Many reports describing the sensitivity and specificity of 131
I- or 123
I-MIBG scans for detecting NB concerned patients treated with moderate-dose chemotherapy; the MIBG findings confirmed the widespread residual NB seen with other staging modalities.2
In contrast, more recently, we4
reported on the utility of comprehensive evaluations for defining response of high-risk NB to contemporary dose-intensive induction chemotherapy; one conclusion was that MIBG scintigraphy and BM testing were prerequisites for accurate determination of disease status,4
although MIBG uptake may also be seen in mature tumor. We now present a complementary report on the sensitivity of standard staging studies for detecting an unsuspected relapse in patients with high-risk NB who had previously achieved CR/VGPR. Other reports have highlighted the utility of MIBG scans in relapse but did not present comparisons with results of comprehensive concurrent staging studies7–13
or covered a heterogeneous patient population (eg, all stages, CR or resistant NB, symptomatic or unsuspected relapse).13,14
Hence, those reports did not identify which test might be best for monitoring.
Through ≥ 3 years from enrollment onto formal treatment protocols, MSKCC patients with high-risk NB undergo a battery of tests to assess disease status every 2 to 4 months. The principal aim is to define the anti-NB activity of the treatment using RFS. That monitoring policy has resulted in the large experience with detecting unsuspected relapse presented in this report. The salient finding is the significantly superior sensitivity of 123I-MIBG scan compared with 131I-MIBG scan, BM histology, bone scan, CT, and urine catecholamine levels.
A vital secondary consideration in the strict monitoring policy is to detect relapse early, when the tumor burden is still small. The hypothesis is that prolonged survival and possibly even cure would be less likely if relapse involves extensive or bulky disease. In fact, the MSKCC experience shows that asymptomatic patients whose monitoring includes 123
I-MIBG rather than 131
I-MIBG scans have less extensive relapse, which might partly account for their significantly longer survival from relapse () and from diagnosis (). The availability of better treatments may also play a role in the longer survival. A localized relapse () can be treated with focal radiotherapy and recently devised chemotherapy regimens (eg, ABT-75115
) that allow good quality of life; the resulting CR can be consolidated with emerging biologic therapies, including retinoids and immunotherapy. In contrast, achieving CR is far less likely with an extensive relapse, even using aggressive, and perforce toxic, treatments.
State of the art 123
I-MIBG scintigraphy, including single-photon emission CT imaging, vastly enhances NB detection, although it is still possible that small lesions can be missed. Thus, among our 91 asymptomatic patients whose monitoring included 123
I-MIBG scan, 25 patients (27%) would have been categorized as being in CR/VGPR had they not undergone that scan (), and 22 of these 25 patients had only a single focus of abnormal uptake (). The outstanding advantage of 123
I-MIBG scan is in earlier detection of osteomedullary relapse. These results suggest that periodic 123
I-MIBG scans may be essential for valid estimation of the duration of RFS. It seems that caution should be used when referring to CR/VGPR rates of, and RFS rates after, treatments in the 1990s, before MIBG scans became part of the standard evaluation of response and when 131
I-MIBG (rather than 123
I-MIBG) scan was widely used. In one large national study, for example, MIBG scan was included in the monitoring of only 18% of patients.17
Bone scan remains useful at diagnosis for assessing metastatic involvement of cortical bone,18–20
which may have prognostic importance and is, therefore, of interest regarding the efficacy of treatments. For patients who achieve CR, however, bone scan is no longer indicated as part of the routine monitoring work-up because of its significantly lower sensitivity for detecting asymptomatic and unsuspected relapse compared with 123
I-MIBG scan (P
Several drawbacks to 123
I-MIBG scans for detecting unsuspected relapse merit attention. First, failure to detect BM relapse in seven (25%) of 28 patients studied by 123
I-MIBG scan supports retaining BM studies for confirming remission status. Second, lack of MIBG avidity, which was noted in two (2%) of 91 patients studied by 123
I-MIBG scan at MSKCC and has been noted in up to 6% to 10% of NB patients,13,14,21,22
should prompt use of positron emission tomography for monitoring in such patients.23,24
Third, suboptimal visualization by 123
I-MIBG scan of small lesions in liver or brain means that special attention should be paid to those sites,25–27
especially in patients who may have risk factors (eg, history of lumbar puncture) for relapse in those organs.
Among the patients with false-negative 123
I-MIBG scans at asymptomatic/unsuspected relapse, urine catecholamine elevations were found in only one of 12 patients. Explanations for this unsatisfactory detection rate include small tumor burden at relapse, a correlation between poor MIBG avidity and low catecholamine production, and decreased catecholamine production in some treated NBs.13
High urine catecholamine excretion was not the sole indicator of relapse in any of our patients, but it served as a helpful confirmatory purpose. Others have also found catecholamine levels to be less than optimal for monitoring NB patients,13,14
suggesting that normal catecholamine levels are associated with a limited extent of recurrent disease.
Concerns about radiographic carcinogenicity, especially in children,28
prompt reservations about follow-up imaging of pediatric cancer patients. Magnetic resonance imaging or ultrasonography should replace CT in monitoring patients with low- or intermediate-risk NB treated by surgery ± chemotherapy. In contrast, for patients with high-risk NB, the relatively small amount of radiation from CT, added to that already received with local radiotherapy (routinely used to assure local control), may not justify the financial cost of magnetic resonance imaging. Regarding scintigraphy, bone scans can be dispensed with in routine follow-up, and the radiation absorbed dose with 123
I-MIBG (which is one tenth of the dose with 131
) is less than the low levels associated with the minor subcellular damage that is readily repaired by the body's physiologic protective mechanisms.30
In conclusion, just as they proved mandatory for accurate classification of response to contemporary dose-intensive induction chemotherapy,4 123
I-MIBG scan and BM testing should be performed regularly to assure the most meaningful data on duration of RFS, which constitutes an important end point in comparing the efficacy of different treatment programs. Furthermore, comparisons of RFS results with those of past treatment programs may be of limited value if the latter did not include regular monitoring with 123
I-MIBG scans and BM testing. After 3 years from the start of treatment, in the off-therapy setting, a reasonable approach might be to tailor surveillance evaluations to the likelihood of relapse (based on clinical and biologic features) of each individual patient, while taking into account the risk-benefit ratio and financial costs of the tests; for example, more evaluations might be warranted in patients whose NB was refractory to induction therapy.
Prolonged survival despite persistence or relapse of NB is an emerging phenomenon.31–34
Although one reason might be the detection of less extensive relapses through improved surveillance, as with 123
I-MIBG rather than 131
I-MIBG scan, another reason might be the identification of better treatments in recent years, including novel therapies with modest toxicity. Not only do the latter allow good quality of life, but it is plausible that in some patients, they will help achieve cure.