Iodine-131-meta-iodobenzylguanidine therapy for patients with high-risk neuroblastoma

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the efficacy of 131I-MIBG therapy in patients with newly diagnosed, relapsed and/or refractory high-risk NBL.

Background

Description of the condition

Neuroblastoma (NBL) is the most common extra cranial solid tumour of childhood, derived from the sympathetic nervous system (Gurney 1996). The median age of diagnosis is 18 months. According to the International NBL Staging System (INSS), NBL is classified in four stages, 1 to 4, with a special stage termed 4S. Children with stage 4 NBL present with metastatic disease at diagnosis, mainly involving lymph nodes and bone marrow. The defining characteristics of high-risk NBL include an age of more than one year, metastatic disease, unfavourable Shimada histology and MYCN amplification (Bernstein 1992; Shimada 1995; Shimada 1999). Current high-risk treatment consists of intensive multi-agent chemotherapy induction, extensive surgical resection of the primary tumour, external beam irradiation of residual primary tumour, myelo-ablative chemotherapy (Yalcin 2010) and maintenance with differentiation and immunotherapy. Despite this very intensive treatment, children with advanced-stage high-risk NBL still have a poor prognosis; the long-term survival is less than 40%. This poor outcome necessitates the search for new therapies (Matthay 1999; Simon 2011)

Description of the intervention

The majority of NBL tumours accumulate meta-iodobenzylguanidine (MIBG). When radiolabeled with 123I-, MIBG can be used for imaging and when labelled with 131I- it can be used as a form of targeted radiotherapy (Hattner 1984; Suc 1996). In general, the radiopharmaceutical 131I-MIBG has shown in different studies around the world to have a significant antitumour efficacy against NBL, both in a phase 2, palliative setting and upfront in newly diagnosed patients (Hutchinson 1991; Klingebiel 1991a; Klingebiel 1991b; Lashford 1992; Lumbroso 1991; Matthay 1998; Matthay 2007; Simon 2011; Voute 1991). More than 95% of NBL tumours have an active uptake of 131I-MIBG (Leung 1997). Given the unsatisfactory results of high-intensity induction chemotherapy it is rational to add 131I-MIBG, as 'targeted radiotherapy', to the treatment of high-risk NBL.

Extensive experience exists with 131I-MIBG treatment of children with NBL. Hoefnagel et al reported the value of 131I-MIBG in the detection of NBL (Hoefnagel 1985). In the next years it became clear that there was also a role for therapeutic use of 131I-MIBG. Initially 131I-MIBG therapy was given to patients with recurrent NBL (Matthay 1998; Matthay 2001). After some time, a second group of patients was included, patients with residual disease after chemotherapy and surgery. From these studies it became clear that the most prominent response was obtained in patients with a large tumour burden at the time of 131I-MIBG treatment (Matthay 1998; Matthay 2001). This finding has served as the basis for a study performed in Amsterdam, with the objectives to document response in untreated children with stage IV or non-operable stage III disease, and to further characterise the side-effects of 131I-MIBG treatment. The study was closed in 1999. In summary, 131I-MIBG therapy has a very high response rate at induction of high-risk NBL patients and can be combined with induction chemotherapy followed by mega-therapy and autologous stem cell transplantation. In this study, the chemotherapy was not dose intense and since then we have learned that dose intense chemotherapy results in better outcome (De Kraker 2008). The current Dutch Childhood Oncology group high-risk NBL 2009 treatment protocol combines upfront 131I-MIBG with induction chemotherapy followed by mega-therapy and ASCT. Matthay et al. reported in 2009 the results of a phase I study in refractory or relapsed high-risk NBL patients. It showed that closely spaced infusions of 131I-MIBG can be administered safely using autologous stem cell transplantation without dose-limiting non-haematological toxicity and with rapid and reliable reconstitution of haematopoiesis. Twenty one patients were evaluated in the study, responses included two partial responses, eight mixed responses, three stable disease and seven progressive disease (Matthay 2009).

How the intervention might work

131I-MIBG is a radiopharmaceutical; it is a radio labelled molecule similar to noradrenalin which can be taken up by NBL tissue (Hattner 1984). When NBL has taken up the 131I-MIBG, it releases gamma and beta irradiation (gamma and beta emitting isotope) which can irradiate the neighbouring NBL cells and killing them by causing double strand DNA breaks and damage to lipid bilayer (Hutchinson 1991; Matthay 2007).

Why it is important to do this review

At the moment the prognosis for high-risk NBL patients is still very poor. Relapses remain common, despite the achievement of a complete clinical remission after induction therapy. The place of 131I-MIBG in high-risk treatment is not yet well established.

Objectives

To assess the efficacy of 131I-MIBG therapy in patients with newly diagnosed, relapsed and/or refractory high-risk NBL.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomised controlled trials (RCTs), clinically controlled trials (CCTs), non-randomised single-arm trials with historical controls and cohort studies examining the efficacy of 131I-MIBG therapy in patients with newly diagnosed, relapsed and/or refractory high-risk NBL. Cross-sectional studies, case-reports and case series (i.e. a series of non-consecutive patients) will be excluded. A cohort study is defined as a study in which a group of consecutive patients treated for high-risk NBL was followed from diagnosis onwards. The described study could be the original cohort or a subgroup of the original cohort based on well-defined inclusion criteria.

We will exclude studies including less than 10 patients.

Types of participants

Patients with newly diagnosed, relapsed and/or refractory high-risk NBL. The defining characteristics of high-risk NBL include an age of more than one year, regional or metastatic disease, unfavourable Shimada histology or MYCN amplification. Patients with esthesioneuroblastoma and/or newly diagnosed patients who received prior chemotherapy will be excluded. If studies include both eligible and non-eligible patients the results of only eligible patients should be available in order to be included in the review.

Types of interventions

131I-MIBG therapy.

Types of outcome measures

Primary outcomes
  • Response as measured by the International Neuroblastoma Response Criteria (Brodeur 1993)

  • Overall survival (as defined in the original study)

  • Event-free survival, defined as the time span that follows therapy during which there are no objective signs of recurrence or other events (as defined in the original study)

  • Progression-free survival, defined as the time elapsed between treatment initiation and tumour progression or death from any cause

For newly-diagnosed high-risk NBL patients we are especially interested in analysing response, overall survival and event-free survival; for refractory or relapsed high-risk NBL patients in progression-free survival and response.

Secondary outcomes
  • Toxicity and adverse events, as defined in the original studies. We will particularly look at haematological, cardiovascular, hepatic problems and sialoadenitis as short-term events. Long-term events would be thyroid dysfunction and secondary malignancies

  • Dose intensity after 131I-MIBG treatment: the actual administered amount of 131I-MIBG mega Becquerel/micro Curie (MBq/mCi) and time span of delivering chemotherapy induction treatment after 131I-MIBG therapy

  • Yield of peripheral stem cell collection during harvest sessions (defined as the mean number of collected autologous haematopoeitic stem cells)

  • Number of successful peripheral stem cell harvests (defined as more than 2x106/kg autologous haematopoeitic stem cells)

  • Number of peripheral stem cell harvest sessions necessary to obtain a sufficient amount of autologous haematopoeitic stem cells (i.e. more than 2x106/kg autologous haematopoeitic stem cells)

  • Percentage of patients in which bone marrow harvest is performed

  • Stem cell engraftment defined as the time to haematopoeitic recovery after myeloablative chemotherapy and autologous stem cell transplantation will be measured for each of the haematopoeitic cell lineages

Stem cell harvest can take place at any stage of the treatment protocols (i.e. before or after 131I-MIBG therapy).

Search methods for identification of studies

See: Cochrane Childhood Cancer Group methods used in reviews (Kremer 2012). We will not impose language restrictions. Searches will be updated every two years.

Electronic searches

We will search the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), MEDLINE in PubMed (from 1945 to present) and EMBASE in Ovid (from 1980 to present).The search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) are shown in the appendices (Appendix 1; Appendix 2; Appendix 3)

Searching other resources

We will locate information about trials not registered in CENTRAL, MEDLINE or EMBASE, either published or unpublished, by searching the reference lists of relevant articles and review articles. We will handsearch the conference proceedings of the International Society for Paediatric Oncology, Advances in Neuroblastoma Research and American Society of Clinical Oncology published between 2008 and 2012. We will scan the International Standard Randomized Controlled Trial Number (ISRCTN) Register and the National Institute of Health Register for ongoing trials (http://www.controlled-trials.com/).

Data collection and analysis

Selection of studies

After performing the search strategy described previously, two authors will independently select studies meeting the inclusion criteria. All discrepancies between reviewers will be resolved by consensus. Otherwise, final resolution will be achieved by using a third-party arbitrator. We will obtain in full any study which seems to meet the inclusion criteria on grounds of the title and/or abstract for closer inspection. We will clearly state details of reasons for exclusion of any study considered for this review.

Data extraction and management

Two authors will independently perform data extraction using standardised data extraction forms. Discrepancies between authors will be resolved by discussion. If this is impossible, we will achieve final resolution using a third-party arbitrator. Data will be extracted on the following items.

  • Study characteristics, including:

    • design;

    • number of patients enrolled in the study;

    • number of patients fulfilling the pre-defined inclusion criteria.

  • Participants characteristics, including:

    • gender

    • age at time of diagnosis (range, mean and/or median);

    • stage of disease according to the INSS;

    • newly diagnosed, relapsed or refractory disease;

    • tumour biology and genetic aberrations (MYCN amplified and loss of heterozygosity chromosome 1P);

    • tumour localisation (primary and metastasis).

  • Interventions, including:

    • schedule of 131I-MIBG treatment and total amount of 131I-MIBG administered (MBq/mCi);

    • additive (radio-sensitizing) therapeutics (dose and schedule) during 131I-MIBG treatment and chemotherapy schedules thereafter.

  • Outcome measures (as described above)

  • Length of follow-up

Assessment of risk of bias in included studies

Two authors will independently perform the assessment of risk of bias of the included studies. For RCTs and CCTs we will use the risk of bias items as described in the module of the Cochrane Childhood Cancer Group (Kremer 2012), which are based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The assessment of risk of bias in observational studies will be based on previously described checklists according to Evidence-Based Medicine Criteria (Grimes 2002; Laupacis 2004). See Table 1 for the definitions of the different risk of bias criteria. The risk of bias in included studies will be taken into account in the interpretation of the review's results. We will resolve discrepancies between reviewers by consensus. If this is impossible, we will achieve final resolution using a third-party arbitrator.

Table 1. Risk of bias criteria for observational studies
  1. MIBG: meta-iodobenzylguanidine; NBL: neuroblastoma

 Internal validityExternal validity
Study group

Selection bias (representative: yes/no):

If the described study group consisted of more than 90% of the high-risk NBL patients treated with 131I-MIBG included in the original cohort

Or

If it was a random sample of these patients with respect to important prognostic factors (i.e. age, stage according to INSS (bone marrow involvement), MYCN amplification and loss of chromosome 1p), type of disease (i.e. newly diagnosed, relapsed, refractory) and cancer treatment

Reporting bias (well defined: yes/no):

If the mean, median or range of the cumulative 131I-MIBG dose was mentioned

And

When it was described what other treatment (including the received doses) was given

Follow-up

Attrition bias (adequate: yes/no):

If the outcome was assessed for more than 90% of the study group of interest (++)

Or

If the outcome was assessed for 60-90% of the study group of interest (+)

Reporting bias (well-defined: yes/no):

If the length of follow-up was mentioned

Outcome

Detection bias (blind: yes/no):

If the outcome assessors were blinded to the investigated determinant

Reporting bias (well-defined: yes/no):

If the outcome definition was provided

Measures of treatment effect

If a control group is available dichotomous variables will be analysed using risk ratios (RRs); continuous outcomes will be analysed using mean differences (MDs); survival will be analysed using hazard ratios (HRs). We will use the Parmar's method if HRs have not been explicitly presented in the study (Parmar 1998). If no control group is available we will use the prevalence to analyse tumour response and adverse effects; other outcomes will be summarised descriptively. All results will be presented with the corresponding 95% confidence intervals (CIs).

Dealing with missing data

When relevant data regarding study selection, data extraction and risk of bias assessment are missing, we will attempt to contact the study authors to retrieve the missing data. We will extract data by the allocated intervention, irrespective of compliance with the allocated intervention, in order to allow an intention-to-treat analysis. If this is not possible, this will be stated and we will perform an 'as treated' analysis.

Assessment of heterogeneity

We will assess heterogeneity both by visual inspection of the forest plots and by a formal statistical test for heterogeneity, that is the I2 statistic. In the absence of significant heterogeneity (I2 < 50%) (Higgins 2011), we will use a fixed-effect model for the estimation of treatment effects. Otherwise, we will explore possible reasons for the occurrence of heterogeneity and take appropriate measures.

Assessment of reporting biases

In addition to the evaluation of reporting bias as described in the Assessment of risk of bias in included studies section, we will assess reporting bias by constructing a funnel plot where there are a sufficient number of included studies (that is at least 10 studies included in a meta-analysis). When there are fewer studies the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2011).

Data synthesis

We will enter data into the Cochrane Collaboration's statistical software, Review Manager (Review Manager 2011), and undertake analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will include outcome measures only if it was the intention of the study to perform the necessary assessments in all patients (that is, not only optional or only performed in some centres). We will perform pooling of results only if studies are comparable with regard to important prognostic factors [i.e. age, stage according to INSS (bone marrow involvement), mycN amplification and loss of chromosome 1P], treatment and used outcome definitions. Patients with newly-diagnosed, relapsed and refractory disease will be analysed separately. Different study designs will be taken into account in the analyses. Studies for which pooling of results is not possible will be summarised descriptively.

Sensitivity analysis

For all outcomes for which pooling is possible we will perform sensitivity analyses for all risk of bias criteria separately. We will exclude studies with a high risk of bias and studies for which the risk of bias is unclear and compare the results of studies with a low risk of bias with the results of all available studies.

Acknowledgements

We thank Edith Leclercq for her help with developing the search strategies for the different databases. We also thank Dr. M Gaze and Prof. Dr. T Simon who kindly agreed to peer review our manuscript. The editorial base of the Cochrane Childhood Cancer Group is funded by Stichting Kinderen Kankervrij (KiKa).

Appendices

Appendix 1. Search strategy for CENTRAL (The Cochrane Library)

1. For 'Neuroblastoma' the following text words will be used:

neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR ganglioneuroblastomas OR neuroepithelioma OR neuroepitheliomas OR Peripheral Primitive Neuroectodermal Tumors OR Peripheral Primitive Neuroectodermal Neoplasm OR Primitive Neuroectodermal Tumor, Extracranial OR Neuroectodermal Tumor, Peripheral OR Neuroectodermal Tumors, Peripheral OR Peripheral Neuroectodermal Tumor OR Peripheral Neuroectodermal Tumors OR Tumor, Peripheral Neuroectodermal OR Tumors, Peripheral Neuroectodermal OR pPNET OR PNET OR PNET* OR Peripheral Primitive Neuroectodermal Tumor OR Extracranial Primitive Neuroectodermal Tumor OR Extracranial Primitive Neuroectodermal Tumors OR Neuroectodermal Neoplasm, Peripheral Primitive OR Neuroectodermal Tumor, Peripheral Primitive

2. For '131I-meta-iodobenzylguanidine' the following text words will be used:

131I-Meta-iodobenzylguanidine OR MIBG OR 131I-MIBG OR 131I-metaiodobenzylguanidine OR Iodine-131 Metaiodobenzylguanidine OR Iobenguane (131I) OR (3-Iodo-(131I)benzyl)guanidine

Final search 1 AND 2

The search will be performed in title, abstract or keywords

[* = zero or more characters]

Appendix 2. Search strategy for MEDLINE (PubMed)

1. For 'Neuroblastoma' the following MeSH headings and text words will be used:

neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR ganglioneuroblastomas OR neuroepithelioma OR neuroepitheliomas OR (Peripheral Primitive Neuroectodermal Tumors OR Peripheral Primitive Neuroectodermal Neoplasm OR Primitive Neuroectodermal Tumor, Extracranial OR Neuroectodermal Tumor, Peripheral OR Neuroectodermal Tumors, Peripheral OR Peripheral Neuroectodermal Tumor OR Peripheral Neuroectodermal Tumors OR Tumor, Peripheral Neuroectodermal OR Tumors, Peripheral Neuroectodermal) OR (pPNET OR PNET OR PNET*) OR Peripheral Primitive Neuroectodermal Tumor OR Extracranial Primitive Neuroectodermal Tumor OR Extracranial Primitive Neuroectodermal Tumors OR Neuroectodermal Neoplasm, Peripheral Primitive OR Neuroectodermal Tumor, Peripheral Primitive

2. For '131I-meta-iodobenzylguanidine' the following MeSH headings and text words will be used:

131I-Meta-iodobenzylguanidine OR 131I-MIBG OR 131I-metaiodobenzylguanidine OR Iodine-131 Metaiodobenzylguanidine OR Iobenguane (131I) OR (3-Iodo-(131I)benzyl)guanidine OR Iodine Radioisotopes/therapeutic use OR 3-Iodobenzylguanidine/therapeutic use

Final search 1 AND 2

[* = zero or more characters]

Appendix 3. Search strategy for EMBASE (Ovid)

1. For 'Neuroblastoma' the following Emtree terms and text words will be used:

    1. exp neuroblastoma/

    2. (neuroblastoma or neuroblastomas or neuroblast$).mp.

    3. (ganglioneuroblastoma or ganglioneuroblastomas or ganglioneuroblast$).mp.

    4. (neuroepithelioma or neuroepitheliomas or neuroepitheliom$).mp.

    5. exp neuroectoderm tumor/ or (peripheral primitive neuroectodermal tumors or peripheral primitive neuroectodermal tumours).mp.

    6. (peripheral primitive neuroectodermal neoplasm or peripheral primitive neuroectodermal neoplasms).mp.

    7. (peripheral neuroectodermal tumor or peripheral neuroectodermal tumors or peripheral neuroectodermal tumour or peripheral neuroectodermal tumours).mp.

    8. (pPNET or PNET or PNET$).mp.

    9. (peripheral primitive neuroectodermal tumor or peripheral primitive neuroectodermal tumour).mp.

    10. (extracranial primitive neuroectodermal tumor or extracranial primitive neuroectodermal tumors or extracranial primitive neuroectodermal tumour or extracranial primitive neuroectodermal tumours).mp.

    11. or/1-10

2. For '131I-meta-iodobenzylguanidine' the following Emtree terms and text words will be used:

    1. exp "(3 iodobenzyl)guanidine i 131"/ or 131I-Meta-iodobenzylguanidine.mp.

    2. 131I-MIBG.mp.

    3. 131I-metaiodobenzylguanidine.mp.

    4. Iodine-131 Metaiodobenzylguanidine.mp.

    5. Iobenguane 131I.mp.

    6. "(3 iodobenzyl)guanidine"/

    7. Iodine Radioisotopes.mp. or exp radioactive iodine/

    8. radiopharmaceutical agent/ad, dt

    9. or/1-8

Final search 1 AND 2

[mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name; / = Emtree term; $=zero or more characters; ad=drug administration; dt=drug therapy]

Declarations of interest

None known.

Sources of support

Internal sources

  • Dutch Cochrane Centre, Netherlands.

    Training

External sources

  • Stichting Kinderen Kankervrij (KiKa), Netherlands.

    Financial

  • Koningin Wilhelmina Fonds (KWF), Netherlands.

    Financial

Ancillary