Radiolabeled Somatostatin Analogue Therapy Of Gastroenteropancreatic Cancer

Radiolabeled Somatostatin Analogue Therapy Of Gastroenteropancreatic Cancer Lisa Bodei, MD, PhD,*,† Dik J. Kwekkeboom, MD, PhD,†,‡ Mark Kidd, PhD, DABCC,§ Irvin M. Modlin, MD, PhD, DSc, MA, FRCS,†,║ and Eric P. Krenning, MD, PhD†,§ Peptide receptor radionuclide therapy (PRRT) has been utilized for more than two decades and has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic gastroenteropancreatic neuroendocrine neoplasms (NENs) or neuroendocrine tumors (NETs). The two most commonly used radiopeptides for PRRT, 90Y-octreotide and 177 Lu-octreotate, produce disease-control rates of 68%-94%, with progression-free survival rates that compare favorably with chemotherapy, somatostatin analogues, and newer targeted therapies. In addition, biochemical and symptomatic responses are commonly observed. In general, PRRT is well tolerated with only low to moderate toxicity in most individuals. In line with the need to place PRRT in the therapeutic sequence of gastroenteropancreatic NENs, a recently sponsored phase III randomized trial in small intestine NENs treated with 177Luoctreotate vs high-dose octreotide long-acting release demonstrated that 177Lu-octreotate significantly improved progression-free survival. Other strategies that are presently being developed include combinations with targeted therapies or chemotherapy, intra-arterial PRRT, and salvage treatments. Sophisticated molecular tools need to be incorporated into the management strategy to more effectively define therapeutic efficacy and for an early identification of adverse events. The strategy of randomized controlled trials is a key issue to standardize the treatment and establish the position of PRRT in the therapeutic algorithm of NENs. Semin Nucl Med 46:225-238 C 2016 Elsevier Inc. All rights reserved.

Introduction

N

euroendocrine neoplasms (NENs) or neuroendocrine tumors (NETs) generally exhibit slow-growing behavior, but may sometimes be aggressive.1 Most of the NENs originate in the gastroenteropancreatic (GEP) and bronchopulmonary system.2 GEP NENs were previously considered as a rare disease; however, it is now apparent that both their incidence (3.65/100,000/y) and prevalence are increasing (35 of 100,000).3,4 Patients may present either with symptoms

*Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy. †LuGenIum Consortium, Milan, Rotterdam, London, Bad Berka. ‡Nuclear Medicine Department, Erasmus Medical Center, Rotterdam, The Netherlands. §Wren Laboratories, Branford, CT. ║Department of Gastroenterological Surgery, Yale School of Medicine, New Haven, CT. Address reprint requests to Lisa Bodei, MD, PhD, Division of Nuclear Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. E-mail: [email protected], [email protected]

http://dx.doi.org/10.1053/j.semnuclmed.2015.12.003 0001-2998/& 2016 Elsevier Inc. All rights reserved.

related to excessive bioactive peptide and amine secretion or, if nonfunctional, with symptoms related to local effects (mass, obstruction, or bleeding).5 Given the ubiquity of the lesions and the nonspecific nature of the symptomatology, as well as a general lack of awareness of the disease, diagnosis is often at a late stage of the disease. Thus, most (60%-80%) are metastatic at presentation. Even functional tumors are diagnosed late because their protean symptoms (flushing, diarrhea, sweating, and bronchospasm) are frequently misinterpreted as representative of menopause, irritable bowel disease, anxiety states, allergy, or asthma, respectively. As a result, in many instances at initial identification of the disease, curative treatments are no longer possible.2 Extension beyond the primary lesion usually involves regional lymph nodes, and the commonest site of distant metastasis is hepatic. Therapeutic strategies for the most part are, therefore, directed at primary resection followed by a focus on the eradication or control of hepatic metastatic disease.6 Advanced disease involves peritoneal deposits, bone, brain, and pulmonary sites, although other less common locations including the breast, heart, and skin may rarely 225

L. Bodei et al.

226 occur.7 Staging of the disease has been defined by a number of groups and generally follows variations of the TNM classification (research excellence frameworks). Tumors themselves have been the subject of a number of evolving systems. The most recent iteration is provided by World Health Organization (WHO)/European Neuroendocrine Tumor Society (ENETS) 2010 classification. In this system, GEP NENs are divided into categories of disease based upon histologic criteria and a grading system (G1-G3) based upon measurement of a percentage index provided by a proliferative marker (Ki67).8 Although the grading criteria for each group have evolved with time, currently G1 ¼ Ki67 ≤ 2, G2 ¼ Ki67 3–20, and G3 ¼ Ki67 4 20. The fundamental consideration is that all GEP NENs are deemed to be malignant. A basic analysis of G1-G2 NENs indicates that disease stage, primary tumor site, histologic grade, sex, race, age, and length of disease are predictors of outcome.9 Survival is influenced by stage at diagnosis, worse for regional involvement, and the worst for metastatic tumors.10 More sophisticated prognostic nomograms using multivariate analysis and hazard ratio calculations have provided a more exact delineation of GEP NEN disease and would likely become even more accurate with the inclusion of molecular characterization of individual tumors.11 An optimal management strategy includes a clinical assessment of the patient followed by characterization of the primary tumor and thereafter delineation of the grade and stage of the lesion. Whenever possible and clinically apposite, removal of the primary tumor should be initially undertaken to obviate the mass effects and consequences of local extension (bleeding, pain, and obstruction) and diminish the likelihood of distant metastatic spread. The management of residual disease depends upon the biological nature of the tumor, the location

of lesions, and the extent of disease. Surgery remains the only potentially curative option, but radical resections are rarely attainable given that metastatic disease is usually present at diagnosis.10,12 Given the paucity of rigorous prospective randomized trials and the diversity of treatment strategies used in different centers, postsurgical therapeutic strategy is usually defined by consensus discussion (institutional tumor board), evaluation of evolving literature data, and local experience or proclivities.13 In an empiric sense, however, the choice of therapy is generally dependent on the primary therapeutic aim for the individual. This may range widely and extend from an attempt at complete surgical eradication of the disease in locally confined lesions to only palliation of symptoms in individuals with extensive and major tumor burden. In principle, therapeutic strategies are primarily focused on reducing the size and number of metastatic lesions, and ameliorating symptoms with the objective of increasing both quality of life and conferring survival benefit14 (Fig. 1). The surgical options include en bloc resection of the primary, removal of hepatic metastases, ablation using radiofrequency, and, in some instances, hepatic transplantation.15 Interventional radiology techniques include embolization of hepatic metastases (with or without chemotherapeutic agents) or the use of microspheres loaded with yttrium-90 (90Y).16 Medical therapy ranges from the use of bioactive agents (somatostatin analogues [SSAs] or interferon), to conventional chemotherapy. In functional tumors such as gastrinomas or insulinomas, it also includes symptomatic treatment (proton pump inhibitors or antihypoglycemic agents). More recently, a variety of novel agents (everolimus, sunitinib, and bevacizumab) with putative molecular targets (eg, mammalian target of rapamycin, vascular endothelial growth factor) have been used with varying degrees of efficacy.17 One of the most clinically relevant recent

Figure 1 Therapeutic algorithm for enteropancreatic neuroendocrine neoplasms. BEV, bevacizumab; CAP, capecitabine; EBRT, external-beam radiotherapy; EVE, everolimus; IFN, interferon; IR, interventional radiology; PL, platinum-based regimens; Suni, sunitinib; STZ, streptozotocin; TEM, temozolomide.

Radiolabeled SSAs therapy therapeutic innovations has been the development of somatostatin receptor (SSTR)-targeted radionuclide therapy or peptide receptor radionuclide therapy (PRRT). This strategy involves the use of a carrier molecule (octreotide derivatives) to which are attached a variety of different radionuclides, including indium-111 (111In), 90Y, and lutetium-177 (177Lu).18 Both the choice of the carrier molecule and the specific radionuclide confer different benefits in targeting and radiation delivery.19 The therapeutic strategy of PRRT has been utilized for more than two decades20 and has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic GEP, bronchopulmonary, and other NENs. It was first used in 1992 at Erasmus University, Rotterdam, as the next logical progression from their original development of the SSTR-targeted diagnostic technique, namely the in vivo localization of NENs using (111In-DTPA0-D-Phe1)-octreotide or 111 In-pentetreotide. The two most commonly used radiopeptides for PRRT, 90Y-octreotide and 177Lu-octreotate, produce disease-control rates of 68%-94%.18,19,21–24 In addition to overt evidence of tumor shrinkage, biochemical and symptomatic responses are commonly observed.25 Of particular therapeutic relevance is the outcome both for progressionfree survival (PFS) and overall survival (OS). These compare favorably with SSAs, chemotherapy, and more recent usage of “targeted” therapies such as everolimus and sunitinib.26,27 A major advantage of PRRT as opposed to other treatments is the opportunity to identify and quantify the target, the SSTR, before initiation of therapy.28 Thus in contrast to other treatment strategies, target quantification and therapeutic dose delivery can be accurately defined and quantified.27 In general, PRRT is well tolerated with only low to moderate toxicity in most individuals. To ensure diminution of adverse events, it is mandatory to undertake necessary precautions including the coadministration of amino acids.18,27 The organs at risk for long-term toxicity are the kidneys and bone marrow. There is a mild loss of renal function (grade three to four toxicity after 90Y-peptides 3%9%, grade four toxicity after 177Lu-peptides [r0.4%]). Subacute and transient hematological toxicity is mild in approximately 90% of cases. Myelodysplastic syndrome (MDS) and sporadic instances of leukemias have been reported in approximately 2% of cases.18,19,22,27,29,30

Technique The paradigm of PRRT efficacy is defined by a number of parameters. Firstly, the overexpression of SSTR at the NEN tumor cell membrane. Secondly, after binding to the receptor internalization of a suitably radiolabeled SSA as per normal receptor recycling dynamics. Thirdly, subsequent release of the radioactivity directly into the tumor cell interior (Fig. 2). To evaluate the magnitude of this process and estimate the radioactivity concentration, all PRRT protocols include a baseline assessment of the SSTR density obtained in vivo with conventional 111In-pentetreotide scintigraphy or 68Ga-SSAPET-CT. These measurements provide a basis for a determination of clinical efficacy. It has been established that an uptake

227

Figure 2 Strategy and mechanism of action of PRRT. The somatostatin analogue is linked to the radionuclide via a specific chelator. This radio-analog complex binds to the membrane somatostatin receptor and is internalized. Thus, radioactivity is transported into the intracellular receptor-recycling compartment of the NEN cell, where it exerts its action in proximity to the nucleus. Recently, somatostatin receptor antagonists, which do not internalize, but recognize more binding sites, have been introduced in clinical practice, resulting in greater tumor-absorbed doses. SSA, somatostatin analogue; SSR, somatostatin receptor.87

greater than that of kidneys or spleen (on planar scintigraphic images) or both is correlated with objective response in  60% of individuals.27 The quantification of this uptake utilizing 68 Ga-DOTATOC PET-CT has indicated that a high maximum standard uptake value threshold of 416 has sensitivity and specificity of 95% and 60%, respectively, in the prediction of responsive lesions.31

Systemic Administration Standard clinical protocols of PRRT consist of the systemic administration of a radiolabeled SSA, fractionated in sequential cycles (usually four to five), every 6-9 weeks, until the intended cumulative activity has been delivered. The latter value depends on the limitations primarily imposed by the estimated degree of renal and bone marrow irradiation. Treatment can be repeated to a limited extent, should disease progression occur after initial response. Coadministration of positively charged amino acids (lysine or arginine) and a fluid load is utilized to reduce the renal radioactivity dose through competitive inhibition of the proximal tubular reabsorption of the radiopeptide.19 This mechanism involves receptor-mediated endocytosis by megalin and possibly, and to a lesser extent, fluidphase endocytosis.32,33

Intra-Arterial Administration PRRT with either 90Y-DOTATOC or 177Lu-DOTATOC has been tested intra-arterially in the management of hepatic metastases based upon the high first-pass effect (higher hepatic arterial radioligand concentration) during intra-arterial

228 administration. This results in a higher hepatic tumor uptake than that obtained with intravenous administration, but also with binding to extrahepatic tumors. Studies of G1/G2 GEP NENs identified partial þ complete responses in 60%.34,35 A further advance on the intra-arterial strategy is the successful use of alpha-emitters in individuals with very advanced disease that has been progressive after conventional PRRT, because of the short path length and the high linear energy transfer of the alpha particles, resulting in a high tumor cell lethality with limited damage to untargeted tissue.36

PRRT Results PRRT therapy was initiated in 1992 as an investigational strategy in individuals with advanced NEN disease in which all other treatment modalities had failed. Despite the severity of these “last resort” situations, the observed efficacy of PRRT led to confidence that the strategy would be of utility in earlier phases of the NEN disease. Subsequent studies demonstrated that tumor load, especially in the liver, as well as grading and performance status were relevant parameters for predicting PRRT outcome. Analysis of the initial data obtained led to the conclusion that treatment in a phase of “early” progression rather than a “wait and see” approach, to treat in a state of overt progression, was more effective.37 A further consideration that emerged was that the efficacy was to some extent related to the location (type) of the type of disease. Thus, pancreatic NENs were noted to be more responsive to PRRT compared with other types of NENs, although they frequently relapse earlier 24 (Table 1). Additional factors to be considered include the tumor dose and volume, as well as the specific biological features of the lesion. Thus, more advanced tumors and highgrade tumors are less responsive to treatment because of lower SSTR expression and the presence of increased genetic mutations, as demonstrated by genomic analysis (eg, p53).38

PRRT With 111In-Pentetreotide The recognition that the use of increased activity of the diagnostic compound 111In-pentetreotide would enable transformation of a diagnostic strategy into a therapeutic modality provided the initial basis for the development of PRRT. Thus by the 1990s, PRRT was initiated as a single center trial in the treatment of very advanced, metastatic NENs. The basis of the strategy reflects internalization of the peptide or receptor complex facilitating the effects of Auger and conversion electrons emitted by 111In, decaying in close proximity to the cell nucleus. However, clinical results using this strategy resulted in few partial remissions although symptomatic improvement was frequently observed.18,39 As a consequence of the development of 1,4,7,10-tetra-azacyclododecane-N,N0 , N00 ,N000 -tetra-acetic acid (DOTA) (see later) chelated octreotide, β-emitting radionuclides such as the pure β-emitter 90 Y, with higher energy and longer particle range could be evaluated.

L. Bodei et al.

PRRT With 90Y-Somatostatin Analogues High-energy β emitters such as 90Y (maximum energy Eβmax ¼ 2.27 MeV, penetration range Rβmax ¼ 11 mm, and half-life T1/2 ¼ 64 h) seemed more suitable for PRRT. Such radionuclides not only exhibited a direct killing of SSTR-positive cells but also exerted a simultaneous crossfire that targeted adjacent receptor-negative tumor cells. To facilitate labeling and optimize ligand radionuclide stability of the radionuclide in the circulation, a new analogue, Tyr3-octreotide with a similar pattern of affinity for SSTRs, was developed at Novartis. In addition, this complex exhibited the advantages of high hydrophilicity and tight binding to the bifunctional chelator DOTA.40 This new chelator strategy (90Y-DOTA0,Tyr3)octreotide or 90Y-DOTATOC or 90Y-octreotide was initially used in the treatment of metastatic NENs in 1996.41 The encouraging objective and symptomatic response deriving from the application of several cycles of PRRT with 90Yoctreotide led to further studies aimed at examining the potential of PRRT in NEN disease.22 Based upon the initial encouraging results, 90Y-octreotide thereafter became the most widely used radiopeptide in the first decade of PRRT experience.23,42,43 The published results reflect a number of individual phase I-II studies performed independently by numerous centers, whose clinical protocols included schedules based upon the administration of per cycle and cumulative radioactivity. The latter were established using previous dose escalation studies, local clinical experience or 86Y-octreotide PET dosimetry or both.44 As a result of this diversity of protocol, substantial differences among individual protocols then occurred in respect of inclusion criteria, administered activities (eg, fixed or scaled to body weight), number of cycles, intervals between cycles, and kidney protection by amino acids. These issues, in many centers, have largely contributed to the lack of standardization of PRRT for many years. A rigorous direct comparison between individual studies from different centers that were undertaken is, therefore, currently not feasible. Nevertheless, the aggregate of reported studies indicate that objective responses are apparent in 4%-38%.18,21,22,26,45–48 In a study undertaken at Basel University, 39 patients with NEN (mostly GEP) received four cycles of 90Y-octreotide, with a cumulative activity of 7.4 GBq. Objective responses (WHO criteria) were identified in 23% (n ¼ 9), with a complete remission in two patients, a partial response in seven and a disease stabilization in 27. Pancreatic NENs (n ¼ 13) exhibited a better objective response (38% partial þ complete) than other tumor types. Significant amelioration of related symptoms was noted in the majority (63%). In this series, three patients with progressive bronchial tumors were also included and all demonstrated disease stabilization after PRRT.49 In a multicenter phase I study, including 86Y-octreotide PET dosimetry,44 carried out in Rotterdam, Louvain, and Tampa, 60 patients with GEP NENs were treated with four cycles of 0.9, 1.8, 2.8, 3.7, 4.6, and 5.5 GBq/m2 of 90Y-octreotide administered at 6-9 weekly intervals. The initial assessment of 32 evaluable patients indicated that objective responses (southwest oncology group [SWOG] criteria) were evident.

Radiolabeled SSAs therapy

Table 1 PRRT Clinical Results in GEP-NEN Based Upon the Different Treatment Schedules Utilized

90

Y-Octreotide

Schedule

Patients CR

PR

DCR

Progression Response Outcome (Median PFS or at Baseline Criteria TTP)

7.4 GBq/m2 in four cycles49 2.96-5.55 GBq/cycle  278 0.93-2.78 GB/m2/cycle50 4.4 GBq/cycle  323 1-10 cycles (median ¼ 2), various activity22

36 GEP 21 GEP 58 GEP 90 SI 821 GEP

20% 28% 9% 4% 38%

92% 71% 71% 74.4% n.a.

100% n.a. 81% 100% n.a.

WHO WHO SWOG SWOG RECIST

Not assessed TTP 10 months TTP 29 months PFS 16 months n.a.

28% 31% 21%

81% 88% 81%

43% 76% 88%

SWOG RECIST SWOG

PFS 33 months TTP 36 months PFS 20 months in reduced dosage, not reached in full dosage PFS 34 months PFS 36 months PFS 33 months PFS not reached (Lu) vs 8.4 months (LAR)

177

Lu-octreotate 27.8-29.6 GBq in three to four cycles26 3.7-29.2 GBq in four to six cycles of 3.7-7.4 GBq21 Mean 25.5 GBq in five cycles, normal subjects; mean 17.8 GBq in risk patients56

Combinations with 177Lu

4% 0% 0% 0% 0.2%

310 GEP 2% 39 GEP 3% 52 P 8%

32 GBq in four cycles48 Median 25.7 vs 18.4 GBq (normal vs risk patients)58 32 GBq in four cycles59 27.8-29.6 GBq in three to four cycles vs octreotide LAR 60 mg/mo60

68 P 43 SI 61 SI 201 SI

0% 60.3% 7% 0% 0% 13.1% 19% (Lu) vs 3% (LAR) CR þPR

85.3% 84% 91.8% 58% (Lu) vs 20% (LAR)

67.6% 100% 75.4% 100%

SWOG SWOG SWOG RECIST

31 GB1 in four cycles þ capecitabine, 1650 mg/m2 (14 d per cycle)64 31 GBq in 4three cycles þ 5-FU65 31 GB1 in four cycles þ capecitabine 1500 mg/m2 (14 days d per cycle) þ temozolomide (100-200 mg/m2)66 31 GB1 in four cycles þ everolimus (from 5-10 mg daily for 24 weeks)67

33 GEP

0%

24%

94%

100%

RECIST

68 GEP 33 GEP

0% 29% 16% 41%

68% 94%

85.2% 100%

RECIST RECIST

Median PFS not reached in a 16-month follow-up n.a. PFS 31 months

16 GEP

0%

94%

100%

RECIST

n.a.

44%

CR, complete response; DCR, disease-control rate (CR þ PR þ stability); n.a., not available or assessed; P, pancreatic; PR, partial response; SI, small intestine.

229

230 These constituted  9% partial and 9% minor responses.43 In a reanalysis of the 58 assessable patients (treated with cumulative activities of 1.7-32.8 GBq), a 57% clinical benefit, including stabilization and minor responses (SWOG criteria) was observed. Objective responses were described in 5%. The observed OS was  37 months (median) and PFS was  29 months. These results were considered to be superior to the 12-month OS of a historical group treated with 111Inpentetreotide.39 Characteristically, patients stable at baseline had a better OS than those who were progressive at baseline. The extent of disease at baseline was also a predictive factor for survival.50 The results of two phase I-II studies and a retrospective evaluation in 141 patients were published by the Milan group in 2004. SSTR-positive tumors (mainly GEP NENs and bronchial tract NENs) were treated with a cumulative activity of 7.4-26.4 GBq of 90Y-octreotide, divided into 2-16 cycles, administered 4-6 weeks apart. The objective response rate was 26%, including partial and complete responses (SWOG criteria). Disease stabilization was observed in 55% and progression was noted in 18%. The mean duration of response ranged from 2-59 months (median 18). The majority who responded had GEP NENs (3 gastric, 26 pancreatic, 27 small intestinal, and 2 rectal). Pancreatic tumors showed higher responses. Individuals who were stable at baseline exhibited a better outcome (partial and complete responses in 32%) than individuals with progressive disease (partial and complete responses in 24%).42 A multicenter study in 2010 evaluated the role of 90Yoctreotide in 90 patients with symptomatic, metastatic “carcinoids” (small bowel NENs). The data identified stabilization of tumor response (SWOG criteria) in 74% as well as a durable amelioration of symptoms related to the tumor mass and the hypersecretion of bioactive amines.23 This trial reported a PFS of 16 months and an OS of 27 months. More recently, the Basel group published the results of an open-label phase II trial in 1109 patients treated with 90Yoctreotide, divided into multiple cycles of 3.7 GBq/m2 each. Objective morphologic responses (response evaluation criteria in solid tumors [RECIST] criteria) were observed in 378 (34.1%), biochemical responses in 172 (15.5%), and symptomatic responses in 329 (29.7%). In this series, the NEN groups were 265 small bowel and 342 pancreatic tumors. The rates of objective response were 26.8% and 47%, respectively. A longer survival was correlated with tumor and symptomatic response. The best predictor of survival was tumor uptake at baseline determined by OctreoScan.22 Studies have also been undertaken with 90Y-DOTATATE. A total of 60 patients with histologically proven GEP NENs were treated with 4.1-16.2 GBq per patient (mean 3.7 GBq per therapy) in one to three cycles. After 6 months of PRRT completion, a partial response was evident in 13 patients (23%), whereas the remaining had stable disease (77%). The median PFS was 17 months and the median OS was 22 months. Hematological toxicity WHO grades three and four were noted during therapy in 10%, which persisted in 5%. After 24 months of follow-up, renal toxicity grade two was seen

L. Bodei et al. in seven (11.6%) and the authors emphasized the need for careful renal monitoring.45

PRRT With 177Lu-Somatostatin Analogues In 2000, the development of a new analogue, octreotate (Tyr3, Thr8-octreotide), that exhibited a six-fold to nine-fold higher affinity for SSTR2 initiated a new phase of the PRRT evolution. As this analogue had a slightly higher renal dwell-time, the chelated analogue [DOTA]0-Tyr3-octreotate or DOTATATE was labeled with a dual β-γ-emitter (177Lu) that possessed an Eβmax ¼ 0.49 MeV, Rβmax ¼ 2 mm, and T1/2 ¼ 6-7 days. This compound (177Lu-octreotate) was thereafter investigated in several clinical phases I and II studies21,26,37,51 and shown to enhance efficacy and greater manageability, due to a lower dosimetric burden to the kidney. An additional advantage was provided by the possibility of obtaining both scintigraphic images and dosimetric studies at the same time as a property of 177 Lu was its gamma photon coemission. Currently this compound represents the most frequently used radiopeptide for PRRT (Figs. 3 and 4). The first clinical, prospectively designed trials were undertaken at Erasmus University, Rotterdam. Individual phase II studies evaluated a series of 504 patients, 310 of which with GEP NEN were considered for objective response and survival analyses. A cumulative activity of 22.2-29.6 GBq of 177Luoctreotate was administered in four intended cycles of 7.4 GBq each. Complete and partial remissions occurred in 2% and 28%, with minor responses in 16% and stabilization in 35%, respectively (SWOG criteria). The median OS was 448 months and the median PFS was 33 months. A “direct comparison” with data obtained from similarly published patient series indicated a 40-72-month survival benefit for PRRT-treated individuals. Although these data are not derived from prospective randomized phase III trials, this substantial survival difference likely provides a reasonable reflection of the therapeutic effect of PRRT.26 Response benefit was more frequent in individuals with limited liver involvement and a high uptake on baseline 111In-pentetreotide scintigraphy. Conversely, progression was significantly more frequent in those with a low performance score and extensive disease at enrolment. Categorization of objective responses identified that pancreatic NENs tended to respond better than other GEP NENs, and that functioning tumors, for example, pancreatic gastrinomas, tended to relapse after a shorter interval (median time-to-progression 20 months vs 436 in the remaining GEP NENs).24 In the same patient group, 177Lu-octreotate treatment was also associated with a significant improvement in the global health or quality of life on various symptom scales, particularly fatigue, insomnia, pain, as well as emotional, and social functions.25,52 The effect was more frequent in individuals with tumor regression, but paradoxically was also evident in those with progressive disease.52 Of note was the fact that there was no significant decrease in quality of life in individuals asymptomatic before therapy (Table 2).25 The results of a phase I-II escalation dose study aimed at defining toxicity and efficacy of 177Lu-octreotate was published

Radiolabeled SSAs therapy

231

A

B

E

C

D

F

Figure 3 The efficacy of 177Lu-DOTATATE in a 53-year-old woman with a NET of the small bowel, metastatic to the liver and bone. Images after each of four cycles of 200 mCi of 177Lu-octreotate, (A-D) show progressively lower tumor uptake, indicating tumor response. (E and F) PR on CT 6 months after the last PRRT.

in 2011.21 A cohort (n ¼ 51) with unresectable or metastatic NENs, mainly of GEP origin, were divided into two dosage groups. First group received escalating activities from 3.7-5.18 GBq and the second from 5.18-7.4 GBq with dosimetry-based cumulative activities up to 29 GBq. Partial and complete responses were observed in 15 patients (32.6%). The median time-to-progression was 36 months, with an OS of 68% at 36 months. Nonresponders and patients with extensive tumor involvement were noted to have a lower survival.21 A meta-analysis undertaken in 2015 included six studies with a total of 473 GEP NENs, and evaluation of the data concluded that 177Lu-octreotate is an effective option for patients with inoperable or metastatic NENs and that both RECIST and SWOG criteria provide similar evaluation of responses, with a disease-control rate of 81% and 82%, respectively.53

Bone Metastases Despite the fact that evaluation of bone metastases does not contribute to treatment evaluation, whether SWOG or RECIST, it was initially considered that bone metastases were not amenable to PRRT. However, the efficacy of PRRT in bone

metastases has been demonstrated in a retrospective series (n ¼ 68) treated with 177Lu-octreotate (four intended cycles, 8.1 GBq each, at 3-month intervals; followed up for a median of 48 months). The observed objective response rate was comparable to other studies of PRRT in GEP NENs, with 2.9% and 33.8% complete and partial responses, respectively. The median PFS was 35 months. Individuals with PRRTresponsive bone metastases exhibited longer OSs (median, 56 vs 39 months). In this patient group, high neuron-specific enolase (NSE) values and Ki67 4 10% were associated with a shorter OS. Of note was the observation that Karnofsky performance status and multifocal bone metastatic disease did not limit the efficacy of PRRT.54,55

Organ-Specific PRRT Pancreas With the recognition of pancreatic and small intestine NENs as separate biological and molecular neoplastic entities, current studies have tended to address the role of PRRT in singlesystem pathologies. A prospective phase II study used 177Lu-octreotate in a cohort (n ¼ 52) with advanced well or moderately differentiated pancreatic NENs. Based on the reported, possible

L. Bodei et al.

232

A

B

Figure 4 Response to 177Lu-DOTATATE-PRRT for a rectal NEN with a massive (21.5 cm diameter) inoperable right-lobe liver metastasis. Previous therapy included surgery (rectosigmoid resection) and chemotherapy (capecitabine). (A) Anterior view, whole body scan after the initial cycle #1 of 177Lu-DOTATATE. (B) 68Ga-DOTATOC MIP image after PRRT completion (four cycles), three cycles of transarterial embolization, and an additional course of PRRT with 177Lu-octreotate (cumulative activity 43 GBq). Significant shrinkage of the dominant hepatic lesion to a diameter of 1.5 cm evident on CT.

existence of risk factors for renal toxicity, such as hypertension and diabetes, patients were divided into two groups treated with different levels of activity. Thus, full dose (21-28 GBq) was compared with a reduced dose (11-20 GBq) for a normal and risk subset of subjects, respectively. Both regimens resulted

in antitumor efficacy. PFS was not reached at the time of the analysis in the cohort treated with the full-dose regimen, whereas it was 20 months in individuals treated with a reduced dose. This suggests the full-dose scheme should be recommended, whenever possible.56

Table 2 Symptom Control After PRRT Number of Symptom Patients 90

Y-Octreotide

479 47 63 65 14 14

177

Lu-Octreotate 111 10

n.s., not specified.

Median Duration Symptomatic Prior or Concomitant Use Response, N (%) of Response (wk) of SSA, N (%)

Carcinoid related n.s. Functional P-NENs Flushing 63 (70) Diarrhea Flushing 15 (38) Diarrhea Diarrhea Uncontrolled symptoms

164 (62) n.s.

Reference

– –

22

33 (51) 38 (60) 9 (64.3) 6 (42.9)

9.7 13.8 – –

23

74 (67) 7 (70)

– –

143 (29.9) 7 (14.9)

49 25 65

Radiolabeled SSAs therapy A recent retrospective study evaluated a cohort with metastatic pancreatic NENs (n ¼ 68, 52% at their first systemic treatment) treated with 177Lu-octreotate (four intended cycles, 8 GBq each, at 3-month intervals). In this group, 68% were in progression at enrolment. Partial responses were noted in 60%, with a median PFS of 34 months. Multivariate analysis indicated that G1 tumors had a longer PFS. Reduced performance status (KPS r 70), a high liver burden (Z25% of volume), and increased NSE (415 ng/mL) were associated with a poorer prognosis.48 To better define the predictors of long-term outcome, the same group undertook a multivariate analysis in a cohort of metastatic GEP NENs (n ¼ 74) who had previously undergone PRRT with 177Lu-octreotate (four cycles, 7.9 GBq each, at 3-month intervals). A Ki67 index 410%, a Karnofsky performance status r70, a tumor burden in the liver Z25%, and a baseline NSE 415 ng/mL were independent predictors of shorter survival. However, even individuals with Ki67 4 10% benefited from PRRT, with a median PFS of 19 months as opposed to 26 months for the entire cohort.37 A separate study by van Vliet et al considered 29 nonresectable or borderline resectable or oligometastatic (r3 liver metastases) nonfunctioning pancreatic NENs. This group was treated with 177Lu-octreotate with neoadjuvant intent. After PRRT, successful surgery could be performed in nine patients (31%) (Whipple procedure [n ¼ 6], pylorus-preserving pancreaticoduodenectomy [n ¼ 1], and splenopancreatectomy [n ¼ 1]). PFS was significantly longer in operated patients (69 vs 49 months). A further comparison with 90 plurimetastatic subjects treated in the same fashion provided a PFS of 25 months.57 This study supports the proposal of early treatment and the possibility of downstaging tumors with PRRT. Small Intestinal NENs A phase II study of PRRT in 43 progressive G1-G2 tumors from the Meldola group applied the same principle of reducing cumulative activities (median 25.7 vs 18.4 GBq) in patients at risk for delayed renal or hematological toxicity. Both activities proved to be safe and effective (84% disease-control rate [SWOG criteria] and PFS of 36 months) in all patients. It is noteworthy that PET FDG-negative patients exhibited a significantly longer PFS than those with an FGD-positive scan.58 A more recent study by the Bonn group utilized the standard approach and described the benefit of 177Lu-octreotate in a uniformly treated group (four cycles of 7.9 GBq each). A total of 61 patients with unresectable small intestine tumors, in progression or with uncontrolled symptoms were included, treated, and followed up for 62 months. Disease-control rate was 91.8 (SWOG criteria). Median PFS was 33 months, OS was 61. Objective response was significantly associated with longer survival. Independent predictors of shorter PFS were functionality and high plasma chromogranin A levels 4600 ng/mL at baseline.59 The most recent study of SI NETs using 177Lu-DOTATATE was undertaken by a consortium sponsored by advanced accelerator applications. This is a two-continental phase III randomized trial of 177Lu-DOTATATE vs high-dose octreotide long-acting repeatable in patients with inoperable, progressive,

233 midgut carcinoid tumors. Preliminary results indicate that Lu-octreotate significantly improves PFS (PFS not reached vs 8.4 months; hazard ratio 0.21).60 177

Salvage Therapy Despite the demonstrated efficacy of PRRT for GEP NENs, most of the subjects relapse after 2-4 years. Several groups, therefore, have evaluated the application of a second, lowdosage course of PRRT. The first indication of the feasibility of this approach came from the Rotterdam group who described the use of a salvage protocol with 177Lu-octreotate.53 Patients in progression were enrolled after an initial response to PRRT with 177Lu-octreotate at standard cumulative activities (22.2-29.6 GBq). In this series, 32 patients with bronchial or GEP NENs received two additional cycles of 177Lu-octreotate, with a cumulative activity of 15 GBq. Objective responses occurred in eight patients (two partial and six minor responses), whereas stabilization was identified in further eight patients. The median time-toprogression was 17 months. Both the response rates and duration over time were lower than during the initial treatment. Nevertheless, “salvage therapy” was well tolerated by the majority and has been proposed as a viable option for this category of patient.61 A more recent analysis by the Meldola group included 26 subjects in progression after an initial treatment with 90Yoctreotide.54 All patients had preserved kidney and hematological parameters and received an intended cumulative activity of 14.8-18.5 GBq of 177Lu-octreotide in four or five cycles. Disease-control rate was 84.6%, and the median PFS 22 months (95% CI 16 months—not reached) was comparable to that obtained after 90Y-octreotide (28 months; 95% CI: 20-36 months). Tumor burden and number of liver metastases were significant negative prognostic factors.62

Combination Therapy This concept is consistent with recent therapeutic trends in oncology, and PRRT users have themselves focused on combinations of therapy. A variety of different studies have demonstrated feasibility and efficacy. However, prospective randomized controlled studies are needed to define the exact benefit of this approach. The use of the radiosensitizer chemotherapy agent, capecitabine, together with 177Lu-octreotate is the current most commonly used strategy. An initial study in a small group (n ¼ 7) of progressive GEP NENs using four cycles of standard activity of 177Lu-octreotate followed by capecitabine (1650 mg/m2) for 2 weeks was undertaken with encouraging results.63 No severe toxicity, particularly hand-foot syndrome or hematological or renal-associated toxicity was evident. Objective responses were observed. This report prompted further studies. A subsequent phase II study of progressive NENs (n ¼ 33) treated with four cycles of 7.8 GBq of 177Luoctreotate followed by capecitabine 1650 mg/m2 (2 weeks) produced a 24% objective response with 70% stable disease

L. Bodei et al.

234 and 6% progression without adjunctive toxicity (RECIST criteria).64 The first results of a randomized prospective trial comparing 177 Lu-octreotate plus capecitabine vs 177Lu-octreotate, at Rotterdam, are expected in 2016. A more recent version of the chemoradiotherapy protocol utilized 5-fluorouracil (5-FU) as opposed to its oral prodrug capecitabine.57 A retrospective analysis of 68 patients with progressive disease or uncontrollable symptoms from NENs showed that the combination strategy (median cumulative activity of 177Lu-octreotate 31 GBq and 200 mg/m2/24 h 5-FU, from 4 days before to 3 weeks after PRRT cycle two to four) resulted in 70% benefit for at least 6 months for symptomatic patients and 68% disease-control rate in progressive disease. Nonpancreatic primary site, dominant liver metastases, lesions o5 cm, and the use of 5-FU were associated with objective response.65 A combination of 177Lu-octreotate with capecitabine and temozolomide was studied in a phase I-II trial of 35 advanced low-grade NENs, with the aim of evaluating safety and efficacy.58 Standard 7.8 GBq of 177Lu-octreotate every 8 weeks was combined with 14 days of capecitabine 1500 mg/m2 and, in successive cohorts, to escalating doses of temozolomide (100, 150, and 200 mg/m2 in the last 5 days of each capecitabine cycle). Treatment was well tolerated without dose-limiting toxicities. Complete responses were observed in 15%, partial response in 38%, and stable disease in 38%. Responses tended to be higher in gastropancreatic than in small intestine primaries. Median PFS was 31 months.66 An alternative combination phase I study evaluated the combination of everolimus with 177Lu-octreotate in 16 subjects with advanced GEP NENs.59Standard PRRT (four cycles of 7.8 GBq each) was administered in cohorts of patients receiving escalating doses of everolimus (from 5-10 mg daily for 24 weeks). The maximum tolerated dose of everolimus was 7.5 mg (hematological and renal toxicity). The overall response rate was 44%, with no progression over the period of treatment. The best response occurred in pancreatic NENs, where four of five patients achieved 80% reduction of disease.67

Combinations of 90Y-Peptides and 177 Lu-Peptides Protocols combining both 177Lu-peptides and 90Y-peptides have been assessed with the purpose of utilizing the synergistic

different physical properties of each radionuclide. Theoretically, this approach should allow simultaneous treatment of both large lesions (exploiting the higher energy and penetration range of the particles emitted by 90Y) and small lesions (exploiting the lower energy and penetration range of 177Lu). Combination-radionuclide PRRT was undertaken in a cohort of 69 Danish patients treated in Basel.61 Complete responses were noted in 5 (7.4%), partial remissions in 11 (16.2%), and stabilization in 42 (61.8%) of cases. The median PFS was 29 months. Pancreatic NENs responded better than small bowel tumors.46 This strategy, however, remains to be validated in prospective, randomized studies, rather than empirically designed single-armed 177Lu and 90Y protocols.68,69 The differences observed in the latter indicate that very large cohorts of patients are needed.

PRRT Safety Profile Renal Accumulated clinical experience and evidence accumulated over the past two decades and have demonstrated that PRRT with 90Y-peptides and 177Lu-peptides is generally well tolerated and that adverse events are modest. Acute side effects are usually mild (nausea and rarely, emesis) and are correlated to the (type of) coadministration of amino acids used to reduce renal exposure to radiation. Other adverse modest events (commonly fatigue) and the exacerbation of an endocrine syndrome or hormonal crisis (infrequently, approximately 1% and mainly occurring in the treatment of functional tumors) represent the cytotoxic effects of the radiopeptide. Chronic and permanent effects in the kidneys and the bone marrow are generally mild if the necessary precautions (renal protection with amino acids; dosage fractionation and attention to specific risk factors [eg, hypertension or previous nephro- or myelotoxic chemotherapy regimens]) are undertaken19,22,46,49,70 (Table 3). It has been demonstrated that the usage of appropriate dosimetry improves the delivery of elevated absorbed doses to the tumor, with relative sparing of healthy organs (kidneys and bone marrow).71 Renal irradiation occurs due to the reabsorption of the radiopeptides in the proximal convoluted tubules, with a subsequent accumulation in the renal interstitium, where the radioactivity exerts its action inducing vasculitis and fibrosis. Studies with external radiotherapy indicate a renal threshold of tolerance in the range of 23-27 Gy. The recently introduced

Table 3 Long-Term PRRT Toxicity in GEP NENs 90

Y-Octreotide

177

Lu-Octreotate

Patients

Follow-Up (Mo)

Renal Toxicity

MDS

Acute Leukemia

Reference

40 39 58 1109 358

19 6 18 23 30

10% Grade one 3% Grade two 3% Grade four 9.2% Grade three or four 2.8%

0 0 1 1 7 (1.95%)

0 0 0 1 5 (1.4%)

78 49 50 22 30

504 51 74 290

19 29 21 30

0.4% Grade four 24% Grade one 1.3% Grade three or four 0%

3 0 3 6 (2.06%)

0 0 0 2 (0.69%)

26 21 70,81 30

Radiolabeled SSAs therapy bioeffective dose, which reflects more accurately the type of irradiation generated by PRRT, estimates the renal threshold for toxicity at approximately 40 Gy.44,72 Renal toxicity is significantly decreased when positively charged amino acids, such as lysine and arginine, are coinfused with the radioligand. These competitively inhibit proximal tubular radiopeptide reabsorption by saturating the apical membrane megalin, resulting in a 9%-53% reduction in renal radioactive dosage.73 Overall, a mild loss of renal function over time occurs, with a median decline in creatinine clearance of 7.3% per year for 90Y-octreotide and 3.8% per year for 177Luoctreotate.74 Nevertheless severe, end-stage renal damage remains rare with 177Lu-octreotate and only sporadic cases are reported in literature.18 Earlier concerns of high numbers of renal problems reported were mostly associated with the use of 90 Y-peptide PRRT, and reflected administration of very high activities in the absence of amino acid renal protection or renal protection with too low lysine and arginine amounts.75 Long-term evaluation has indicated that a higher and more persistent decline in creatinine clearance and the consequent development of renal toxicity is more likely to occur in the presence of preexisting risk factors, for example, long-standing hypertension or poorly controlled diabetes or both.74,76 Overall, PRRT with 90Y-peptides is more frequently associated with a reduction of renal function, presumably reflecting the specific physical characteristics of the 90Y radionuclide, namely the much larger particle penetration into the kidney. A long-term evaluation of renal toxicity in a group (n ¼ 28) undergoing PRRT with dosimetric analysis showed that, of the 23 treated with 90Y-octreotide, a low (28 Gy bioeffective dose) threshold was observed with risk factors (mainly hypertension and diabetes), in comparison to 40 Gy in the absence of such risk factors.76 In a retrospective series (n ¼ 1109) treated with 90Yoctreotide, 103 subjects (9.2%) experienced grade four to five permanent renal toxicity.22 Multivariate regression revealed that the initial kidney uptake was predictive of severe renal toxicity. However, it seems likely that this relatively high incidence was related to the high-administered activities per cycle (3.7 GBq/m2 body surface, namely activities of approximately 6.4 GBq per cycle in a standard male). Furthermore, individuals with preexisting impairment of renal function were not excluded from PRRT. A further consideration is that infusion of protective amino acids was not routinely employed in the earlier phases of the study.75 Recently, the results of an analysis of long-term tolerability of PRRT (n ¼ 807) treated with 90Y-octreotide, 177Lu-octreotate, or the combination (Lu: 34.4%, Y: 44.4%, Lu þ Y: 19.5%) provided additional PRRT toxicity information. This analysis illuminated the lack of a clearly definable role for previous clinical parameters (such as diabetes, hypertension, and chemotherapy) considered to be responsible. Nephrotoxicity, transient and persistent, was detectable in 279 (34.6%) and severe in 1.5%. 90Y-peptides or the combination of 90Ypeptides or 177Lu-peptides showed greater nephrotoxicity than 177Lu-peptides alone. However, o30% of the toxicities could be modeled by clinical parameters. Hypertension and anemia were noted to be the most relevant risk factors. It seems

235 probable that a unique individual susceptibility to toxicity, possibly of genetic origin, might play a role.77 An accurate assessment of glomerular filtration rate, as a measure of renal function, (Gates method), was carried out after PRRT (n ¼ 74) with a median of 21-month (range: 12-50) follow-up. The evaluation included potential risk factors, such as diabetes mellitus, hypertension, and chemotherapy. Results confirmed an alteration in glomerular filtration rate, with a relative yearly reduction of 1.8 ⫾ 19%. A total of 16 patients experienced a more pronounced reduction (410 mL/min/y). However, toxicity was only evident in one. None of the described clinical factors, including the cumulative administered activity, contributed significantly to the decline of renal function.70

Hematological From a hematological perspective, PRRT is generally well tolerated. Subacute toxicity with severe WHO grade three or four toxicity occurs in o13% after 90Y-octreotide and in  10% after 177Lu-octreotate. Nevertheless, sporadic cases of MDS or even overt acute leukemia have been reported,19 possibly in the order of 2%. Although predicted absorbed doses are lower than the conventional threshold for toxicity, both acute and permanent bone marrow damage remains a cause for concern, particularly in the event of repeated radionuclide administrations.42 Dose-finding phase I studies indicate that the maximum cumulative administrable activity per cycle of 90Y-octreotide, with renal protection, is 5.18 GBq, as determined by limiting hematological toxicity.78 Investigations employing the dose-limiting toxicity method were abandoned, as published data identified that 7.4 GBq could be safely used as a maximum activity per cycle,79 which dose was based on the experience of thyroid cancer therapy with 131I, a radionuclide with similar characteristics as 177Lu.80 In data from a cohort with GEP NENs (n ¼ 33) treated in a salvage study, toxicity results were encouraging. Thus, retreatment with median 18 GBq of 177Lu-octreotate (two to four cycles, up to a median cumulative activity of 44.3 GBq: range: 30-84) resulted in neither severe nephrotoxicity nor MDS during the follow-up (37 ⫾ 16 months from initial PRRT and 23 ⫾ 7 months from the start of salvage PRRT).81 An analysis of 203 patients treated with four intended cycles of 8 GBq each at 3-month intervals, included the assessment of risk factors, including bone metastases, chemotherapy, or cumulative administered activity. The incidence of MDS was 1.4%. Myelosuppression was almost invariably reversible and the cumulative administered activity and initial cytopenia were the most important risk factors for myelotoxicity.81 An analysis of a group (n ¼ 807) treated with 90Y-octreotide, 177 Lu-octreotate, or the combination, showed that MDS occurred in 2.35%. This study also noted that “classical” risk factor, such as chemotherapy, was only associated with toxicity in 30%. Associated clinical features, such as platelet toxicity grade and the increasing duration of PRRT were relevant. This led to speculation that unidentified individual susceptibilities, presumably of a genetic basis, provide a propensity to radiation-associated disease.77

L. Bodei et al.

236 Recent studies demonstrated that 177Lu-octreotate could be safely utilized even in florid bone metastases, with extreme bone replacement and potential higher exposure of bone marrow. Significant G3/G4 reversible hematological toxicity occurred in 35% (n ¼ 4) of 11 patients. Toxicity either resolved spontaneously (one case) or was controlled by support therapy (three cases). A return to baseline values was obtained in 23 months after completion of PRRT.82 Finally, the issue of a potential increased toxicity of everolimus, when administered after the completion of PRRT, was addressed in a limited GEP NENs study (n ¼ 24). The group pretreated with PRRT had no significant adjunctive toxicity compared with the naïve group. Major events were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine aminotransferase (8.3%).83 A recent retrospective multicentric study, however, provided data inconsistent with these observations and suggested that the issue required further clarification. The likelihood that the combination with everolimus, which has well described adverse, would not yield greater toxicity needs rigorous analysis. This issue is of considerable clinical significance given the increasingly frequent use of sequential multidisciplinary strategies employing both treatments.84

Future Advances In reality, when prediction of outcome (efficacy and tolerability) becomes a major issue, in view of the multidisciplinary sequencing of long and expensive therapies, and where both conventional (morphologic or functional) imaging and biomarkers show their limitations, molecular tools, such as transcript analysis of specific circulating NET mRNA signature show promising results. A circulating multianalyte 51-gene NET signature demonstrated significant advantage in early detection of residual disease of surgically treated patient or in the assessment of SSA response.85,86 Preliminary results show advantage in defining and predicting response to PRRT.30 Molecular analysis of nephrotoxicity and hematotoxicity genes in cohorts of treated patients is likely to further improve the prediction of toxicity.

Conclusions PRRT has become a well-accepted effective therapeutic modality for inoperable or metastatic GEP, bronchopulmonary, and other NENs over the past two decades. It is overall well tolerated with most recipients experiencing only moderate toxicity if the necessary precautions are undertaken. The two most commonly used radiopeptides, 90Y-octreotide and 177Luoctreotate, produce significant objective response rates, with positive effect on PFS and OS. In addition, both biochemical and symptomatic responses are commonly observed. The first results of a very recent randomized trial have demonstrated the benefit of PRRT in small intestine NENs. Sophisticated molecular tools need to be incorporated into the management strategy to more effectively define therapeutic efficacy and early identification of adverse events. The strategy of randomized

controlled trials is a key issue to standardize the treatment and establish the position of PRRT in the therapeutic algorithm of NENs.

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