DISCUSSION
The results of this study suggest that Th-131I-MIBG
administered shortly before HD CT BuMel and ASCT is a feasible, safe and
effective regimen in patients with advanced NB. To our knowledge, this
cohort is the largest described in the literature on HR-NB patients
treated with this combination.
Treatment of high-risk NB is currently a challenge for pediatric
oncologists. Indeed, despite the improvement obtained with recent
protocols, event-free survival (EFS) remains unsatisfactory. Data from
the Italian registry [3] on the outcome of NB patients over
the years showed a steady improvement in OS in patients with lower
stages of disease; in stage 4 patients, by contrast, after a significant
increase from the 1980s to the 1990s (from 6.7% to 20.6%), OS remained
stable in the early 2000s (29.3 %). More recently, data from the
randomized HR-NBL1/SIOPEN trial showed a 3-year rate of EFS in HR-NB
(stage 4) ranging from 33 to 49% according to the HD CT regimen (CEM vs
BuMel), and indicated that BuMel was the better of the two conditioning
regimens in stage 4 [2] . Moreover, the 5-year overall
survival rate of HR-NB patients in the Children’s Oncology Group between
2005 and 2010 was 50% [17] . These poor outcomes mean that
it is mandatory to explore new therapeutic approaches, since the benefit
of intensified chemotherapy seems to be approaching the end of its
potential.
Th-131I-MIBG has proved to be an effective and
reliable targeted therapy in relapsed or newly diagnosed NB, with an
overall response rate of about 30% in several studies[17-24] , the majority of which have concerned small series
of patients treated with various schedules of
Th-131I-MIBG, either alone or combined with various
myeloablative chemotherapies. The rationale of
Th-131I-MIBG lies in the propensity of NB cells to
internalize 131I-MIBG within the cytoplasm and
mitochondria through norepinephrine transporter channels, thereby
delivering a lethal radiation dose to the tumor while limiting the
damage to healthy tissues [23, 24] . Moreover, its activity
seems to be increased by combination with other agents.
Previous studies have focused on the safety of combining
Th-131I-MIBG and myeloablative treatments. Gaze et al.[25] reported the feasibility and good tolerability of
Th-131I-MIBG combined with melphalan and total-body
irradiation in 5 children with advanced NB. In larger numbers of
patients, other groups [7, 26] found that the addition of
Th-131I-MIBG to a CEM regimen did not affect the
toxicity profile of CEM or bone marrow reconstitution after ASCT.
Moreover, Lee et al. reported the results of incorporating 131I-MIBG
treatment into tandem therapy with ASCT and chemotherapy in which CEC
(carboplatin + etoposide + cyclophosphamide) and TM (thiotepa +
melphalan) were used as the first and second HDCT regimens,
respectively) [27] .
The combination of Th-131I-MIBG with HD CT BuMel has
previously been reported by French et al. [28] . In 8
children with refractory NB who received HD BuMel 6-8 weeks after
Th-131I-MIBG, no significant impact on
treatment-related toxicity was seen and 5 of 7 evaluable patients with
refractory disease achieved either a complete or partial response. More
recently, in a case series of 9 patients,Ferry et al. [29]confirmed the safety of Th-131I-MIBG (up to 24 mCi/kg)
and topotecan combined with HD CT BuMel, administered 2 months later.
In our study, a cohort of 28 children with advanced HR-NB, either newly
diagnosed or relapsed, received Th-131I-MIBG (median
dose 8.5mCi/Kg) shortly (median 17 days) before HD CT BuMel because of
poor response to treatment. This combination proved feasible and
well-tolerated, since the toxicities observed were no greater than would
be expected after HD BuMel[2] and no toxic death occurred.
Th-131I-MIBG did not seem to influence the time to
engraftment or organ toxicities.
VOD/SOS was diagnosed in only 2 patients (7.1 %), who did not present
any significantly different features. This incidence is considerably
lower than that reported after Busulphan in the HR-NBL1/SIOPEN trial
(18%) [2] but similar to that seen among NB patients in
the Italian Pediatric Hemato-Oncology Association Group study on the
incidence of VOD/SOS [30] .
Hypothyroidism was observed in more than one third of patients and can
therefore be regarded as a high-incidence late complication after these
treatments. This could be due to an increased risk of thyroid failure
following high-dose chemotherapy with busulphan and melphalan in
patients previously treated with Th-131I-MIBG, despite
the administration of thyroid-blocking treatment before this latter.
That adding Th-131I-MIBG before HD CT can improve
disease response or survival in HR-NB patients has already been
hypothesized in previous studies [7-9, 21, 28, 29] .
However, the retrospective nature of our study, which did not include a
control group of patients with the same features who did not receive
Th-131I-MIBG, prevents us from drawing any definitive
conclusions regarding the effectiveness of this approach. Nevertheless,
considering the dismal prognosis of the patients included, the overall
disease response (67.8%) and the OS probability observed (53% and 41%
at 3 and 5 years, respectively), we may suggest that the combination of
Th-131I-MIBG given 2-3 weeks before HD BuMel and ASCT
is a potentially valid approach in advanced NB patients with MIBG-avid
disease.
Despite these encouraging results, our study has some limitations, such
as its retrospective, single-center nature, which may have introduced a
selection bias, thereby reducing the reliability of our data.
Nevertheless, the main strength of this study lies in the number of
patients treated by means of the same approach; this aspect is
particularly valuable in a subgroup of patients with a very poor
prognosis who require the collaboration of a multidisciplinary team, in
that it yields useful information on the clinical effect of this
treatment.
Another limitation concerns the relatively low median activity of131I-MIBG administered in these patients, in
comparison with more recent therapeutic approaches [31,32] ;
this may have reduced its potential antitumor effect. However, the doses
of 131I-MIBG in our patients were in line with, or slightly higher than,
those that had proved effective in previous studies in which 131I-MIBG
was not combined with chemotherapy) [33].
Recent data on the positive role of immunotherapy with antibody anti-GD2
in improving survival in HR-NB [31, 32] could suggest that
Th-131I-MIBG administration shortly before HD BuMel
should be included in a sequential approach with immunotherapy in HR-NB
patients with MIBG-avid disease. For this purpose, it would be advisable
to centralize poorly responsive patients with MIBG-avid disease in
centers with proven expertise in the administration of
Th-131I-MIBG and in the management of HD CT and ASCT.
Moreover, these centers should share protocols for treatment, thyroid
blockade, patient surveillance and the monitoring of residual
radioactivity.
Randomized prospective studies are needed in order to confirm the
feasibility and the impact of the above-described strategy on the
long-term outcome of HR-NB patients and to define both the131I-MIBG activity with the highest efficacy/toxicity
ratio and the best timing for combination with high-dose chemotherapy.
The next SIOPEN phase II protocol VERITAS (ClinicalTrials.gov
Identifier: NCT03165292 ), which will compare topotecan plus
Th-131I-MIBG versus HD CT with Thiotepa before
HD CT BuMel in very HR NB patients, may provide useful information on
these issues.