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Neuroendocrine Tumors: Therapy with Radiolabeled Peptides

  • Lisa BodeiEmail author
  • Laura Gilardi
  • Duccio Volterrani
  • Giovanni Paganelli
  • Chiara M. Grana
  • Mark Kidd
  • Irvin M. Modlin
Living reference work entry

Abstract

Treatment of neuroendocrine tumors (NETs) is typically multidisciplinary and should be individualized according to the tumor histology, lesion extent, patient performance status, and symptoms. Surgery is the only potentially curative option. NET liver metastases are typically hypervascular, and chemoembolization or bland embolization of the hepatic artery, performed mechanically by microspheres or chemically with cytotoxic agents, can lead to significant necrosis. Medical therapy is directed at the control of symptoms and/or reducing tumor growth. Strategies range from the use of bioactive agents (somatostatin analogues or interferon) to conventional chemotherapy. PRRT uses radiolabeled somatostatin analogue peptides to treat unresectable or metastasized NETs. The therapeutic strategy of PRRT has been utilized for more than two decades and is accepted as an effective therapeutic modality in the treatment of inoperable or metastatic GEP, bronchopulmonary, and other NETs. PRRT with either 90Y-DOTATOC or 177Lu-DOTATATE is generally extremely well tolerated, with modest toxicity to the target organs, such as the kidneys and bone marrow. The chapter illustrates the efficacy and safety features of these compounds.

Keywords

Neuroendocrine tumors PRRT Therapy 177Lu-DOTATATE 90Y-DOTATOC 

Glossary

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

5-FU

5-Fluorouracil

BED

Bioeffective radiation dose

BP

Bronchopulmonary

CEA

Carcinoembryonic antigen, a tumor-associated marker

CgA

Chromogranin A, a tumor-associated marker for neuroendocrine tumors

CI

Confidence interval

CR

Complete response

CT

X-ray computed tomography

DOTA

2-(4-Isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (macrocyclic coupling agent to label compounds of biological interest with metal radionuclides)

DOTATATE

DOTA-Tyr3-Thr8-octreotide

DOTATOC

DOTA-Tyr3-octreotide

FDA

United States Food and Drug Administration

GEP

Originated in the gastroenteropancreatic tract

GFR

Glomerular filtration rate

Gy

Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)

KPS

Karnofsky performance status

LCNEC

Large-cell neuroendocrine carcinoma

MDS

Myelodysplastic syndrome

MEN

Multiple endocrine neoplasia

MIRD

Medical internal radiation dose

MR

Mixed response

MRI

Magnetic resonance imaging

mTOR

Mammalian target of rapamycin

NEN

Neuroendocrine neoplasia

NET

Neuroendocrine tumor

NSE

Neuron-specific enolase

OLINDA

Organ level internal dose assessment/Exponential modeling

OS

Overall survival

PET

Positron emission tomography

PET/CT

Positron emission tomography/Computed tomography

PFS

Progression-free survival

PR

Partial response

PRRT

Peptide receptor radionuclide therapy

QoL

Quality of life

RECIST

Response evaluation criteria in solid tumors

SCLC

Small-cell lung cancer

SD

Stabilization of disease

SPECT

Single-photon computed tomography

SPECT/CT

Single-photon computed tomography/Computed tomography

SSA

Somatostatin analog

SSTR

Somatostatin receptor

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

SWOG

Southwest Oncology Group, an organization supported by the National Cancer Institute of the United States to conduct clinical trials in adult cancers

TTP

Time to progression

VEGF

Vascular endothelial growth factor

WHO

World Health Organization

Therapy with Radiolabeled Peptides

Overall Therapeutic Strategy

Treatment of neuroendocrine tumors (NETs) is typically multidisciplinary and should be individualized according to the tumor histology, lesion extent, patient performance status, and symptoms. 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 [1]. Whenever possible and clinically/technically feasible, removal of the primary tumor should be undertaken to prevent the consequences of local events (bleeding, obstruction, perforation) and locoregional invasion and reduce the likelihood of metastatic spread. Surgery is the only potentially curative option; however, effective en bloc resections can only be obtained in 20% of cases due to the frequent presence of metastatic disease [2]. The surgical options include en bloc removal of the primary tumor, resection of hepatic metastases, radiofrequency ablation, and, in selected cases, hepatic or even enteric transplantation [3]. Tumors located in the head of the pancreas or in the duodenum are resected using the Kausch–Whipple pancreaticoduodenectomy procedure, while neuroendocrine tumors (carcinoids) of the distal ileum are managed by ileal resection and/or right hemicolectomy [4]. For bronchial carcinoids, lung resection surgery, including lymphadenectomy, is the option of choice. In the situation of more aggressive categories of thoracic NETs (large cell and small cell neuroendocrine carcinomas, LCNEC and SCLC, respectively), surgery is seldom feasible, and the outcomes are quite poor [5]. Liver transplantation for GEP-NETs remains controversial and can be proposed in selected situations (Milan criteria) when the liver is the sole site of disease, usually in a setting of stable metastases from intestinal NETs and low Ki67 index [6]. The definitive treatment for pheochromocytoma/paraganglioma is surgical. Laparoscopic removal of intra-adrenal and extra-adrenal pheochromocytomas is regarded as the surgical technique of choice [7]. Operative mortality is less than 1%, if adequate preparation with alpha and beta blockade is undertaken in the event of catecholamine-secreting tumors [8, 9]. Cortex-sparing adrenalectomy can be performed in hereditary, frequently bilateral, tumors, while malignant and diffusely spread tumors are approached utilizing conventional transabdominal resection. Interventional radiology techniques are helpful to treat multiple or dominant metastatic hepatic lesions not amenable to surgical resection. NET liver metastases are typically hypervascular, and chemoembolization or bland embolization of the hepatic artery, performed mechanically by microspheres or chemically with cytotoxic agents, can lead to significant necrosis. More recently radioembolization with 90Y-labeled microspheres have been reported to have excellent results [10, 11, 12]. Other ablative techniques employed in routine approach to liver metastases include “umbrella” radiofrequency ablation, cryoablation, and high-intensity focused ultrasound (HIFU) ablation [13, 14]. Medical therapy is directed at the control of symptoms and/or reducing tumor growth. Strategies range from the use of bioactive agents (somatostatin analogues (SSAs) or interferon) to conventional chemotherapy. In functional tumors such as gastrinomas or insulinomas, symptomatic treatment with proton pump inhibitors or anti-hypoglycemic agents, respectively, is effective. More recently, a variety of novel agents (everolimus, sunitinib, and bevacizumab) with putative molecular targets (e.g., mTOR, VEGF) have been introduced with varying degrees of efficacy [15]. Everolimus and sunitinib have been approved by FDA for the treatment of pancreatic NETs. Early reports of efficacy have been tempered by concerns regarding adverse advents [16]. Traditional chemotherapy has little place in well-differentiated NETs, since most of them are indolent. Nevertheless, several studies have reported efficacy of the combination capecitabine + temozolomide in pancreatic NETs [17, 18].

Somatostatin analogue biotherapy is regarded as a basic therapeutic agent for the management of NETs. The over expression of somatostatin receptors (SSTR) on NETs allows effective targeting and hence effective treatment of symptoms due to hyper or paroxysmal secretion of bioactive peptides and amines. There is some inhibitory effect growth of primary and metastatic lesions, but it is limited and difficult to predict or define given limitations in imaging sensitivity and suboptimal biomarker availability [19]. All SSTR subtypes bind somatostatin (both 14- and 28-amino-acid isoforms) and its analogues with varying degrees of efficacy. Somatostatin has an extremely short plasma half-life (about 2 min) and cannot be used for clinical purposes. Octreotide and lanreotide are two somatostatin analogues with high affinity for sst 2 receptor, moderately high affinity for sst 5, and intermediate affinity for sst 3 [20]. Somatostatin analogues are generally well tolerated, and long-acting formulations effectively control symptoms in up to 70% of patients, although tachyphylaxis frequently occurs [21]. Objective partial responses are identifiable in less than 10% [22]. Individuals with a clinical syndrome (flushing and diarrhea) have a reduced survival (5-year survival of 21%, 38 months median survival from the first facial flushing, 23 months from the biological diagnosis). Thus, SSA therapy, which reduces symptomatology and its sequelae, improves quality of life and decreases tumor growth, has merit, and is widely used as an initial therapeutic strategy [23]. An Italian multicenter trial [24] in NETs of various origins (using octreotide 0.5–1 mg t.i.d.) demonstrated symptomatic and biochemical responses in 73% and 77% of patients, respectively, with only 3% objective (partial) responses in carcinoids. The use of high-dose lanreotide (up to 12 mg/day) gave similar biochemical and symptomatic responses, as well as similar tumor responses (partial responses in 5% of patients) [25]. In the medical treatment of advanced SCLC, both octreotide and lanreotide were able to reduce growth factors, such as IGF-1, but did not show any antitumor efficacy [26, 27, 28, 29]. Recently, an agonist with broader SSR affinity (pasireotide) has been introduced in the clinical practice to overcome resistance to octreotide or lanreotide. Current efficacy data appear limited and substantial adverse events have limited its utility [30].

Peptide Receptor Radionuclide Therapy (PRRT)

Neuroendocrine cells are typically regulated by numerous hormones, acting via specific receptors on the membrane surface. These receptors are usually 7-transmembrane domain G-protein-coupled receptors. The presence of a suitable density of internalizing somatostatin receptors (SSTR) on the cell surface of NETs is the basis for a somatostatin receptor-targeted therapy. Agonists binding to somatostatin receptors are internalized into endosomes and activate post-receptor mechanisms, such as adenyl cyclase, phospholipase, and ion channels, that are responsible for activation of the biological/pharmacological events within the cell. The receptor is either recycled on the membrane surface or entrapped into lysosomes for degradation. This retention into the lysosomes enables a radionuclide-based peptide diagnosis and/or therapy, depending on the radionuclide utilized (Figs. 1, 2, and 3 [31]).
Fig. 1

Somatostatin receptor scintigraphy with 111In­pentetreotide in a patient with multiple neck paragangliomas

Fig. 2

PET/CT with 68Ga-DOTANOC. Suspect relapse of paraganglioma in a patient who had previously undergone a pararenal paraganglioma excision. PET discloses a paraganglioma within the thorax, close to the superior vena cava. Subsequent surgery confirmed the PET finding

Fig. 3

Peptide receptor radionuclide therapy rationale: the internalization and intracellular retention of a suitably radiolabeled peptide (Adapted from Gray et al. [31])

Peptide receptor radionuclide therapy (PRRT) uses radiolabeled peptides to treat unresectable or metastasized NETs. The radiopharmaceutical is concentrated in the tumor cell, where the sensitive targets, such as DNA, can be attained. To estimate the radioactivity concentration in tumors, all PRRT protocols include a baseline assessment of the SSTR density, obtained in vivo with the conventional 111In-pentetreotide scintigraphy or 68Ga-SSA-PET/CT. The information obtained with these exams is used to determine the probability of clinical efficacy. It has been established that an uptake greater than that of kidneys and/or spleen (on planar scintigraphic images) is correlated with an objective response in ~60% of individuals [32]. The quantification of this uptake utilizing 68Ga-DOTATOC PET/CT has indicated that a SUVmax threshold of >16 has sensitivity and specificity of 95% and 60%, respectively, in the prediction of tumor response [33].

PRRT consists in the systemic administration of a radiolabeled somatostatin analogue, in sequential cycles up to a cumulative activity that is calculated on renal irradiation. Cycles are usually administered 6–12 weeks apart in order to ameliorate any potential hematological toxicity. To mitigate any renal risk, PRRT is usually accompanied by the coadministration of nephroprotective amino acids, such as lysine and arginine that diminish the renal absorbed dose by 50–60% [34].

Given the high first-pass extraction of the radiopeptides, the technique of intrahepatic arterial administration has been investigated with some success in clinical trials, although further information is needed to rigorously define its efficacy and safety [35].

The therapeutic strategy of PRRT has been utilized for more than two decades and is accepted as an effective therapeutic modality in the treatment of inoperable or metastatic GEP, bronchopulmonary, and other NETs [36]. It was initially utilized in 1992 at Erasmus University, Rotterdam, as a logical step following the introduction by this group of somatostatin receptor scintigraphy with [111In-DTPA0-D-Phe1]-octreotide or 111In-pentetreotide [37]. The two most commonly used radiopeptides for PRRT, 90Y-octreotide and 177Lu-octreotate, produce disease-control rates of 68–94% (SWOG or RECIST based) (Table 1) [34, 41, 42, 44, 50, 51]. In addition to tumor volume reduction, biochemical and symptomatic responses are commonly (up to 70%) observed [52]. The resulting progression-free survival (PFS) and overall survival (OS) rates compare favorably with SSAs, chemotherapy, and more recent usage of “targeted” therapies such as everolimus and sunitinib [32, 43]. The preliminary results of the current phase III randomized trial (NETTER-1) unequivocally indicated the clear advantage of 177Lu-octreotate over high-dose SSAs in midgut NETs, in terms of PFS, OS, and objective response [53].
Table 1

Review of the efficacy of PRRT with 90Y-DOTATOC and 177Lu-DOTATATE

 

Schedule

Patients

CR

PR

DCR

Progression at baseline

Response criteria

Outcome (median PFS or TTP)

90Y-octreotide

7.4 GBq/sqm in 4 cycles [38]

36 GEP

4 %

20 %

92 %

100 %

WHO

Not assessed

2.96–5.55 GBq/cycle × 2 [39]

21 GEP

0 %

28 %

71 %

n.a.

WHO

TTP 10 m

0.93–2.78 GB/sqm/cycle [40]

58 GEP

0 %

9 %

71 %

81 %

SWOG

TTP 29 m

4.4 GBq/cycle × 3 [41]

90 SI

0 %

4 %

74.4 %

100 %

SWOG

PFS 16 m

1–10 cycles (median 2), various activity [42]

821 GEP

0.2 %

38 %

n.a.

n.a.

RECIST

n.a.

177Lu-octreotate

27.8–29.6 GBq in 3–4 cycles [43]

310 GEP

2 %

28 %

81 %

43 %

SWOG

PFS 33 months

3.7–29.2 GBq in 4–6 cycles of 3.7–7.4 GBq [44]

39 GEP

3 %

31 %

88 %

76 %

RECIST

TTP 36 months

Mean 25.5 GBq in 5 cycles, normal subjects; mean 17.8 GBq in risk patients [45]

52 P

8 %

21 %

81 %

88 %

SWOG

PFS 20 months in reduced dosage, not reached in full dosage

32 GBq in 4 cycles [46]

68 P

0 %

60.3 %

85.3 %

67.6 %

SWOG

PFS 34 months

Median 25.7 vs. 18.4 GBq (normal vs. risk patients) [47]

43 SI

7 %

0 %

84 %

100 %

SWOG

PFS 36 months

32 GBq in 4 cycles [48]

61 SI

0 %

13.1 %

91.8 %

75.4 %

SWOG

PFS 33 months

27.8–29.6 GBq in 3–4 cycles vs. octreotide LAR 60 mg/month [49]

201 SI

19 % (Lu) vs 3 % (LAR) CR + PR

20 % (Lu) vs 58 % (LAR)

100 %

RECIST

PFS not reached (Lu) vs. 8.4 months (LAR)

Modified from Bodei et al. [36], with permission

PRRT with 111In-octreotide was initiated in the 1990s by Eric Krenning and coworkers at Erasmus University, in Rotterdam. A subsequent multicenter trial demonstrated some clinical benefit due to the Auger and conversion electrons emitted by indium-111 in close proximity to the cell nucleus. Despite these premises, partial remissions were unusual [54]. Higher-energy and longer-range emitters, such as pure β-emitter Yttrium-90 (Emax 2.27 MeV, Rmax 11 mm, T1/2 64 h), were considered more suitable for therapeutic purposes. Therefore, a new analogue, Tyr3- octreotide, with a similar pattern of affinity for somatostatin receptors, was developed. This analogue exhibited high hydrophilicity, simple labeling with 111In and 90Y, and tight binding to the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane- N,N′,N″,N′′′-tetraacetic acid), to form 90Y-[DOTA]0-Tyr3-octreotide or 90Y-DOTATOC [55]. As a consequence of this optimization in 2000, the newer analogue {octreotate (Tyr3,Thr8-octreotide)}, with six to ninefold higher affinity for SSTR2, was introduced into clinical practice. The chelated analogue [DOTA]0-Tyr3-octreotate or DOTATATE can be labeled with the β–γ-emitter lutetium-177 (Eβmax 0.49 MeV, Rβmax 2 mm, T1/2 6.7 days) (Fig. 4).
Fig. 4

Chemical structures of 90Y-­DOTATOC and 177Lu­DOTATATE, the most used radiopeptides for PRRT. Note the substitution of a natural Thr in the eight octreotide amino acid in 177Lu-­DOTATATE. This modification increases the affinity for the SSTR2 receptor by six to nine fold

In principle, Auger electron emitters represent an attractive alternative to β-particle emitters for cancer therapy if they can be placed intracellularly, especially in close proximity to (or within) the nuclear DNA. Incorporation of Auger electron emitters into the DNA is a particularly efficient source of irradiation, capable of inducing cell death with virtually no damage to the surrounding cells. However, nuclear translocation of radiolabelled somatostatin analogues has never been clearly demonstrated so far, and PRRT is currently performed primarily with β-emitters to maximize ionization in the region of the nucleus [56, 57].

The most widely used radiopeptides are 90Y-DOTATOC and 177Lu-DOTATATE based upon their optimal pharmacokinetic considerations. Yttrium-90 has a higher β-particle emission compared to lutetium-177. The analysis of the residence times for DOTATATE and DOTATOC, calculated by means of the 177Lu-labeled peptides, indicated that residence times for DOTATATE are significantly longer in kidney and tumor (ratios DOTATATE:DOTATOC = 1.4 and 2.1, respectively). This property enables the delivery of higher tumor doses although a similar increase in renal exposure occurs [58]. Based upon this consideration (higher tumor dose), 177Lu appears of more benefit for labeling DOTATATE; while given the higher renal dose burden, 90Y appears more useful in labeling DOTATOC.

A high expression of somatostatin receptors is a critical variable for determining the inclusion criteria of an individual for effective PRRT. As opposed to other treatments, the unique opportunity to identify and quantify the target (SSTR) prior to initiation of therapy informs the likelihood of success with PRRT [59]. Assessment of SSTR expression enables the possibility of quantification of the absorbed dose [32]. These values as well as the evaluation functioning somatostatin receptor overexpression can be accurately determined by somatostatin receptor imaging with either 111In-pentetreotide or 68Ga-SSA-PET/CT (Fig. 5). While immunohistochemistry for sst 2 can provide information on receptor status, it should be regarded as representing a “photographic image” taken at the moment of bioptic sampling and provides no information in respect of the actual internalizing capacity and the possible evolution with time of receptor density.
Fig. 5

Tumors candidates to PRRT are those with an uptake on planar images at least equal to the one of the normal liver (grade 1, image b), higher than that (grade 2, image c) or higher than the one of kidneys and spleen, the “hottest” organs at 111In­-pentetreotide scintigraphy (grade 3, image d)

The development of molecular tools, such as transcript analysis of specific circulating NET mRNA signature, has demonstrated exciting possibilities in facilitating prediction of outcome (efficacy, tolerability). Such information is of considerable clinical utility in determining the most effective multidisciplinary sequencing of extensive and expensive therapies, particularly since conventional (morphologic/functional) imaging and biomarkers have been demonstrated to have substantial limitations in predicting effective therapy or defining progression and outcome. The introduction into clinical practice of measurement of circulating multianalyte 51-gene NET molecular signature has demonstrated significant advantage in early detection of residual disease of surgery-treated patient or in the assessment of somatostatin analogue response [60, 61]. Preliminary results indicate highly effective prediction of response to PRRT and accurate monitoring of therapeutic efficacy [62].

PRRT Safety

PRRT with either 90Y-DOTATOC or 177Lu-DOTATATE is generally extremely well tolerated, with modest toxicity to the target organs, such as the kidneys and bone marrow. Toxicity may be divided into acute, subacute, and long term. Acute side effects include mild nausea (25%), more rarely vomiting, related to the coadministration of renal protective amino-acid solutions, which is easily controlled or prevented by proper anti-nausea preparations, and abdominal pain (10%) [63]. Subacute effects comprise mild to moderate fatigue, depending also on the extent of disease, which is common in the 7–10 days following the therapy and mild (grade 1) alopecia, which is frequently reported after 177Lu-DOTATATE [64]. The most common subacute side effect is hematologic toxicity, which is mild (WHO grades 1 or 2) and transient in 85–90% of patients [36]. Severe (grades 3 and 4) toxicity occurs in 10–15% of patients irrespective of the radiopeptide; however, this is usually reversible and rarely requires transfusion or granulocyte support [63, 65]. Chronic and permanent effects in the kidneys and the bone marrow, such as renal function loss and reduction of bone marrow reserve, are rare and generally mild. The likelihood of such adverse events is significantly ameliorated if the necessary precautions, such as renal protection with amino acids and dosage adaptation to the clinical scenario, are undertaken. Secondary myeloproliferative diseases (myelodysplastic syndrome and leukemia) are extremely rare but have been noted [34, 38, 42, 64, 66, 67] (Table 2). Whether they represent a specific toxicity or susceptibility to an as yet unidentified genomic predisposition remains to be determined.
Table 2

Summary of long-term tolerability of PRRT with 90Y-­DOTATOC and 177Lu-­DOTATATE

 

Patients

Follow-up (months)

Renal toxicity

MDS

Acute leukemia

Reference

90Y-octreotide

40

19

10 % grade 1

0

0

[39]

39

6

3 % grade 2

0

0

[38]

58

18

3 % grade 4

1

0

[40]

1,109

23

9,2 % grade 3/4

1

1

[42]

358

30

2.8 %

7 (1.95 %)

5 (1.4 %)

[68]

177Lu-octreotate

504

19

0.4 % grade 4

3

0

[43]

51

29

24 % grade 1

0

0

[44]

74

21

1.3 % grade 3/4

3

0

[67, 69]

290

30

0 %

6 (2.06 %)

2 (0.69 %)

[68]

Modified from Bodei et al. [36], with permission

Renal Toxicity

The kidneys are considered the critical “at risk” organs in PRRT, particularly after 90Y-DOTATOC administration. Proximal tubular reabsorption of the radiopeptide and the subsequent retention in the interstitium result in renal irradiation. Nephrotoxicity is increased in patients with preexisting long-standing and poorly controlled hypertension or diabetes. Given the high kidney retention of radiopeptides, positively charged molecules, such as L-lysine and/or L-arginine, are used to competitively inhibit the proximal tubular reabsorption of the radiopeptide. This leads to a reduction in the renal dose by 9–53% [70, 71] and can be further reduced by ~40% by prolonging infusion over 10 h and up to 65% by prolonging it over 2 days after radiopeptide administration. This time frame covers almost the entire renal elimination phase of the isotope [72, 73]. Kidney radiation toxicity is typically evident several months after irradiation due to the slow repair characteristics of renal cells (Fig. 6). The accepted renal tolerated dose is 23–25 Gy, as proposed by the National Council on Radiation Protection and Measurements (NCRPM). It has however more been determined that 23 Gy to the kidneys causes detrimental deterministic effects in 5% of patients within 5 years [75, 76].
Fig. 6

The influence of risk factor on the course of renal parameters. Patients with risk factors for delayed renal toxicity (mainly long­standing and poorly controlled hypertension and diabetes) had more marked and persistent reduction in creatinine clearance and a lower bioeffective dose (BED) threshold for renal toxicity than did patients without risk factors (Adapted from Bodei et al. [74])

Long-term evaluation of renal toxicity in a cohort (n = 28) undergoing PRRT with 90Y-DOTATOC and dosimetric analysis showed that, of the 23 treated with 90Y-octreotide, a low (28 Gy BED) threshold was observed with risk factors (mainly long-standing hypertension and/or poorly controlled diabetes), in comparison to 40 Gy in the absence of such risk factors [74]. These observations are consistent with the evidence that a higher and more persistent decline in creatinine clearance and the consequent development of renal toxicity are more likely to occur in the presence of preexisting risk factors [76]. The reason for the more frequent association of 90Y-PRRT with renal function reduction is intrinsic to the specific physical characteristics of the 90Y radionuclide, namely, the much more extensive intrarenal particle penetration.

In a retrospective series (n = 1,109) treated with 90Y-octreotide, 103 subjects (9.2%) experienced grade 4–5 permanent renal toxicity [42]. Multivariate regression analysis indicated that the initial kidney uptake was predictive of severe renal toxicity. However, this relatively high incidence was possibly related to the high administered activities per cycle (3.7 GBq/m2 body surface, namely, activities of about 6.4 GBq per cycle in a standard male). In addition, subjects with preexisting impairment of renal function were not excluded from PRRT, and infusion of protective amino acids was not a routine procedure in the initial phases of the study [77].

Recently, the results of an analysis of long-term tolerability of PRRT (n = 807) treated with 90Y-octreotide, 177Lu-octreotate, or the combination (177Lu, 34.4%; 90Y, 44.4%; 177Lu + 90Y, 19.5%) have provided additional information on the issue of PRRT tolerability. The large numbers included in this analysis allowed clarification of the exact role for preexistent clinical parameters (such as diabetes, hypertension, and chemotherapy) in the determination of toxicity. Nephrotoxicity (transient and persistent) was detectable in 279 (34.6%) and was severe in 1.5%. 90Y-peptides or the combination of 90Y/177Lu-peptides showed greater nephrotoxicity than 177Lu-peptides alone. However, <30% of toxicities could be modeled by clinical parameters of which hypertension and anemia were identifiable as the most relevant risk factors. These results suggest that an individual susceptibility to radiation-associated disease, possibly of genetic origin, might play a determinant role [68].

An accurate assessment of glomerular filtration rate (GFR), as a measure of renal function (scintigraphic Gates’ method), was carried out after PRRT (n = 74) with a median of 21 months (range 12–50) follow-up. The evaluation included potential risk factors, such as diabetes mellitus, hypertension, and chemotherapy. Results confirmed an alteration in GFR, with a relative yearly reduction of 1.8 ± 19%. Sixteen patients experienced a more pronounced reduction (>10 ml/min/year). 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 [69].

Hematological Toxicity

PRRT is generally well tolerated. Hematologic toxicity is typically mild (WHO grades 1–2) and transient within few weeks from treatment completion. Severe, grade 3 or 4, toxicity may occur in <15% patients, with either 90Y-DOTATOC or 177Lu-DOTATATE, and are also generally reversible within 2–3 months. In ~50% recovery may be longer (mean 12 months in a series of 203 177Lu-octreotate-treated patients) [63, 67]. Tumor diffusion in the bone marrow is a common feature in these cases [78]. PRRT is well tolerated, and severe, grade 3 or 4, hematological toxicity only occurred in <13% of patients treated with 90Y-DOTATOC and ~10% of those treated with 177Lu-DOTATATE (Table 2) [38, 39, 40, 43].

Sporadic cases of myelodysplastic syndrome (MDS) or even overt acute leukemia have been reported in ~2% [63]. Although predicted absorbed doses are lower than the conventional threshold for toxicity, both acute and permanent bone marrow damage remain a cause for concern, particularly when repeated radionuclide administrations are planned or the patients undergo several potentially myelotoxic treatments [36]. 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 dose-limiting hematological toxicity [39]. Investigations employing the dose-limiting toxicity method were abandoned, since published data identified that 7.4 GBq could be safely used as a maximum activity per cycle [79]. This dosage was based on the experience of thyroid cancer therapy with 131I, a radionuclide with physical characteristics similar to 177Lu [65].

In data from a cohort with GEP-NENs (n = 33) treated in a salvage study, toxicity results were encouraging. Thus, re-treatment 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) [80].

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 identified as the most important risk factors for myelotoxicity [67].

An analysis of a large group of 807 subjects treated with 90Y-octreotide, 177Lu-octreotate, or the combination showed that MDS occurred in 2.35%. This study also noted that commonly considered risk factors, such as prior chemotherapy, were associated with toxicity in up to 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, could better explain the radiation-associated disease at the low marrow doses commonly obtained with PRRT [68].

Recent studies demonstrated that 177Lu-octreotate can be safely utilized even in the presence of diffuse bone metastases, with severe bone replacement and potential elevated exposure of bone marrow. Significant G3/G4 reversible hematological toxicity occurred in 35% (n = 4) of 11 patients. Toxicity either resolved spontaneously (n = 1) or was controlled by support therapy (n = 3). A return to baseline values was obtained in 23 months after completion of PRRT [81].

Dosimetry in PRRT

Measuring the radiation burden to normal organs and malignant lesions is necessary to select the appropriate dose for therapy. The potential risk of kidney and red marrow toxicity limits the amount of radioactivity that may be administered. Indeed, when tumor masses are irradiated with suitable doses, volume reduction may be observed [82].

Techniques for radio-dosimetric estimates are illustrated in detail in chapter “Radiobiology and Radiation Dosimetry in Nuclear Medicine” of this text. Briefly, they include the generation of time–activity curves in normal organs and tumor lesions, based on data obtained from serial images recorded using a diagnostic activity of 111In-pentetreotide or 86Y-DOTATOC PET for 90Y-DOTATOC PRRT or with 177Lu-DOTATATE directly [83, 84] (Table 3).
Table 3

Absorbed radiation dose estimates following PRRT with 90Y-DOTATOC and 177Lu-DOTATATE. Values are organ absorbed doses per unit activity (Gy/GBq); mean ± SD or median (range)

 

90Y-DOTATOC

177Lu-DOTATATE

Organ

Dose (Gy/GBq)

Reference

Dose (Gy/GBq)

Reference

Red marrow

0.03 ± 0.01

Cremonesi et al. [84]

0.07 ± 0.01

Kwekkeboom et al. [101]

0.17 ± 0.02

Forrer et al. [85]

0.04 (0.02–0.06)

Cremonesi et al. [83]

0.09 (0.03–0.18)

Rodrigues et al. [89]

0.04 ± 0.02

Wehrmann et al. [90]

0.05 ± 0.00

Förster et al. [87]

0.02 ± 0.03

Krenning et al. [86]

0.06 ± 0.02

Helisch et al. [88]

  

0.12 ± 0.02

Menda et al. [100]

  

Kidneys

6.05 (unprotected)

Kwekkeboom et al. [101]

1.65 ± 0.47 (unprotected); 0.88 ± 0.19 (protected)

Kwekkeboom et al. [101]

3.84 ± 2.02 (unprotected)

Cremonesi et al. [84]

0.62 (0.45–17.74)

Cremonesi et al. [83]

2.84 ± 0.64

Forrer et al. [85]

0.9 ± 0.3

Wehrmann et al. [90]

2.44 (1.12–4.5)

Rodrigues et al. [89]

(0.32–1.67)

Sandstrom et al. [94]

2.73 ± 1.41

Helisch et al. [88]

  

1.71 ± 0.89 (1.20–5.10)

Jamar et al. [75]

  

2.24 ± 0.84 (1.1–3.8)

Menda et al. [100]

  

Adapted with permission from Bodei et al. [59]

Radiation dosimetry of normal organs and malignant lesions provides an insight for optimizing the delivery of radiation, allowing maximization of the absorbed dose to the tumor while minimizing the dose delivered to normal organs. Absorbed doses are largely dependent on the administered activity, radionuclide used, and individual organ mass. Absorbed or biological effective doses in organs are calculated from the spatial activity distribution of the radionuclide as a function of time. This distribution is obtained from planar scintigraphy, SPECT/CT, or PET/CT images. The computer codes used to derive the dose vary from a simple and reproducible method based on standard phantoms, such as MIRD, OLINDA, which may not necessarily represent the organ anatomy of a single individual, to accurate but complicated and time-consuming codes utilizing personalized Monte Carlo simulations [91, 92].

Dosimetry is an obligatory procedure in planning external radiotherapy, yet the prediction of the dose–response relationship in nuclear medicine therapy remains inaccurate. This is due to the large variability in the individual organ volume, diversity of biodistribution and tumor uptake among individuals, the lack of uniform tissue distribution of the radioactivity, the inaccuracy of the absorbed dose to the kidneys in predicting renal toxicity, and, finally, the difficulty in modeling organs such as the bone marrow. These variables when summated render the accurate prediction of toxicity difficult [83, 93]. As a consequence, dosimetry is not widely performed, and skepticism among clinicians is pervasive. However, dosimetry is the only form of personalization that takes into account the actual radiation dose – namely, the effector of the desired effect – delivered to the target tissue and therefore represents a worthwhile area for development and its refinement.

The initial clinical studies that assessed the individual tolerance to radiopeptides identified clinical factors that could modify the renal dose threshold for radiopeptides, suggesting a consequent modification of the PRRT schedule [74]. Subsequently, based on the conventional dose thresholds of tolerance of the bone marrow and kidneys, Sandström et al. demonstrated that the same scheme of PRRT (four cycles of 200 mCi each of 177Lu-octreotate) could result in different absorbed doses at the targets. Thus conversely, a substantial number of patients could tolerate higher cumulative activities or number of cycles – hence higher tumor doses and, potentially, efficacy. On the contrary a not irrelevant number of patients could tolerate lower cumulative activities or number of cycles – possibly inefficient to control the tumor [94]. This represents a major step toward a dosimetry-based personalized treatment.

PRRT Efficacy

Experience with 111In­Octreotide

Objective responses were rare due to the short range of the emission (0.0025 μm) of the particles. Among 40 patients treated with cumulative doses of 20–160 GBq, 1 partial remission, 6 minor remissions, and 14 stabilization of disease were reported. Mild hematological toxicity was observed, but three cases of myelodysplastic syndrome (MDS) or leukemia occurred in those treated with high activities (>100 GBq) and high estimated bone marrow doses (about 3 Gy). In a separate GEP-NETs study (n = 27), partial responses occurred in 2 of 26 patients with measurable disease. Renal insufficiency was reported in one patient, although possibly not treatment-related [54, 95].

Experience with 90Y-­DOTATOC

GEP-NET Tumors

All the published results derive from phase I to II trials and reflect heterogenous patient selection, inclusion criteria, treatment schemes, and dosages (cumulative activities ranged from 2 to 32 GBq). This has diminished the ability to derive rigorous conclusions. Complete and partial remissions were registered in 10–30% of patients, a higher rate than that obtained with 111In-pentetreotide (~5%). In the initial report, 29 persons were treated with a dose-escalation scheme consisting of four or more cycles of 90Y-DOTATOC with cumulative activities of 6.12 ± 1.35 GBq/m2. Twenty showed disease stabilization, two had partial remission, four had minor remission, and three progressed [96]. In a subsequent study (n = 39) four equal intravenous injections were administered with a total of 7.4 GBq/m2 of 90Y-DOTATOC. The objective response rate was 23%, with complete remission in 2, partial remission in 7, and stabilization in 27. Pancreatic NETs (n = 13) exhibited a higher objective response rate (38%). A significant reduction of clinical symptoms was recorded in 83% of patients with diarrhea, in 46% of patients with flushing, in 63% of patients with wheezing, and in 75% of patients with pellagra [38]. Toxicity was generally mild and involved the kidney and the bone marrow. However, renal insufficiency was reported in five individuals who did not receive renal protection during the therapy. Severe hematological toxicity occurred in individuals receiving high cumulative activities [72].

In cohorts receiving up to an administered activity of 5.55 GBq per cycle, reversible grade 3 hematological toxicity was noted in 43% of patients injected with 5.18 GBq, which was defined as the maximum tolerated dose per cycle. None developed acute or delayed kidney toxicity, although follow-up was short. Partial and complete responses were reported in 28% of 87 patients with NETs [39].

In the multicenter phase 1 study, 60 patients received escalating activities of up to 14.8 GBq/m2 in four cycles or up to 9.3 GBq/m2 in a single dose, without reaching the maximum tolerated single administration. All patients received renal protection. Three patients suffered dose-limiting toxicity: one with hepatic toxicity, one grade 4 thrombocytopenia, and one MDS. Four of 54 patients (8%) treated with the maximum allowed dose underwent a partial response, and 7 patients (13%) had minor responses. The median time to progression in the 44 patients showing stable disease, minor or partial response, was 30 months [97].

A multicenter study (2010) evaluated the role of 90Y-octreotide 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 [41]. This trial reported a PFS of 16 months and an overall survival of 27 months.

Figure 7 illustrates an example of objective response to 90Y-DOTATOC in a patient affected by gross liver metastases from a resected pancreatic insulinoma treated with 23 GBq in seven cycles.
Fig. 7

Illustrates an example of objective response to 90Y-DOTATOC in a patient affected by massive liver metastases from a resected insulin­secreting pancreatic neuroendocrine tumor after treatment, treated with 90Y­DOTATOC (23 GBq in seven cycles) (ac CT scans)

In respect of survival after 90Y-DOTATOC, a phase I–II study of GEP-NETs (n = 58) treated with 1.7–32.8 GBq reported a clinical benefit (including stabilization and minor response) in 57% (with true objective response in 20%), a median overall survival of 36.7 months (vs. 12 months in the historic group treated with 111In-pentetreotide), and a median progression-free survival of 29.3 months. Characteristically, patients stable at baseline had a better overall survival than those progressive at baseline, while the extent of disease at baseline was an additional predictive factor for survival [40].

A favorable clinical response after 90Y-DOTATOC, as determined by a scoring system that included weight, patient-assessed health score, Karnofsky score, and tumor-related symptoms, was reported in 14/21 patients who were treated with 13.3 GBq in three cycles [98].

More recently, the Basel group published the results of an open-label phase II trial in 1,109 patients with different NET lesions (GEP, BP, and other endocrine tumors, such as medullary thyroid cancer, paraganglioma, and neuroblastoma) treated with 90Y-octreotide, divided into multiple cycles of 3.7 GBq/m2 each. Objective morphologic responses (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® [42].

Other Endocrine and Endocrine­Regulated Tumors

Limited experiences in the treatment of medullary and follicular thyroid carcinomas, lymphoproliferative disorders, pheochromocytomas, and paragangliomas have been reported. 90Y-DOTATOC (7.5–19.2 GBq in two to eight cycles) was administered to 21 patients with metastatic medullary thyroid carcinoma with positive OctreoScan®, progressive after conventional treatments. Two patients (10%) obtained a complete response (CR), as evaluated by CT, MRI, and/or ultrasound, while a stabilization of disease (SD) was observed in 12 (57%); 7 (33%) failed to respond to therapy. The duration of the response ranged from 3 to 40 months. Using biochemical parameters (calcitonin and CEA), a complete response was observed in one patient (5%), while partial response occurred in five (24%) and stabilization in three (14%). Twelve had progression (57%). Complete responses were observed in those with lower tumor burden and calcitonin values at the time of the enrolment. Medullary thyroid cancers showed a lower response rate compared to classic GEP-NETs; nevertheless, patients with smaller tumors and higher uptake of the radiopeptide tended to respond better [99].

In a phase I study involving 17 children and young adults (2–24-year-old) affected by SSTR-positive tumors (including neuroblastomas, MEN2B, and gliomas), patients were treated with 90Y-DOTATOC (1.1–1.85 GBq/m2 per cycle for a total of three cycles, administered 6 weeks apart). Partial response according to the Pediatric Oncology Group criteria was observed in 12%, while 29% exhibited minor responses; the most obvious clinical benefit was overall improved quality of life. Thus, PRRT with 90Y-DOTATOC is effective and well tolerated also in young patients [100].

Experience with 177Lu-­DOTATATE in GEP-NETs

The somatostatin analogue [DOTA0, Tyr3, Thr8]-octreotide or DOTATATE has a ninefold higher affinity for the SSTR2 compared with [DOTA0,Tyr3]octreotide in vitro. Radiolabeling with the β/γ-emitter lutetium-177 yielded tumor regressions and prolonged animal survival in a rat model [55]. The compound 177Lu-octreotate was thereafter investigated in several clinical phase I and II studies [43, 44, 101, 102] and shown to have enhanced efficacy and greater manageability, due to a lower dosimetric burden to the kidney. An additional advantage is provided by the possibility of obtaining both scintigraphic images and dosimetric studies simultaneously since 177Lu exhibits gamma photon co-emission. Currently this compound represents the most frequently used radiopeptide for PRRT.

In a preliminary report by the Rotterdam group, GEP-NETs (n = 35) were treated with 3.7, 5.6, or 7.4 GBq of 177Lu-DOTATATE per cycle, up to a final cumulative activity of 22.2–29.6 GBq. Complete and partial responses were noted in 38% with no serious adverse events observed [79].

In a larger study (n = 131) of somatostatin, receptor-positive tumors were treated up to a cumulative activity of 22.2–29.6 GBq of 177Lu-DOTATATE. One developed renal insufficiency, and another hepatorenal syndrome. Severe hematological toxicity occurred in <2% of the administrations. In the 125 evaluated patients, complete remission was observed in 3 (2%), partial remission in 32 (26%), minor response in 24 (19%), and stable disease in 44 (35%), while 22 (18%) progressed. Better responses were more frequent in the case of a high uptake on baseline OctreoScan® scintigraphy and when a limited number of liver metastases were present, while progression was significantly more frequent in those with a low performance score and extensive disease at enrollment. Median time to progression was more than 36 months, comparing favorably to chemotherapy. A categorization of objective response showed again that pancreatic tumors tended to respond better than other GEP tumors, although pancreatic gastrinomas tended to relapse in a shorter interval (median TTP 20 months vs. >36 in the rest of GEP tumors). In addition, 177Lu-DOTATATE significantly improved the global health/QoL and various function and symptom scales in individuals with metastatic disease. The effect was more frequent in patients obtaining tumor regression but, surprisingly, was observed also in progressing patients [51, 103]. Of note was the fact that there was no significant decrease in QoL in individuals asymptomatic prior to therapy [52].

An enlargement of the previous series to 504 subjects treated with 177Lu-DOTATATE was undertaken. Efficacy was evaluated in 310, along with the confirmation of the occurrence of complete and partial remissions in 2 and 28% of cases, demonstrated a survival benefit of 40–72 months, compared to historical controls treated with chemotherapy. Reported prognostic factors for predicting tumor remission (CR, PR, or MR) as treatment outcome were uptake on the OctreoScan® (P < 0.01) and Karnofsky performance status (KPS) > 70 (P < 0.05). The degree of uptake at OctreoScan® is crucial and can be regarded roughly as a surrogate of the future absorbed dose provided by the therapy. 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, e.g., pancreatic gastrinomas, tended to relapse after a shorter interval (median time to progression 20 months vs. >36 in the remaining GEP-NENs) [43].

Figure 8 illustrates an example of objective response in a patient with liver and bone metastases from ileal neuroendocrine carcinoma treated with 177Lu-DOTATATE (24 GBq in five cycles).
Fig. 8

Serial functional and morphologic imaging in a young male patient affected by liver and bone metastases from ileal neuroendocrine carcinoma treated with 177Lu­DOTATATE (24 GBq in five cycles). Basal evaluation (a177Lu-­DOTATATE scintigraphy; c MRI) showed extensive liver involvement. Final evaluation (b177Lu­ DOTATATE scintigraphy; d MRI) showed an almost complete response

It is interesting to note that a small proportion of patients, responding to PRRT with either SD or mixed response at the first evaluation 3 months after therapy completion, showed a further objective response at 6 and 12 months of follow-up [43]. These observations allow speculation on the possible radiobiological implications, such as a “bystander effect,” triggered by the low dose rate, protracted irradiation of lutetium-177.

The results of a phase I–II escalation dose study aimed at defining toxicity and efficacy of 177Lu-octreotate were published in 2011 [44]. A cohort (n = 51) with unresectable/metastatic NENs, mainly of GEP origin, were divided into two dosage groups. One group received escalating activities, from 3.7 to 5.18 GBq and the second from 5.18 to 7.4 GBq, with dosimetry-based cumulative activities up to 29 GBq. Partial and complete responses were observed in 15 (32.6%). The median time to progression was 36 months, with an overall survival of 68% at 36 months. Nonresponders and patients with extensive tumor involvement were noted to have a lower survival [44].

Efficacy in Skeletal Involvement

It was generally considered, at the beginning of the PRRT experience, that bone metastases were less responsive to PRRT and that therefore these patients should receive additional therapies to treat skeletal locations. Despite the fact that neither SWOG nor RECIST criteria however include the evaluation of bone metastases, more recent studies indicate that PRRT is efficient in bone metastases. In a retrospective series (n = 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 PRRT-responsive bone metastases exhibited longer overall survivals (median 56 vs. 39 months). In this group, high neuron-specific enolase (NSE) values and Ki67 > 10% were associated with a shorter overall survival. Of note was the observation that Karnofsky performance status and multifocal bone metastatic disease did not limit the efficacy of PRRT [104].

Efficacy in Different Types of NETs

Pancreatic NETs

Recent advances on pathobiological and molecular genomics have indicated that pancreatic and small intestine NETs are two separate entities. Therefore, current studies have tended to address the role of PRRT in single-system pathologies.

A prospective phase II study used 177Lu-octreotate in a cohort (n = 52) with advanced well-/moderately differentiated pancreatic NETs. Based on the reported existence of putative risk factors for renal toxicity (hypertension and diabetes), patients were divided into two groups treated with different levels of activity. Thus, a full dose (21–28 GBq) was compared to 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, while it was 20 months in individuals treated with a reduced dose. This suggests the full-dose scheme should be recommended, when possible [45].

A recent retrospective study evaluated a cohort with metastatic pancreatic NENs (n = 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 ≤ 70), a high liver burden (≥25% of volume), and increased NSE (>15 ng/ml) were associated with a poorer prognosis [56]. To better define the predictors of long-term outcome, the same group undertook a multivariate analysis in a cohort of metastatic GEP-NENs (n = 74) who had previously undergone PRRT with 177Lu-octreotate (four cycles, 7.9 GBq each, at 3-month intervals). A Ki67 index >10%, a Karnofsky performance status ≤70, a tumor burden in the liver ≥25%, and a baseline NSE >15 ng/ml were independent predictors of shorter survival. However, even individuals with Ki67 > 10% benefited from PRRT, with a median PFS of 19 months as opposed to 26 months for the entire cohort [102].

A separate study by van Vliet E et al. considered non-resectable or borderline resectable or oligometastatic (≤3 liver metastases) nonfunctioning pancreatic NETs (n = 29). This group was treated with 177Lu-octreotate with neoadjuvant intent. After PRRT, successful surgery could be undertaken in nine individuals (31%) [Whipple procedure (n = 6), pylorus-preserving pancreaticoduodenectomy (n = 1), and spleno-pancreatectomy (n = 1)]. PFS was significantly longer in those in whom surgery could be undertaken (69 vs. 49 months). A further comparison with 90 plurimetastatic subjects treated in the same fashion provided a PFS of 25 months [105]. This study supports the proposal of early treatment and the possibility of downstaging tumors with PRRT.

Small Intestinal NETs

A phase II study of PRRT in progressive G1-G2 tumors (n = 43) 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. Of note is the observation that [18F]FDG-PET-negative patients exhibited a significantly longer PFS than those with an [18F]FDG-positive scan [47].

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). The cohort (n = 61) included unresectable small intestine tumors, in progression or with uncontrolled symptoms, which were treated and followed 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 CgA levels >600 ng/mL at baseline [48].

The recent phase III study of small intestine NETs using 177Lu-DOTATATE named NETTER-1 was undertaken by a bicontinental multicentric group sponsored by Advanced Accelerator Applications (AAA). This randomized trial compared 177Lu-DOTATATE vs. high-dose octreotide in patients with inoperable, progressive, midgut carcinoid tumors. Preliminary results indicate that 177Lu-octreotate significantly improves PFS (PFS not reached vs. 8.4 months; hazard ratio 0.21) [49].

Efficacy of Repeated Treatments: Salvage Therapy

The Rotterdam group published the results of salvage therapy with 177Lu-DOTATATE in NET patients with progressive disease after initial response to PRRT with the same agent administered with cumulative activities of 22.2–29.6 GBq. A total of 32 patients received two additional cycles of 177Lu-DOTATATE totaling 15 GBq, with ensuing new objective response in 8 (two partial and six minor responses) and stabilization of disease in 8; median time to progression in those responding was 17 months. Although the rate of response was lower than that observed after primary treatment and tumor response lasted for shorter periods, salvage therapy represents a valuable option in individuals with advanced disease, who have relapsed after responding to a first course of PRRT [106].

A more recent analysis by the Meldola group included 26 subjects in progression after an initial treatment with 90Y-octreotide. 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%, the median PFS 22 months (95% CI 16 months – not reached) and 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 [107].

Efficacy of PRRT in Combination with Chemotherapy or Biomolecular Agents

This concept is consistent with recent combinatorial therapeutic trends in oncology. A variety of different studies have demonstrated feasibility and efficacy. However, adequately powered, optimally randomized, and rigorously analyzed studies are required to define the exact benefit of this approach.

A phase II study of NET patients with progressive disease (n = 33) used a regimen including four cycles of 177Lu-DOTATATE (7.8 GBq) plus the radiosensitizer chemotherapy agent capecitabine (1,650 mg/m2), for the following 2 weeks. No additional toxicity was observed, while objective response (according to RECIST criteria) was achieved in 24%, stable disease in 70%, and disease progression in 6% [108].

A more recent adaptation of the chemoradiotherapy protocol utilized 5-fluorouracil (5-FU) as opposed to its oral prodrug capecitabine. A retrospective analysis of patients with progressive disease (n = 68) or uncontrollable symptoms from NETs reported 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 2–4) resulted in 70% benefit for at least 6 months for symptomatic patients and 68% disease-control rate in progressive disease. Non-pancreatic primary site, dominant liver metastases lesions <5 cm, and the use of 5-FU were associated with objective response [109].

A combination of 177Lu-octreotate with capecitabine and temozolomide was studied in a phase I–II trial of advanced low-grade NETs (n = 35), with the aim of evaluating safety and efficacy. Standard dosages (7.8 GBq) of 177Lu-octreotate every 8 weeks were combined with 14 days of capecitabine 1,500 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 [110].

An alternative combination phase I study evaluated the combination of everolimus with 177Lu-octreotate in subjects with advanced GEP-NETs (n = 16). Standard PRRT (four cycles of 7.8 GBq each) was administered in cohorts of patients receiving escalating doses of everolimus (from 5 to 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 optimal response occurred in pancreatic NENs, where four of five patients achieved 80% reduction of disease [111].

Efficacy of Combinations of 90Y- and 177Lu-Peptides

Protocols combining both 177Lu- and 90Y-peptides have been assessed with the purpose of exploiting the different physical properties of each radionuclide. Theoretically, this approach should result in a synergistic effect and 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). Combined 90Y- and 177Lu-PRRT was undertaken in a Danish cohort of 69 subjects treated in Basel. Complete responses were noted in 5 (7.4%), partial remissions in 11 (16.2%), and stabilization in 42 (61.8%). The median PFS was 29 months. Pancreatic NENs responded better than small bowel tumors [66]. However, to ascertain if this strategy is advantageous in terms of response and tolerability over more conventional PRRT protocols, validation is required in adequately powered and randomized trials with long-term follow-up, rather than empirically designed single-armed 177Lu and 90Y protocols [112, 113].

Conclusions

PRRT has become a well-established effective therapeutic modality for inoperable or metastatic GEP, bronchopulmonary, and other NETs over the last two decades. Experience with 90Y-octreotide and 177Lu-octreotate from phase I to II studies and the preliminary results of the phase III studies in intestinal NETs suggest antitumor activity and a consistent survival benefit. PRRT is overall well tolerated by the majority with only moderate toxicity if the necessary precautions are undertaken. The two most commonly used radiopeptides, 90Y-octreotide and 177Lu-octreotate, produce significant objective response rates, with positive impact on PFS and OS. In addition, both biochemical and symptomatic responses are commonly observed. Molecular analysis of nephro- and hematotoxicity genes in cohorts of treated patients is likely to further improve the prediction of toxicity [36].

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Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Lisa Bodei
    • 2
    Email author
  • Laura Gilardi
    • 1
  • Duccio Volterrani
    • 4
  • Giovanni Paganelli
    • 5
  • Chiara M. Grana
    • 1
  • Mark Kidd
    • 3
  • Irvin M. Modlin
    • 3
    • 6
  1. 1.Division of Nuclear MedicineEuropean Institute of OncologyMilanItaly
  2. 2.Molecular Imaging and Therapy Service, Department of RadiologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Wren LaboratoriesBranfordUSA
  4. 4.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly
  5. 5.Nuclear Medicine and Radiometabolic UnitsIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCSMeldolaItaly
  6. 6.Yale School of MedicineNew HavenUSA

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