W A van der Zwan and PRRT in neuroendocrine tumors 172:1 R1–R8 Review others

GEP–NETS UPDATE therapy in neuroendocrine tumors

Wouter A van der Zwan, Lisa Bodei1, Jan Mueller-Brand2, Wouter W de Herder, Larry K Kvols3 and Dik J Kwekkeboom Correspondence Department of , Erasmus MC, University Medical Center, s-Gravendijkwal 230, 3015CE Rotterdam, should be addressed The Netherlands, 1Department of Nuclear Medicine, European Institute of Oncology, Milan, Italy, 2Department of to W A van der Zwan Nuclear Medicine, University Hospital Basel, Basel, Switzerland and 3Department of GI Oncology, H. Lee Moffitt Email Center and Research Institute, Tampa, Florida, USA [email protected]

Abstract

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 - 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 PRRTwith 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. European Journal of Endocrinology European Journal of Endocrinology (2015) 172, R1–R8

Invited Authors’ profiles: Dik Kwekkeboom, MD works for the Department of Nuclear Medicine at the University Hospital, Erasmus MC, Rotterdam, The Netherlands. His major research interest is peptide receptor imaging and he coordinates the studies on therapy with the radiolabelled somatin analog 177Lu-octreotate in patients with neuroendocrine tumors. He has numerous publications in international journals and textbooks, mainly in the field of endocrinology and peptide receptor and therapy.

Wouter A van der Zwan currently works as research physician within the peptide receptor radionuclide therapy (PRRT) team at the Department of Nuclear Medicine of the Erasmus MC, Rotterdam and is directly involved in the treatment of patients affected by a with PRRT. Besides the clinical care of patients undergoing PRRT, his work includes conducting scientific research on the early and late effects, and optimization of PRRT.

www.eje-online.org Ñ 2015 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-14-0488 Printed in Great Britain

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Introduction

The majority of gastroenteropancreatic neuroendocrine progression-free survival (PFS) varying from 17 to 29 tumors (GEPNETs) express somatostatin receptors and months, and median overall survival (OS) from 22 to 37 can be treated with radiolabeled somatostatin analogs. months (Table 2) (1, 2, 3, 4, 5). In a recent report on the The majority of patients that have been treated with treatment effects of 90Y-DOTATOC in a large group of this so-called peptide receptor radionuclide therapy patients, the response to 90Y-DOTATOC was associated (PRRT) had inoperable metastatic disease, and 70–90% of with longer survival (8). them had liver metastases (1, 2, 3, 4, 5). 177Lutetium (177Lu) is a medium energy b-emitter, with a maximal tissue penetration of 2 mm. 177Lu also emits low-energy g-rays, allowing scintigraphy and PRRT: efficacy subsequent using the same, therapeutic, Because at that time somatostatin analogs labeled with compound. The somatostatin analog [DOTA0,Tyr3] b-emitting were not available for clinical octreotate differs from [DOTA0,Tyr3]octreotide only in use, early studies in the 1990s used high activities of that the C-terminal threoninol is replaced with threonine, the Auger emitting [111In-DTPA0]octreotide resulting in a higher affinity for the somatostatin receptor (111In-octreotide) for PRRT. These treatments often subtype 2 than octreotide (9). The treatment effects of resulted in symptom relief in patients with metastasized [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) therapy neuroendocrine tumors (NETs), but objective tumor were described in a large group of GEPNETs patients (5). responses were rare (Table 1) (6, 7). Complete response (CR) was found in five (2%) patients, The next generation of analogs used in PRRT consisted partial response (PR) in 86 (28%), and minor response of a modified somatostatin analog, [Tyr3]octreotide, and a (MR) in 51 (16%) patients (Table 2). Prognostic factors for different chelator, DOTA instead of DTPA, which allows predicting tumor response (CR, PR, or MR) as treatment stable binding of the b-emitting radionuclide 90Yttrium outcome were high uptake on the Octreoscan, Karnofsky (90Y). Its maximal tissue penetration is 12 mm and its half performance score O70, and low metastatic load to the life is 2.7 days. [90Y-DOTA0,Tyr3]octreotide (90Y-DOTA- liver. Median time to progression was 40 months from TOC) was used in several phase-1 and phase-2 PRRT trials start of treatment. Progression of disease was more in various countries (Table 1). The registered objective common in patients with an extensive disease or in a responses range from 4 to 33%. Differences in cycle doses poor general clinical condition (Karnofsky score !70%,

European Journal of Endocrinology and administered cumulative dose, as well as differences in significant weight loss, the presence of bone metastases). patient characteristics (included tumor types, patient Several of these factors that had a significant impact on performance status), make it virtually impossible to PFS were also found in another study (10). Median OS compare these studies. Different studies report median was 46 months (Table 2). It may be postulated that

Table 1 Tumor responses in patients with gastroenteropancreatic neuroendocrine tumors, treated with different radiolabeled somatostatin analogs.

Tumor response

Center (reference) Ligand n CR PR MR SD PD CRCPR (%)

Rotterdam (6) [111In-DTPA0]octreotide 26 0 0 5 (19%) 11 (42%) 10 (38%) 0 New Orleans (7) [111In-DTPA0]octreotide 26 0 2 (8%) NA 21 (81%) 3 (12%) 8 Milan (13) [90Y-DOTA0,Tyr3]octreotide 21 0 6 (29%) NA 11 (52%) 4 (19%) 29 Basel (14, 15, 41) [90Y-DOTA0,Tyr3]octreotide 74 3 (4%) 15 (20%) NA 48 (65%) 8 (11%) 24 Basel (15, 41) [90Y-DOTA0,Tyr3]octreotide 33 2 (6%) 9 (27%) NA 19 (57%) 3 (9%) 33 Multicenter (1) [90Y-DOTA0,Tyr3]octreotide 58 0 5 (9%) 7 (12%) 33 (61%) 10 (19%) 9 Multicenter (2) [90Y-DOTA0,Tyr3]octreotide 90 0 4 (4%) NA 63 (70%) 11 (12%) 4 Copenhagen (3) [90Y-DOTA0,Tyr3]octreotide 53 2 (4%) 10 (19%) NA 34 (64%) 7 (13%) 23 Warsaw (4) [90Y-DOTA0,Tyr3]octreotate 58 0 13 (23%) NA 44 (73%) 3 (5%) 23 Rotterdam (5) [177Lu-DOTA0,Tyr3]octreotate 310 5 (2%) 86 (28%) 51 (16%) 107 (35%) 61 (20%) 29 Gothenburg (42) [177Lu-DOTA0,Tyr3]octreotate 26 0 6 (38%) NA 8 (50%) 2 (13%) 38 Lund (43) [177Lu-DOTA0,Tyr3]octreotate 12 0 2 (17%) 3 (25%) 5 (40%) 2 (17%) 17 Milan (10) [177Lu-DOTA0,Tyr3]octreotate 42 1 (2%) 12 (29%) 9 (21%) 11 (26%) 9 (21%) 31

CR, complete response; PR, partial response; MR, minor response; SD, stable disease; PD, progressive disease.

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Table 2 Survival data in patients with gastroenteropancreatic neuroendocrine tumors, treated with different radiolabeled somatostatin analogs.

Liver metastases Center (reference) Ligand n (percentage of patients) PFS (months) OS (months)

Multicenter (1) [90Y-DOTA0,Tyr3]octreotide 58 – 29 37 Multicenter (2) [90Y-DOTA0,Tyr3]octreotide 90 72 16 27 Copenhagen (3) [90Y-DOTA0,Tyr3]octreotide 53 87 29 – Warsaw (4) [90Y-DOTA0,Tyr3]octreotide 58 85 17 22 Rotterdam (5) [177Lu-DOTA0,Tyr3]octreotate 310 89 33 46

PFS, progression free survival; OS, overall survival.

early treatment with PRRT can increase the PFS and OS. fatigue, hematologic or renal toxicity, mild hair loss However, in a retrospective series of 68 patients suffering (observed with 177Lu-octreotate), impairment of male from advanced pNET, 35 patients received PRRT as fertility or, more rarely, an exacerbation of a clinical first-line treatment. The outcome regarding PFS and OS syndrome. The most common subacute side-effect of did not differ from patients treated with PRRT in a later PRRT, occurring within 4–6 weeks after therapy, is setting (11). hematologic toxicity. Hematologic toxicity is caused by In a large group of (nearly 300) patients treated with irradiation of the bone marrow. Usually hematologic PRRT and who had a long follow-up, it was shown that toxicity is mild and reversible. More serious, WHO grade quality of life (QoL) and also symptomatology improved 3 or 4 toxicity may occur in !15% of patients (1, 3, 8, 10, in 40–70% of cases, depending on the preexistence of 13, 14, 15, 16). a certain symptom (12). This is important because the Long-term serious side-effects of PRRT are renal failure months to years that are gained after PRRT can only be or myelodysplastic syndrome (MDS)/leukemia (Table 3). called promising if the time that is gained is free of serious Proper protection, with the co-infusion of side-effects or symptomatology that affect QoL. By positively charged amino acids, is mandatory in PRRT. contrast, it was shown that the years gained after PRRT With advances in expertise and knowledge about PRRT, show an improved QoL, as judged by the patients cases of severe, end-stage, renal damage are currently themselves, according to a validated questionnaire (12). very rare. However, despite kidney protection, loss of kidney function can occur after PRRT, with a creatinine

European Journal of Endocrinology clearance loss of about 3.8% per year for 177Lu-octreotate PRRT: side-effects and 7.3% per year for 90Y-DOTATOC (17). Studies have PRRT is generally well tolerated. Acute side-effects are demonstrated that a higher and more persistent decline usually mild and self-limiting. Nausea or, more rarely, in creatinine clearance is more frequent if risk factors vomiting is related to the concomitant administration of for delayed renal toxicity are present, particularly nephro-protective amino acids. Other, more subacute long-standing and poorly controlled diabetes and side-effects are related to the radiopeptide itself, such as hypertension (18).

Table 3 Long-term toxicity in patients with neuroendocrine tumors, treated with different radiolabeled somatostatin analogs.

Toxicity

Center (reference) Ligand n FU Creatinine MDS Leukemia

Milan (13) [90Y-DOTA0,Tyr3]octreotide 40 19 10% Grade 1 0 0 Basel (14) [90Y-DOTA0,Tyr3]octreotide 41 15 0 0 0 Basel (15, 41) [90Y-DOTA0,Tyr3]octreotide 39 6 3% Grade 2 0 0 Multicenter (1) [90Y-DOTA0,Tyr3]octreotide 58 18 3% Grade 4 1 0 Basel (16) [90Y-DOTA0,Tyr3]octreotide 31 12 12.9% Grade 3/4a 00 Copenhagen (3) [90Y-DOTA0,Tyr3]octreotide 53 17 0 1 0 Basel (8) [90Y-DOTA0,Tyr3]octreotide 1109 23 9.2% Grade 3/4a 11 Rotterdam (5) [177Lu-DOTA0,Tyr3]octreotate 504 19 0.4% Grade 4 3 0 Milan (10) [177Lu-DOTA0,Tyr3]octreotate 51 29 24% Grade1 0 0

FU, follow-up; MDS, myelodysplastic syndrome. Grades pertain to World Health Organization (WHO) classification. aToxicity based on glomerular filtration rate.

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With adequate renal amino acid protection, grade 3–4 the combined therapy of 5-fluorouracil (5-FU) and PRRT, a renal toxicity occurs in !3% of patients (Table 3). One randomized trial was started comparing treatment with recent study, however, states a grade 3–4 renal toxicity 177Lu-octreotate with and without capecitabine (the oral in 9% of their patients (8). This relatively high incidence prodrug of 5-FU) (Xeloda; Roche) in patients with could be related to relatively high activities administered GEPNETs (29). Results of another non-randomized phase per cycle and to the fact that patients with pre-existing II study treating patients with a combination of capecita- reduced kidney function were not excluded from treatment. bine and 177Lu-octreotate demonstrated tumor control The possible lack of use of amino acids in the first years and stabilization in 94% of the 33 included patients. of this study must also be taken into account (19). However, due to grade 3 capecitabine-induced angina, Serious side-effects of PRRT on the bone marrow, three patients discontinued the drug, but were able such as MDS or leukemia, have been reported by various to complete the intended four cycles of PRRT (30). groups. An exact measure of these events is frequently Feasible results were also published for the combination hampered by their occurrence in heavily pretreated of capecitabine and 90Y and patients and the short follow-up of the patients. 111In-octreotide radiopeptide therapy (31, 32). The use These events are rare and the causal relationship with of radiosensitizing agents is, therefore, not limited to the PRRT may be controversial, because of the previous combination of one specific type of radionuclide. treatments, such as chemotherapy or radiotherapy. Their New applications of PRRT may include the neoadju- frequency seems higher after 177Lu-octreotate than after vant use of PRRT for pancreatic NETs. A few case reports 90Y-DOTATOC, but also in analyses with long patient have described the neoadjuvant use of PRRT in patients follow-up, their frequency does not exceed 2% of patients with pancreatic NETs who could be operated on success- (D J Kwekkeboom, unpublished observation). fully after PRRT (33, 34). As surgery is the only curative option for patients with GEPNETs, this neoadjuvant treatment is very promising. PRRT: variants PRRT may also be used in an adjuvant setting after Over the last years, there have been a number of attempts surgery of GEPNETs, preventing tumor development to improve PRRT using different approaches. after spread due to manipulation of the tumor during From experiments in rats, it became clear that surgery or preventing further growth of already present 90Y-labeled somatostatin analogs may be more effective micrometastases. In an animal study, therapy with for larger tumors, and 177Lu-labeled somatostatin analogs 177Lu-octreotate prevented or significantly reduced the

European Journal of Endocrinology may be more effective for smaller tumors, while their growth of tumor deposits in the liver after injection of combination may be the most effective (20). Several tumor cells via the portal vein mimicking preoperative retrospective, non-randomized patient studies seem to tumor spill (35). To detect a difference in survival and/or indicate the same (21, 22, 23). A recent follow-up report on tumor recurrence rate in patients treated with and without the efficacy of the combination of PRRT Seregni et al. adjuvant PRRT, a large, multicenter trial with years of (22, 24) reported an objective response rate in 43% of follow-up would be needed. the cases, whereas in their initial report an objective response rate of 67% was found. Prospective, randomized PRRT as salvage therapy controlled studies are needed to ultimately prove that PFS is better when using a combination of radionuclides. Although tumor response rates after initial treatment with Several groups have investigated the feasibility of PRRT are encouraging, CR is rare and eventually the locoregional, i.e. intraarterial, administration of radio- residual tumor(s) will progress again. Retreatment with labeled somatostatin analogs (25, 26, 27, 28). It results in a extra cycles of PRRT as salvage therapy may be considered higher uptake of radioactivity in liver metastases when better alternatives are not available. It has been and tumor response rates seem higher than with reported that ‘salvage’ therapy with two additional cycles i.v. administration. Long-term responses and toxicity are of 177Lu-octreotate does not lead to serious hematological not available yet. or nephrotoxic side-effects. However, the tumor response The application of radiosensitizing chemotherapeu- rate was lower compared with initial treatment (36). tical agents in the treatment of tumors with external beam It seems that long-lasting PFS after the initial treatment irradiation may lead to increased anti-tumoral efficacy and with PRRT also predicts a prolonged PFS after salvage another way to improve PRRT. After proving the safety of therapy (37).

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Discussion facts that may invalidate such comparisons should be PRRT is a promising new treatment modality for inope- considered: i) the patient populations that undergo liver- rable or metastasized GEPNET patients (Fig. 1). Complete directed therapies or PRRT may be different (for instance and partial responses obtained after treatment with patients who had Whipple-procedures are excluded from 90Y-DOTATOC are in the same range as after treatment the first, whereas patients who have somatostatin-receptor- with 177Lu-octreotate. negative tumors are excluded from the second); and Most studies report objective response rates in 20–35% ii) the results for PRRT pertain to patients with limited of patients. Also, outcome in terms of PFS and OS (from 16 as well as extensive liver involvement. From multivariate to 33 months, and from 22 to 46 months, respectively) analysis, it is known that patients extensive liver involve- compares very favorably with that for somatostatin ment perform worse (5, 10).Itmay,however,beassumed analogs, chemotherapy, or new, ‘targeted’ therapies. that in patients with predominant liver disease, PRRT They also compare favorably to PFS data for liver-directed performs better in terms of PFS than liver-directed therapies. therapies, i.e. , chemoembolization, or treat- There is a need for randomized controlled trials ment with 90Y-labelled microspheres. However, several comparing PRRT to ‘standard’ treatment, that is treatment

Response assessment after completion of PRRT A PRRT

Baseline FU 3 months FU 6 months FU 12 months

Planar scintigraphy 24 h after 200 mCi PRRT administration European Journal of Endocrinology

PRRT cycle 1 PRRT cycle 2 PRRT cycle 3 PRRT cycle 4

B Biochemical response during and after treatment with PRRT

2500

g/l) 2000 µ 1500 1000 500 Serum CgA ( 0

Baseline FU 3 months FU 6 months Post-PRRT 1 Post-PRRT 2 Post-PRRT 3 Post-PRRT 4 FU 12 months

Figure 1 Example of partial response after four cycles of [177Lu-DOTA0,Tyr3] (post-injection) demonstrated intense uptake by the receptor- octreotate (cumulative dose of 29.6 GBq) in a patient with a positive liver metastases and the pancreatic mass. During metastasized pancreatic neuroendocrine tumor. (A) Upper row: consecutive treatment cycles, less tumor mass was observed baseline CTscan demonstrated a mass within the pancreatic body indicating tumor response. (B) Plot depicts serum chromogranine with diffuse liver metastases. CT scans after treatment again A (CgA) concentrations at baseline, 6 weeks after each adminis- demonstrated multiple liver metastases and the pancreatic mass. tration of PRRT (Post-PRRT) and during follow-up. Owing to However, the lesions clearly diminished in size and some a radiation-induced inflammatory reaction of tumor tissue, disappeared. Lower row: planar scintigraphy performed 24-h pi an increase in CgA levels was observed in response to PRRT.

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with agents that have proven benefit when tested in large multivariate analysis that tumor response other than randomized trials (Sandostatin LAR in metastatic midgut progressive disease did not result in significant differences carcinoids and everolimus and sunitinib in inoperable in PFS or OS (i.e. patients with PR had no longer PFS than and/or metastatic pancreatic NETs). The same holds for those with stable disease) (5). It should also be kept in mind liver-directed therapies. A randomized study comparing that in the vast majority of patients, the goal of treatment PRRT with 177Lu-octreotate to high-dose Sandostatin is not cure, but prevention of disease progression. With a LAR treatment in patients with progressive metastatic limited number of treatment options, combining treat- midgut carcinoids was recently started in Europe and ment modalities at the beginning may leave the attending the USA. A study comparing PRRT to sunitinib or everolimus physician empty-handed later on. in patients with pancreatic NETs is expected to follow soon. Recently, the results of new targeted therapies for the treatment of GEPNETs have been presented. Treatment Conclusions with sunitinib (Sutent; Pfizer, Inc., New York, NY, USA), PRRT is a new and valuable treatment modality for patients a tyrosine kinase inhibitor, resulted in a longer median with inoperable or metastasized GEPNETs. PRRT is PFS than placebo (11 vs 5 months) in patients with generally well tolerated and acute side-effects are usually pancreatic NETs (38). Also, treatment with everolimus mild and self-limiting. Most studies report rates of 15–35% (Afinitor; Novartis Pharmaceuticals), an inhibitor of in terms of objective response rates. In terms of PFS and OS, mammalian target of rapamycin (mTOR), resulted in a PRRT compares favorably to registered pharmaceutical longer median PFS than placebo (11 vs 5 months) in and liver-directed therapies. Combining PRRT with patients with pancreatic NETs (39). The combination of radiosensitizing chemotherapeutical agents or combining PRRT with sunitinib or everolimus, or the sequential use 90Yand177Lu as tandem-treatment may improve the of PRRT with one of these compounds, may be of interest anti-tumoral efficacy. Another way to improve uptake of in the treatment of patients with pancreatic NETs. the is by intraarterial administration The next question to be addressed is then, whether in case of high tumor load in the liver. Randomized clinical combining PRRT with liver-directed therapies, or, for that trials comparing PRRT with other treatment modalities matter, with targeted therapies, such as treatment with should be undertaken to determine the best treatment everolimus or sunitinib, could improve treatment results in options and treatment sequelae for patients with GEPNETs. terms of percentage objective responses, or, preferentially, PFS and OS. The results of such an approach in a sequential

European Journal of Endocrinology setting, i.e. 90Y-microsphere treatment after failure to or Declaration of interest reprogression after PRRT, were recently published and hold The authors declare that there is no conflict of interest that could be great promise (40). The question to be answered, however, perceived as prejudicing the impartiality of the review. is whether a combination of PRRT and liver-directed therapy performed within a limited time-span from one another (for instance 3–4 months) results in a better PFS Funding than a strategy in which liver-directed therapy is reserved This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. until after (renewed) tumor progression. This same question can be asked for the combination of PRRT with chemotherapy with, for instance, temozolomide and Author contribution statement capecitabine or with everolimus or sunitinib. Such com- All authors have read this final version of the manuscript and have agreed binations, in our view, are promising only of their result in with its present form. All authors contributed equally. The enclosed manuscript has not been submitted to any other journal. a longer PFS/OS than when using a sequential approach, in which the second treatment is only started if the disease progresses after the first. A higher percentage of objective responses with a combinatorial approach may not be References

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Received 16 June 2014 Revised version received 29 July 2014 Accepted 12 August 2014

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