the same reason [21] .


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Recent literature

Multiple studies providing robust statistics have been published in the recent past. Review of all these studies is important to highlight the improvement in overall survival statistics in patients with NETs. Ezziddin et al. [22] , in a retrospective study of 74 patients with metastatic GEP-NET who were treated with PRRT using 177Lu-octreotate, concluded that there was significant improvement in long-term outcome following PRRT. Notable result from this study was the fact that even patients with Ki-67 >10% achieved good treatment response following PRRT. The same group further narrowed down the statistics for G1/G2 pancreatic NETs in 68 patients with inoperable metastatic disease, and achieved outstanding survival rates and treatment outcomes [23] . Though somatostatin receptor scintigraphy-PET/CT imaging forms the backbone of imaging for assessment of response to PRRT, Severi et al. [24] highlighted the role of FDG PET/CT in a retrospective analysis of 52 patients with advanced G1/G2 GEPNETs. They concluded that, following treatment with PRRT, FDG PET positivity is suggestive of treatment refractoriness developing in the tumor, whereas negative FDG PET is suggestive of good treatment response and predictor of good outcome. Kashyap et al. [25] treated this subset of patients with FDG PET positive metastatic NET, using combination of PRRT and chemotherapy (5-fluorouracil), which was referred as ‘peptide receptor chemoradionuclide therapy.’ In 52 patients who had failed conventional treatment regimes, peptide receptor chemoradionuclide therapy resulted in a median progression-free survival (PFS) of 48 months, which was more effective as compared with alternate treatment strategies. Claringbold et al. [26] conducted a Phase I/II study combining 177Lu-octreotate with capecitabine and temozolomide for treatment of low-grade GEP-NETs. Median PFS of 31 months was achieved and median overall survival (OS) was not reached at 24 months follow-up in 90% patients. Also, no adverse events were reported in any patient. Sabet et al. [27] assessed the PRRT-induced long-term changes in renal parameters based on GFR analysis on 99m Tc-DTPA renal clearance studies, and reported no serious long-term impairment in renal function. The Bad Berka experience

Y DOTATOC (in Germany, the first patient was treated by myself in July 1997) and/or 177Lu DOTATATE (in use in our center since 2004) as well as other radiolabeled somatostatin analogs like 90Y DOTATATE, 177Lu DOTATOC and 177Lu DOTANOC have been applied alone or in combination over the last years at the Bad Berka Neuroendocrine Tumor Center. The clinical indication was estab-

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Figure 1. Case of operated G1 NET of pancreas.68GaDOTATOC PET/CT study (A–E) on MIP images, there is faint tracer uptake present in the skull region as well as intense somatostatin receptor expression of extensive, bilobar liver metastases and of a lesion in the spine. Axial fused images show multiple hepatic metastases (B&D), and metastatic foci in the lumbar vertebra (C) and in the brain (E). The patient was treated with three courses of PRRT (2800 MBq 90Y-DOTATOC followed by 177Lu – DOTATOC PRRT administering 5800 and 4900 MBq, respectively). Post-thearpy serial followup MIP images (2a-c) demonstrate partial response of the liver lesions and complete remission (by molecular imaging criteria) of the brain and of the skeletal metastases.MIP: Maximum intensity projection.

lished by a multidisciplinary tumor board in patients with progressive neuroendocrine tumors, nonresponsive to octreotide/interferon treatment or chemotherapy. 177Lu DOTATATE was predominantly used for smaller metastases or in patients with impaired renal or hematological function. Our group was the first to systematically use 177Lu and 90Y consecutively in the same patient (DUO-PRRT). Over 3000 treatment cycles in >900 patients have been performed up to now.

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Figure 2. Case of operated G1 NET of pancreas. (A–C) Serial MIP images of 68Ga-DOTATOC PET/ CT done after each cycle of PRRT shows significant molecular regression of metastatic liver lesions, with no new lesions elsewhere

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Four hundred fifty-four patients (mean age 59.1 years, 248 male, 206 female) received a total of 1303 treatment cycles (mean activity 4.1 GBq, minimum 1.05 GBq, maximum 7.5 GBq per cycle, time between cycles 3–6 months). Number of patients/cycles: 111 pts/1 cycle; 106/2; 74/3; 75/4; 42/5; 23/6; 9/7; 1/8. For kidney protection, patients were well hydrated and received an l-lysine/l-arginine solution (1500 ml) infused intravenously for 4 h beginning 30 min before PRRT. Patients were selected based on high SSTR expression on 68Ga somatostatin receptor PET/ CT [28] . Before each new treatment cycle, restaging was performed by morphologic (CT/MRI) and molecular imaging ( 68Ga DOTA-NOC PET/CT, in selected cases also FDG or fluoride PET/CT), blood chemistry and tumor markers (Chromogranin A, serotonin, specific hormones). Renal function was serially determined by Tc-99m MAG3 scan/clearance (TER) and by Tc-99m DTPA/GFR measurements [29] . Tumor Dosimetry (MIRD/OLINDA) was performed after PRRT (using 177Lu DOTATATE) [30] . All data were entered in a structured ACCESS database (284 items /patient). The documented statistics for tumor response in patients with NETs of nonpancreatic origin and pancreatic NET (pNET) after a mean follow-up of 2 years were as follows: complete remission, partial remission, minor response after three cycles (progressive disease before) was seen in 52% of patients with pNET (48% in other nonpancreatic NET); disease was stabilized in 39% of pNET as compared with 45% in nonpancreatic NET. Objective tumor responses (including improvement of clinical symptoms) were observed in 93% (in 91% of pNET) of the patients. Hematotoxicity (mainly erythrocytopenia, rarely neutropenia and thrombocytopenia) occurred in less than 15% of all patients. MDS developed in five patients (all of them also received chemotherapy before). There was no instance of end stage renal toxicity in any of the patients with normal baseline renal function parameters. Serum creatinine and TER/GFR remained unchanged in most patients receiving 177Lu DOTATATE alone (n = 417 cycles). Dose fractionation during PRRT thus proved to be valuable in patients without any pre-existing risk factors and under appropriate nephroprotection – leading to significant reduction in the probability and magnitude of renal toxicity. Risk factors include chemotherapy, diabetes mellitus, hypertension, Hedinger’s syndrome and cachexia [31,32] . Retrospective analysis was performed using our database in 1000 patients (age 4–85 years) with metastatic and/or progressive NETs, undergoing 1–9 cycles



of PRRT at our center using Lu-177 (n = 331), Y-90 (n = 170) or both (n = 499). Median total administered activity was 17.5 GBq. Patients were followed up for up to 132 months after the first cycle of PRRT. Well-differentiated NETs (G1–2) accounted for 54%. Most patients (95.6%) had undergone at least one previous therapy (surgery 86.8%, medical therapy 55%, ablative therapy 14.2% and radiotherapy 3.4%). The median OS of all patients from the start of PRRT was 52 months. Median OS according to radionuclide used: Y-90 24 months, Lu-177 55 months or both 64 months; according to the grade of tumor: G1–87 months, G2–55 months, G3–28 months, unknown–50 months; and according to origin of primary tumors: pancreas-45 months, small intestine-77 months, unknown primary-55 months, lung-36 months. Median PFS measured from the last therapy cycle was 22 months, comparable for pancreatic (23 months) and small intestinal (25 months) NETs [33] . The overall better survival statistics as compared with contemporary studies was primarily due to the nephron-protection regime strictly incorporated into the therapy protocol. A German multi-institutional registry study with prospective follow-up in 450 patients indicates that PRRT is an effective therapy for patients with G1–2 neuroendocrine tumors, irrespective of previous therapies, with a survival advantage of several years compared with other therapies and only minor side effects. (Figures 1–3) Median OS of all patients from the start of treatment was 59 months. Median PFS measured from last cycle of therapy accounted to 41 months. Median PFS of pancreatic NET was 39 months. Similar results were obtained for NET of unknown primary (median PFS: 38 months) whereas NET of small

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bowel had a median PFS of 51 months. Side effects like °3–4 nephro- or hematotoxicity were observed in only 0.2 and 2% of patients, respectively. Future perspective

These include: • DUO-PRRT; • TANDEM-PRRT (administration of 177Lu and 90 Y labeled SSTR analogs concurrently on the same day); • Intra-arterial PRRT (for improved dose delivery to liver metastases); • Combined PRRT (in combination with other treatment modalities); • Transarterial chemoembolization, selective internal radiation therapy, radiofrequency ablation; • Chemotherapy doxorubicin);

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• Kinase inhibitors (e.g., sunitinib, sorafenib, everolimus and others); • Antibodies (e.g., bevacizumab); • Improved peptides (e.g., use of somatostatin receptor antagonists); • Intraoperative use of probes after PRRT with 177Lu labeled peptides; • Improved dosimetry and radioprotection; E

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Figure 3. Personalized PRRT in metastatic thymic NET (A-G). After resection of the primary tumor, the patient developed pleural and mediastinal metastases in 2006. Treatment with 90Y and 177Lu-DOTATOC was performed initially in 2006, with close monitoring of renal function and hematological parameters. There was no extrathoracic spread of the disease for 2 years. Relapse was seen in October 2009 (B; arrows), when again two courses of PRRT were administered. Intrathoracic disease relapse was noted in October 2011 (D; arrows), October 2013 (F; arrows) and again in May 2014 (G; arrows). The patient received PRRT at every relapse. The aim was to keep the disease stable and confined to the thorax. There was no hematotoxicity, renal function parameters remained stable and quality of life was excellent over many years throughout the treatment.



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Review Baum, Puranik & Kulkarni • Newer targets; • Prostate-specific membrane antigen; • Neurotensin. Conclusion

PRRT lends a significant benefit in PFS as well as in OS in metastasized and/or progressive G1–2 NETs as compared with other treatment modalities and regardless of previous therapies. Combination of Lu-177 and Y-90 (DUO)-based PRRT may be more effective than either radionuclide alone. Thus, in patients with progressive NETs, fractionated, personalized PRRT with lower doses of radioactivity given over a longer period of time (Bad Berka Protocol) is effective even in advanced cases and results in excellent therapeutic responses. Up to ten cycles of PRRT, given over several years were tolerated very well by most patients. Severe renal toxicity can be completely avoided or reduced by nephroprotection applying aminoacids; hematological toxicity is usually mild to moderate (except for some cases of MDS which occurs in 2–3%). Quality of life can be significantly improved. Though cure is rarely possible, excellent palliation with significant improvement of symptoms

can be achieved by PRRT. In addition, neoadjuvant PRRT could be administered in cases of inoperable NET so as to render the tumor operable by inducing radiation-induced necrosis and decrease in tumor size. Use of intra-arterial PRRT (>100 treatments were already performed up to now at our center) is more effective for selectively targeting liver metastases and large, inoperable primary tumors. PRRT should only be performed at specialized centers as NET patients need highly individualized interdisciplinary treatment and long-term care. PRRT can be effectively combined with transarterial chemoembolization, radiofrequency ablation, chemotherapy (e.g., using capecitabine/5-FU, temozolomide or doxorubicin), and kinase inhibitors (e.g., everolimus). Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Executive summary • Peptide receptor radionuclide therapy (PRRT) is highly effective in the management of neuroendocrine tumors, even in advanced cases and lends a benefit in overall survival from time of diagnosis, of several years. There is a significant improvement of clinical symptoms and excellent palliation can be achieved. • ’Personalized’ treatment regimen – primary end point to be achieved varies with every tumor phenotype, and one should be absolutely clear of what are the goals to be achieved for every patient. • In patients with progressive neuroendocrine tumors, fractionated, personalized PRRT with lower doses of radioactivity given over a longer period of time (Bad Berka Concept) results in good therapeutic responses. By this concept, severe hematological and/or renal toxicity can be avoided and the quality of life can be improved. • Sequential (DUO) and concurrent (TANDEM) PRRT are more effective in progressive neuroendocrine tumors than using either radiopeptide alone.

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