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Initial Experience With Gallium-68 DOTA-Octreotate PET/CT and Peptide Receptor Radionuclide Therapy for Pediatric Patients With Refractory Metastatic Neuroblastoma

Kong, Grace MBBS (Hons), FRACP, FAANMS; Hofman, Michael S. MBBS (Hons), FRACP, FAANMS; Murray, William K. MBBS, FRCPA, FRCPath; Wilson, Sharyn BAppSc, MHlthSc; Wood, Paul MBBS, BPharm, MSc, FRACP; Downie, Peter MBBS, FRACP; Super, Leanne MBBS, FRACP; Hogg, Annette BAppSc, PhD; Eu, Peter BSc (Pharmacy), MSc (Radiopharmacy); Hicks, Rodney J. MBBS (Hons), MD, FRACP

Journal of Pediatric Hematology/Oncology: March 2016 - Volume 38 - Issue 2 - p 87–96
doi: 10.1097/MPH.0000000000000411
Original Articles

Rationale: Pediatric patients with refractory neuroblastoma have limited therapeutic options. Neuroblastoma may express somatostatin receptors (SSTRs) allowing imaging with 68Ga-DOTA-Octreotate (GaTATE) positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT). We reviewed our experience with this theranostic combination.

Materials and Methods: GaTATE studies (8 patients; 2 to 9 years old) were reviewed and compared with 123I-MIBG or posttreatment 131I-MIBG studies. Immunohistochemistry (IHC) for SSTR subtype 2 was performed in 5 patients. Four patients received PRRT.

Results: GaTATE PET showed additional disease in 38% (3/8 patients), and upstaged 1 patient by detecting marrow involvement. IHC detected SSTR 2 in all patients assessed. Six patients were deemed suitable for PRRT on imaging. Four patients received 17 cycles of palliative PRRT (10 111In-DOTATATE; 5 177Lu-DOTATATE; 1 combined 111In and 177Lu-DOTATATE; 1 combined 177Lu and 90Y-DOTATATE) with no significant toxicity attributed to PRRT. All had objective responses. Two survivors are now 40 and 56 months from PRRT commencement.

Conclusions: GaTATE PET was positive in a high proportion of patients with refractory neuroblastoma, correlating with SSTR 2 on IHC, with additional disease identified compared with MIBG imaging. PRRT seems safe, feasible, with responses observed in patients with progression despite multimodality treatment. These data support ongoing clinical trials in such patients.

*Centre for Cancer Imaging

Department of Pathology

Translational Research Laboratory, Peter MacCallum Cancer Centre

§Children’s Cancer Centre, Monash Health, Victoria

Department of Paediatrics, Monash University

#Children’s Cancer Centre, Royal Children’s Hospital Melbourne, Melbourne

Department of Medicine

**The Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Vic., Australia

The authors declare no conflict of interest.

Reprints: Rodney J. Hicks, MBBS (Hons), MD, FRACP, Centre for Cancer Imaging, The Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Vic. 3002, Australia (e-mail:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Received February 14, 2015

Accepted June 30, 2015

Neuroblastoma is the most common extracranial malignant solid tumor in childhood. It arises from neural crest derivatives and constitutes approximately 8% of pediatric malignancy, with 65% of primary tumors found in the adrenals and the remainder elsewhere along the sympathetic nervous chain.1 Prognosis varies widely according to the age at diagnosis, the extent of disease, and the tumor biology.2 There is a variable disease course with spontaneous regression or maturation to benign ganglioneuroma observed in some patients, whereas others behave in an aggressive manner with high mortality despite multimodality therapy.1,3

There are currently effective salvage therapies for patients with low-risk to intermediate-risk disease including localized relapse. However, treatment of recurrent or refractory multifocal disease in high-risk neuroblastoma after multimodality therapy remains a clinical challenge with no effective salvage therapies.3,4 Radionuclide therapy using 131I-MIBG has been used either as a single agent in this setting after conventional therapy, or more recently in combination with myeloablative therapy before autologous bone marrow transplantation for tumors with high MIBG uptake.1 Although toxicity seems limited at administered activities up to 450 MBq/kg with useful disease palliation and responses in 18% to 37%, benefits are often temporary.3,4 Dose escalation is often associated with hematopoietic toxicity particularly in heavily pretreated patients. When used in combination with chemotherapy, autologous stem-cell support is generally required.3–5 Therefore, development of other targeted radioactive therapies may improve outcome in these difficult cases, particularly those that have either failed 131I-MIBG or who have low uptake of 123I-MIBG at known sites of disease.

Studies using autoradiography and immunohistochemistry (IHC) have indicated expression of somatostatin receptor (SSTR) in up to 77% to 89% of neuroblastoma cells.6–9 111In-pentetreotide (Octreoscan) has been the conventional technique used to identify SSTR. SSTR imaging can now be performed on combined positron emission tomography/computed tomography (PET/CT) by substituting gallium-68 for indium-111. PET provides superior imaging resolution and speed, as well as multislice CT for anatomic correlation.10 Use of octreotate (68Ga-DOTATATE or GaTATE) has a higher affinity for SSTR subtype 2 (SSTR 2) receptors.11 In the adult neuroendocrine tumor (NET) population, GaTATE PET provides additional information and allows assessment of suitability for peptide receptor radionuclide therapy (PRRT),12–16 and PRRT has been successfully used with high activity 111In-, 177Lu-, or 90Y-labeled somatostatin analogs for adult NET patients.17,18

There are limited studies evaluating the use of SSTR PET for imaging and selecting pediatric neuroblastoma for PRRT.19,20 In this study, we evaluated consecutive GaTATE PET/CT performed at our center for pediatric neuroblastoma patients to assess SSTR expression, its incremental value compared with MIBG scintigraphy, and potential impact on assessing suitability for PRRT, representing a theranostic paradigm. To confirm the feasibility of using PRRT for patients with neuroblastoma, the presence of SSTR 2 was investigated on tumor or bone marrow tissue using IHC and correlated with GaTATE PET/CT imaging findings. We also report intermeditate-term outcomes of 4 patients who were subsequently treated with PRRT.

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Patient Characteristics

Eight patients, 2 to 9 years old, with 68Ga-DOTATATE studies performed from October 2008 to January 2012 were retrospectively reviewed. All had known residual neuroblastoma despite heavy pretreatment including chemotherapy, and 7 had 131I-MIBG treatments and were being considered for PRRT. 131I-MIBG treatments were administered for palliative intent (usually dose escalated from 100 to 250 MBq/kg over 2 to 3 cycles as tolerated).

A total of 11 GaTATE PET/CT studies were performed. Three follow-up studies were excluded due to the lack of contemporaneous MIBG imaging. Hence, baseline studies of 8 patients were included in the analysis with the aims of assessing any incremental value compared with MIBG scintigraphy and impact on suitability for PRRT (Table 1).



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GaTATE PET/CT and Image Analysis

68Ga-DOTA-octreotate was synthesized using an onsite 68Ge/68Ga generator (IDB Holland BV, the Netherlands). GaTATE (2.6 MBq/kg) was administered intravenously and images were acquired after an approximate 60-minute uptake period on a PET/CT scanner (GE Discovery STE or Siemens Biograph 64) using low-dose noncontrast CT (GE SmartDose or Siemens CAREDose 4D).

Blinded scoring of number and sites of abnormalities and semiquantitative uptake analysis by measuring the maximum standardized uptake value (SUVmax) were performed by 2 nuclear medicine physicians. Comparison was made with diagnostic 123I-MIBG (n=5) or posttreatment 131I-MIBG scans (n=3) performed with SPECT or SPECT/CT. Sites of additional disease, the concordance and degree of SSTR expression at known MIBG-avid disease sites, and suitability for PRRT were assessed. The degree of SSTR expression: score 0=no uptake abnormality; score 1=faint uptake; score 2=clear uptake but less than or equal to background liver activity; score 3=uptake greater than liver; score 4=uptake equal or greater than spleen.17 An uptake score of ≥3 on GaTATE PET/CT was considered suitable for PRRT.

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Archived formalin-fixed paraffin-embedded neuroblastoma tissue from 5 patients were obtained and assessed. The 17 specimens included primary and relapse tumors in resection specimens, core biopsies, and bone marrow trephines and paraffin sections were stained for expression of SSTR 2, chromogranin A, glucose transporter 1, hexokinase 2, and Ki-67, as well as routine hematoxylin and eosin staining. The antibodies used were: monoclonal rabbit anti-human SSTR 2 antibody (1:250, Clone UMB1; Abcam), monoclonal mouse anti-human chromogranin A (1:400, Clone DAK-A3; DakoCytomation), monoclonal mouse anti-human glucose transporter antibody (1:200, Clone SPM498; Thermo Fisher Scientific), monoclonal mouse anti-human hexokinase II antibody (1:150, Clone 3D3; Abcam), and monoclonal rabbit anti-Ki-67 (1:50, Clone SP6; Cell Marque). Sections (4 μm) of the paraffin blocks were prepared and mounted on positively charged microscope slides. Immunostaining was performed using the automated Ventana Benchmark Ultra System (Ventana Medical Systems, Tucson, AZ). The slides were then counterstained using Mayers hematoxylin before scoring.

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Patients Treated With PRRT

Four patients (3 to 9 years old) received PRRT commencing July 2009 to November 2012, referred by their pediatric oncologist for palliative treatment based on progressive, symptomatic disease and high SSTR avidity on GaTATE PET/CT. PRRT was given with informed consent under a special access scheme that is available to Australian patients when conventional therapies have failed or deemed unsuitable. 177Lu chloride was sourced from IDB Holland and radiolabeled to the peptide octreotate kindly provided by the Erasmus Medical Centre, Rotterdam, Holland, using established methods with DOTA as the chelating agent to form 177Lu-DOTA-octreotate (177Lu-DOTATATE). 111Indium chloride (Mallinckrodt, Le Petten, the Netherlands) and Yttrium-90 (Perkin Elmer, Waltham, MA) were labeled onto octreotate (Auspep, Vic., Australia).

Three patients received 111In-DOTA-octreotate (111In-DOTATATE) therapy (2 to 4 cycles, given 6 to 8 wk apart), administered by slow intravenous infusion. Patients were inpatients for radiation safety purposes. Activity administered per cycle (2 to 6.6 GBq, approximately 100 to 150 MBq/kg) was chosen based on disease burden, hematological parameters, renal function, and weight-adjusted for the equivalent adult dose in our institution (7 to 12 GBq).21 Three patients received 177Lu-DOTATATE. One was performed as a single cycle of 177Lu-DOTATATE, the other 2 patients received 6 further cycles of 177Lu-DOTATATE for progressive disease after 111In-DOTATATE therapy (each cycle 3 to5 GBq, approximately 125 to 230 MBq/kg), given as slow intravenous injection as an outpatient, with renoprotective amino acid infusion (12.5 g lysine, 12.5 g of arginine in 500 mL over 4 h, dose adjusted to weight and body surface area), and premedications with dexamethasone and granisetron. Blood tests (full blood count, urea and electrolytes, liver function tests) were performed 2 and 4 weeks after PRRT. Toxicity was graded using the Common Toxicity Criteria of the National Cancer Institute, version 3.0. Follow-up GaTATE PET/CT studies were performed 2 to 3 months posttreatment. Patients were followed until cutoff date of December 1, 2014 or death.

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GaTATE PET/CT demonstrated high tumor-to-background uptake at all known disease sites. The median SUVmax was 6.7 (range, 3.9 to 15.3) at the site of most intense uptake. Additional sites of disease were detected in 3 of the 8 studies (38%). Of these, the time between GaTATE PET/CT and MIBG imaging was 13, 70, and 79 days. One was upstaged by identification of unexpected marrow involvement, confirmed on bone marrow biopsy.

GaTATE PET/CT demonstrated concordant or additional sites of SSTR uptake higher than background liver in 6 of the 8 (75%) studies, indicating suitability for PRRT (Fig. 1). Lower but definite GaTATE uptake (intensity score <3) was shown in 2 studies but was considered unsuitable for PRRT (Fig. 2).





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IHC Results

SSTR 2 was detected in all 5 patients where tissue was available for analysis. Time between the samples obtained in relation to GaTATE scan was 2 to 26 months (median, 13 mo). There were low levels of glucose transporter 1and hexokinase 2 in tumors from all these patients possibly correlating with the increased differentiation and concomitant reduced proliferation of the cells. In contrast, the levels of chromogranin A (a neuroendocrine secretory protein that is elevated in a range of NETs including neuroblastoma) and SSTR 2 were significantly high in all patients. This finding overall correlates with the high degree of tracer uptake visualized on GaTATE PET imaging (Table 2).



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PRRT Toxicity and Follow-up

A total of 17 administrations of PRRT were given to 4 patients, including 10 cycles of 111In-DOTATATE, 5 cycles of 177Lu-DOTATATE therapy, 1 cycle of combined 111In-DOTATATE and 177Lu-DOTATATE, and 1 cycle of combined 177Lu-DOTATATE and 90Y-DOTATATE (Table 3). No significant acute side effects were attributed to PRRT. Late toxicity was primarily hematologic. One patient had moderate baseline thrombocytopenia due to heavy pretreatment with chemotherapy and 131I-MIBG, and developed grade 4 thrombocytopenia following 177Lu-DOTATATE associated with progressive bone disease that was considered to be the major etiological factor. One patient developed grade 3 thrombocytopenia 6 weeks after combined 111In-DOTATATE and 177Lu-DOTATATE therapy with known diffuse marrow disease and baseline thrombocytopenia secondary to prior chemotherapy. This patient developed pancytopenia (nadir of grade 4 anemia, grade 2 leukopaenia) in the setting of concomitant chemotherapy (temozolamide), and blood counts recovered with supportive measures without clinical complications. One patient tolerated 7 cycles of PRRT before developing pancytopenia after combined 177Lu/90Y-DOTATATE requiring blood and platelet support, but was difficult to differentiate whether this was due to intensified PRRT or concurrent/ongoing chemotherapy (topotecan and cyclophosphamide) with progressive marrow disease. No significant renal toxicities, myelodysplastic syndrome, or leukemia had occurred.



Two patients remain alive at last follow-up (40 and 56 mo from first PRRT treatment). One patient experienced an early clinical response to 111In-DOTATATE treatment, with mixed imaging response at 3 months. Restaging following further local radiotherapy and trial of phase 1 therapy showed ongoing bony progression with moderate to high SSTR expression at areas of pain, especially in exophytic skull lesion. In the absence of other therapeutic options, further PRRT was given (1 cycle of combined 111In-DOTATATE with 177Lu-DOTATATE, and further cycle of 177Lu-DOTATATE with oral temozolamide). Temozolamide (alkylating agent) has been shown to be effective against neuroblastoma,22 primary brain tumors,23 and brain metastases24 in heavily pretreated patients, has good oral bioavailability, with evidence of its effect as a radiosensitizing agent.25 The rationale for its use with PRRT is based on the relatively low level of myelosuppression, organ toxicity, ease of administration (given orally), and tolerable emesis. Dose was 100 mg/m2/d given orally for 21 consecutive days, commenced at the start of PRRT. Restaging showed a remarkable functional, morphologic, and symptomatic response maintained at 13 months but with subsequent small volume progression (Fig. 3). Single-agent temozolamide was continued for approximately 6 months, and the patient has remained clinically well and stable (followed until study cutoff date) without ongoing treatment.



The other patient had a favorable partial response 3 months after induction 111In-DOTATATE therapy, with sustained stability on GaTATE PET/CT images and remained clinically well 14 months after the first treatment. Surveillance scan showed new multifocal small volume bone disease and further PRRT was administered including 2 cycles of 177Lu-DOTATATE (second cycle with oral etoposide) with almost complete normalization of GaTATE PET/CT at 3 months. Topoisomerase inhibitors (such as etoposide) have also been shown to have activity against relapsed or refractory neuroblastoma26; given in lower doses as oral metronomic therapy, etoposide can retain antitumor activity in patients who are refractory to intravenous etoposide by inhibiting angiogenesis.27 Oral administration is generally well tolerated, and the side-effect profile of emesis and myelosuppression is minimized. Dose was 50 mg/m2/d given orally for 21 days. This patient, however, again had imaging relapse and received further 177Lu-DOTATATE with temozolamide, resulting in favorable partial response. However, there was evidence of marrow progression 2 months later with right thigh pain, and augmentation of PRRT with further cycle of 177Lu-DOTATATE (4 GBq) with 90Y-DOTATATE (1 GBq) was selected rather than combining with chemotherapy. The high uptake associated with large disease burden would likely lead to sink effect and relatively lower radiopharmaceutical concentration in physiological organs including kidneys, thus limiting potential nephrotoxicity,28 even with addition of 90Y-DOTATATE. The context of rapidly progressive disease and limited therapeutic options further provided rationale for this approach. This resulted in significant scan and symptomatic response indicating relapsing but radiosensitive disease. Despite this, disease progression was evident that was complicated by pancytopenia, possibly exacerbated by ongoing chemotherapy after his last PRRT (Fig. 4). It was decided by the treating team to treat with further various regimens of chemotherapy (oral temozolamide, temozolamide an irinotecan, TVD-topotecan, vincristine, and doxorubicin) rather than further PRRT despite high SSTR uptake. This resulted in a partial response for around 9 months until significant symptomatic extensive marrow relapse recurred. In view of minimal therapeutic options and continuing high SSTR and MIBG uptake at sites of relapse, decision was for further targeted PRRT and MIBG therapy for palliative symptomatic and disease control.



Two patients are deceased due to progressive disease. One patient died approximately 2 months after treatment despite initial symptomatic and partial scan response. The other died 19 months after commencing PRRT also despite a good symptomatic response that was maintained for over 12 months. Allowing for small patient numbers, the estimated median best progression-free period from PRRT was approximately 10.5 months (2 to 20 mo).

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Magnetic resonance imaging and CT are generally the first imaging tests performed to stage neuroblastoma, but these may underestimate the extent of metastatic disease. Although MIBG imaging has been the cornerstone of molecular imaging assessment and has been incorporated into consensus guidelines with sensitivities over 85% and specificities over 90%,2,29–31 our study has shown that GaTATE PET/CT was positive for concordant SSTR expression in a high proportion of patients with residual neuroblastoma. Additional sites of disease were shown in up to 38% (3/8 patients) compared with MIBG imaging. In addition, GaTATE PET/CT can be completed in <90 minutes from tracer administration, significantly shorter than 111In-pentetreotide or 123I-MIBG scans, which usually require 24 to 48 hours of uptake. Rapid image acquisition times (<10 min) can also be achieved in infants, which has advantages with respect to compliance or minimizing anesthetic duration. It also enables noninvasive quantitation for individualized dosimetry estimates for body habitus and tumor burden for subsequent PRRT.32 The incremental diagnostic information and convenient imaging protocol suggest GaTATE PET/CT could become the preferred molecular imaging technique for pediatric neuroblastoma patients. Further prospective studies to assess GaTATE PET/CT for primary staging, to measure SSTR expression as part of the initial molecular workup, for diagnostic and therapeutic purposes would be useful to evaluate whether PRRT might be an alternative to 131I-MIBG in first-line treatment of neuroblastoma.

Importantly, this study has shown that a high proportion of neuroblastoma patients (75%, 6/8 patients) demonstrated sufficient SSTR uptake to indicate suitability for targeted PRRT; an encouraging finding given these patients had failed conventional treatments and had limited further treatment alternatives. A recent study by Gains et al20 also supported the use of GaTATE PET/CT to select children for PRRT. Although SSTR expression in neuroblastoma cells had been previously demonstrated in several studies, this is, to our knowledge, the first study to correlate GaTATE PET/CT findings with SSTR expression on IHC. We confirmed that SSTR 2 expression, the target of GaTATE imaging and PRRT, was detected on tissue or bone marrow trephine IHC from all patients assessed. This corresponded with the high uptake visualized on GaTATE scans, therefore supporting rationale for PRRT in this pediatric population. This also suggests that IHC staining of SSTR 2 should be considered on initial biopsy or staging, to provide further disease characterization and to identify the presence of this molecular target for imaging and potential therapy. Of note, samples from several patients that showed mild SSTR 2 staining in fact demonstrated high lesional uptake on GaTATE imaging. We postulate these could be related to tumor heterogeneity. The tissue may have been sampled from an area of lower SSTR expression in tumors with variable receptor expression. Therefore, performing GaTATE PET/CT is prudent to fully characterize disease phenotype, guide optimal biopsy site, and to assess the extent of SSTR expressing disease especially if PRRT is contemplated.

A phase I trial using 90Y-DOTATOC in children with solid tumors and high SSTR expression reported no significant dose-limiting toxicities, and was effective with 12% partial, plus 29% minor response rates.33 However, we have concerns in using this agent in young children. Although 90Y, due to its longer beta emitting particle range may be more effective for larger tumors, it can be associated with toxicity secondary to irradiation of adjacent normal tissues. This is highly relevant in children who often have diffuse marrow involvement and smaller organs than adults. Nephrotoxicity from direct radiation exposure of radiation-sensitive cortical glomeruli from reabsorption sites in the proximal convoluted tubules34 is of particular concern. Small renal volume is an important risk for nephrotoxicity with 90Y-DOTATOC.35 In adults, 90Y-DOTATOC therapy has been reported to be associated with grade 4 to 5 renal toxicity in approaching 10% of cases36 but seems to be a much less significant issue with 177Lu-DOTATATE.37,38

We, therefore, initially selected 111In-DOTATATE as the radiopharmaceutical of choice for pediatric patients with marrow involvement on the basis that the Auger electrons have a markedly shorter path-length compared with the beta particles of 90Y or 177Lu. This would theoretically be less toxic to adjacent normal bone marrow. In patients with more confined marrow involvement or primarily soft tissue involvement, 177Lu is an attractive choice, especially given its proven efficacy, which compares favorably with limited alternative treatment approaches in adult patients with NET.17,18 For patients with mixed distribution of disease, a combined approach was used when further treatment was required if the patient had tolerated single-agent treatment previously. Further, when there is a large burden of disease and little uptake in the kidneys on staging GaTATE PET/CT, despite theoretical concerns regarding its potential nephrotoxicity, 90Y-DOTATATE may be an effective option, as demonstrated in one of our patients.

Our initial experience of the 4 patients who received PRRT suggests that this treatment is feasible, well tolerated, with no direct renal toxicities, supporting the results of the only other study using 177Lu-DOTATATE PRRT in treatment of 6 pediatric patients with neuroblastoma.20 In our series, despite ongoing progressive disease resulting in the death of 2 patients, early symptomatic and partial imaging responses were achieved in all patients after initial induction treatments. Both survivors achieved early favorable symptomatic improvement, and 1 had sustained GaTATE PET/CT response up to 14 months after first PRRT and normalization of urinary catecholamines, suggesting favorable therapeutic benefit. In addition, our group has used concomitant radiosensitizing 5-flurouracil chemotherapy with high-activity 111In-DOTATATE39 and 177Lu-DOTATATE therapy38,40 without incremental toxicity for treatment of adult NET, and this approach should also be considered in high-risk neuroblastoma patients to further improve efficacy. Given that our patients were heavily pretreated with chemotherapy and subsequently progressed on PRRT, we elected to escalate treatment by combining PRRT with etoposide or temozolamide as a radiosensitizer. This approach was associated with tolerable myelosuppression and excellent responses, suggesting feasibility of combining PRRT with radiosensitizing chemotherapy in such patients. These results are very encouraging given minimal other therapeutic options, these children having failed prior treatment with chemotherapy and 131I-MIBG. However, unlike adult NET patients who would receive an induction course of 3 to 4 cycles of PRRT, in this palliative setting we only used cycles of treatment for symptomatic control, which was typically achieved within days of each cycle of treatment, and again at disease recrudescence, with the objective of having as little toxicity as feasible. Given the limited cycles in which PRRT was given at a time, better disease control or regression may be achievable with more aggressive regimen in less heavily pretreated patients, similar to adult NET patients protocols.41,42

Of course, this retrospective study has recognized limitations, relating to the small sample size reflective of rarity of these tumors. A noticeable limitation is the interval between prior MIBG imaging and GaTATE PET/CT, and use of SPECT rather than most current SPECT/CT technology in some patients. However, as all patients were considered to have failed or to have been unsuitable for 131I-MIBG therapy based on prior 123I-MIBG scanning, we felt it was inappropriate to repeat scanning purely for correlative purposes. The GaTATE PET/CT scans were performed to decide whether PRRT might be a suitable palliative therapy. Nevertheless, our results are concordant with a recent study, which showed GaTATE to have higher sensitivity than 123I-MIBG in phaeochromocytoma and neuroblastoma patients.19 There was also a lack of histologic verification of all new GaTATE PET/CT findings, but this is unlikely to be ethical or practical, particularly in young pediatric patients with widespread metastatic disease. Further, as standard treatment protocols mandate use of 131I-MIBG as the salvage radionuclide therapy of choice, the study population was limited to compassionate use in patients who had failed multiple lines of prior therapy, many of whom had preexisting impairment of marrow reserves and organ function. Treatment with PRRT was also administered using an individualized approach rather than a fixed protocol. However, the overall favorable response in the setting of failed conventional therapies with tolerable toxicity would support the use of PRRT and radiosensitizing chemotherapy in larger studies using more uniform protocols to assess therapeutic benefit and outcome, and currently, a phase IIa trial of 177Lu-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma is being performed in the United Kingdom. Future studies should also consider incorporating this into first-line therapy clinical trials.

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GaTATE PET/CT identified additional sites of disease when compared with MIBG imaging suggesting that it is a useful staging technique. It was positive in a high proportion of patients with known residual neuroblastoma and highly concordant with SSTR expression on IHC, indicating sufficient SSTR expression to allow consideration of PRRT as a new potential treatment option. The combination of SPECT/CT with MIBG to assess noradrenaline transporter function and PET/CT with GaTATE to assess SSTR expression may be optimal to stage, provide prognostic information, and determine therapeutic options. Our initial experience primarily in using high-activity 111In-DOTATATE and 177Lu-DOTATATE therapy suggests it is feasible, well tolerated, with responses observed even in patients who have progressed on multimodality treatment, and with tolerable acute toxicities. Our preliminary results of combining 177Lu-DOTATATE with temozolamide and etoposide may warrant more aggressive treatment protocols, including use in combination with other types of radiosensitizing chemotherapy in high-risk patients with residual or relapsed disease, particularly with diffuse marrow infiltration, perhaps including stem-cell rescue.

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The authors would like to thank the parents of these children for their support in agreeing to receive novel treatment options. Thank you to our pediatric nurses, Frances Ness and Jessy Thambiraj for coordinating scans and therapeutic interventions; to radiopharmacy and radiochemistry team of Peter Eu, Wayne Noonan, and Peter Roselt for their expertise; and to our nuclear medicine and PET technologists. R.J.H. has been the recipient of a Translational Research Grant from the Victorian Cancer Agency that partially funded the GaTATE PET/CT scans in these patients.

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neuroblastoma; PET; peptide receptor; radionuclide therapy; immunohistochemistry; DOTATATE; Ga-68

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