Radionuclide Therapy in Neuroendocrine Tumours: A Systematic Review

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Overview

Radionuclide Therapy in Neuroendocrine Tumours: A Systematic Review K.Y. Gulenchyn *, X. Yao y, S.L. Asa z, S. Singh x, C. Law jj * Department

of Nuclear Medicine, Hamilton Health Sciences & St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada Department of Oncology, McMaster University, Hamilton, Program in Evidence-based Care, Cancer Care Ontario, Toronto, Ontario, Canada z Department of Pathology, University Health Network, Toronto, Ontario, Canada x Neuroendocrine Clinic, Sunnybrook Health Sciences, Toronto, Ontario, Canada jj Department of Surgery, University of Toronto, Toronto, Ontario, Canada y

Received 27 June 2011; received in revised form 11 November 2011; accepted 14 December 2011

Abstract The purpose of this systematic review was to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced neuroendocrine tumour (NETs). A literature search was carried out in MEDLINE and EMBASE from January 1998 to November 2010. The Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, including over 1100 English-language cancer guidelines from January 2003 to June 2010, were also checked. No existing systematic reviews or clinical practice guidelines based on a systematic review or randomised controlled trials focusing on this topic were found. Twenty-four fully published articles were abstracted and summarised: 16 articles focused on five peptide receptor radionuclide therapy (111In-DTPAOC, 90Y-DOTALAN, 90Y-DOTATOC, 90Y-DOTATATE, and 177Lu-DOTATATE) and eight focused on 131I-MIBG treatment. Limited evidence from a historical comparison of studies in one centre supported that 177Lu-DOTATATE might be associated with greater clinical outcomes compared with 90 Y-DOTATOC or 111In-DTPAOC. The severe toxicities for 177Lu-DOTATATE included hepatic insufficiency in 0.6%, myelodysplastic syndrome in 0.8% and renal insufficiency in 0.4% of patients in this study. Insufficient evidence suggested efficacy of 131I-MIBG in adult NET patients, but the overall tumour response rate from 131I-MIBG was 27e75% for malignant neuroblastoma, paraganglioma or pheochromocytoma. Haematological toxicities were the main severe side-effects after 131I-MIBG and 4% of patients developed secondary malignancies in one study. To date, peptide receptor radionuclide therapy seems to be an acceptable option and is relatively safe in adult advanced NET patients with receptor uptake positive on scintigraphy, but patients’ renal function must be monitored. 131 I-MIBG may be effective for malignant neuroblastoma, paraganglioma or pheochromocytoma, but its side-effects need to be considered. No strong evidence exists to support that one therapeutic radiopharmaceutical is more effective than others. Well-designed and good-quality randomised controlled trials are required on this research topic. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words:

131

I-MIBG; neuroendocrine tumour; peptide receptor radionuclide therapy; systematic review

Statement of Search Strategies Used and Sources of Information MEDLINE and EMBASE were searched from 1 January 1998 to 4 November 2010. Alternative terms for peptide receptor radionuclide therapy, seven therapeutic radiopharmaceuticals in Table 1 or 131I-MIBG; alternative terms for neuroendocrine tumour (NET) or different types of NET

Author for correspondence: K.Y. Gulenchyn, 1200 Main Street West, HSC-1P15, Hamilton Ontario, Canada L8N 3Z5. Tel: þ905-521-2100x75667; Fax: þ905-546-1125. E-mail address: [email protected] (K.Y. Gulenchyn).

were used to search literatures and then ‘AND’ was used to combine the results of these two searches (details can be obtained by contacting the corresponding author). The following resources were also checked for existing systematic reviews and clinical practice guidelines: the Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, which included guidelines identified in and/or published by the National Guideline Clearinghouse, the National Health and Medical Research Council, the New Zealand Guidelines Group, the American Society of Clinical Oncology, the European Society for Medical Oncology and the European Neuroendocrine Tumour Society, among others.

0936-6555/$36.00 Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2011.12.003

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308 Table 1 Radiopharmaceuticals considered by this systematic review Name 111

In-DTPAOC

Alternative name [111indium-DTPA0]octreotide, indium-DTPA-D-Phe-octreotide, 111 indium-pentetreotide 111 indium-DOTA-TYR3-octreotate, 111 indium-octreotate 90 yttrium-DOTA-TYR3-octreotide, 90 yttrium-SMT487, 90yttrium-edotreotide 90 yttrium-DOTA-lanreotide 90 yttrium-DOTA-TYR3-octreotate, 90 yttrium-octreotate 177 lutetium-DOTA-TYR3-octreotide, 177 lutetium-octreotide 177 lutetium-DOTA-TYR3-octreotate, 177 lutetium-octreotate 131 iodine-metaiodobenzylguanidine, 131 iodine-iobenguane 111

111

In-DOTATATE

90

Y-DOTATOC

90

Y-DOTALAN Y-DOTATATE

90

177

Lu-DOTATOC

177

Lu-DOTATATE

131

I-MIBG

Introduction Neuroendocrine tumours (NETs) constitute a heterogeneous group of neoplasms originating from endocrine cells that secrete biogenic amines and polypeptide hormones. The clinical behaviour of NETs is enormously variable; they may be hormonally active or endocrinologically nonfunctioning, ranging from very slow-growing tumours to highly aggressive and very malignant tumours. Recent classifications subdivide them into well-differentiated endocrine tumours (grade 1) that will probably have a benign behaviour, poorly differentiated endocrine tumours that have a higher mitotic rate and proliferation index using the antibodies to Ki67 (grade 2) and poorly differentiated neuroendocrine carcinomas [1]. Recently, the incidence of NETs has gradually increased worldwide. In terms of the data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database and the Norwegian Registry of Cancer (NRC), the overall Caucasian NET incidence was 4.44 per 100,000 in the USA and 3.24 per 100,000 in Norway from 1993 to 2004 [2]. SEER and NRC, however, found a marked increase of 37e40% and 72%, respectively, in the period 2000e2004 compared with 1993e1997 in the two countries. No matter what the cause of increasing incidence (such as improving diagnostic techniques), more NET patients will ultimately require appropriate treatment. Surgery is currently the only available curative treatment for NET patients, but for patients who have inoperable primary, recurrent or metastatic disease, few therapeutic options are available. The overall survival time after various combinations of chemotherapy can be 12e24 months, but such therapies can have significant side-effects and a negative impact on the quality of life (QOL) [3]. Recently, octreotide long-acting release proved to lengthen time to tumour progression in patients with metastatic midgut NETs in a randomised controlled trial (RCT) [4] and two RCTs showed that two novel biological agents (sunitinib

295

and everolimus) were useful in malignant pancreatic NET patients [5,6]. Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been identified as a promising therapeutic option and seven therapeutic radiopharmaceuticals (Table 1) have been used to treat patients with NETs in the past decade. A number of small studies and case series have shown that PRRT has few serious adverse effects and is associated with improving patients’ outcomes, such as tumour response and progression-free survival (PFS) [7]. However, this evidence has never been systematically reviewed. Another available radionuclide agent that has also been used for treating NETs since the late 1970s is 131I-MIBG. Similarly to PRRT, there have been a number of studies in which 131I-MIBG has shown some value in the treatment of certain NETs (e.g. pheochromocytomas or paragangliomas) [8]. As with PRRT, this evidence has never been systematically reviewed. The purpose of this systematic review is to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced NET. Small cell lung cancer is not included because it behaves as a very different clinical entity compared with other NET types and is usually treated under the lung cancer category.

Materials and Methods Literature Search A literature search was carried out using MEDLINE and EMBASE from 1 January 1998 to 4 November 2010. Alternative terms for PRRT, seven therapeutic radiopharmaceuticals in Table 1 or 131I-MIBG; alternative terms for NETs or different types of NET were used to search the literature and then ‘AND’ was used to combine the results of these two searches (details can be obtained from the corresponding author). The following resources were also checked for existing systematic reviews and clinical practice guidelines: the Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines (the Inventory) [9], which included guidelines identified in and/or published by the National Guideline Clearinghouse, the National Health and Medical Research Council, the New Zealand Guidelines Group, the American Society of Clinical Oncology, the European Society for Medical Oncology and the European Neuroendocrine Tumour Society, among others. Over 1100 English language cancer control guidelines and standards released from 2003 to June 2010 in the Inventory were checked. Study Selection Criteria Inclusion criteria Articles were eligible for inclusion if they were: 1. Full text reports published from 1 January 1998 to 4 November 2010.

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2. Clinical practice guidelines based on a systematic review, systematic reviews, RCTs, prospective studies or retrospective studies that reported on at least one clinical outcome. 3. Prospective studies that had 30 patients. 4. Retrospective studies that had 100 patients because retrospective studies have a greater potential for bias than prospective studies and thus can be more difficult to interpret. 5. Studies that reported or compared the effects of any of eight therapeutic radiopharmaceuticals listed in Table 1 on any of the following clinical outcomes: complete response, partial response, minor response, stable disease, PFS, overall survival, QOL and toxicity.

Exclusion criteria Articles were excluded if they met any of the following criteria: 1. Were published in a language other than English. 2. Were non-systematic reviews, animal studies, letters, editorials or commentaries. 3. Did not report any outcomes for radionuclide therapy separately in which systemic therapy or surgery was immediately applied after radionuclide therapy. Data Analysis Any subgroup data for which sample sizes were <30 should be considered carefully because they usually have extremely large 95% confidence intervals and are unlikely to be statistically significant. STATA 11.0 was used as statistical software for statistical calculation purposes and for producing figures. A two-sided significance level of a ¼ 0.05 was assumed.

Results Literature Search Results No existing systematic reviews or clinical practice guidelines based on a systematic review focusing on radionuclide therapy in malignant NET patients were found. Kwekkeboom et al. [10] developed a clinical guideline about PRRT in NET patients. However, they did not conduct a systematic review and all fully published studies in their guideline were retrieved by the MEDLINE and EMBASE searches in this systematic review. Of 2504 citations identified from the electronic searches (Figure 1), 2428 articles were excluded after reviewing the titles and abstracts and 44 papers were disqualified after reviewing the full texts, leaving 32 eligible articles [11e42]. The reference lists of the included articles were hand-searched and no further eligible papers were found. Several identified articles were multiple reports from the same or overlapping study populations. For example, the

2504 Initial search results from MEDLINE and EMBASE from January 1, 1998 to November 4, 2010 2428 were excluded after title and abstract reviews 76 potentially relevant studies for full text reviews 44 studies did not meet study selection criteria 32 studies were included in the systematic review

Fig 1. Flow of studies considered for this systematic review.

Kwekkeboom 2008 study [22] updated the 2003 [28] and 2005 studies [29] by the same group. To avoid reporting duplicated information, only the Kwekkeboom 2008 study [22] was summarised and analysed in the tables and text. However, The Teunissen 2004 study [17], Teunissen 2009 study [23] and van Essen 2010 studies [26] included a subset of patients from the Kwekkeboom 2008 study [22]. Because they reported new information and data beyond the Kwekkeboom 2008 study, these articles are summarised in the tables and text. Finally, 24 articles were abstracted and summarised in this systematic review: 16 focused on PRRT [11e26] and eight focused on 131I-MIBG treatment [32e39]. Study Design There were no RCTs identified. Among the 16 articles in the PRRT category, one was a prospective comparative design [16] and others were single-arm prospective designs (seven were phase II trials and one was a phase I trial) [11e15,17e26]; the sample size for a study ranged from 31 to 504 and the total sample size was 1179. Among the eight studies in 131I-MIBG therapy category, six were prospective single-arm studies (two were phase II trials and one was a phase I trial) [32e34,37e39], one was a retrospective comparative study [36] and another was a retrospective single-arm study [35]; the sample size ranged from 30 to 164 and the total sample size was 612. In the PRRT category, all the patient tumours were receptor uptake positive on octreotide/lanreotide scintigraphy before PRRT. The range of patient ages was 18e88 years. The NET types of patients were various, but neuroblastoma was not found in these articles except for one study [21], which did not report NET types. Apart from two papers with unclear patient stages [11,14], eight articles included only stage IV patients [17,18,20e24,26], four articles included 85% of patients with stage IV disease [15,16,19,25] and two articles included stage III or IV patients [12,13]. All the patients had prior treatments, such as surgery, chemotherapy, octreotide, external beam radiation, biotherapy or a combination of these therapies, except for those in one study [21], which had unclear pretreatment information. No patients had previous PRRT except for those in the van Essen 2010 study [26], which

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308

investigated the additional two-cycle 177Lu-DOTATATE treatment. In the 131I-MIBG therapy category, all the patients showed that at least one lesion was positive on the 123 I-MIBG or 131I-MIBG scintigraphy. The range of patient ages was 0.5e70 years. Five studies recruited only stage IIIeIV neuroblastoma patients with a median age of 2.0e6.6 years [32,33,35,37,38], one study enrolled stage IIIeIV patients with various NETs [34], one study enrolled stage IV midgut carcinoid patients [36] and one study recruited stage IV paraganglioma or pheochromocytoma patients [39]. All the patients had prior treatments, such as surgery, chemotherapy, octreotide, external beam radiation, biotherapy or a combination of these therapies, except for the patients in the de Kraker 2008 study [38], who did not receive prior chemotherapy (some of them only had initial surgery) and five inoperable pheochromocytoma patients in the Castellani 2000 study [34] who did not receive any treatments before 131I-MIBG therapy. No patients received prior 131I-MIBG therapy in the eight studies, apart from one patient in one study [32]. Administered Dose and Treatment Schema The administered dose and treatment schema varied significantly among studies. In the PRRT category, no eligible studies investigated the efficacy of 111In-DOTATATE or 177Lu-DOTATOC. The minimum cumulative administered dose was 1.85 GBq with 90Y-DOTALAN in the Virgolini 2002 study [14] and the maximum cumulative administered dose was 29.6 GBq with 177Lu-DOTATATE in the Kwekkeboom 2008 study [22]. In the van Essen 2010 study [26], patients with an earlier benefit from pre-treatment with 177 Lu-DOTATATE 18.5e29.6 GBq in the Kwekkeboom 2008 study [22] who experienced progressive disease received another two-cycle 177Lu-DOTATATE treatment, thus the maximum cumulative administered dose was 44.4 GBq for some patients. In the 131I-MIBG therapy category, only three of eight studies reported the cumulative administered dose data [36,38,39]: the minimum cumulative dose was 7.4 GBq in the de Kraker 2008 study [38]; the maximum cumulative dose was 118.1 GBq in the Gonias 2009 study [39]. Study Quality The study qualities were assessed according to the NewcastleeOttawa Scale [43], which is used in nonrandomised studies method group workshops of the Cochrane Collaboration to illustrate issues in data extraction from primary non-randomised studies [44]. Overall, the study qualities were poor to moderate (A detailed table can be obtained from the corresponding author). Twentytwo single-arm articles prospectively included various advanced NET patients and the administered doses and treatment schemas of radionuclide therapy were recorded clearly. One prospective comparative study was conducted in one clinical centre [16]; in one retrospective comparative study, patients in the control and intervention groups

297

were drawn from two different centres [36]. Except for one study [26], where the investigators stated that they were unclear if the additional 177Lu-DOTATATE would work in progressive patients who had benefitted from previous 177 Lu-DOTATATE treatment, all the other studies seemed to be designed based on the previous case reports or very small sample size studies that showed therapeutic radiopharmaceuticals resulting in some response in NET patients. Only one study specified that outcome assessment of tumour responses was blind with respect to treatment [16]. Eighteen articles had sufficient follow-up time [11e14,16,19,20,22,24e26,32e37,39]. All but one study [17] analysed 80% of patients for at least one clinical outcome. Outcomes A meta-analysis of trial results was not feasible. The various clinical centres differed in radionuclide therapy interventions, doses and treatment schema for the same intervention, patient characteristics, NET types, tumour status at baseline and criteria for evaluating tumour response, making meaningful results from pooling data impossible. Survival time/rate For the PRRT category in Table 2, eight articles reported survival outcomes [11,13,16,19,22,24e26]. In five of the six articles that reported a median overall survival time, it ranged from 16 months for patients with progressive stage IV medullary thyroid cancer treated with 90Y-DOTAOC [20] to 46 months for patients at stage IV in various gastroenteropancreatic (GEP) NETs treated with 177Lu-DOTATATE [22]; in the sixth article, the median overall survival time was 15 months for patients who had an earlier benefit from pre-treatment with 177Lu-DOTATATE and whose disease progressed again and received additional 177 Lu-DOTATATE [26]. Three articles also reported that patients with a complete response, a partial response or stable disease after PRRT had a longer overall survival time than patients with progressive disease [22,25,26]. Three studies were conducted in the same clinical centre at different time periods [13,19,22]: the median overall survival and PFS times was 37 and 14 months, respectively, for various stage IIIeIV GEP NET patients treated by 90 Y-DOTATOC [19]; and 46 and 33 months, respectively, for various stage IV GEP NET patients treated by 177LuDOTATATE [22]. No statistically significant difference existed between the intervention group (14 patients treated with 111In-DTPAOC and five patients treated with 131 I-MIBG) and the control group (12 patients without treatment) for overall survival and PFS rates at the end of the Nguyen 2004 study [16]. For the 131I-MIBG category in Table 3, five studies reported survival outcomes [32,33,36,37,39]. In three studies focusing on stage IIIeIV neuroblastoma patients with a median age of 2e6.6 years, the median overall survival rate was 6 months in the Matthay 1998 study [32], the overall survival rate at 1 year was 49% and at 2 years was

298

Table 2 Clinical outcomes of response on imaging and survival time/rate for peptide receptor radionuclide therapy Study

Neuroendocrine tumour (NET) type

Tumour status/ stage at baseline

Number for Response on imaging Overall response analysis (%) time/rate Complete Partial Minor Overall response rate (confidence interval) response response response (95% confidence rate rate rate interval)

Progression-free survival time/rate (confidence interval)

111

In-DTPAOC [13]* Various [16]y

Progressive/symptomatic, stage IIIeIV Various (intervention) Progressive/ Various (control) symptomatic, stage IIIeIV (97% in stage IV)

0%

3%

15%

18% (6e30)

NR

NR

19 (95%) 12 (100%)

0% 0%

5% 0%

0% 0%

5% (0e15) 0%

In favour of intervention group at 15 months, but no difference at study end

In favour of intervention group at 15 months

41 (100%)

2%

22%

0%

24% (11e37)

76% (60e92) at 24 months NR NR

NR

14 39 13 12 87

(100%) (100%) (100%) (100%) (100%)

0% 5% 8% 0% 5%

36% 18% 31% 8% 23%

0% 0% 0% 0% NR

66 (100%)

5%

21%

NR

116 (100%)

4%

22%

0%

36% (11e61) 23% (10e36) 39% (12e66) 8% (0e23) Complete response þ NR partial response ¼ 28% (19e37) Complete response þ partial response ¼ 26% (15e37) 26% (18e34) NR

58 (100%)

0%

9%

12%

21% (11e31)

47 (100%)

0%

11%

11%

22% (10e34)

31 (100%)

NA

90 (100%)

0%

4%

0%

4% (0e8)

Unclear

34 (100%)

NR

NR

NR

Stage IV

32 (100%)

0%

44%

0%

90

Y-DOTATOC [11]z Various

[15]z

[12]*

EPT Various EPT Intestinal Various

Mixedx, unclear stage Progressive, stage IIIeIV (97% in stage IV) Mixedx, stage IIIeIV

Progressive, stage IIIeIV [18]z

Various

[19]*

Various GEP NETs

[20]

MTC

[24]*

Various carcinoids

94% of patients were progressive, stage IV Mixedx, stage IIIeIV (90% in stage IV) Progressive, stage IIIeIV Progressive, stage IV Progressive, stage IV

NR NR

NR

NR

19e54 (median 37) months Around 21% at 60 monthsjj 1e107 (median 16) months Median 27 months

9e20 (median 14) months NR

18% (5e31)

NR

NR

44% (27e61)

NR

NR

NR Median 16 months

90

Y-DOTALAN [14]z Carcinoid 90

Y-DOTATATE [21]{ Various

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308

40 (80%)

Progressive, 85% of patients in stage IV

Mixedx, stage IV

Progressive, stage IV

57 (95%)

0%

23%

0%

23% (12e34)

43 22 25 14 28 25 14

0% 0% 0% 0% 0% 0% 0%

35% 23% 24% 21% 40% 29%

0% 0% 0% 0% 0% 0% 0%

35% 23% 24% 21% 18% 40% 29%

(21e49) (5e41) (7e41) (0e42) (4e32) (21e59) (5e53)

2%yy 1% 6% 0% 0% 0% 0%

28% 22% 36% 32% 42% 6% NR

16% 17% 18% 10% 33% 18% NR

46% 40% 60% 42% 75% 24% NR

(40e52) (33e47) (49e71) (25e59) (51e100) (9e39)

(72%) (37%) (100%) (56%) (97%) (86%) (48%)

310 (62%) 188 72 31 12 33 (100%) 20 (100%)

Median 22 months; median 10 months for progressive disease patients versus median 24 months for stable disease or partial response patients (P value < 0.05)

Median 17 months; median 5 months for progressive disease patients versus median 20 months for stable disease or partial response patients (P value < 0.05)

Median 46 months, patients with progressive disease have shorter survival

Median 33 months

Median 15 months; patients with progressive disease have shorter survival

NR

EPT, endocrine pancreatic tumour; GEP, gastroenteropancreatic; MTC, medullary thyroid cancer; UO, unknown origin; NR, not reported; NA, not applicable. * Tumour response was assessed by the Southwest Oncology Group criteria: complete response, complete disappearance of all measurable and evaluable disease; partial response, sum of products of all lesions decreased by 50% for at least 3e6 weeks, no new lesions and no progression of evaluable lesions. y Tumour response was assessed by the World Health Organization (WHO) criteria. The intervention group included 14 patients treated with 111In-DTPAOC and five patients treated with 131I-MIBG. z Tumour response was assessed by WHO criteria: complete response, disappearance of all known disease determined by two observations not less than 4 weeks apart; partial response, sum of products of all lesions decreased by >50% for at least 4 weeks, no new lesions, no progression of any lesions. x Some patients were progressive and others were stable. jj Data were measured from Fig. 2 in the original paper. { Tumour response criteria were not specified. ** Tumour response was assessed by the Response Evaluation Criteria in Solid Tumours: complete response, complete disappearance of all target and non-target lesions for at least 4 weeks; partial response, sum of the maximum diameter of all lesions decreased by >30%, no new lesions, no progression of disease. yy A complete response was only called if both conventional imaging and the octreotide scintigraphy had normalised.

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308

[25]** Various GEP NETs at 6 months At 12 months At 24 months Foregut at 6 months At 12 months Midgut at 6 months At 12 months At 24 months 177 Lu-DOTATATE [22]* Various GEP NETs Carcinoid Non-functioning EPT UO Gastrinoma [26]* Various GEP NETs Carcinoid

299

300

Table 3 Clinical outcomes of response on imaging and survival time/rate for Study

131

I-MIBG therapy

Tumour status/ stage at baseline

Number for analysis (%)

Response on imaging Complete response rate

Partial response rate

Mixed response rate

Overall response rate (95% confidence interval)

[32]*

Neuroblastoma

30 (100%)

3%

33%

10%

[33]y

Neuroblastoma

Refractory and relapsed, stage IIIeIV (80% in stage IV) Stage IIIeIV Stage III

43 (100%) 13 (100%)

2% 0%

28% 15%

Stage IV

30 (100%)

3%

Stage IIIeIV Stage IIIeIV Progressive, stage IV

41 (91%) 21 (95%) 58 (100%)

2% 0% NR

Progressive, stage IV

59 (100%)

NR

Refractory or relapsed or progressive disease, stage IIIeIV ST  B/BM with HCT B/BM with HCT ST  B/BM without HCT Stage IV Stage IV

163 (99%)

8%

28%

3%

7% 15% 0% 2% 9%

25% 35% 29% 63% 18%

3% 2% 6% 10% 0%

[34]z [36]

[37]y

[38]yjj [39]{

Various Neuroblastoma Midgut carcinoid (intervention) Midgut carcinoid (control) Neuroblastoma

Neuroblastoma Paragangliomas, pheochromocytomas

72 55 31 41 45

(99%) (100%) (100%) (93%) (90%)

Overall survival time/rate (confidence interval)

Progression-free survival rate (confidence interval)

46% (28e64)

1e51 (median 6) months

NR

2% 8%

32% (18e46) 23% (0e46)

NR

33%

0%

36% (19e53)

24% 24%

0% 0%

26% (13e39) 24% (6e42)

NR 92% (78e100) at 5 years 40% (24e56) at 5 years NR

39% (32e46)

35% 52% 35% 75% 27%

(24e46) (39e65) (18e52) (62e88) (14e40)

NR 63% (47e75) at 5 years 47% (34e59) at 5 years (no statistic difference) 49% at 1 year, 29% at 2 years

NA 64% (46e82) at 5 years

NR NR

18% at 1 yearx

NA 47% (31e63) at 5 yearsx

ST, soft tissue; B, bones; BM, bone marrow; HCT, haematopoietic cell transplant; NR, not reported; NA, not applicable. * Tumour response was assessed by the International Neuroblastoma Response Criteria (INRC) (1988 version): complete response, no tumour for primary lesion and metastases, and homovanillic acid (HVA)/vanillylmandelic acid (VMA) are normal; partial response, no new lesions, all lesions reduced 50%, 0e1 bone marrow samples with tumour, and HVA/ VMA decreased 50%; mixed response, between partial response and stable disease (defined as no new lesions, <50% reduction but <25% increase in any existing lesion). y Tumour response was assessed by INRC (1993 version): complete response, no tumour for primary lesion and metastases, and catecholamines are normal; partial response, no new lesions, all lesions reduced >50%, no more than one positive bone marrow site allowed; mixed response was defined as the same as INRC 1988 version. z Tumour response was assessed by the International Union Against Cancer: complete response, complete disappearance of all known disease for at least 1 month; partial response, 50% decrease in sum of products of two largest perpendicular diameters of all tumour masses for at least 1 month. x Event-free survival rate. jj After 131I-MIBG treatment, patients got surgery and/or other treatments. Thus, the final survival data were inappropriate to show in this table. { Tumour response was assessed by their own criteria: complete response, all lesions visible disappearance on computed tomography/magnetic resonance imaging scan; partial response, the sum of the longest diameter of index lesions decreased 30%.

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Neuroendocrine tumour type

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308

29% in the Matthay 2007 study [37], whereas the PFS rate was 92% (confidence interval 78e100%) for stage III patients and 40% (confidence interval 24e56%) for stage IV patients at 5 years in the Garaventa 1999 study [33]. Patients in the Matthay 1998 and 2007 studies were either refractory to conventional therapy or relapsed, but all the patients in the Garaventa 1999 study did not have a complete response at the end of first-line therapy, which may explain why these patients had a high PFS rate. For stage IV paraganglioma or pheochromocytoma patients with the accumulated dose of 18.2e118.1 GBq, the overall survival rate was 64% (confidence interval 46e82%) and the PFS rate was 47% (confidence interval 31e63%) at 5 years in the Gonias 2009 study [39]. In one comparative study (131I-MIBG treatment versus no treatment) [36], the overall survival rates did not differ between the intervention and control groups (63% versus 47%, P value ¼ 0.10) for patients with progressive stage IV midgut carcinoid. Response on imaging Some PRRT studies, such as the Kwekkeboom 2008 study [22], reported the minor response rate as a reduction in tumour size between 25 and 50% because NETs grow slowly in general. For this reason, the sum of complete, partial and minor response rates is thought to be a reasonable tumour response item and called the overall response rate in this systematic review. For the 131I-MIBG studies, the overall response rate is defined as the sum of complete, partial and mixed response (between partial response and stable disease) rates. For the PRRT category in Table 2, three different criteria were used to evaluate tumour response: the Southwest Oncology Group criteria, the World Health Organization (WHO) standard criteria and the Response Evaluation Criteria in Solid Tumours. The different criteria had different definitions, especially for partial response, stable disease and progressive disease [45], making the comparison among studies difficult (see their definitions under Table 2). For 111In-DTPAOC, the overall tumour response rate was 18% (confidence interval 6e30%) for various progressive stage IIIeIV NET patients [13] and 5% (confidence interval 0e15%) in the intervention group of 19 patients (five patients received 131I-MIBG therapy) in the Nguyen 2004 study [16]. For 90Y-DOTATOC, the overall response rate range was 24% (confidence interval 11e37%) to 28% (confidence interval 19e37%) for various mixedstatus stage IIIeIV NET patients [11,12,18]; 26% (confidence interval 15e37%) and 23% (confidence interval 10e36%) for various progressive stage IIIeIV NETs in two studies [12,15], respectively; 21% (confidence interval 11e31%) for various mixed-status stage IIIeIV GEP NET patients [19]; 22% (confidence interval 10e34%) for various progressive stage IIIeIV GEP NET patients [19]; and 4% (confidence interval 0e8%) for various progressive stage IV carcinoid patients [24]. For 90Y-DOTALAN, the overall response rate was 18% (confidence interval 5e31%) for carcinoid patients [14]. For 90Y-DOTATATE, the overall response rate was 44% (confidence interval 27e61%) for various stage IV NET patients [21]; and 23% (confidence

301

interval 12e34%) for various stage IV GEP NET patients [25]. For 177Lu-DOTATATE, the overall response rate was 46% (confidence interval 40e52%) for various stage IV GEP NET patients, 40% (confidence interval 33e47%) for carcinoid patients, 60% (confidence interval 49e71%) for nonfunctioning endocrine pancreatic tumour patients and 75% (confidence interval 51e100%) for 12 gastrinoma patients in one study [22]; and 24% (confidence interval 9e39%) for various stage IV GEP NET patients who were progressive after they had benefitted from the previous 177 Lu-DOTATATE treatment [26]. Figure 2 shows the overall response rates by different PRRT for studies with a sample size of 30 patients who had not received previous PRRT. For the 131I-MIBG category in Table 3, the data for tumour response on imaging were reported in six studies. Three studies used the 1993 version of International Neuroblastoma Response Criteria (INRC) [33,37,38], one study used the 1988 version of INRC [32], one study used the International Union Against Cancer criteria [34] and the sixth study created its own criteria to assess tumour response [39] (see their definitions under Table 3). The overall response rate range was 32% (confidence interval 18e46%) to 75% (confidence interval 62e88%) for stage IIIeIV neuroblastoma patients [32,33,37,38]; 26% (confidence interval 13e39%) for patients with various stage IIIeIV NETs [34]; and 27% (confidence interval 14e40%) for patients with stage IV paragangliomas or pheochromocytomas [39]. Figure 3 shows the overall response rates for 131I-MIBG therapy by different NET types for studies with 30 patients. Quality of life The self-reported assessment of QOL using five different tools was available in seven studies [11,14,15,17,18,24,25] for four therapeutic radiopharmaceuticals (90Y-DOTATOC, 90 Y-DOTALAN, 90Y-DOTATATE and 177Lu-DOTATATE) of PRRT (a detailed table can be obtained from the

lcl

overall_rate

ucl

Various NETs (111In-DTPAOC) [13] Various NETs (90Y-DOTATOC) [11] Various NETs (90Y-DOTATOC) [15] Various NETs (90Y-DOTATOC) [12] Various NETs (90Y-DOTATOC) [18] Various GEP-NETs (90Y-DOTATOC) [19] Various carcinoids (90Y-DOTATOC) [24] Various carcinoids (90Y-DOTALAN) [14] Various NETs (90Y-DOTATATE) [21] Various GEP-NETs (90Y-DOTATATE) [25] Various GEP-NET (177Lu-DOTATATE) [22] 0

10

20 30 40 50 95% confidence intervals

60

70

Fig 2. Overall response rates (defined as the sum of the complete response, partial response and minor response rates) with 95% confidence intervals by different peptide receptor radionuclide therapy (PRRT). Lcl, lower confidence interval; ucl, upper confidence interval; NET, neuroendocrine tumour; GEP, gastroenteropancreatic.

302

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308 lcl

overall_rate

ucl

Neuroblastoma [32]

Neuroblastoma [33]

Neuroblastoma [37]

Neuroblastoma, no chemo [38]

Various NETs [34]

Paragan_Pheo [39] 10

20

30

40 50 60 70 95% confidence intervals

80

90

Fig 3. Overall response rates (defined as the sum of the complete response, partial response and mixed response rates) with 95% confidence intervals for 131I-MIBG therapy. NET, neuroendocrine tumour; lcl, lower confidence interval; ucl, upper confidence interval; chemo, chemotherapy; Paragan_Pheo, paraganglioma or pheochromocytoma.

corresponding author). The QOL improved for some patients in all studies, but no comparison among different studies or among different therapeutic radiopharmaceuticals can be made because of clinical heterogeneity. No QOL assessment was reported among the eight 131I-MIBG therapy studies. Toxicity Data on toxicity from PRRT are summarised in Table 4. The WHO criteria were used for toxicity grading in seven articles [12e14,21,22,24,25] and the National Cancer Institute grading criteria in four articles [11,15,18,20] and three articles did not specify toxicity criteria [16,19,26]. Nausea and vomiting were common during therapy. The severe toxicities include: for 111In-DTPAOC, 8% of patients developed myelodysplastic syndrome (MDS) and/or leukaemia in one study [13]; for 90Y-DOTATOC, 0.9e3.4% of patients developed grade 4 renal toxicity in three studies [18e20] and 2% of patients developed MDS in one study [19]; for 90 Y-DOTALAN, no severe toxicity was found in one study [14]; for 90Y-DOTATATE, 30% of patients developed grade 2 renal toxicity at 2 years in one study [25]; for 177Lu-DOTATATE, 0.6% of patients developed hepatic insufficiency, 0.8% developed MDS and 0.4% developed renal insufficiency in one study [22]. For studies investigating the efficacy of 90 Y-DOTATOC, 90Y-DOTATATE or 177Lu-DOTATATE, lysine and arginine amino acid solution was infused to protect kidney function for each patient. Toxicity data after 131I-MIBG therapy are summarised in Table 5. The WHO criteria were used for toxicity grading in one study [33], version 2.0 of Common Terminology Criteria for Adverse Events was used in one study [37] and version 3.0 was used in another study [39]. Other studies did not specify the criteria used for assessing toxicity. Forty-three per cent of patients had bone marrow replacement (21% of these patients had prior myeloablative

therapy) and one patient developed secondary leukaemia in the Matthay 1998 study [32]. Five per cent of patients in the Garaventa 1999 study [33] and 2% in the Matthay 2007 study [37] who had heavy pre-treatments developed leukaemia or MDS; 39% needed autologous bone marrow replacement and 9% died in the de Kraker 2008 study [38]. In the Garaventa 2003 study, five (4%) 3e5-year-old children with stage IIIeIV neuroblastoma developed secondary malignancies after 131I-MIBG therapy being used either as part of first-line therapy or as salvage therapy for resistant or recurrent disease: one acute non-lymphoblastic leukaemia, one chronic myelomonocytic leukaemia, one malignant schwannoma, one rhabdomyosarcoma and one angiomatoid malignant fibrous histiocytoma [35]. It is noteworthy that after accumulative doses of at least 63.3 GBq 131I-MIBG , 4% of patients who did not have prior radiation or chemotherapy developed MDS and acute myeloid leukaemia in the Gonias 2009 study [39]. In addition, 4% developed acute respiratory distress syndrome, 4% developed bronchiolitis obliterans organising pneumonia and 2% had pulmonary embolism in this study.

Discussion To date, no RCTs of therapeutic radiopharmaceuticals of PRRT or 131I-MIBG therapy against placebo or other therapies have been conducted to evaluate PRRT or 131I-MIBG therapy benefit on PFS or overall survival. Efficacy analyses in this systematic review are based primarily on prospective studies with 30 patients and retrospective studies with 100 patients. Peptide Receptor Radionuclide Therapy Category No strong conclusion can be made that one therapeutic radiopharmaceutical of PRRT is more effective than others for malignant NET patients. It seems that 177Lu-DOTATATE is more effective than 111In-DTPAOC and 90Y-DOTATOC from the comparisons with historical controls. However, the results from these comparisons should be interpreted with caution [22]. Except for one study [21], 15 articles specified that patients had various treatments before PRRT. Cwikla et al. [25] reported that anaemia after PRRT was observed in 35% of patients treated with previous chemotherapy and only in 10% who were not [25]. Therefore, haematological toxicity in PRRT studies may be increased by previous chemotherapy and/or external beam radiation therapy or other systemic therapy. Although kidney-protecting agents were used in most studies, at least grade 2 renal toxicity was still observed in six studies [13,18e20,22,25], especially for 90 Y-DOTATATE, 30% of patients developed grade 2 renal toxicity at 2 years [25]. There are many unknown aspects of PRRT for malignant NET patients whose tumours were positive on octreotide scintigraphy. For instance, the PRRT studies to date have been largely focused on terminal patients with a ‘salvage’

Table 4 Toxicity from peptide receptor radionuclide therapy (PRRT) Study

Number for analysis (%)

Kidney protecting agent

Gastrointestinal toxicity

Haematological toxicity

Genitourinary toxicity

Other toxicity

In-DTPAOC [13]* 40 (80%)

NR

NR

MDS and/or leukaemia with grade 4 platelet: 3 patients; platelet transfusion: 2 patients ; grade 3 lymphocyte: 18 patients and grade 4: 12 patients; grade 3 anaemia: 7 patients

Grade 1 toxicity serum creatinine: 1 patient

[16]y

No

No significant toxicity

No significant toxicity by In-DTPAOC; pancytopenia: 1 of 5 patients by 131I-MIBG

No significant toxicity

In men: after 20e30 GBq, serum inhibin B significantly decreased; after 50e70 GBq, FSH and LH levels significantly higher No significant toxicity

Grade 1e3 lymphocytopenia: 14 patients; grade 3 anaemia and thromobocytopenia: 2 patients Grade 3e4 lymphocytopenia: 23%; grade 3 anaemia: 3%. All were reversible.

No

NR

Grade 2 renal toxicity: 1 patient at 5 months after PRRT

NR

Grade 3 toxicity WBC and/or platelets: 3 patients with 5.18 GBq/cycle Grade 3 lymphopenia: 9 patients; grade 3 pancytopenia: 3 patients Dose-limiting grade 4 thromobocytopenia: 1 patient; MDS: 1 patient at 2 years Grade 2 transient leucopenia: 3 patients; grade 3 transient thrombopenia: 1 patient

Grade 1 renal toxicity: 2 patients

NR

Grade 4 renal toxicity: 1 patient

NR

9 (16%) patients had >15% decline in CCr and 2 patients had end-stage renal disease Renal toxicity: 2 patients transient grade 1, 3 patients permanent grade 1, and 1 patient grade 4 at 26 months

NR

111

90 Y-DOTATOC [11]z 41 (100%)

111

8% amino acid at 0.5 h before PRRT

[15]z

39 (100%)

8% amino acid 500 ml at 0.5 h before PRRT and 2000 ml after PRRT

[12]*

87 (100%)

L-lysine

[18]z

116 (100%)

8% amino acid 0.5 h before PRRT up to 3.5 h

[19]y

58 (100%)

2000 ml of amino acid solution 0.5 h before PRRT

[20]z

31 (100%)

2000 ml of amino acid solution 0.5 h before PRRT until 3 h after PRRT

and L-arginine amino acids

Nausea, vomiting and flush during injection: 11 patients; no other significant toxicity During injection, nausea: 48%, vomiting: 29%; no other significant toxicity Nausea and vomiting (grade 1e2): 50% of patients Nausea and vomiting: 23% of patients within 24 h after PRRT Dose-limiting grade 3 liver toxicity: 1 patient Grade 1 nausea: 5 patients

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308

19 (95%) in intervention group

NR

(continued on next page)

303

304

Table 4 (continued) Study

Number for analysis (%)

Kidney protecting agent

Gastrointestinal toxicity

[24]*

90 (100%)

2000 ml of amino acid solution with about 28 g of both lysine and arginine 0.5 h before PRRT to over 4 h

A dosage adjustment or interruption of PRRT: 12 patients; discontinued PRRT: 9 patients Grade 3e4 nausea, Grade 3e4 lymphopenia: Grade 3 oliguria: vomiting and abdominal 14 patients 1 patient, grade pain (associated with 3 dysuria: amino acid): 27 patients 1 patient and grade (36%); grade 3e4 diarrhoea: 4 renal failure: 5 patients; grade 3 ascites: 1 patient; 3 patients; grade they lasted 6, 42 and 3 constipation: 1 patient 6 days, respectively

No

No change in liver function parameters caused by PRRT

No severe toxicity

No

NR

L-lysine

and L-arginine amino acid before and after PRRT

NR

No

NR

1500 ml amino acid (13.5 g lysine and 17 g arginine in each infusion) 1.5e2 h before PRRT

In the first cycle, mild nausea: 9 patients; vomiting: 5 patients (some due to amino acid); flushing: 3 patients; abdominal pain: 4 patients No

Grade 3 leucocytosis: 3 patients; grade 3 platelet: 1 patients; grade 3 anaemia: 3 patients Grade 3e4 leucopoenia: 5 patients; grade 3e4 anaemia 6 patients; grade 3 platelet depletion: 1 patient Grade 3e4 thrombocytopenia: 2 patients (4%), grade 3 leucopenia and anaemia: 1 patient Grade 3 thrombocytopenia: 1 patient Grade 3 anaemia: 2 patients; grade 3 thrombocytopenia: 1 patient No

No significant renal toxicity

Headaches in the first cycle: 2 patients

No significant renal toxicity

NR

No significant renal toxicity Renal toxicity grade 2: 3 patients; grade 3: 2 patients Grade 2 renal toxicity: 7 patients

NR

Grade 3e4 haematological toxicity: 9.5% of patients; MDS: 4 patients

Renal insufficiency: 2 patients

Hormonal crises: 6 patients hospitalised; grade 1 hair loss: 62% of patients

Genitourinary toxicity

Other toxicity

Grade 3e4 asthenia: 6 patients; grade 3 fatigue: 6 patients; grade 3 anorexia: 5 patients; grade 3e4 carcinoid syndrome: 6 patients, grade 3 flushing: 7 patients

90

Y-DOTATATE [21]* 32 (100%)

[25]*

60 (100%) after PRRT

57 (95%) at 6 weeks after PRRT

56 (93%) at 6 months 40 (67%) at 12 months

No

23 (38%) at 24 months

No

No

NR

NR

177

Lu-DOTATATE [22]* 504 (100%)

2.5% lysine and 2.5% arginine starting 0.5 h before PRRT up to 4 h

Nausea, vomiting and abdominal discomfort or pain; hepatic insufficiency: 3 patients with liver metastases

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308

90 Y-DOTALAN [14]* 39 (100%)

Haematological toxicity

NR, not reported; MDS, myelodysplastic syndrome; FSH, follicle-stimulating hormone; LH, luteinising hormone; WBC, white blood cell; CCr, creatinine clearance rate; IU, international unit; TT, total testosterone; SHBG, sex hormone binding globulin; FT4, free thyroxine; T3, triiodothyronine; rT3, reverse triiodothyronine; ACTH, adrenocorticotropic hormone; HbA1c, glycosylated haemoglobin. * The World Health Organization criteria were used for toxicity grading. y No criteria for toxicity grading were reported. z The National Cancer Institute grading criteria were used for toxicity grading.

2.5% lysine and 2.5% L-arginine starting 0.5 h before PRRT to 4 h 33 (100%) [26]y

[23]

35 (90%) men; 66 (84%) for thyroid hormone analysis

2.5% lysine and 2.5% arginine starting 0.5 h before PRRT up to 4 h

In men, mean serum inhibin B decreased and FSH increased significantly at 3 months, and returned to near baseline levels later, but inhibin B was still significantly decreased at 24 months. TT and SHBG decreased significantly at 24 months. An increase of LH level at 3 months and returned to baseline levels later. In 21 postmenopausal women, FSH and LH were decreased. Of 66 patients, two developed persistent primary hypothyroidism. FT4 and rT3 decreased. ACTH stimulation test showed an adequate response of serum cortisol (>550 nmol/l). Five patients developed elevated HbA1c (>6.5%). NR Grade 3e4 thrombocytopenia: No kidney failure NR 5 patients

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308

305

approach; there have been no studies to determine the effect of this novel targeted therapy either in early stage NET patients or in patients with a recent diagnosis of metastases who might benefit from this therapy because they still have relatively limited tumour bulk. Recently, investigators of two RCTs have reported positive results in the use of biological agents to compare with placebo in malignant pancreatic NET patients: sunitinib significantly prolonged PFS (11.4 versus 5.5 months, P value < 0.001) [5]; everolimus resulted in longer PFS (11.0 versus 4.6 months, P value < 0.001) [6]. Should these drugs be used before, after, or in combination with PRRT? No high-quality studies compared PRRT alone or combined with other treatments (such as chemotherapy). Kwekkeboom et al. [46] reported that the radiation emitted from 177lutetium had a lower tissue penetration range than that from 90 yttrium and postulated that 177Lu-DOTATATE might be especially important for small NETs, but the association between tumour size and effectiveness was not discussed further. 131

I-MIBG Therapy 131

I-MIBG may be effective for malignant neuroblastoma in paediatric patients, paraganglioma, or pheochromocytoma. For malignant NET patients with no uptake on octreotide scintigraphy or renal insufficiency and positive uptake on 123I-MIBG scintigraphy, 131I-MIBG therapy may be a treatment option. However, the haematological toxicity, severe infections and secondary malignancies after 131 I-MIBG therapy need to be considered, especially in high doses, although some toxicity may be increased in the setting of prior treatments. Ongoing Trials The National Cancer Institute clinical trials database (http://www.cancer.gov/clinicaltrials) and the European clinical trial register (https://www.clinicaltrialsregister.eu/ ctr-search/) were searched on 20 December 2010 for trials that would potentially meet the eligibility criteria. Seven relevant trials for PRRT and seven for 131I-MIBG therapy were found. None of them was identified as an RCT for PRRT. There is an RCT to study observation, combination chemotherapy, radiation therapy and/or autologous stem cell transplant to compare their effectiveness in young patients with neuroblastoma. However, 131I-MIBG therapy in this study was not addressed under a randomised setting [47]. Before this systematic review was submitted for publication, one ongoing trial focusing on 90Y-DOTATOC in various metastasised NET patients published its main results [48]. During a median follow-up of 23 month, longer survival was found in patients with a morphological, biochemical or clinical response. The overall tumour response rate was 34.1%, which is consistent with the reports from other included articles on 90Y-DOTATOC. However, it found that 9.2% of patients experienced grade 4e5 permanent renal toxicity, especially for older patients with a low glomerular filtration rate or high renal tracer uptake at baseline.

306

Table 5 Toxicity from

131

I-MIBG therapy

Study

Number for analysis (%)

Haematological toxicity

Other toxicity

[32]*

30 (100%)

KCIO4 and KI 1 h before 131I-MIBG to 21 days or for 42 days for patients with 0.67 GBq/kg MIBG; a Foley catheter

Mild nausea and vomiting during the first 2 days: most patients; grade 2 hypertension during infusion: 2 patients; mouth dryness: 3 patients; asymptomatic hypothyroidism: 2 patients

[33]y

43 (100%)

Iodine given for 5 days before and 8 days after MIBG

[34]*

37 (82%)

Oral iodine

After first cycle among 29 patients: grade 4 thrombocytopenia: 62% of patients and 46% had ANC < 500/ml; grade 4 thrombocytopenia and/or neutropenia: 80% among patients with 0.44 GBq/kg 131I-MIBG; 43% of patients had BMR in patients with  0.56 GBq/kg 131I-MIBG. After other cycles among 10 patients: BMR: 4 patients, secondary leukaemia: 1 patient with seven previous years of alkylating agents and etoposide In stage III patients, grade 3: 3 patients and grade 4 thrombocytopenia: 2 patients. In stage IV patients among 58 assessed courses, grade 4 thrombocytopenia: 19 times; myeloid leukaemia: 2 patients with heavy chemotherapy before 131I-MIBG Grade 2e3: 15 patients

[35]z

119 (100%)

Iodine 5 days before until 8 days after 131 I-MIBG

Acute non-lymphoblastic leukaemia that resulted in death: 1 patient at 1.5 years after 131I-MIBG; chronic myelomonocytic leukaemia: 1 patient at 4 years after 131I-MIBG and died of chronic graft versus host disease

[37]x

164 (100%)

KCIO4 and KI; a Foley catheter

HCT: 49 patients; PT: 76 patients among patients with 0.67 GBq/kg MIBG and 12 patients among patients with 0.44 GBq/kg 131I-MIBG; MDS/AML: 4 patients with heavy pre-treatments

[38]*jj

44 (100%)

KI for 14 days

Autologous BMR: 17 patients; death: 4 patients

[39]{

49 (98%)

KCIO4 and KI; a Foley catheter

Grade 3e4 neutropenia: 87% of patients; grade 3e4 thrombocytopenia: 83% of patients; grade 3e4 anaemia: 8% of patients; MDS and acute myeloid leukaemia: 2 patients with at least 63.3 GBq and none of them had prior radiation or chemotherapy

Interstitial pneumopathy that resulted in death: 1 patient; hypothyroidism requiring replacement treatment: 15 patients

Hypothyroidism: 5 patients; hypotension: 1 patient Malignant schwannoma that resulted in death: 1 patient at 7 years after 131I-MIBG; rhabdomyosarcoma that resulted in death: 1 patient at 14 years after 131I-MIBG; angiomatoid malignant fibrous histiocytoma: 1 patient Grade 3: 36 patients and grade 4: 15 patients, including 34 infectious episodes and 18 proven infections; retroperitoneal mesothelioma: 1 patient; asymptomatic grade 1 hypothyroidism: some patients Elevated plasma thyrotrophin: 10 of 22 assessed patients and 5 patients needed thyroxine treatment Acute respiratory distress syndrome: 2 patients; bronchiolitis obliterans organising pneumonia: 2 patients; pulmonary embolism: 1 patient; fever with neutropenia: 7 patient; acute hypertension: 10 patients; hypogonadism: 4 patients; infection: 1/2 patients**

KCIO4, potassium perchlorate; KI, potassium iodide; ANC, absolute neutrophil count; BMR, bone marrow replacement; HCT, haematopoietic cell transplant; PT, platelet transplantation; MDS, myelodysplastic syndrome; AML, acute myeloblastic leukaemia. * No criteria for toxicity grading were specified. y The World Health Organization criteria were used for toxicity grading. z The outcome of this study only focused on secondary malignancy; all these five patients had prior chemotherapy. x The Common Terminology Criteria for Adverse Events version 2.0 were used for toxicity grading. jj Haematological toxicity was assessed before surgery etc. treatments. { The Common Terminology Criteria for Adverse Events version 3.0 were used for toxicity grading. ** Showed two patients in the original abstract, but one patient in Table 2 (p. 4164).

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308

Toxicity protecting agent

K.Y. Gulenchyn et al. / Clinical Oncology 24 (2012) 294e308

Conclusions To date, PRRT seems to be an acceptable option and is relatively safe with renal protection of lysine and arginine amino acid solution in adult patients with advanced NETs, but patients’ renal functions still need to be monitored, especially for 90Y-DOTATOC and 90Y-DOTATATE. 131I-MIBG may be effective for malignant neuroblastoma in paediatric patients, paraganglioma or pheochromocytoma, but haematological toxicity, severe infections and secondary malignancies need to be considered. Insufficient evidence exists to suggest 131I-MIBG’s efficacy for adult neuroendocrine carcinoma patients. No strong evidence exists to support that one therapeutic radiopharmaceutical is more effective than others. Well-designed and good-quality RCTs are required to investigate the efficacy of PRRT in neuroendocrine cancer patients. Additionally, well-designed and good-quality RCTs to investigate the efficacy of 131I-MIBG in malignant NET patients with negative uptake on octreotide scintigraphy or renal insufficiency and positive uptake on 123 I-MIBG or 131I-MIBG scintigraphy are encouraged.

Acknowledgements The Ontario Ministry of Health and Long-term Care through Cancer Care Ontario provide funds to support this project. The Program in Evidence-based Care is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-term Care. The authors would like to thank the Neuroendocrine Radionuclide Therapy Expert Panel in Ontario (T. Besanger, M. Coleman, D. Gray, B. Ivo, L. Kaizer, E. Leung, R. Pugash, R. Reid and R. Wong) for their comments on the early draft of this project.

Conflict of Interest Statement Three authors (K.Y. Gulenchyn, X. Yao and S.L. Asa) declared they had no conflicts. Two others (S. Singh and C. Law) declared conflicts and reported receiving more than $5000 in a single year from consulting fees, honoraria and/ or other support from Novartis and Pfizer pharmaceutical companies. Both these authors also declared that they had received research grant support from Novartis.

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