Advances in Peptide Receptor Radionuclide Therapy

Advances in Peptide Receptor Radionuclide Therapy Amir Sabet, MD,* Hans-Jürgen Biersack, MD, PhD,† and Samer Ezziddin, MD, PhD‡ Peptide receptor radionuclide therapy (PRRT) is a very effective treatment modality for advanced neuroendocrine tumors (NETs), representing a teaching model for truly targeted antitumor therapy. With the growing cumulative evidence of PRRT in various treatment settings, we are witnessing increased perception of this modality as a potent treatment option in advanced disease. Although most data derives from retrospective analyses, results from prospective comparative evaluations, such as the NETTER-1 trial, are eagerly awaited and should help to raise PRRT to a higher level of evidence. At the same time, as increased levels of evidence are anticipated by prospective evaluations, further methodological improvements are going on in different ways and aspects of radionuclide therapy, mainly regarding the radiopharmaceuticals, the combination with other radionuclides or cytotoxic drugs, and the route of administration. Although diversity of PRRT increases—not supporting cumulative evidence as opposed to uniform treatment—it is very likely to achieve significant increase of efficacy by these efforts in the near future. As the intraarterial administration of PRRT agents in liver-dominant metastatic disease has the potential to improve outcome, it would have to be shown as to which patients would benefit from this approach, to what extent the benefit would be, and to when it would justify the increased efforts for patients and treating institutes. The approach of combining cytotoxic or radiosensitizing drugs with the PRRT agents seems to trigger a major boost of efficacy in pancreatic NET. The midterm future would show the extent of benefit in terms of long-term outcome and would probably lead to inclusion into clinical routine for this particular NET entity. The translation of somatostatin-receptor antagonists into human application represents another major source of significant improvement in terms of PRRT’s benefit-toxicity ratio. Eventually, it may not be completely unlikely to see another radiopharmaceutical being regarded as the PRRT agent of choice in the midterm future. Semin Nucl Med 46:40-46 C 2016 Elsevier Inc. All rights reserved.

E

ffective treatment options for well-differentiated neuroendocrine tumors (NETs) in the stage IV disease that is in the inoperable metastatic stage are limited. Well-differentiated NETs are generally not overly sensitive to cytotoxic chemotherapy.1-4 Although moderate response rates have been observed with novel treatments including inhibitors of tyrosine kinase or mammalian target of rapamycin in patients with pancreatic NET, survival benefit is not impressive and a

*Department of Nuclear Medicine, University Duisburg-Essen, Essen, Germany. †Department of Nuclear Medicine, University of Bonn, Bonn, Germany. ‡Department of Nuclear Medicine, Saarland University, Homburg, Germany. *Address reprint requests to Samer Ezziddin, Department of Nuclear Medicine, Saarland University, Kirrberger St, Geb. 50, D-66424 Homburg, Germany. E-mail: [email protected]

40

http://dx.doi.org/10.1053/j.semnuclmed.2015.09.005 0001-2998/& 2016 Elsevier Inc. All rights reserved.

considerable portion of patients discontinue treatment because of severe toxicity.5-8 For unresectable NET of nonpancreatic origin, priorly referred to as carcinoids, treatment with somatostatin analogues is the recommended first-line therapy with predominantly antisecretory and antiproliferative effects.9,10 This modality can prolong time-to-progression but has little cytoreductive capacity. Effective treatment options for somatostatin analogue-refractory patients with uncontrolled functional symptoms or progressive metastatic disease are limited.10,11 Radionuclide therapy of carcinoids with 131Imeta-iodobenzylguanidine (131I-MIBG) has mainly resulted in symptomatic disease control with only minor cytoreductive potential.12-14 Originating from the neural crest, a very common feature of NETs is the ability to express receptors for regulatory peptides including somatostatin receptors (SSTRs). Peptide receptor radionuclide therapy (PRRT) is a

Advances in peptide receptor radionuclide therapy tumor-directed systemic treatment exploiting the abundance of SSTRs, especially sst2, on the cell membrane of welldifferentiated NETs.15-18

Establishment of 177LuOctreotate as the Preferred Compound for PRRT Early experiences with PRRT using high activities of 111InDTPA-pentetreotide showed disappointing results regarding tumor response.19,20 Subsequently, ß-emitter radionuclides have been coupled to sst2 ligands to form the radiopeptide compounds used in PRRT. First PRRT agents with ß-emitter radionuclides used 90Yttrium and modified somatostatin analogue Tyr3-octreotide, with DOTA instead of DTPA as chelating molecule, to ensure stable binding. PRRT with 90YDOTA-Tyr3-octreotide (90Y-DOTATOC) resulted in considerably better response rates and replaced the treatment with 111 In-DTPA-0-octreotide.21 Incidence of severe myelosuppression and renal failure after PRRT with 90Y-labeled peptides led to investigation of various strategies to reduce toxicity.21-26 Accordingly, two amino acids in DOTATOC compound, namely phenylalanine and threoninol, were substituted with tyrosine-threonine to build DOTA-Tyr3-octreotate (DOTATATE) with significantly higher affinity to the main target somatostatin-receptor sst2.16 Owing to lower energy and shorter particle range of the ß particles emitted by 177Lutetium (177Lu) compared to 90Y (2 vs 11 mm), 177 Lu-based PRRT may be associated with lower dose to normal tissue. Labeling DOTATATE with 177Lu (177Luoctreotate) has become the most important improvement of the last decade to reduce the radiation dose to the dose-limiting organs, especially kidney and bone marrow.27-33 Furthermore, gamma emission by 177Lu enables intratherapeutic whole body imaging, which can be used to visualize and quantify target uptake and absorbed dose.34

Nephrotoxicity After PRRT With 177 Lu-Octreotate High radiation doses during PRRT with 90Y-labeled peptides can lead to renal impairment and even delayed end-stage renal disease.23,26,35 The coinfusion of positively charged amino acids as competitive inhibitors of proximal tubular reabsorption may reduce the renal dose ranging from 9%-53% and is currently the established nephroprotective regimen in clinical PRRT.25,28,36 As illustrated in Table 1, the various rates of significant renal toxicities (grades 3-4) after 90Y-labeled PRRT have been reported.21,22,32,37,38 In the current largest study on 1109 patients, Imhof et al24 observed permanent renal toxicity of grades 4-5 in 103 patients (9.2%). PRRT with 177Lu-labeled peptides results in less propensity to renal impairment, probably due to less irradiation of the radiosensitive glomeruli during each course of treatment.37,39 However, continuous radiation during PRRT with a relative low dose rate to arteriolar-glomerular area may lead to clinically

41 evident impairment months after the treatment.36,40,41 Contribution of cumulative absorbed doses to renal impairment could only be evaluated when long-term follow-up of treated patients became available (Table 1).31,32,36,40 Furthermore, sensitive methods such as 99mTc-DTPA, 99mTc-MAG3, or 51 Cr-EDTA clearance tests have proved essential to capture minor PRRT-induced changes in glomerular filtration rate.36,40,41 Serial glomerular filtration rate measurements with 99m Tc-DTPA have shown slight renal impairment after treatment with 177Lu-octreotate but significant nephrotoxicity (ZCTCAE, grade 3) has been rare.42 Accordingly, in a comparative study, persistent nephrotoxicity was observed in none of 290 patients receiving 177Lu-octreotate as opposed to 10 of 358 patients (2.8%) treated with 90Y-DOTATOC.43 Neither the known risk factors for nephrotoxicity after 90Ybased PRRT (eg, arterial hypertension and diabetes mellitus) nor higher cumulative activities were significantly associated with more pronounced renal function loss after 177Lu-based PRRT.32,42,44,45 This evidence of long-term renal safety disputed the need for dose reduction or strict patient selection regarding kidney function in 177Lu-based PRRT.37,44,46-48 Nevertheless, baseline impairment of renal function contributed to hematological toxicity after PRRT with 177Lu-octreotate in a very recent study on 51 patients.49

Hematotoxicity After PRRT With 177 Lu-Octreotate A limit for the maximum absorbed dose of 2 Gy to the bone marrow has been suggested to avoid bone marrow hypoplasia.30,50,51 But all models being applied until date, including bone marrow aspiration, blood concentration of radioactivity, and the Medical Internal Radiation Dose scheme, are associated with specific difficulties and limited precision.27,52 Furthermore, there is a high interindividual variability in hematological alterations after the same absorbed dose to the red marrow.27,52 The limited predicting value of dosimetry measurements necessitates analysis of patients with sufficient follow-up duration to determine prognosis and clinical significance of myelosuppression after PRRT with 177Lu-octreotate. In a study of 203 patients, significant but reversible hematotoxicity occurred after 4.6% of administrations (11% of patients). Aggravation of preexisting anemia caused treatment discontinuation in one patient, and three patients (1.4%) developed myelodysplastic syndrome 414 months after termination of PRRT.53 Similarly, satisfying results have been observed in a large cohort of 504 patients reporting significant hematotoxicity in 3.6% of administrations and 9.5% of patients (Table 1).31 Comparing these results with those of 90 Y-based PRRT reporting severe hematotoxicity in 142 of 1109 patients (12.8%) underlined better tolerabilily of 177Lubased PRRT.24 Accordingly, in a large retrospective study on 807 patients, 177Lu-octreotate proved to be safer than 90YDOTATOC regarding both hematological and renal toxicity.43 These findings have underlined the outstanding toxicity profile of PRRT with 177Lu-octreotate, which also compares favorably with reported toxicities of common chemotherapy regimens

A. Sabet et al.

42 Table 1 Long-Term Toxicity After PRRT References

Radioligand

N

Tx Cumulative Median Nephrotoxicity Hematotoxicity Cycles Activity (GBq) FU (mo) Grade (3/4) (%) (Grade 3/4) (%)

Valkema et al95 Kwekkeboom et al31

90

Y-DOTATOC LuDOTATATE 90 Y-DOTATOC 90 Y-DOTATOC 90 Y-DOTATOC 177 LuDOTATATE 177 LuDOTATATE

54 504

2-4 3-4


1-15 29.6-37.8

90 1109 53 51

2-4 2 2 3-4

8.8-18.6 3.7-37
4.5-18.3 3.7-29.2

74/ 203

3

358


4

Bushnell et al96 Imhof et al24 Pfeifer et al97 Bodei et al. (2011)32 Sabet et al42, Sabet et al. (2013) 53 Bodei et al43

177

90

Y-DOTATOC

18 19

3 0.4

1.7 9.5

o33 23 17 60

3.3 9.2 5.6 1.9

15.5 12.8 49 0

4.9-37.8

21/31

1.3

11.3

1.1-26.5

30

6.1

14.2

3/4, Grades of toxicities according to CTCAE; FU, follow-up; N, number of patients; Tx, treatment.

including 5-fluorouracil orstreptozocin (20%-30%, grades 3/4) and sunitinib (430%, grades 3/4) for pancreatic NET.54-58 Recent studies on large and heterogeneous patient cohorts have allowed the analysis of risk factors.31,53 Initial cytopenia, floride bone metastatic involvement, and high cumulative administered activity especially Z30 GBq have proved to be the major risk factors for significant toxicity after PRRT with 177 Lu-octreotate. Fortunately, myelosuppression has remained reversible even in patients with late stage and disseminated osseous infiltration.59 The remarkable outcome in highly advanced bone marrow infiltration encourages consideration of PRRT with 177Lu-octreotate in late metastatic stages, especially with the absence of treatment alternatives.

Combination of Radionuclides for PRRT Clinical experiences and reported patient series confirm the comparable efficacy of 177Lu-based and 90Y-based PRRT in NET with similar survival outcome (Table 2). Thus, 177Luoctreotate PRRT producing outstanding treatment tolerance and low overall toxicity is regarded as the compound for PRRT.30,39,58,60,61 Because of the complementary characteristics of β particles emitted by 90Y and 177Lu, combined PRRT using both radionuclides (the so-called “cocktail” approach)

has been generally believed to achieve better results in patients with metastatic NETs showing tumor lesions of various sizes and heterogenous receptor distribution. In a retrospective study on 486 patients receiving Z3 cycles of either 90YDOTATOC or alternating sequential 90Y-DOTATOC and 177 Lu-DOTATOC, the latter mixed treatment resulted in significantly longer survival (5.5 vs 3.6 years) with similar rates of significant toxicities.62 Another study reported superiority of combined PRRT with intravenous application of 90Y or 177LuDOTATATE in a treatment session compared with 90YDOTATATE alone.63 No report is currently available comparing the efficacy of combined PRRT with that of 177Luoctreotate. However, in a study by Bodei et al,43 PRRT with 177 Lu-octreotate alone has proved safer than combined PRRT with lower incidence of both hematotoxicity and nephrotoxicity.

Repeat PRRT With 177LuOctreotate in the Salvage Setting Substantial numbers of patients who initially respond to PRRT would eventually experience the relapse of progressive disease and repeat PRRT with 90Y-labeled peptides tied to substantial risk of severe toxicity.26,41,64 Recent studies have demonstrated the safety of repeat PRRT with 177Lu-octreotate using a median

Table 2 Tumor Response and Survival After PRRT References 95

Valkema et al Kwekkeboom et al31 Bushnell et al96 Cwikla et al35 Pfeifer et al97 Bodei et al44 Ezziddin et al98

Radioligand

N

DCR (%)

ORR (%)

PFS (mo)

OS (mo)

90

58 310 90 58 53 39 74

81 80 88 97 89.5 77 89.2

9 29 4 23 23 31 36.5

29 33 16 17 29 36 26

37 46 27 22 NA NA 55

Y-DOTATOC Lu-DOTATATE 90 Y-DOTATOC 90 Y-DOTATATE 90 Y-DOTATOC 177 Lu-DOTATATE 177 Lu-DOTATATE 177

DCR, disease control rate; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

Advances in peptide receptor radionuclide therapy of two extra cycles per year.45,65 Expectedly, higher incidence of relevant hematotoxicity (after 16.5% of administrations) have been observed after high cumulative activities.45 A more pronounced renal function loss has also been reported in these patients receiving up to 83.7 GBq. However, bone marrow recovery was observed in all patients and no significant renal impairment occurred during follow-up.45,65 Although the reported tumor response rates have been generally lower compared with initial treatments, disease control could be seen in more than 60% of administrations, which lasted for more than a year.45,65 Furthermore, long-lasting progressionfree survival (PFS) after the initial PRRT may predict a prolonged PFS after salvage therapy.45 Also in patients previously treated with 90Y-DOTATOC, retreatment with 177 Lu-octreotate beginning at least 12 months after the initial PRRT could achieve a median PFS of 22 months; significant bone marrow and renal toxicities each were observed in only one patient.66 These reports reveal the feasibility of repeat PRRT with 177Lu-octreotate in the frequently observed setting of recurrence after initial response to PRRT.

PRRT in the Neoadjuvant Setting Neoadjuvant use of 90Y-DOTATATE was first reported in a patient with initially inoperable P-NET.67,68 Successful attempts have also been reported after treatment with 177Luoctreotate with and without concurrent 5-fluorouracil chemotherapy.68-70 Very recently, van Vliet et al71 published their experience in 29 patients with unresectable nonfunctioning pancreatic NET (n ¼ 15) with or without oligometastatic liver involvement (r3 lesions, n ¼ 14). Following neoadjuvant PRRT with 22.2-29.6 GBq 177Lu-octreotate successful resection could be performed in 9 patients (31%), and was associated with longer PFS (69 vs 49 months). These promising observations may help define a new role for PRRT in the management of pancreatic NETs.

Intra-Arterial Administration Route for PRRT In contrast to normal liver parenchyma, vascular supply to hepatic malignancies arises mainly from arterial rather than portal hepatic circulation.72 Thus, the first-pass effect after administration of radionuclide into the hepatic arteries may result in superior uptake and better response of liver metastases. Selective hepatic intra-arterial treatment with 111Inoctreotide (mean cumulative dose of 58 GBq, mean number of treatments/patient 11) resulted in objective response in 9 of 16 patients.73 Intraarterial 90Y-DOTA-lanreotide (median activity 1 GBq) has also been safely used for progressive hepatic metastases of NET, achieving partial response in 16% of patients.74 Kratochwil et al75 reported objective response rate of 60% in patients with hepatic metastatic NET after intraarterial PRRT using 90Y-DOTATOC and 177Lu-DOTATOC. These initial feasibility results of preliminary studies encourage

43 exploration of intra-arterial administration in liver-dominant or liver-only disease.

Somatostatin Receptor Antagonists Instead of Agonists for PRRT Binding of radiolabeled somatostatin-receptor agonists to the overexpressed membranous sst2 in NET, triggers a fast and efficient internalization process of the ligand-receptor complex.76 The “recycling” process of the internalized receptors to the plasma membrane is, on the other hand, relatively slow and may take several hours.76,77 The resulting accumulation of intracellular radiolabeled peptides permits successful tumortargeted therapy with radiolabeled somatostatin-receptor agonists.78-80 In contrast, somatostatin-receptor antagonists are not internalized andhence were initially not considered for PRRT. In a preclinical study using a mouse model, Ginj et al81 observed higher tumor uptake and longer retention for 111InDOTA-BASS, a 111In-labeled SSTR antagonist, when compared with 111In-DTPA-octreotate. In a following in vitro study by Cescato et al,82 177Lu-DOTA-BASS binded to considerably more sites (4.2 ⫾ 0.5 folds) when compared with 177Luoctreotate in all nine ileal carcinoids samples. Superior pharmacokinetics have also been reported in an In Vivo study using 111In-DOTA-BASS or 177Lu-DOTA-BASS.83 Further improvement in selective affinity to sst2 has been shown with 177Lu-labeled sst2 antagonist DOTA-[Cpa-c (DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH2] (177Lu-DOTA-JR11). For the first time, Wild et al84 performed an intra-individual comparison of the tumor-to-organ dose ratio for 177Lu-DOTA-JR11 and 177Lu-DOTATATE in four patients with progressive NET and chronic renal insufficiency. 177 Lu-DOTA-JR11 showed a 1.7-10.6 times higher tumor dose than 177Lu-DOTATATE. Although the renal dose was lower after 177Lu-DOTATATE (0.71-1.45 vs 44-2.27 Gy or GBq), tumor-to-kidney and tumor-to-bone marrow dose ratios were 1.1-7.2 times higher after administration of 177 Lu-DOTA-JR11. Consequently, patients were treated with 2-3 cycles of 4.2 ⫾ 1.2 GBq 177Lu-DOTA-JR11 showed no relevant decrease of renal function, that is MAG3-clearance, within 12 months from end of treatment.

Alpha Emitters for PRRT Because of the high linear energy transfer rate and short tissuepenetration range, alpha particles could be potentially very suitable for targeted radionuclide treatment with an extremely high tumoricidal activity and low toxicity rate. A number of preclinical studies have shown the potency and limited toxicity of 225Ac-DOTATOC and 213Bi-DOTATOC.85,86 In a small clinical study by Kratochwil et al,87 treatment with 213BiDOTATOC induced long-lasting response in seven patients refractory to 90Y or 177Lu-DOTATOC.

A. Sabet et al.

44

Radiosensitizing Efforts (ChemoPRRT): Addition of Chemotherapeutic Agents Pancreatic NETs are more sensitive to cytotoxic chemotherapy when compared with other NETs.1,88 Temozolomide-based regimen have proven efficacy in this entity.3,89,90 In a retrospective study on 30 patients with advanced G1-2 P-NET, first-line chemotherapy with capecitabine and temozolomide resulted in a very high objective response rate (ORR ¼ 70%) and a median PFS of 18 months (95% CI: 9-31).4 Although, recent reports indicate a considerably longer PFS after PRRT (95% CI: 26-31),44 the addition of mentioned chemotherapeutic agents may improve efficacy of PRRT. Safety of adding low-dose capecitabine as radiosensitzer to 177 Lu-octreotate was first shown in a small cohort of seven patients by van Essen et al.91 The radiosensitizing dose of capecitabine was fixed at 1650 mg/m2 given orally (bid) for 14 days. Subsequently, a randomized multicenter trial investigated the clinical benefits of this combination. A disease control rate of 94% was achieved in 33 patients with progressive NET. Median follow-up of 16 months was too short to reach median PFS, and overall survival at 1 year was 91% (95% CI: 75%98%).92 In a recent phase II study on 65 patients, hematological toxicity after four cycles of 7.8 GBq 177Lu-octreotate combined with either capecitabine (n ¼ 28) or capecitabine and temozolomide (n ¼ 37) was analyzed.93 Temozolomide was given for 5 days during each of the four cycles of 7.8 GBq 177 Lu-octreotate. Comparing with data for PRRT with 177 Luoctreotate, no considerable increase in myelosuppression attributable to the addition of chemotherapy was observed 94 Myelodysplastic syndrome occurred in two patients (3%) with complex cytogenetic abnormalities.

Perspectives and Outlook With the growing cumulative evidence of PRRT in various settings, we are witnessing increased perception of this modality as a potent treatment option in advanced NET. Although most data derives from retrospective analyses, results from prospective comparative evaluations such as the NETTER-1 trial are eagerly awaited and should help to raise PRRT to a higher level of efficacy evidence. At the same time, as increased levels of evidence are anticipated by prospective evaluations, further methodological improvements are going on in different ways and aspects of radionuclide therapy, mainly regarding the radiopharmaceuticals, the combination with other radionuclides or cytotoxic drugs, and the route of administration. Although diversity of PRRT increases—which does not support cumulative evidence of uniform treatment—it is very likely to achieve significant increase of efficacy by these efforts in the near future. Intra-arterial administration of PRRT agents in liverdominant metastatic disease seems clearly to have the potential to improve outcome, but it would have to be shown as to which patients would benefit from this approach, to what

extent the benefit would be, and to when it would justify its increased efforts for patients and treating institutes. As of now, the approach of combining cytotoxic or radiosensitizing drugs with the PRRT agents seems to trigger a major boost of efficacy in pancreatic NET. The midterm future would show the extent of benefit in terms of long-term outcome and would probably lead to inclusion into clinical routine for this particular NET entity. The advances on the radiopharmaceutical sector, especially with the beginning translation of somatostatin-receptor antagonists into human application, is another compelling source of major further improvement of PRRT regarding the benefittoxicity ratio. So, from initial results and reports, it seems not completely unlikely that we would eventually see another radiopharmaceutical being regarded as the PRRT agent of choice in the midterm future (45-10 years from now).

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