Hindawi Publishing Corporation
`Journal of Oncology
`Volume 2012, Article ID 320198, 10 pages
`doi:10.1155/2012/320198
`
`Clinical Study
`Radiolabeled Somatostatin Analogues Therapy in Advanced
`Neuroendocrine Tumors: A Single Centre Experience
`
`A. Filice,1 A. Fraternali,1 A. Frasoldati,2 M. Asti,1 E. Grassi,3 L. Massi,1
`M. Sollini,1, 4 A. Froio,1 P. A. Erba,1, 4 and A. Versari1
`
`1 Department of Nuclear Medicine, Azienda Ospedaliera Santa Maria Nuova, IRCCS Reggio Emilia, Via Risorgimento 80,
`42100 Reggio Emilia, Italy
`2 Department of Endocrinology, Azienda Ospedaliera Santa Maria Nuova, IRCCS Reggio Emilia, Via Risorgimento 80,
`42100 Reggio Emilia, Italy
`3 Department of Medical Physics, Azienda Ospedaliera Santa Maria Nuova, IRCCS Reggio Emilia, Via Risorgimento 80,
`42100 Reggio Emilia, Italy
`4 Nuclear Medicine Unit, University of Pisa, Via Roma 55, 56125 Pisa, Italy
`
`Correspondence should be addressed to A. Versari, versari.annibale@asmn.re.it
`
`Received 30 April 2012; Revised 25 June 2012; Accepted 26 June 2012
`
`Academic Editor: Marialuisa Appetecchia
`
`Copyright © 2012 A. Filice et al. This is an open access article distributed under the Creative Commons Attribution License, which
`permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`The aim of this study was to assess the efficacy of PRRT in patients with advanced neuroendocrine tumors (NETs). Patients
`and Methods. From January 2007 to August 2011, we enrolled 65 patients (m/f 38/27; mean age 65 years, range 33–83) with
`advanced NETs having enhanced SSTR expression, treated with PRRT. The enhanced expression of SSTR was assessed using
`68Ga-DOTATOC/DOTATATE PET/CT. Among all the enrolled patients, 6 of them were excluded from the present analysis
`since they voluntarily interrupted treatment. Mean activity/cycle of 2.6 GBq (90Y-DOTATOC/DOTATATE) or 6.0 GBq (177Lu-
`DOTATOC/DOTATATE) was administrated intravenously (max 9 cycles). Results. Complete response (CR) was found in 1/59
`(2%) patients, partial remission (PR) in 24/59 (40.5%) patients, stable disease (SD) in 24/59 (40.5%), and progression (PD) in
`10/59 (17%) patients. The overall tumor response rate (CR + PR) was 42.5%. In 40.5% of patients, the disease could be stabilized.
`Overall, 49 out of 59 patients had no tumor progression (83%). Twelve patients out of 59 (20%) had grade 2-3 hematological side
`effects including anemia, thrombocytopenia, and leukopenia. Long-term nephrotoxicity was observed in 3 patients (2 moderate,
`1 severe). Conclusions. PRRT is a promising perspective for patients with advanced NETs.
`
`1. Introduction
`
`Neuroendocrine tumors (NETs) are considered a class of
`rare neoplasms accounting <5% of all tumors. However,
`diagnosis of NETs has increased substantially over the last
`decades and prevalence is now greater than that of any other
`upper gastrointestinal tumor [1]. These tumors originate
`from dispersed neuroendocrine cells, distributed almost
`ubiquitously in the body [2], and occur in 5/100,000 people
`per year [1].
`The most frequent sites of NETs are gastroenteropancre-
`atic tract (GEP NETs), followed by lungs; less frequently skin,
`adrenal glands, thyroid, and genital tracts may be affected.
`
`Different nomenclature systems and classifications have been
`used for NETs.
`Current pathological staging and grading differ between
`Europe and USA; however, both classification systems are
`centered on the primary site of the tumor and histological
`grade. In Europe, the Ki-67 proliferative index is used to
`differentiate tumors of low (<2%), intermediate (2–20%)
`and high (>20%) grade, whereas in the USA, tumors are
`graded as “well-” and “poorly-” differentiated where “well”
`equates to low-intermediate grade and “poorly” equates to
`high-grade tumors [3, 4].
`Up to 80% of GEP NETs express somatostatin receptors
`(SSTR2 and SSTR5 primarily). Therefore, somatostatin
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`analogues have been used for both diagnosis and treatment
`of NETs. 111In-labeled SST-analogues SPECT and 68Ga SST-
`analogues PET/CT represent an accurate methods for NETs
`diagnosis peptide radioreceptor therapy (PRRT) indication
`and patients management [5–8].
`When beta-emitters isotopes as 90Y (T1/2 of 2.67 days,
`maximum range of tissue irradiation of 12 mm) or 177Lu
`(T1/2 of 6.73 days, maximum range of irradiation of 1.5 mm)
`are used to label SST-analogues linked to a chelator, PRRT
`may be performed. After the i.v. injection, the radiophar-
`maceutical will distribute in the body, selectively bind to
`SSTRs, and actively be taken up by the cells through a
`process called receptor-ligand internalization [9, 10]. The
`internalization will ultimately lead to a selective accumu-
`lation of radioactivity in the tumor, thus determining cell
`death. The majority of clinical trials data available is from
`non-randomized retrospective case series. Due to variation
`in patients selection, dosing, scheduling, and total number
`of treatments it can be challenging to draw firm conclusions
`from the literature. However, it seems to be a benefit for
`selected patients with response rates in the range of 40% [11–
`14].
`Here we present the results of a phase II study designed to
`treat disseminated or nonoperable NETs patients with PRRT.
`Patients demonstrated enhanced SSTR expression at PET/CT
`with 68Ga-peptide (DOTATOC/DOTATATE).
`
`2. Materials and Methods
`
`2.1. Study Design. This was a prospective nonrandomized
`single-arm clinical trial performed at the Department of
`Nuclear Medicine, Santa Maria Nuova Hospital, Reggio
`Emilia (Italy). All patients with advanced, progressive NET
`fulfilling the study inclusion criteria were first evaluated
`with 68Ga-peptide PET/CT followed by 111In-peptide dosi-
`metric evaluation to determine both the presence of SSTR
`expression as a target for the following treatment and
`eligibility to PRRT, that is in presence of provisional adsorbed
`doses: (a) >10 Gy to tumor, (b) <10 Gy to the kidneys,
`(c) <6 Gy for the liver, (d) <1.5 Gy for red marrow, (e)
`<3 Gy for lung, and (f) <8 Gy for whole body. In case
`of 177Lu-PRRT (177Lu-DOTATOC/DOTATATE), dosimetric
`evaluation was performed acquiring images during the first
`cycle of therapy. A fractionated treatment protocol was
`followed with the intravenous administration of an average
`activity of 2.6 GBq/cycle for 90Y-PRRT and 6.0 GBq/cycle for
`177Lu-PRRT, respectively, with an interval of about 2 months.
`Toxicity and tolerability were recorded through all the
`study and for additionally 6 months after the study com-
`pletion. Serial follow-up 68Ga-peptide PET/CT imaging was
`repeated after each PRRT cycle during the first part of the
`study as required by our ethic committee. The clinical trial
`was subsequently amended and the number of PET/CT
`examinations reduced to baseline, intermediate (after 2-3
`PRRT cycles), and end-treatment (3–6 months after the
`last PRRT) scans. In order to homogenize data analysis,
`treatment response was assessed comparing PET/CT studies
`performed at baseline and at the end of treatment as well
`
`as patient’s clinical response. The intermediate PET/CT
`evaluation was used only to assess the early progressive
`disease (PD).
`The study was conducted in accordance with Interna-
`tional Conference on Harmonization Good Clinical Practice
`guidelines, the Declaration of Helsinki and it was approved
`by local and national authorities (EudraCT numbers 2006-
`000897-65 and 2008-000983-17).
`
`2.2. Patients. From January 2007 to August 2011, we enrolled
`65 patients (38 men and 27 females; mean age = 65 years,
`range 33–83). All patients presented progressive disease and
`fulfilled the following inclusion/exclusion criteria.
`
`2.2.1. Inclusion Criteria. The inclusion criteria were as fol-
`lows:
`
`inoperable or
`
`(i) Age > 18 years;
`(ii) histological confirmation of NET;
`metastatic disease;
`(iii) presence of at least one measurable lesion;
`(iv) positive 68Ga-peptide PET/CT defined as radiophar-
`maceutical uptake in tumor and/or metastasis higher
`than liver, evaluated within 3 months before PRRT
`(qualitative analysis);
`(v) adequate hematological parameter: hemoglobin level
`(Hb) ≥ 10 g/dL; leucocytes (WBC) ≥ 2.5 × 103/mL;
`platelets (PLT) ≥ 100 × 103/mL;
`(vi) adequate liver and renal function: bilirubin levels
`<2.5 mg/dL; creatinine levels <2 mg/dL;
`(vii) ECOG performance status <2;
`(viii) Signed informed consent;
`(ix) discontinuation of cold SST-analogues treatment at
`least 4 weeks before PRRT;
`(x) Life expectancy of at least 6 months.
`
`2.2.2. Exclusion Criteria. The exclusion criteria were as fol-
`lows:
`
`(i) other treatment (such as chemotherapy or radiother-
`apy) or participation in any investigational drug trial
`within 1 month of PRRT and for the following 2
`months;
`(ii) Pregnancy or lactation;
`(iii) Bone marrow involvement >25%;
`(iv) other concomitant tumors, except “in situ” basal cell
`carcinoma and tumors of the uterine cervix treated
`with radical surgery.
`
`Additionally, before each PRRT cycle the following
`parameters should be maintained: Hb ≥ 10 g/dL, WBC ≥
`2.5 × 103/mL; PLT ≥ 100 × 103/mL, creatinine levels
`<2 mg/dL; bilirubin levels <2.5 mg/dL.
`The final analysis was based on a total of 59 patients
`(m/f 33/26) since 6 patients (2 with GI tumor, 1 with
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`carcinoid tumor of the lung, and 3 with pancreatic tumor)
`voluntarily interrupted the treatment. Tumor was localized
`in the gastrointestinal tract in 19/59 cases (32%), followed by
`pancreas in 16/59 cases (27%) and lung in 13/59 cases (22%).
`In 11/59 patients (19%), the origin was unknown.
`All patients at enrollment had metastatic (stage IV) PD
`(Table 1). Histopathological findings including grading were
`not reported for patients since histological diagnosis was
`performed in different centers thus features were reported
`in different not comparable modalities. Previous treatments
`are reported in Table 2. Diabetes was present in 11/59
`cases and 16/59 patients suffered from blood hypertension.
`Additionally, 9/59 had previous tumors (3/9 prostate cancers,
`3/9 breast cancers, 2/9 large-bowel cancers and 1/59 stomach
`cancer) with a minimal time of free disease of 5 years. Main
`baseline clinical signs and symptoms were diarrhea (18/59),
`pain (12/59), weight loss (7/59), flush (5/59), cough (4/59),
`constipation (3/59), nausea (2/59), and carcinoid syndrome
`(1/59). Additionally, 32/59 patients presented at enrolment
`a variable grade of asthenia. Twenty-seven patients were
`asymptomatic at baseline. Serum baseline CgA levels were
`normal in 19/59 patients.
`
`90Y-, and
`2.3. Radiopharmaceuticals Preparation. 111In-,
`177Lu-peptide (DOTATOC or DOTATATE) were synthesized
`by following internal protocol [15]. Every preparation
`was obtained by carrying out the following steps: (a) a
`3 mL syringe was filled with a 1 mL solution containing
`30 μg of sodium ascorbate and an amount of a 4 mg/mL
`peptide solution proportional to the 90Y-, and 177Lu- or
`111In- activity in order to achieve a radiolabeling specific
`activity of 106 MBq/nmol, 48 MBq/nmol, and 6 MBq/nmol,
`respectively (b) this solution was added to a 3 mL Schott vial
`containing an activity ranging between 7.4 to 30 GBq of 90Y
`chloride solution, between 15 to 60 GBq of 177Lu chloride
`solution or between 222 to 444 MBq of 111In- chloride
`solution (Perkin Elmer, Boston, MA, United States) in 0.05 M
`hydrochloric acid obtaining a 4.6 pH solution; (c) the Schott
`◦
`C in a heating block;
`vial was heated for 30 minutes at 90
`(d) a 5 μL aliquot of the solution was withdrawn for carrying
`out the quality controls by using solid phase extraction or
`chromatographic methods [16]; (e) only for 90Y and 177Lu-
`peptide: the preparation was transferred to a bigger vial
`containing 0.5 mL of 1 mM DTPA solution and diluted with
`20 mL of 0.9% sodium chloride solution [17]; (f) single doses
`for the patients were obtained by fractioning the mother
`solution in vials containing 2 mL of an ascorbic acid/sodium
`ascorbate buffer solution in order to decrease the effects of
`radiolysis. The radiochemical purity of the 111In-, 177Lu-, and
`90Y-peptide preparations was always >99.8%.
`The radiolabeling of 68Ga-peptide was performed by
`means of a modular lab synthesizer (Eckert & Ziegler, Berlin,
`Germany) as already described [18]. Briefly, the fraction of
`about 2 mL of the 68Ge/68Ga-generator eluate containing
`about 80% of the 68Ga activity in 0.1 M hydrochloric acid
`was selected and directed to a reactor vial containing a
`20 μL of peptide solution (1 mg/mL) and 200 μL of a 1.5 M
`sodium formate solution or 140 μL of a 1.5 M sodium acetate
`solution in order to obtain a pH ranging between 3.2 and
`
`Table 1: Site and number of metastasis in the 59 evaluated patients
`at the enrollment in the clinical trial.
`
`Site of metastasis
`
`Bone (21/59)
`Liver (42/59)
`Lung (4/59)
`Lymph nodes (34/59)
`Other (6/59)
`
`≤5
`0/21
`2/42
`0/4
`3/34
`1/6
`
`Number of metastasis
`>5
`21/21
`40/42
`4/4
`31/34
`5/6
`
`Table 2: List of previous treatments in the 59 evaluated patients
`order on the basis of their frequency.
`
`Number of patients
`Previous treatment
`39/59
`Surgery
`25/59
`“Cold” SST analogues
`13/59
`Chemotherapy
`7/59
`TACE or RFTA
`5/59
`External beam radiotherapy
`TACE: intra-arterial hepatic chemoembolization; RFTA: radiofrequency
`thermoablation.
`
`◦
`C for 5 minutes and,
`3.5. The mixture was heated at 100
`then, passed through a light C-18 cartridge. 68Ga-peptide was
`eluted with 0.5–1 mL of a 50% ethanol solution and diluted
`with 8 mL of 0.9% sodium chloride solution. The synthesis
`was carried out in 14 minutes with a mean yield of 63 ± 3%
`(not corrected for decay). Quality controls were performed
`by chromatographic methods as already described, obtaining
`a radiochemical purity always >95% [19].
`
`2.3.1. Pretherapeutic Somatostatin Receptor Imaging. Pre-
`imaging was performed by 68Ga-peptide
`therapeutic
`PET/CT. For this study, PET/CT scans were acquired on a
`GE Discovery at 60 min after injection of about 120 MBq
`of 68Ga-peptide. Seven or eight bed positions with 5 slices
`overlap were acquired for 4 min emission time in 3D. The
`CT-exposure factors for all examinations were 120 kVp and
`80 mA in 0.8 seconds. PET images were reconstructed using
`CT-attenuation correction (OSEM). All studies were visually
`and semiquantitatively assessed. SUV calculations were
`performed on a Xeleris workstation. Mean and maximum
`SUV (activity concentration corrected for patient weight
`and total injected dose) was determined in all lesions and
`recorded.
`
`2.3.2. Selection of Patients Eligible for PRRT. 68Ga-peptide
`PET/CT was considered positive in patients who showed
`uptake in the tumor lesions at least two-times higher than
`the liver; thus they were considered eligible for PRRT and,
`therefore, admitted to dosimetric evaluation.
`
`2.4. Dosimetry. Planar imaging was initially performed after
`the i.v. injection of 185 MBq of 111In-peptide with a dual-
`head gamma camera (Genesys, Philips, The Netherlands)
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`using parallel-hole, medium-energy, general-purpose colli-
`mators. The windows were centered over both 111In- photon
`peaks (247 and 172 keV with a window width of 20%),
`whereas scatter fraction was evaluated at 140 keV (width
`20%).
`In all the patients, whole-body scan and, in selected cases,
`spot images of the abdomen were obtained after 1, 4, 20, 48,
`and 72 hours for control of biodistribution. To determine
`blood clearance, we drew blood samples at 30 and 60 minutes
`and at 4, 20, and 48 hours after injection. Radioactivity in
`blood was measured with a HPGe spectrometer (DSPEC jr
`2.0—Ortec). For dosimetric calculations, regions of inter-
`est were drawn manually on the whole-body scans from
`anterior and posterior projections and ULMDOS software
`(University of Ulm, Germany) was used. Background regions
`were placed on the abdomen or on the thigh for back-
`ground correction. Scans were corrected for background,
`self-absorption, patient thickness attenuation, and organ
`overlapping. Whole-body activity acquired immediately after
`injection was defined as 100% of the injected activity. Data
`were expressed as percentage injected activity as a function
`of time. The resulting time-activity points were fitted to a
`monoexponential or multiexponential curve for whole-body,
`kidneys, liver, spleen, and red marrow to calculate residence
`time. Patient-specific organ masses were also considered.
`The estimated doses delivered to critical organs and to the
`tumor were obtained by the software OLINDA/EXM [20].
`The activity in blood was fitted to a biexponential curve
`to determine the residence time in blood. The dose to
`the red marrow was calculated from the residence time in
`blood, assuming no specific uptake, a uniform distribution
`of activity, and clearance from red marrow equal to that from
`blood. A correction factor of 1 was used as described by
`Cremonesi et al. [21].
`In case of 177Lu-PRRT the dosimetric evaluation was
`performed acquiring images during the first cycle of therapy,
`thanks to the low gamma emission of this isotope.
`
`2.5. Therapy (Administration Protocol). A fractionated treat-
`ment protocol was followed with the intravenous adminis-
`tration of an average activity of 2.6 GBq and 6.0 GBq per
`cycle for 90Y-PRRT and for 177Lu-PRRT, respectively, with an
`interval of about 2 months. For each cycle, patients were hos-
`pitalized for 3 days in accordance with local requirements.
`Thirty minutes before administration of the radiopeptide
`2 L of amino acid solution of Hartmann-Hepa 8 (Ringer’s
`Lactate Hartmann, Proteinsteril Hepa 8%, Mg 5-sulfat) were
`infused, which were continued up to 3 hours after injection
`to inhibit tubular reabsorption of the radioactive tracer.
`Repeated treatments were performed in case of response and
`significant improvement in symptoms and quality of life,
`except in cases of renal toxicity and rejection by the patient
`for further treatment within 3 months. Additional cycles
`were suspended in case of PD.
`
`SPECT gamma camera (Genesys, Philips, The Netherlands)
`or with a dual-head SPECT/CT gamma camera (Symbia-
`T, Siemens, Germany) using parallel-hole, medium-energy,
`general-purpose collimators. The windows were centered
`over 177Lu-PRRT photon peaks (208 keV and 110 keV width
`20% in both cases; scatter window at 160 keV) in case
`of treatment with 177Lu-PRRT; while at 170 keV (20%)
`and 80 keV (55%) in case of treatment with 90Y-PRRT, as
`Bremsstrahlung planar scan. Whole-body scans (acquisition
`time: 25 minutes) and spot images (acquisition time: 10
`minutes) were obtained.
`
`2.7. Assessment of Clinical Benefit and Evaluation of PRRT
`Response. Clinical benefit was assessed comparing baseline
`clinical conditions with end-treatment parameters. In the
`clinical benefit evaluation the worsening of clinical con-
`ditions (i.e., appearance of new sign(s)/symptom(s)) were
`considered as PD. Indeed any significant variations in base-
`line clinical conditions was defined as stable disease (SD).
`Clinical benefit was defined as non-PD/SD. For the follow-
`up blood tests were evaluated, as described in the clinical
`protocol, repeated before and after each treatment cycle
`and every two weeks. Blood tests included hematological
`parameters,
`liver and renal function. Baseline and end-
`treatment serum CgA values were compared and the trend
`was defined as increased, stable (variation over time ≤10%)
`or decreased. All patients were followed for an additional
`6 months after the last radiopharmaceutical administration.
`Acute and long-term adverse events were graded according
`to the Common Terminology Criteria for Adverse Events,
`version 3.0 of the National Cancer Institute [22]. To assess
`response to treatment PET/CT studies performed at baseline
`and at the end of treatment were considered.
`Treatment responses assessed by PET/CT scan were
`defined as follows:
`
`(i) complete response (CR): disappearance of radiophar-
`maceutical uptake in all detectable lesions;
`(ii) partial response (PR): reduction of radiopharma-
`ceutical uptake (>50%) in all detectable lesions in
`absence of appearance of new lesion(s);
`(iii) stable disease (SD): no variation or reduction
`of radiopharmaceutical uptake (<50%) in some
`detectable lesions in absence of appearance of new
`lesion(s);
`(iv) progressive disease (PD): increase >25% of radio-
`pharmaceutical uptake in one or more lesions or
`appearance of new lesions and/or >10% increasing of
`tumor marker.
`
`In this series of patients, we did not assess treatment
`response based on the size of lesions using the CT component
`of PET/CT images or CT scan, but as described above we
`evaluate only the functional response.
`
`2.6. Biodistribution of the Radiotracer. In order to evalu-
`ate the biodistribution of therapeutic activity, after each
`treatment, planar imaging was performed with a dual head
`
`2.8. Statistical Analysis. All values are expressed as median
`and range, as customary for nonparametric data.Correlation
`analysis was performed using the Mann-Whitney test.
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`from previous chemotherapies. Asthenia (grade 2-3, 28/59)
`nausea (grade 1-2, 14/59), vomiting (grade 2-3, 5/59), were
`frequently observed. Stomatitis (grade 2) and gastritis (grade
`1) were also reported in 1 case each. Long-term nephro-
`toxicity was observed in 3 patients (2 moderate; 1 severe
`requiring dialysis). Patients who developed nephrotoxicity
`were treated with 90Y-PRRT receiving 5 (2/3) and 6 (1/3)
`cycles. One of them suffered from both diabetes and blood
`hypertension. Patient who required dialysis had only one
`kidney. Clinical benefit was recorded in 21/59 patients while
`a worsening of clinical conditions was observed in 9/59
`patients. All patients which were asymptomatic at baseline
`and not present modifications of their clinical conditions.
`Best objective response was CR in 1/59 patient (2%), PR
`in 24/59 (40.5%), SD in 24/59 patients (40.5%) while PD
`was demonstrated in 10/59 (17%) of patients. The overall
`tumor response rate considering both CR and PR was 42.5%.
`SUVmax values in the main lesion for both baseline and
`end-treatment 68Ga-peptide PET/CT scans were reported in
`Table 4 based on functional response. A significant difference
`in cumulated administered activity between PD and non-PD
`patients was found as shown by Figure 4.
`Table 5 shows treatment responses based on primary
`tumor site. Table 6 shows results of treatment responses
`based on the type of treatment (90Y-PRRT, 177Lu-PRRT,
`or combined 90Y-PRRT and 177Lu-PRRT) while treatment
`responses based on the numbers of PRRT cycles are reported
`in Table 7. In Table 8 functional response was tabulated
`on the basis of clinical benefit assessment. In the eleven
`patients with both normal baseline and end-treatment serum
`CgA levels functional response assessed by 68Ga-peptide
`PET/CT resulted in 1/11 CR, 5/11 PR, 4/11 SD, and 1/11
`PD. Discordant results between serum CgA levels trend
`over time and 68Ga-peptide results were found in 23/59
`patients. Despite the increase of CgA values 68Ga-peptide
`PET/CT documented a PR in 7 patients and a SD in 6 cases,
`respectively (Table 9). In one patient classified as SD by 68Ga-
`peptide PET/CT, serum CgA levels completely normalized
`after PRRT.
`
`4. Discussion
`
`The development of imaging agents specifically designed to
`target tumor metabolic pathways and associated antigens
`including membrane receptors opens new horizon both for
`the selection of patients candidate to target treatment by the
`in vivo detection of enhanced target expressions as well as for
`the development of new multimodality treatment strategies.
`The expression of SSTRs by NETs made molecular imag-
`ing with specific SST-analogues for specific SSTR subtypes
`the method of choice for their diagnostic workup. In fact
`111In-labeled SST analogues scintigraphy and more recently
`68Ga-DOTA-peptides significantly change the diagnostic
`approach to neuroendocrine tumors. In our study, 68Ga-
`peptide PET/CT as first-selection procedure to determine the
`presence of high SSTR expression and a tumor uptake at least
`two times higher than the liver were considered the criteria
`to be eligible for dosimetric evaluation with 111In-peptide.
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`Figure 1: 68Ga-DOTATOC PET/CT: liver, lung, lymph node, and
`bone metastases from NET of unknown origin.
`
`3. Results
`
`68Ga-DOTATOC/DOTATATE PET/CT was performed in
`all the patients to evaluate the eligibility. Baseline 68Ga-
`DOTATOC/DOTATATE PET/CT demonstrated at least one
`site of radiopharmaceutical uptake.
`Figure 1 shows an example of 68Ga-DOTATOC accu-
`mulation in tumor lesions. 68Ga-DOTATOC positive lesions
`were preferentially localized at liver, lymph nodes, lung, and
`skeleton.
`An end-treatment 68Ga-peptide PET/CT was performed
`in all treated patients about 3–6 months after the last
`PRRT administration except for 6 patients in which PD was
`determined on the basis of worsening of clinical conditions.
`Figures 2 and 3 represent examples of pre- and postther-
`apeutic 68Ga-DOTATOC PET/CT.
`Dosimetric estimates for kidney and bone marrow are
`summarized in Table 3. No toxicities were recorded after
`radiopharmaceutical injection administered for dosimetric
`purpose.
`PRRT cycles were administered at 70 ± 24.6 days apart
`(range 35–140) with a median cumulative activity of 5.5 GBq
`(range 3.6–7.4 GBq). Thirty-five patients received 4 or 5
`PRRT cycles, 10/59 more than 5 cycles while 14/59 patients
`had <4 PRRT cycles. 90Y-PRRT was administered in 33/59
`patients (56%), 177Lu-PRRT in 9/59 patients (15%) while
`17/59 patients (29%) received both 90Y-PRRT and 177Lu-
`PRRT in different cycles. Posttherapeutic scintigraphy con-
`firmed a correct distribution of the radiopharmaceutical in
`all patients.
`In 18/59 (30%) patients no adverse effects after adminis-
`tration of the radiopharmaceuticals were observed. Hema-
`tological toxicity including grade 2-3 anemia, thrombocy-
`topenia and leukopenia occur in 12/59 patients (20%). Two
`of the 12 patients who had hematological toxicity presented
`baseline grade 1 anemia and thrombocytopenia resulting
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`Figure 2: Male, 56 years old, with pancreatic NET and multiple liver metastases. 68Ga-DOTATOC PET/CT before therapy (a) and after
`PRRT (b). The result was a partial response.
`
`(a)
`
`(b)
`
`Figure 3: Male, 73 year old, pancreas NET with liver metastases. 68Ga-DOTATOC PET/CT before (left) and after therapy (right). PRRT with
`90Y-DOTATOC (2 cycles) and 177Lu-DOTATOC (4 cycles) was administered at interval of 2 months. The response was complete in the liver
`but partial in the pancreatics region (arrow).
`
`(a)
`
`(b)
`
`Table 3: Dosimetric estimates for kidney and bone marrow.
`
`90Y-kidney dose (Gy/GBq)
`90Y-bone marrow dose (Gy/GBq)
`177Lu-kidney dose (Gy/GBq)
`177Lu-bone marrow dose (Gy/GBq)
`
`Mean
`2.4E + 00
`9.7E − 02
`3.9 E − 01
`2.81E − 02
`
`Median
`1.5E + 00
`5.8E − 02
`2.5E − 01
`1.29E − 02
`
`SD
`1.9
`0.1
`0.3
`0.04
`
`Range
`0.32–8.90
`0.0047–0.51
`0.05–1.47
`0.0163–0.256
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`7
`
`9
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Cumulated administered activity (GBq)
`
`9
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Cumulated administered activity (GBq)
`
`PD
`
`Non-PD
`
`PD
`
`Objective response
`
`(a)
`
`(b)
`
`9
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Cumulated administered activity (GBq)
`
`PD
`
`Objective response
`
`SD
`
`(c)
`
`Figure 4: (a) Mann-Whitney test plot shows a significant difference in cumulated administered activity between PD and non-PD patients
`(P < 0.001). Similar results (b) have been obtained by using Mann-Whitney test excluding patients who had SD and thus considering only
`patients who had objective response (P = 0.002). When all subgroups of patients are considered (c), the cumulated administered activity
`remains significantly different in PD group versus both objective response and SD groups while no significant differences have been found
`in cumulated administered activity comparing patients who presented objective response and stable disease (P = 0.435). PD = patients who
`presented progressive disease; non-PD = patients who presented complete or partial response or disease stabilization; objective response =
`patients who presented complete or partial response; SD = patients who presented stable disease.
`
`Originally, the study was designed for radiolabelled DOTA-
`TOC but because of problem of commercial availability we
`were obliged to amend the study protocol and substitute
`DOTATOC with DOTATATE. Using 68Ga-peptide PET/CT
`high SSTR expression to be eligible for subsequent PRRT
`was found in our study in all patients. Dosimetric estimates
`confirmed the eligibility of all patients and demonstrated
`that a fractionated treatment protocol with the intravenous
`administration of an average activity of 2.6 GBq/cycle for 90Y-
`PRRT and 6.0 GBq/cycle for 177Lu-PRRT, respectively, with
`an interval about 2 months was within the safety threshold
`of toxicity, particularly for the kidney (the critical organ for
`PRRT) and the bone marrow. Initially for PRRT, we used
`90Y since in our department 177Lu was allowed from 2009.
`Subsequently, the criteria of choice of radionuclide used for
`PRRT was mainly based on tumor size [23] (reserving 90Y
`
`for lesion(s) >2 cm, 177Lu for lesion(s) <2 cm, and 90Y/177Lu
`in presence of both conditions) and on dosimetric estimates.
`Administration of 90Y-PRRT (average activity of about
`2.6 GBq/cycle) and 177Lu-PRRT (average activity of about
`6.0 GBq/cycle) induced disease control in 83% of patients (1
`CR, 24 PR, and 24 SD) with a duration of response of at least
`6 months. In the majority of cases, objective response was
`associated to symptomatic response with an improvement of
`quality of life.
`These responses rates are comparable with data from
`literature [11, 24, 25] demonstrating radiological response
`of 34.1% and clinical response in 29.7% for 90Y-PRRT
`with longer median survival in responders compared to
`nonresponders (44.7 versus 18.3 months) and response
`rates of up to 30% with median time to progression of
`40 months for 177Lu-PRRT [26]. Interestingly,
`in these
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`Table 4: Baseline and end-treatment SUV max values recorder for all patients in the main lesion assessed by 68Ga-peptide PET/CT tabulated
`on the basis of patients’ functional response.
`
`Baseline SUV max value
`Range
`Median
`Mean
`Functional response
`—
`45.3
`45.3
`CR
`6.3–119.9
`29.2
`79.7
`PR
`6.6–82.0
`20.9
`31.1
`SD
`PDc¸
`11.7–55.8
`22
`27.9
`Data from the 4 patients in which PD was assessed using 68Ga-peptide PET/CT.
`
`c¸
`
`Main lesion
`
`End-treatment SUV max value
`Median
`Range
`0.9
`—
`17.8
`3.2–49.1
`28.2
`11.2–61.3
`26
`15.7–74.7
`
`Mean
`0.9
`39.2
`31.2
`35.7
`
`Table 5: Results of treatment responses tabulated on the basis of primary tumor site.
`
`Site of primitive tumor
`GI (19/59)
`Pancreas (16/19)
`Lung (13/59)
`Unknown origin (11/59)
`
`CR
`—
`1/16 (6%)
`—
`—
`
`PR
`8/19 (42%)
`5/16 (31%)
`8/13 (62%)
`3/11 (27%)
`
`SD
`9/19 (47%)
`6/16 (38%)
`3/13 (23%)
`6/11 (55%)
`
`PD
`2/19 (11%)
`4/16 (25%)
`2/13 (15%)
`2/11 (18%)
`
`studies the degree of uptake on the pretreatment 111In-
`peptide was found to be predictive of response to treatment
`and overall survival. Despite the small number of patients,
`combined treatments with labeled peptide using both 90Y
`and 177Lu seem to perform better (no evidence of PD)
`when compared to “single radionuclide” PRRT (8 and 2
`cases of PD administering only 90Y-peptide and 177Lu-
`peptide, resp.). In our patients population, the SUVmax
`value in tha main lesion at baseline 68Ga-peptide PET/CT
`examination compared to end-treatment scan was in line
`with the functional response evaluation. Additionally, in
`our series of patients, cumulated administered activity was
`significantly different in responders and no-responders. In
`agreement with previous reports in literature [25] our data
`supported the hypothesis that progression at baseline could
`be a prognostic factor of objective response to PRRT. Indeed
`previous reports showed also that both SD and objective
`response (CR+PR) in previously progressive patients showed
`the same favorable trend [25]. Finally, PRRT showed bene-
`ficial effect on symptoms in the majority of patients (36%)
`and all asymptomatic patients (46%) remained stable over
`the time. In 39% of our patients discordant results between
`serum CgA trend and 68Ga-peptide findings were observed.
`Particularly, CgA values increased (with variation up to
`+263%) in 68% of patients in which PRRT determined PR
`or SD. Our results on CgA trend and antitumor activity are
`in contrast with previous reported ones in the literature [25].
`However, the majority of our patients assumed proton-pump
`inhibitor as prophylactic therapy and as well known these
`drugs may cause substantial increase of blood CgA levels
`[27] underling the need of a more reliable biomarker to
`monitoring NETs [28].
`The prevalence of partial responses and stable disease
`obtained is mainly related to the advanced stage of the disease
`wh