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Exploiting the MIBG‐avidity of neuroblastoma for staging and treatment

M IBG-avidity is an important feature of neuroblastoma (NB), allowing one-step scintigraphic assessment of, and targeted systemic radiotherapy against, the characteristically widespread osteomedullary and soft tissue disease that occurs in 50–60% of NB patients. In this issue of Pediatric Blood and Cancer, Messina et al. present the first report of semi-quantitative MIBG scoring used to assess treatment response in patients with relapsed NBand high doses of I-MIBG is the remarkable salvage treatment in question. The International Neuroblastoma Response Criteria (INRC) require a multitude of tests for defining disease status, with MIBG scan to be done ‘‘if it is available’’ [1]. In fact, since the 1993 publication of the INRC, MIBG scintigraphy has gained an indispensable role in establishing the extent-of-disease at diagnosis and, thereafter, in patients with high-risk NB. Concerns about false positive and false negative findings have largely waned as several factors have enhanced the reliability of MIBG scans for identifying NB in primary sites and in cortical bone, bone marrow, and lymph nodes (detection of metastases in the central nervous system and liver is less certain). First, I-MIBG is now widely used and provides greater sensitivity and clearer images than I-MIBG. Second, characterization of normal physiological MIBG uptake has helped limit misinterpretations of MIBG scans [2]. Third, single photon emission computerized tomography (SPECT) imaging improves detection and localization of lesions [3]. Finally, standardized operating procedures for MIBG scintigraphy are being established and should eliminate the local technical variations in multicenter settings that introduce a degree of uncertainty about the validity of findings. The old stand-by scintigraphic study for NB—technetium-99m-methylene diphosphonate (Tc-MDP) bone scan—still retains its utility in newly diagnosed patients (to distinguish between NB in cortical bone vs. bone marrow), but it can be dispensed within the routine follow-up of a clinically responding patient since, in that setting, Tc-MDP scans virtually never add to information provided by MIBG scans [4]. Semi-quantitative MIBG scoring systems, including the two systems used by Messina et al., have been tested in patients with newly diagnosed high-risk NB in an attempt to ascertain the utility of MIBG scans in clinical management. A major response has been defined as a ratio of <0.5 for the relative MIBG score (the post-treatment MIBG score divided by the pre-treatment MIBG score). Initial studies involved retrospective reviews of patients treated in the 1980s and 1990s with moderate-dose induction chemotherapy [5–9]. Complete remission (CR) rates were <50%; most patients had readily detectable NB at the end of induction. In contrast, after treatment with the more doseintensive contemporary induction regimens, MIBG scintigraphy yields the only evidence of residual NB in a small percentage of patients and most patients have few if any abnormal MIBG(þ) sites [4,10]; hence, the relative MIBG scores in newly diagnosed patients are now usually <0.5. The current preponderant view is that persistence of MIBG-positivity in multiple sites through induction forebodes a poor outcome. The report by Messina et al. shows advantages and drawbacks of semi-quantitative MIBG scoring in patients being treated for relapse, rather than for newly diagnosed NB. The four participating nuclear medicine specialists had good interobserver concordance for scoring MIBG scans when there was extensive disease but not when there were few MIBG(þ) abnormalities. Major responses as defined by MIBG scans and by the INRC did not always correlate. Thus, among 56 patients, 7 who had MIBG scores indicating a major response did not achieve CR or partial response (PR) by INRC, and 6 patients who had MIBG scores showing no response did in fact achieve CR/ PR by INRC. These discrepancies resulted from a poor correlation between bone marrow involvement and MIBG uptake, from the imprecision of MIBG scans (as compared to computed tomography or magnetic resonance imaging) for assessing changes in the volume of soft tissue masses, and from the frequent failure to distinguish soft tissue from osteomedullary disease (SPECT was not used in this study). Clearly, studies other than MIBG scans remain essential for a comprehensive response evaluation in patients with high-risk NB. Despite the above issues, incorporating semi-quantitative MIBG scoring into the INRC will be a major improvement over the current classification in which MIBG scans are noted as either negative (CR) or positive (any abnormal uptake). Messina et al., as well as past reports cited in their article, document excellent activity of MIBG therapy against chemoresistant NB. Even though it rarely achieves CR [11], and, in the study of Messina et al., a good response did not improve progression-free survival, MIBG therapy might still be a contributing factor to the prolonged survival (with good quality of life) of some NB patients after relapse (see Figure 5a in the