Feasibility, toxicity and response of upfront metaiodobenzylguanidine therapy therapy followed by German Pediatric Oncology Group Neuroblastoma 2004 protocol in newly diagnosed stage 4 neuroblastoma patients

European Journal of Cancer 76 (2017) 188e196

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.ejcancer.com

Original Research

Feasibility, toxicity and response of upfront metaiodobenzylguanidine therapy therapy followed by German Pediatric Oncology Group Neuroblastoma 2004 protocol in newly diagnosed stage 4 neuroblastoma patients K.C.J.M. Kraal a,f,*,1, G.M. Bleeker b,1, B.L.F. van Eck-Smit c, N.K.A. van Eijkelenburg f, F. Berthold d, M.M. van Noesel e,f, H.N. Caron a, G.A.M. Tytgat a,f a

Department of Pediatric Oncology, Emma Children’s Hospital, Amsterdam, The Netherlands Department of Radiology/Nuclear Medicine, NWZ Alkmaar, Alkmaar, The Netherlands c Department of Nuclear Medicine, Academic Medical Centre (AMC), Amsterdam, The Netherlands d Department of Pediatric Oncology and Hematology, University Children’s Hospital, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany e Department of Pediatric Oncology/Hematology, Erasmus MC (EMC)-Sophia Children’s Hospital, Rotterdam, The Netherlands f Princess Ma´xima Centre for Pediatric Oncology, Utrecht, The Netherlands b

Received 3 March 2016; received in revised form 27 September 2016; accepted 6 December 2016

KEYWORDS 131 I-MIBG (metaiodobenzylguanidine); NBL (neuroblastoma)

Abstract Aim of the study: Radiolabelled meta-iodobenzylguanidine (MIBG) is an effective option in treatment of neuroblastoma (NBL) tumours. We studied feasibility, toxicity and efficacy of upfront 131I-MIBG and induction treatment in stage 4 NBL patients. Patients and methods: Retrospective, multi-centre (AMC and EMC) pilot regimen (1/1/2005 e2011). Newly diagnosed stage 4 NBL patients, were treated with 2 courses of 131I-MIBG, GPOH 2004 NBL protocol, myeloablative therapy (MAT) and autologous stem cell rescue (ASCT). 131I-MIBG was administered in a fixed dose. Response rate (RR) was defined as complete remission, very good partial response and partial response. Results: Thirty-two patients, (median age [range] 2.9 [0e11.4] years), 21 received 131I-MIBG therapy, 11 did not because of: MIBG non-avid (N Z 5) and poor clinical condition

Financial support: Stichting Kinderen Kankervrij (KIKA). * Corresponding author: Pediatric Oncologist, AMC, Meibergdreef, Amsterdam, The Netherlands. E-mail address: [email protected] (K.C.J.M. Kraal). 1 The first two authors have contributed equally to this article (joint first authorship). http://dx.doi.org/10.1016/j.ejca.2016.12.013 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.

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(N Z 6). In 95% of eligible patients 131I-MIBG treatment was feasible within 2 weeks from diagnosis. Interval between chemotherapy courses was 25 days (131I-MIBG group) versus 22 days (chemotherapy group). No stem cell support was needed after 131I-MIBG therapy. Stem cell harvest in both groups was feasible, neutrophil recovery was comparable, but platelet recovery post MAT, ASCT was slower for 131I-MIBG-treated patients. RR post 131I-MIBG was 38%, post MAT þ ASCT was 71% (131I-MIBG group), 36% (chemotherapy group) and overall 59%. Conclusions: Induction therapy with 131I-MIBG before the HR GPOH NB 2004 protocol is feasible, tolerable and effective in newly diagnosed stage 4 NBL patients. 131I-MIBG upfront therapy induces early responses. ª 2017 Elsevier Ltd. All rights reserved.

1. Introduction

2. Patients and methods

Neuroblastoma (NBL) is the most common extra cranial solid tumour in childhood, derived from the sympathetic nervous system [1]. The prognosis for patients with HR NBL, was less than 40% for a long time, but this has improved over the last decades [2,3]. A study performed by Yu et al. [4] showed a 20% survival (overall survival [OS] and event free survival [EFS]) benefit of addition of immunotherapy after myeloablative therapy (MAT), followed by autologous stem cell transplantation (ASCT) in HR NBL patients. The 3year EFS of HR NBL patients, treated according to the German Pediatric Oncology Group (GPOH) NB 97 protocol with ASCT has been shown to be 47% [5]. Imaging with 123I-meta-iodobenzylguanidine 123I(MIBG) is a reliable and reproducible method for staging and response evaluation in NBL [6e8]. For targeted treatment, MIBG labelled with 131I has been used successfully [9]. 131I-MIBG has a significant antitumour efficacy against NBL, with response rates (RRs) between 20% and 60% [10e16]. Tandem 131I-MIBG therapy can be given to patients with relapsed/refractory NBL with tumour response or stable disease, and available stem cells. Early second 131I-MIBG therapy safely reduces disease burden in patients with relapsed NBL [17]. Systematic review of studies with 131I-MIBG in NBL by Wilson et al. [18], revealed an objective tumour RR ranging from 0% to 75%. Multivariate analysis of cumulatively administered activity ([AA] measured in GBq) show that there was a positive association between response rate and cumulative AA (p Z 0.001), but no clear relationship between response and AA/kilogram (kg; p Z 0.16). The primary aim of the study was feasibility/toxicity, and the secondary outcomes were: interval between chemo courses, feasibility to harvest stem cells, haematological reconstitution post ASCT and response of 2 courses of upfront 131I-MIBG therapy, followed by the standard arm of the HR GPOH 2004 protocol.

We performed a retrospective, multi-centre (Emma Children’s Hospital [AMC], Amsterdam and the Erasmus MC [EMC] Sophia Children’s Hospital, Rotterdam, the Netherlands), analysis of cohort pilot regimen (1/1/ 2005e2011), including consecutive all newly diagnosed stage 4 NBL patients, age 0e19 years, including <12 months with stage 4/M and MycN amplification (MNA) tumours, after oral informed consent from the parents [19,20]. Patients were excluded from 131I-MIBG therapy if 123 I-MIBG uptake was insufficient, or there was a poor clinical condition (uncontrollable hypertension, orbital masses, pleural effusion). Insufficient MIBG uptake was defined as: insufficient MIBG uptake in the primary tumour and/or metastasis. 131 I-MIBG therapy was indicated in patients with a higher MIBG uptake level in the primary tumour than the physiological liver activity combined with MIBG uptake in known metastases, confirmed by diagnostic 123 I-MIBG imaging. Data were collected from patient medical files, census date for analysis was 1/1/2012. The protocol consisted of two courses of upfront 131I-MIBG therapy, followed by the standard high risk arm of the GPOH NB 2004 protocol (registered in clinical trials. gov; identifier NCT00526318). The standard arm of the HR GPOH NB 2004 protocol consists of induction chemotherapy 6 courses (alternate N5/N6 courses, interval aimed at 21 days), followed by surgery. Patients who reached complete response (CR), very good partial response (VGPR) and partial response (PR) proceeded to MAT ASCT (one mixed response (MR) patient by exemption), followed by radiotherapy to the primary tumour site and retinoic acid (Fig. 1). The first course of 131I-MIBG was aimed to start within 2 weeks from diagnosis. The scheduled interval between the two 131I-MIBG courses was 4 weeks. If the platelet count was below 50  109/L, the second course

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S

* 131

131

7400 MBq (200 mCi)

5500 MBq (150 mCi).

IMIBG

131

IMIBG

I-MIBG therapy

N5/ N6

*

N5/ N6

*

N5/ N6

CEM

Induction chemotherapy

Cis-RA

MAT + ASCT

ConsolidaƟon

Fig. 1. Treatment overview. N5, vindesine, etoposide and cisplatin; N6, vincristine, dacarbacine, ifosfamide and doxorubicine; MAT þ ASCT, myeloablative therapy and autologous stem cell transplantation; CEM, carboplatin, etoposide and melfalan; CisRA Z cis retinoic acid; BM, bone marrow, MRD, minimal residual disease, *Stem cell harvest when bone marrow clear of tumour cells, Radiotherapy, S Z surgery (was performed after N5/N6 courses, optimal timing of surgery was discussed).

was postponed, or, if platelet counts allowed, a 3 week interval was permitted. Patients were admitted to a special nuclear medicine ward and thyroid prophylaxis was prescribed [21]. Patients remained in radiation protective isolation until the exposure rate was less than 20 microsieverts per hour (mSv/h), at 1 m distance. At day 3 and 7 post therapy, a scan was performed to study the 131I-MIBG retention in the tumour and its metastases. In case of inadequate MIBG retention on these post therapy scans, no second course was given. Fixed doses of 131I-MIBG were given; AA was 7400 MBq (megabecquerel)/200 mCi (millicurie; first course) and 5500 MBq/150 mCi (second course). The AA of each 131I-MIBG course- and the cumulative dose/ kg body weight were calculated in GBq/kg (mCi/kg), for the group as a whole and per patient. Haematological toxicity (nadir and range of platelets) at diagnosis, after the first and second 131I-MIBG course and between two induction chemotherapy courses (corrected for surgery) was noted. Patients were eligible for stem cell harvest as soon as the BM was clear of tumour cells. The yield of collected autologous peripheral stem cells, the number of harvest sessions, time to neutrophil (>0.5  109/L) and platelet (>20  109/L) recovery post MAT and ASCT were noted. Response was scored according to the revised INRC criteria [20]. We used the Curie MIBG scoring system for scoring metastasis on a diagnostic 123I-MIBG scan [22]. Response rate (RR) was defined as CR, VGPR and PR. The response to induction treatment was measured post 2 courses of 131I-MIBG, post chemotherapy induction and post MAT and ASCT. The relative extension scores (post therapy Curie score divided by pre therapy Curie score) were calculated at the same time points [7]. Statistics differences between 131I-MIBG group and chemotherapy group were tested with chi-squared and Mann Whitney U test with a significance level of

p Z 0.05 was used. However, since this was not a randomised study, all comparisons should be considered with caution. OS and EFS Kaplan Meier curves were calculated for the entire cohort. OS was measured as the time from start of treatment to death by any cause. EFS was defined as the time from start of treatment to a first event (progression, relapse or death). Table 1 Patient characteristics.

Total number Sex N Male Female Age at diagnosis Median (range) years Genetic aberrations N MNA Unknown 1pLOH Unknown Primary tumour N Abdominal Thoracic Metastases N BM 123 I-MIBG Unknown Urine catecholamines Unknown Therapy N 131 I-MIBG therapy I 131 I-MIBG therapy II Induction chemo Surgery MAT þ ASCT

Overall

131 I-MIBG treatment

Chemotherapy group

32

21

11

19 (59%) 13 (41%)

13 (62%) 8 (38%)

6 (55%) 5 (45%)

2.9 (0e11.4)

3.1 (0e6.2)

2.2 (1.2e11.4)

11 (37%) 2 9 (36%) 7

7 (35%) 1 6 (35%) 4

4 (40%) 1 3 (38%) 3

31 (97%) 1 (3%)

20 (95%) 1 (5%)

11 (100%) 0 (0%)

27 (84%) 29 (90%) 1 29 (100%) 3

17 (81%) 20 (100%) 1 19 (100%) 2

10 (91%) 9 (82%) 0 10 (100%) 1

e e 31 21 (66%) 21 (66%)

21 16 20 16 (76%) 16 (76%)

N/A N/A 11 5 (45%) 5 (45%)

Abbreviations: MNA, MYCN amplification; 1pLOH, 1p loss of heterozygosity; MAT þ ASCT Z myeloablative therapy and autologous stem cell transplantation; N/A, not applicable; N, number; BM, bone marrow; EFS, event free survival; OS, overall survival; MIBG, metaiodobenzylguanidine.

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3. Results 3.1. Patient and tumour characteristics Thirty-two patients with stage 4 NBL were enrolled in this study, 21/32 patients received upfront 131I-MIBG treatment, 11/32 were not eligible: MIBG non-avid on the 123I-MIBG scan (N Z 5; 4 primary tumour nonavid, 1 MIBG non-avid skeletal lesions); poor clinical condition (N Z 6). The patient characteristics are shown in Table 1. The median age (range) of the overall study cohort was 2.9 (0e11.4) years, in the 131I-MIBG group this was 3.1 years (0e6.2) and 2.2 years (1.2e11.4) in the chemotherapy group. Overall, the percentage MNA and 1p loss of heterozygosity in the NBL tumours was 37% and 36%, respectively. Twentyseven out of 32 patients had BM disease at diagnosis and in 29/31 the diagnostic 123I-MIBG scans indicated MIBG avid metastatic disease. 3.2. Therapy Twenty-one patients were treated with a first course of I-MIBG, 16 with a second. Reasons for not giving a

131

191

second course of 131I-MIBG therapy were: insufficient MIBG retention (N Z 2), thrombocytopaenia combined with clinical deterioration (N Z 1) and PD (N Z 2) of which 1 patient died during MIBG I therapy. Twentyone out of 32 (66%) patients underwent surgery and MAT þ ASCT, 76% in the 131I-MIBG group and 45% in the chemotherapy group. Two patients in the chemotherapy group died of toxicity; 1 patient died due to multi-organ failure and another due to surgical complications (see flowchart [Fig. 2]). 3.3.

131

I-MIBG treatment

The median (range) interval from diagnosis to MIBG-I was 9 [1e15] days (Table 2). Twenty out of 21 patients received MIBG within 14 days. Due to logistic reasons for 1 patient, it took 15 days before MIBG treatment could be started. The median (range) interval of MIBGI to MIBG-II was 28 (median; with a range of 19e43) days (N Z 16), 14/16 patients received 131I-MIBG-II (<28e35 days). The interval MIBG-II to N5 I was 29 (21e49) days. The median (range) AA of MIBG-I was 0.45 (0.17e0.56) GBq/kg (12.0 [4.7e15.2] mCi/kg); -MIBG-II was 0.37 (0.25e0.53) GBq/kg (9.8 [6.6e14.3]

Fig. 2. Flowchart patients. NBL, neuroblastoma, PD, progressive disease, N, number, HD, high dose, i.o., instead of, ASCT, autologous stem cell transplantation.

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Table 2 Interval times of Pat. No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

131

Interval

I-MIBG, dose of 131

131

I-MIBG (days)

I-MIBG, response (INRC) and

I-MIBG scan (Curie score) for

I-MIBG therapy

DxMIBG Ie MIBG MIBG I MIBG I MIBG II II-N5 I GBq/kg (mCi/kg)

MIBG II GBq/kg (mCi/kg)

12 12 8 3 1 11 2 13 11 14 9 2 9 5 15 6 9 11 6 8 7

0.46 0.24 0.42 0.41 0.53 0.39 0.41 e e e e 0.37 0.29 0.36 0.36 0.33 0.29 0.25 0.52 0.27 e

Median 9 (range) (1e15)

123

131

0.46 0.46 0.56 0.41 0.38 0.53 0.45 0.41 0.17 0.53 0.34 0.49 0.39 0.53 0.47 0.44 0.40 0.34 0.52 0.36 0.56

(12.5) (12.4) (15.2) (11.3) (10.3) (14.3) (11.3) (11.1) (4.7) (14.3) (9.1) (13.3) (10.6) (14.4) (12.8) (12.0) (10.7) (8.7) (14.1) (9.8) (15.2)

131

I-MIBGetreated patients.

Response (INRC) Cum. MIBG GBq/kg (mCi/kg)

28 28 27 28 27 32 25 # # # # 19 21 27 35 21 28 43 28 42 #

28 30 30 29 35 24 29 # # # # 23 21 29 26 31 22 28 49 21 #

(12.5) (6.6) (11.4) (11.3) (14.3) (10.7) (11.1)

0.92 0.70 0.98 0.82 0.91 0.92 0.86 0.41 0.17 0.53 0.34 (10.0) 0.86 (7.9) 0.68 (9.6) 0.89 (9.6) 0.83 (9.0) 0.77 (8.0) 0.69 (6.8) 0.59 (14.1) 1.04 (7.3) 0.63 0.56

(25.0) (19.0) (26.6) (22.6) (24.6) (25.0) (22.4) (11.1) (4.7) (14.3) (9.1) (23.3) (18.5) (24.0) (22.4) (21.0) (18.7) (15.5) (28.2) (17.1) (15.2)

28 (19e43)

29 0.45 (12.0) 0.37 (9.8) MIBG II: GBq/kg: (21e49) (0.17e0.56) (0.25e0.53) 0.85 (0.63e1.04) (4.7e15.2) (6.6e14.3) mCi/kg: 23.0 (17.1e28.2) MIBG I: GBq/kg: 0.41 (0.17e0.56) 11.1 (4.7e15.2)

Curie score

Post 2 Post Post Dx MIBG N6 III MAT ASCT

Post 2 Post Post MIBG N6 III MAT ASCT

VGPR MR MR e VGPR VGPR MR MR PD PR PR NR PD NR PD MR PR PD PR PR PD (death)

0 0 14 e 1 2 0 2 0 12 2 8 6 16 25 20 8 17 2 5 e

VGPR CR CR PR CR VGPR CR CR PR PR CR PR PR PR MR PR PD PR PR CR

CR PR CR CR CR PR CR PD PD PR CR PR VGPR PR PD VGPR e PD CR CR

5 17 21 4 22 17 2 20 6 12 1 8 6 25 24 20 21 16 15 21 e

16.5 5 (1e25) (0e25)

0 e 0 0 0 2 0 0 e 7 0 e e 1 25 4 e 12 0 0 e

0 0 0 e 0 2 0 0 e 7 0 2 0 2 e 1 e e 0 0 e

0 0 (0e25) (0e7)

Abbreviations: MAT þ ASCT Z myeloablative therapy and autologous stem cell transplantation; N5, vindesine, etoposide and cisplatin; N6, vincristine, dacarbacine, ifosfamide and doxorubicine; CR, complete response, VGPR, very good partial response, PR, partial response, MR, mixed response. #No second MIBG: PD death N Z 1, PD N Z 1, insufficient MIBG retention N Z 2, thrombocytopaenia N Z 1.

mCi/kg). For the patients receiving 2 courses of 131IMIBG, the cumulative AA 131I-MIBG was 0.85 [0.63e1.04] GBq/kg and 23.0 [17.1e28.2] mCi/kg), and for the patients receiving only 1 course of 131I-MIBG, the median AA was 0.41 (0.17e0.56) GBq/kg and 11.1 (4.7e15.2) mCi/kg.

3.4. Chemotherapy courses The median (range) interval between courses of chemotherapy (N5 IeN6 III) was 25 [23e27] days in the 131 I-MIBG group, 22 [20e26] days in the chemotherapy group, and overall 24 [21e26]. The interval between N5-

Table 3 Interval between two induction chemotherapy courses (corrected for surgery). Treatment modalities

131

N5 IeN6 I N6 IeN5 II N5 IIeN6 II N6 IIeN5 III N5 IIIeN6 III N6 III  MAT þ ASCT Overall time per coursea N 5I  MAT þ ASCT N 5Ie N6 III

27 24 23 27 26 33 26 25

I-MIBG treatmenta

Chemotherapy onlya

Overalla

(21e34) (20e49) (21e41) (20e44) (21e40) (20e44)

21 21 20 23 26 30

25 21 22 24 26 32

(20) (18) (19) (19) (18) (15)

23 22

(20e32) (20e32) (19e34) (14e30) (21e31) (28e34)

(10) (10) (8) (8) (6) (4)

(20e34) (20e49) (19e41) (14e44) (21e40) (20e44)

25 24

Abbreviations: MAT þ ASCT Z myeloablative therapy and autologous stem cell transplantation; N5, vindesine, etoposide and cisplatin; N6, vincristine, dacarbacine, ifosfamide and doxorubicine. a Interval time in days (median and range) (Number).

K.C.J.M. Kraal et al. / European Journal of Cancer 76 (2017) 188e196

Table 4 Response according to the International Neuroblastoma Response Criteria. CR VGPR PR MR NR PD TD NE N Overall responsea Post induction 8 2 10 1 Post MAT þ ASCT 9 5 5 0 131 I-MIBG treatmenta Post MIBG 0 3 5 5 Post induction 7 2 7 0 Post MAT þ ASCT 8 2 5 0 Chemotherapy onlya Post induction 1 0 3 1 Post MAT þ ASCT 1 3 0 0

0 0

9 11

2 2

0 0

32 32

2 0 0

5 5 6

0 0 0

1 0 0

21 21 21

0 0

4 5

2 2

0 0

11 11

CR, complete response, VGPR, very good partial response, PR, partial response, MR, mixed response, NR, no response, PD, progressive disease, NE, not evaluable, TD, toxic death, N, number; MIBG, metaiodo-benzylguanidine therapy, MAT þ ASCT, myeloblative therapy and autologous stem cell transplantation. a Response according to International Neuroblastoma Response Criteria [20].

I to MAT ASCT was 26 (23e33) days in the 131I-MIBG group and 23 (20e30) days in the chemotherapy group and overall 25 (21e32) days (Table 3).

193

was 0.5 or less, after 2 courses of MIBG in 10/21 patients (48%) and post MAT and ASCT in 14/16 patients (88%). For the chemotherapy group, the median Curie score was at diagnosis 8 (range 0e24), post induction 4 (0e16), post MAT ASCT 2 (0e14). This is a decrease of 75% between diagnosis and post MAT ASCT. The relative extension score post MAT and ASCT was 0.5 or less in 4/6 patients (66%; data not shown). Following MIBG-II, 5 patients developed PD, of which 4 continued with chemotherapy and showed response, 1 patient died. Furthermore, 4 patients had PD during induction (N Z 1 post N6-I and N Z 3 post N6-III). Sixteen patients proceeded to MAT ASCT. One other patient developed PD post MAT ASCT. The overall progression rate was 6/21 patients (29%) from diagnosis to MAT ASCT. In the chemotherapy group, the RR post induction and -MAT ASCT was 4/11 (36%). There were 4 patients who developed PD during induction (N Z 1 post N6-I, N Z 1 post N5-II and N Z 2 post N6-III), two patients died due to toxicity. Five patients went on to MAT ASCT. The progression rate was 5/11 (45%).

3.5. Response

3.5. Haematological toxicity

The RR post induction was 20/32 (63%) and post MAT ASCT 19/32 (59%). The progression rate was 11/32 (34%). In the 131I-MIBG group, the RR post 131I-MIBG was 8/21 (38%), post induction 16/21 (76%) and post MAT ASCT 15/21 (71%; Table 4). The median Curie score for the 131I-MIBG group at diagnosis was 16.5 (median) with a range of 1e25, after 2 courses of MIBG 5 (0e25), post induction 0 (0e25), post MAT ASCT 0 (0e7), respectively. This is a decrease of 70% between diagnosis and the end of two courses of MIBG and 100% between diagnosis and post MAT and ASCT (Table 2). The relative extension score

At diagnosis, the median (range) overall platelet count was 346 (64e746), comparable in the 2 groups. The nadir (range) of the platelets post MIBG I was 112 (17e393) and post MIBG II was 111 (20e206). In the 131 I-MIBG group, the nadir of the platelet counts were lower compared with the chemotherapy group in between chemotherapy courses (data not shown). The planned interval between two chemotherapy courses, shown in Table 3, is more informative. Especially, since this interval (median) was slightly longer (25 days) in the MIBG group than in the chemotherapy group (22 days) and overall 24 days.

Table 5 Stem cell harvest yield and reinfusion. 131

Chemotherapy only

Overall

17 1 (1e3)

8 1.5 (1e2)

25 1 (1e3)

16 2*

7 1

23 3

5.5 (0.8e32.3) 15.9 (0.3e31.4)

3.5 (1.2e7.1) 6.6

4.4 (0.8e32.3) 6.6 (0.3e31.4)

16 1

5 3

21 4

25 (12e194) 11 (8e34)

14 (14e48) 11 (10e18)

I-MIBG treatment

Harvest: (N) Number of harvest sessions Type of harvest PBSC BM Yield of harvest: (CD34þ  106/kg) PBSC BM ASCT Reinfusions No reinfusions Haematological recovery post MAT ASCT Platelets (>20  109/L) days Neutrophils (>0.5  109/L) days

Abbreviations: N, number, PBSC, peripheral blood stem cell; BM, bone marrow; ASCT, autologous stem cell transfusion. Yield of harvest: median (range)  106/kg CD34þ. *Poor PBSC harvest. Haematological recovery: median (range) days.

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3.6. Stem cell harvest yield and reinfusion

4. Discussion

In the 131I-MIBG group, in 17 of 21 patients (81%), stem cells were harvested in 1 (median, range 1e3) session (Table 5). Two patients had a yield of peripheral stem cell harvest of <2.0  106/kg CD34þ and needed an additional BM harvest. The yield of PBSC-harvested stem cells was 5.5 (0.8e32.3), median (range) and BM harvest 15.9 (0.3e31.4)  106/kg CD34þ. Sixteen of 17 (94%) patients proceeded to MAT with reinfusion of their stem cells. In the chemotherapy group, in 8 of 11 patients (73%), stem cells were successfully harvested, with a median (range) number of harvest sessions of 1.5 [1,2] and one patient had a yield of PBSC harvest <2.0  106/kg CD34þ, and also underwent an additional BM harvest. The yield of PBSC-harvested stem cells was 3.5 (1.2e7.1), median (range) and BM harvest 6.6  106/kg CD34þ. Five of 8 (63%) of the patients proceeded to MAT þ ASCT. Overall, harvest was performed in 25/32 (78%) patients, failure to harvest PBSC occurred in 3/25 (12%) of the patients. There was no significant difference in harvest results between the 2 groups of patients (Table 5). The platelet recovery (>20  109/L) post MAT þ ASCT in median (range) days was: 25 (12e194) in the 131I-MIBG group and 14 (14e48) days for the chemotherapy group. The neutrophil recovery (neutrophils > 0.5  109/L) post MAT þ ASCT in median (range) days was comparable: 131I-MIBG group 11 (8e34); chemotherapy group 11 [10e18] days (Table 5).

This pilot study shows that it is feasible to start upfront I-MIBG therapy within 2 weeks after diagnosis of NBL. The cumulatively administered 131I-MIBG dose of 0.85 (0.637e1.04) GBq/kg (23.0 (17.1e28.2) mCi/kg), is high compared with doses reported in other 131I-MIBG studies [18]. This high cumulatively administered 131IMIBG therapy dose could be given to newly diagnosed stage 4 neuroblastoma patients (being chemo-naı¨ve). The median interval between chemotherapy courses was 25 days. In the patients receiving 131I-MIBG, the median intervals were slightly longer. Our interval of 25 days is in concordance with the GPOH NB 97 (27 days)/-04 (22 days) studies (personal communication F Berthold). Our study shows a post induction RR of 63% and post MAT and ASCT of 59%. This RR as a whole is comparable, but not superior to RR reported in other 131 I-MIBG therapy studies in newly diagnosed patients (3; 23e24). The International Society of Paediatric Oncology European Neuroblastoma (SIOPEN) group reports 21% not in CR after induction. The COG group describes RR between 69% and 73% (CR, VGPR and PR). In consecutive GPOH studies, after 6e8 courses of chemotherapy (end of induction), RR 69e87% (CR, VGPR and PR) are reported. In the 131I-MIBG group, the RR post 131I-MIBG was 38%, post induction 76% and post MAT ASCT 71%. In the chemotherapy group, the RR post induction and -MAT ASCT was 36%. Overall, the patients in the 131I-MIBG group had a better RR and survival than patients in the chemotherapy group. We think that the chemotherapy group patients were sicker compared with 131I-MIBG group, with a higher median Curie score at diagnosis, this is a potential selection bias. Furthermore, this being a nonrandomised study, any comparison should be interpreted carefully. Also, both groups had a high percentage of MNA, however other studies by Pearson et al. [23] and Kreisman et al. [25] have reported similar percentages (33e44%) . Several studies have reported that approximately one-third of patients treated with administered activity >12 mCi/kg 131I-MIBG, require support with ASCT to prevent for prolonged myelosupression, especially thrombocytopaenia [11,15,26,27]. In our study, despite the high doses of administered 131I-MIBG, no stem cell support was needed. The platelet toxicity (median nadir) after each 131I-MIBG course was very mild, in the 131IMIBG group, the nadir of the platelet counts were lower compared with the chemotherapy group in between chemotherapy courses, but without delay in recovery. The addition of MIBG therapy did not result in a substantial delay in chemotherapy intervals. Over time, the intervals between chemotherapy courses have decreased due to a learning curve. In our study, it was feasible to harvest stem cells in 78% of the patients, and there was

3.7. Outcome The 3-year OS in our patient cohort was 57% and the 3year EFS was 40% (Fig. 3). The 3-year OS/EFS in patients having received 131IMIBG therapy was 63/47% versus chemotherapy group 46/27%. E F S a n d O S w h o le c o h o r t 100

P e r c e n t s u r v iv a l

EFS 80

OS

60 40 20 0 0

2

4

6

8

t im e f r o m d ia g n o s is ( y e a r s )

Fig. 3. EFS and OS whole cohort, 3 years. EFS Z 40%, 3 years OS Z 57%, EFS, event free survival, OS, overall survival, n Z 32.

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no difference between the 2 groups. The yield of the stem cells was comparable to data reported in the literature [28]. The platelet recovery post MAT þ ASCT took longer in the 131I-MIBG group than in the chemotherapy group but was similar to the recovery times reported in the literature [28,29]. A limitation of this pilot study is the small number and selection bias of patients receiving upfront 131I-MIBG therapy, since patients in poor clinical condition at diagnosis did not receive upfront 131I-MIBG therapy. Strength of this study is, that patients have been treated in only 2 centres, making the set of data very uniform and complete. The optimal time point for the incorporation of 131IMIBG therapy in stage 4 NBL treatment protocols is still not defined. Even if patients are in CR, before MAT ASCT, post 131I-MIBG scans can reveal MIBG avid lesions (not avid on 123I-MIBG), suggesting that there is (minimal) residual NBL disease [17]. For the future studies, we consider giving 131I-MIBG before MAT þ ASCT, to intensify this therapy.

[8]

[9]

[10]

[11]

[12]

[13]

5. Conclusion Induction therapy with 131I-MIBG before the HR GPOH NB 2004 protocol is feasible, tolerable and effective in newly diagnosed stage 4 neuroblastoma patients.

[14]

Conflict of interest statement [15]

None declared.

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