Discussing relapse treatments in the UK
Posted: 15 Feb 2013 12:00 PM PST
Navigating a path through relapsed neuroblastoma is a challenge for parents regardless of
geography. However, treatment following relapse is generally determined, at least in the first
instance, by locally available options and prevailing attitudes which differ between countries,
institutions, and even individual oncologists.
In 2011 Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH), the German research
group, published results of a study showing that for a small sub-group of patients who
responded to salvage chemotherapy and underwent a second autologous stem cell transplant
(ASCT), the potential for long-term survival justified aggressive second line treatment (1).
Dr John Maris, Chief of Oncology at Children’s Hospital of Philadelphia (CHOP), and leader in
neuroblastoma research takes a somewhat different view: “In contrast to the approach at the
time of the initial diagnosis, when the focus is to provide intensive therapy within as short a time
as feasible, the approach to relapse needs to focus on neuroblastoma as a chronic disease that
can often be managed for years.” (2)
In the United Kingdom relapsed neuroblastoma has historically been treated with a
combination of chemotherapy and radiotherapy for the purposes of palliation only. In more
recent times a pathway of sorts has evolved comprising salvage chemotherapy, radiotherapy and
surgery,
131I-MIBG
therapy, and ch14.18 monoclonal antibody therapy with subcutaneous
aldesleukin-2 (IL-2) and oral isotretinoin (13-cisRA). This paper discusses the different
elements of relapse treatment in the UK, availability of early phase clinical trials, and possible
future plans.
Chemotherapy
In most cases of metastatic relapse, a patient in the UK will initially be treated with one of two
different chemotherapy combinations; topotecan, vincristine, and doxorubicin (TVD), or
temozolomide and irinotecan (TEM/IRN). The choice between the two will sometimes be
guided by the patient’s treatment history. For example, on the standard SIOPEN protocol,
resistance to induction therapy is followed in the first instance by cycles of TVD, so in a
subsequent relapse TEM/IRN would likely be favoured if it had not been used before. However,
for a frontline responder the decision seems to be generally driven by individual and
institutional experiences of the two combinations.
Topotecan, Vincristine, and Doxorubicin
The principal published clinical research for TVD was conducted by an Italian group in 2003, in
a Phase II study that treated 25 children; 19 refractory and 6 recurrent (3). The overall response
rate was 64%, and in the 6 patients with recurrent disease there were 3 complete remissions
(CR), 1 partial remission (PR), 1 stable disease (SD) and 1 progressive disease (PD). SIOPEN
instituted a further Phase II study of TVD for children failing to respond to first-line treatment
(Rapid COJEC) on HR-NBL-01/ E-SIOP, but as yet no results have been reported (4).
TVD is given over a period of 7 consecutive days; topotecan as 30-minute infusion on Days 1-5,
and vincristine and doxorubicin administered intravenously as a 48-hour continuous infusion
starting an hour after the end of topotecan on Day 5. Children receiving TVD may require blood
and/or platelet transfusions, and G-CSF is normally used between rounds in response to
neutropenia. Admission to the hospital for treatment of febrile neutropenia is also not
uncommon. Oral mucositis is the most frequent non-hematologic toxicity, and the potential for
doxorubicin-induced cardiotoxicity means an echocardiogram (ECG) should be performed at
regular intervals whilst a patient continues on this therapy.
Repeat cycles of TVD, in the absence of progressive disease or persistent side-effects, usually
occur every 3 weeks, or when neutrophil and platelet counts are above 1000μ/L, and
100,000μ/L, respectively.
Temozolomide and Irinotecan
A number of papers have reported on the use of temozolomide and irinotecan for the treatment
of relapse in various solid tumor types, including neuroblastoma. Both have been studied
separately (5,6,7,8), as well as in combination using various dose levels and administration
schedules (9,10,11,12,13). Studies such as ANBL0421 (12) suggested TEM/IRN could be used as
a chemotherapeutic backbone alongside inhibitors and other novel agents. Subsequently a
number of new Phase I/II trials have opened abroad that use TEM/IRN in combination with
bevacizumab (14), temsirolimus or ch14.18 (15), dasatanib and rapamycin (16), and MLN8237
(17).
Amongst the research are studies from Memorial Sloan-Kettering in which 12 of 36 patients
showed evidence of disease regression (10), and the Children’s Oncology Group (COG) in which
8 of 55 patients (44 relapse, 11 refractory) had objective responses (CR+PR) (12). Interestingly,
in the only available documented Phase II trial of temozolomide alone reponses (CR+PR) were
observed in 5 of 25 patients (14 relapse, 9 refractory, 2 non-metastatic Myc-N) (8). Such results
are comparable with those from the combination studies, albeit with a caveat that only very
small numbers of patients were involved.
In the UK this combination is normally administered on a 5-day out-patient regimen; oral
temozolomide followed by irinotecan as a 1-hour intravenous infusion. Common toxicities are
bone marrow suppression, nausea and diarrhea. Repeat cycles are every 3 or 4 weeks, subject to
adequate count recovery and resolution of side-effects. Treatment with TEM/IRN is often well
tolerated, and generally considered to be milder than TVD in terms of toxicity. Some children
suffer very few side-effects, and are able to maintain an excellent quality of life. However, for
others the nausea and diarrhea can be extremely severe and debilitating.
Imodium (loperamide) is usually prescribed for the diarrhea. COG advocates continuous
administration of oral antibiotics (cefpodoxime or cefixime) as prophylaxis in patients who
previously experienced severe bouts of diarrhea following TEM/IRN (12), however this is not
normal procedure in the UK.
Other Options
Whilst TVD and TEM/IRN are the most widely administered chemotherapy combinations for
relapse in the UK, and one of them will almost certainly be used initially, they are not the only
options available.
Combination therapy using cyclophosphamide (Cyclo) and topotecan (Topo) has been the
subject of a number of studies in the U.S. (18,19,20). In the COG Phase II randomised study of
Cyclo/Topo vs Topo alone — the largest ever conducted in children with refractory or recurrent
neuroblastoma — responses (CR+PR) were observed in 18 of 57 patients (20). Cyclo/Topo is
currently used as a chemotherapy backbone for Phase II clinical trials from Memorial SloanKettering Cancer Center (MSKCC) and the Neuroblastoma and Medulloblastoma Translational
Research Consortium (NMTRC) (21,22).
Cyclo/Topo is typically administered on an out-patient basis over 5 consecutive days. Each drug
is given separately as a 30-minute intravenous infusion, after antiemetics. Continuous hydration
is given for between 3 and 6 hours, and together with intravenous mesna (Uromitexan) is used
for the prevention of hemorrhagic cystitis, a potential side-effect of cyclophosphamide.
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Treatment is generally well tolerated, though patients will commonly require G-CSF and blood
products between cycles. Treatment repeats every 3 weeks, or after recovery of adequate bone
marrow function and resolution of other side-effects.
Other chemotherapy combinations that have been studied in Phase I trials include
temozolomide and topotecan (TOTEM), and vincristine, irinotecan, and temozolomide (VOIT)
(23, 24). A Phase II trial of TOTEM is currently ongoing in mainland Europe (25).
A recently published retrospective study on the treatment of refractory or relapsed
neuroblastoma with high-dose ifosfamide, carboplatin, and etoposide (HD-ICE) reported
disease regressions in 14 of 17 new relapse patients, and 13 of 26 refractory patients (26). HDICE is most commonly associated with, and administered at, MSKCC. This aggressive salvage
regimen is not typically used to treat relapsed neuroblastoma in the UK.
It’s clear there is no chemotherapy combination that has been shown to be generally superior for
dealing with relapses. As with all treatments, what works for some children may not work so
well for others. However, a number of clinical trials currently enrolling children across a range
of institutions in the U.S. favour either temozolomide and irinotecan, and to a lesser extent
cyclophosphamide and topotecan as a chemotherapeutic backbone to which additional
experimental drugs are added. None of these trials are currently available in the UK.
131I-MIBG
131I-MIBG
Therapy
(Metaiodobenzylguanidine) therapy may be an appropriate treatment option for
children having MIBG avid (or MIBG positive) disease i.e. that is visible on an MIBG scan.
MIBG non-avid (or MIBG negative) tumors are rare, though less so at relapse than initial
diagnosis.
131I-MIBG
is molecular radiotherapy that uses radiation as a drug, targeting the
noradrenaline transporter molecule (NET) expressed by neuroblastoma. The principle of MIBG
therapy is identical to that of an MIBG scan, the difference being that the objective is to deliver a
large enough dose of internal radiation to destroy neuroblastoma cells inside the body.
131I-
MIBG has been used in neuroblastoma treatment for over 20 years. Whilst not having curative
potential by itself, it does have proven efficacy and should certainly be considered as part of a
wider relapse treatment strategy.
In the UK 131I-MIBG therapy has formed a core part of the treatment of relapsed neuroblastoma
over the last few years. After receiving chemotherapy, patients have generally gone on to receive
two rounds of 131I-MIBG therapy before moving on to ch14.18 monoclonal antibody therapy.
131I-MIBG
has been the subject of studies on both sides of the Atlantic (27,28). The leading UK
expert in the field of radionuclide therapy in the treatment of neuroblastoma is Dr Mark Gaze of
University College London Hospitals (UCLH). The largest trial of 131I-MIBG therapy was a Phase
II conducted by University of California, San Franscisco (UCSF), Children’s Hospital of
Philadelphia (CHOP), and University of Michigan. One hundred and sixty-four patients with
progressive, refractory or relapsed high-risk neuroblastoma received two different dose levels of
131I-MIBG
depending whether or not they had hematopoietic stem cells available for post-
therapy bone marrow rescue. Overall response rate (CR+PR) was 36%, and was significantly
higher for patients who had disease limited to either bones and bone marrow or soft-tissue,
compared to those with both (29).
DuBois and Matthay’s 2008 paper in Nuclear Medicine and Biology provides an extensive
review of research investigating in vitro, in vivo, and clinical applications of radiolabeled MIBG
for neuroblastoma (30).
Administration of
131I-MIBG
requires a patient to be isolated in a special lead-lined treatment
room until such time as the radioactive iodine has been excreted from the body, and their
radiation level is safe enough for them to be around other people. Normal length of inpatient
stays are around a week, after which patients are discharged with restrictions on using public
transport and being around other children. Whilst in isolation, contact with ‘comforters and
carers’ is kept largely to a minimum, and those needing to enter the room must carry a
measuring device so their own cumulative levels of radiation exposure can be monitored. Due to
the specialist facilities required for administration of MIBG therapy, it is currently only available
at University College Hospital (UCH), The Royal Marsden (RMH), and The Christie within the
UK. Repeat administrations are usually carried out two weeks apart. Anecdotal evidence
suggests late responses may occur in patients treated with
131I-MIBG,
however, as most patients
follow-up with additional therapies this is impossible to quantify.
131I-MIBG
therapy has relatively few immediate side-effects and is usually well tolerated. There
is a propensity for hypertension, particularly in patients whose blood pressure is already
elevated. The primary toxicity is to the bone marrow, especially when administered with
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concomitant chemotherapy, and patients require a re-infusion of their own stem cells after the
end of treatment. It may therefore not be the most appropriate treatment for a patient with no
cryopreserved stem cells, however this isn’t an absolute rule applied in every case. Some studies
have suggested that the use of individual dosimetry-based treatment planning for repeated
131I-
MIBG administrations could be used to maximise the delivered dose with predictable resultant
bone marrow toxicity (28,31). This would enable individualised treatment based upon factors
such as bone marrow reserve, availability of stem cells, etc.
A recent SIOPEN study to evaluate the use of
131I-MIBG
and topotecan in neuroblastoma
(MATIN) treated 69 patients across 5 European centres, 46 refractory and 23 relapsed.
Unsurprisingly, the treatment was found to be most effective in refractory patients who had not
previously undergone any myeloablative therapy e.g. high-dose chemotherapy. (32)
A search of ClinicalTrials.gov lists an ongoing Phase I dose escalation trial of
131I-MIBG
in
combination with vorinostat (33) that is open in New Approaches to Neuroblastoma Therapy
(NANT) centres across the United States, and a pilot study of
131I-MIBG
given with irinotecan
and vincristine (34) being run out of UCSF. Steven DuBois, MD at UCSF is principal investigator
for both.
177Lu-DOTATATE
Therapy
An alternative form of molecular radiotherapy, that so far has only been used to treat children in
the UK and Australia, is
177Lu-DOTATATE
(LuDO) therapy. This treatment works on precisely
the same principle as 131I-MIBG, but instead of NET expression it targets somatostatin receptors
that are also frequently expressed on neuroblastoma cells. In order for a patient to be a
candidate for this type of treatment they must have positive uptake on a
68Ga-DOTATATE
PET/CT. This scan detects the presence of the somatostatin receptor type 2 targeted by the
therapy, without which treatment will be ineffective.
A pilot study of
68Ga-DOTATATE
/
177Lu-DOTATATE
conducted at UCLH between 2008 and
2010 enrolled 8 children, of whom 6 had positive imaging and were eligible for treatment (35).
Encouraging results led to a Phase I-II trial being planned to start in 2012 (see NB Globe report
here). It’s not clear from publicly available information whether such a trial was ever formally
initiated, however, patients have continued to receive LuDO therapy at UCH. According to the
UK Clinical Research Network database a new trial of
177Lu-DOTATATE
in children with
refractory or relapsed neuroblastoma is now being setup (36).
The main toxicities associated with LuDO observed during the pilot study were nausea, renal,
and hematologic, although all children who were enrolled had been heavily pre-treated with
multiple chemothereuptic agents and prior
131I-MIBG
therapy. Early reports suggest that
DOTATATE may not result in the same degree of bone marrow suppression as
177Lu-
131I-MIBG,
obviating the need for stem cell rescue after treatment. Normal length of inpatient stay for
LuDO is 2 or 3 nights, significantly shorter than
131I-MIBG,
an obvious benefit in terms of the
amount of time younger children must spend in isolation.
177Lu-DOTATATE
is still in its infancy in terms of treatment of neuroblastoma, and does not
have anything like the track record of
be considered if results of a
compares favourably to
131I-MIBG.
That said it is definitely something that should
68Ga-DOTATATE
131I-MIBG
scan show good uptake. Myelosuppression
and may allow repeat administrations without the need for
regular blood or platelets, and possibly stem cell rescue. For patients whose disease is MIBGnegative, radionuclide therapy may still be a treatment option now that LuDO therapy is
available.
Future research may include starting to examine the use of
131I-MIBG
and
177Lu-DOTATATE
in
some sort of combination therapy, rather than repeat administrations of one or the other. The
theory of this approach being that having two distinct targets (NET and somatostatin receptors)
through which to deliver doses of radiation may yield better results.
Surgery & External Beam Radiotherapy
Clearly there is little to be said in terms of these forms of treatment. Depending on the type of
relapse (localised vs metastatic), location of tumor, previous treatment history, etc. it may be
that surgery or external beam radiotherapy (EBRT) is the most appropriate course of action, or
forms a necessary part of an overall treatment strategy.
Immunotherapy
Renewed focus on immunotherapy for neuroblastoma was fuelled by COG Phase III trial
ANBL0032, that reported in 2009 that adding ch14.18 plus cytokines to existing standard
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frontline treatments for high-risk neuroblastoma significantly improved 2-year Event Free
Survival (EFS) (66% vs 46%). (37,38) Whilst it’s clearly more difficult to achieve a successful
outcome with recurrent disease, it should be remembered that to make it to a Phase III clinical
trial, ch14.18 had to have already demonstrated certain activity in relapse and refractory
patients in earlier studies (39,40). In a Phase II trial (POG9347) of ch14.18 and GM-CSF given
to 27 patients with refractory or recurrent neuroblastoma there was 1 CR, 3 PR, and 2 SD
(41,42).
There is rationale for a child who has responded to second-line chemotherapy and/or MIBG
therapy, and now only has minimal residual disease, to receive immunotherapy and isotretinoin
(13-cisRA) in order to try and achieve long-term remission. For children with limited disease
still visible on imaging or bone marrow biopsies, immunotherapy has itself been effective in
disease reduction and even in achieving remission. In cases of bulky tumors, heavy disease
burden, or progression through other relapse therapies, immunotherapy is unlikely to be a good
treatment option (38).
The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) states
the following regarding Special Exception Access to ch14.18 for patients with relapsed
neuroblastoma in the United States (43) :"For patients with relapsed neuroblastoma having measurable disease, ch14.18 efficacy has been
limited. Therefore, therapies other than ch14.18 received through Special Exception Access
should be sought. The activity of ch14.18 in patients who relapse and have never received
ch14.18 and who have achieved a CR or near CR is not known. Based on the potential similarity
of these patients to newly diagnosed patients with minimal disease, these patients are eligible to
receive ch14.18 through the special exception process as long as they meet the following
eligibility criteria as listed below.

Patients must be diagnosed with neuroblastoma and have recurrent or
refractory disease.

Patients should have received standard therapy appropriate for their stage of
disease at the time of diagnosis.

Patients who have responded to second line therapy with PR, VGPR or CR are
eligible and who do not have RECIST measurable disease are eligible.

Patients must not have received prior anti-GD2 antibody therapy; and

Patients must meet performance scale criteria and organ function as outlined in
ANBL0032 Sections 4.8 and 4.9.
Patients with recurrent disease should strongly consider entry onto research protocols including
those aimed at identifying novel therapies, more effective ways to use ch14.18 or identifying
alternative immunotherapy treatments."
Relapse patients from the UK first began receiving immunotherapy (ch14.18) in 2010, along
with slow responders from HR-NBL-01/ E-SIOP who were ineligible for the R2 randomisation
(ch14.18 plus IL-2 vs. ch14.18 alone). Between 2010 and 2012, families needed to travel to
Universitätsmedizin Greifswald in North-East Germany to receive this treatment, but more
recently a European-wide long-term continuous infusion antibody study has opened, which
should now be available at several UK locations (44).
The administration schedule of the antibody for patients on the long-term continuous infusion
study is different from that on COG and SIOPEN frontline protocols. The aim of the trial, as
with almost all such trials, is not to see if there are treatments that will help children with
relapsed neuroblastoma — that is merely a by-product. Rather, it’s to see whether or not some
new concept can move a step forward on the path towards becoming part of standard care for
treating newly diagnosed patients. In this instance the idea in question is whether ch14.18 can
be administered without the use of intravenous morphine, and yet still achieve the required
levels of ch14.18 and NK cell activation in blood serum samples. If the trial achieves these aims
then theoretically ch14.18 could go on to be administered in an out-patient setting.
In Greifswald, each cycle of immunotherapy (ch14.18 plus IL-2) lasted 18 days in total, including
ch14.18 continuously infused over a 10 day period. This was followed by 14 days of 13-cisRA
differentiation therapy. The new trial has an estimated enrolment of 60 patients, and intends to
vary both antibody duration and dose level. The continuous infusion will run over 10, 14, 15, and
21 days, and three daily dose levels (7 mg/m 2, 10 mg/m2, 15 mg/m2) will be used. As Greifswald
gained more experience administering antibody, the protocol moved away from IV morphine as
standard, and gabapentin (Neurontin) was routinely used instead. Paracetamol was prescribed
as prophylaxis for temperatures caused by IL-2 and, during the week when ch14.18 and IL-2
were given together, metamizole (Analgin, Novalgin, etc.) was also added.
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The potential side-effects of immunotherapy with ch14.18 and IL-2 are wide and varied. The
most common are neuropathic pain, fever, hypotension necessitating fluid support, and
capillary leak syndrome that can cause fluid to accumulate around major organs such as lungs,
kidneys and heart. Patients can experience reduced O2 levels and may need to be given oxygen.
The challenge of giving this treatment in an out-patient setting is not simply about the
management of pain, and the use of morphine.
Whilst relapse treatment over the last couple of years has often led to immunotherapy, times
have changed and children in the UK who now follow standard protocol receive ch14.18 (with or
without IL-2) as part of upfront therapy. Having previously received ch14.18 and subsequently
suffered a relapse, there would seem to be no logical basis for repeating it again. Which means
ch14.18 becoming more the preserve of frontline, and possibly refractory, treatment. It’s
unlikely that ch14.18 anti-GD2 monoclonal antibody therapy, at least in its current form, will
even be available to patients who have already received it before.
Without
immunotherapy,
though,
what
follows
chemotherapy/surgery/radiotherapy/radionuclide therapy to consolidate a positive response?
Further courses of 13-cisRA? The same reasoning would apply; taking it again, at least as a
single-agent, wouldn’t make a great deal of sense. It’s a problem that parents of children
relapsing are going to continue to face.
New Drug Trials
A search of the UK Clinical Research Network (UKCRN) database reveals there are currently no
research studies open in the United Kingdom relating specifically to relapsed (and/or
refractory) neuroblastoma.
There are (at least) 3 pediatric Phase I clinical trials (looking at dosing and safety) across all
solid tumor types, and children with neuroblastoma may be enrolled on these, subject to
meeting eligibility criteria. Such trials are not primarily concerned with efficacy. Drugs are
studied across a range of different tumor types, and based upon these initial results future
studies may be designed to examine their effectiveness in treating children with particular types
of cancer. Conversely, some drugs may show little promise and never make it beyond a Phase I
trial at all.
When considering enrolling on an early phase clinical trial it is important to consider that these
drugs have no proven effectiveness in treating children with neuroblastoma. In most cases they
will have already been used to treat adult cancers, and are now being tested to see what effect, if
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any, they might have against pediatric tumors. These studies are being conducted for research
purposes, and patients are often required to attend hospital for examinations, or to have blood
samples taken, that are of no direct benefit to them. There are also often strict requirements on
blood counts, particularly platelets and neutrophils, that can be difficult for a heavily pre-treated
patient to meet. In a study assessing toxicity, good starting counts are necessary to see what
effect experimental treatments have on bone marrow function.
Ridaforolimus
Ridaforolimus (Rida) is a small-molecule inhibitor of the mammalian target of rapamycin
(mTOR) protein. It is one of number of the same class of drugs, commonly referred to as mTOR
inhibitors, that are currently being trialed in the treatment of cancer in general, and
neuroblastoma in particular. Similar drugs, sirolimus (rapamycin) and temsirolimus (Torisel),
developed by different pharmaceutical companies, are also currently being used in trials for
relapsed/refractory neuroblastoma elsewhere.
MK-8669-056 is a Merck sponsored trial of ridaforolimus in pediatric patients with advanced
solid tumors. Professor Andy Pearson of The Royal Marsden Hospital (RMH), Sutton, is the lead
investigator. Patients receive ridaforolimus orally, at escalating doses starting at 22 mg/m 2
based on body surface area (BSA), for 5 consecutive days each week in consecutive 28-day
cycles.
Details of the trial can be found by following these links to the ClinicalTrials.gov and UKCRN
websites (45,46).
Dalotuzumab and Dalotuzumab/Ridaforolimus
Dalotuzumab (Dalo) is a humanised IgG1 monoclonal antibody that targets the Insulin-like
Growth Factor 1 Receptor (IGF-1R) , a protein found on the surface of cells, and implicated in
the promotion of tumor growth in several cancers. Dalotuzumab is an inhibitor of IGF-1 and
IGF-2.
MK-8669-062 is a Merck sponsored trial of dalotuzumab and dalotuzumab/ridaforolimus in
pediatric patients with advanced solid tumors. Professor Andy Pearson (RMH) is the lead
investigator. The study will have three parts. In part 1, dalotuzumab will be administered alone
to determine the maximum tolerated dose (MTD) in a pediatric population. In part 2,
dalotuzumab and ridaforolimus will be administered in combination, using information from
part 1 of this study, and from the ridaforolimus study MK-8669-056, described above. In part 3
of the study an extended cohort of patients will be enrolled at the combined dose levels
determined in part 2.
Dalotuzumab is administered intravenously over 60 minutes every three weeks. Details of the
trial can be found by following these links to the ClinicalTrials.gov and UKCRN websites
(47,48).
AT9283
AT9283 is a multi-targeted small molecule inhibitor of Aurora Kinases (A and B). These are
enzymes that are essential for cell proliferation, and over-expression or amplification of them,
has been linked to the development of cancer. AT9283 is one of a number of Aurora Kinase
inhibitors currently being studied in the treatment of cancer. Another, MLN8237 (Alisertib), has
already been the subject of a COG Phase I/II study for relapsed and refractory neuroblastoma. A
second COG trial of MLN8237 as a single agent is currently ongoing, and the NANT consortium
are also enrolling patients on a Phase I/II trial of MLN8237 in combination with irinotecan and
temozolomide (17).
AT9283 is the subject of a Cancer Research UK (CRUK) and Children’s Cancer and Leukaemia
Group (CCLG) sponsored Phase I trial in children and adolescents with relapsed and refractory
solid tumors. Lead investigator is Dr Darren Hargrave of Great Ormond Street Hospital
(GOSH). Initial enrolment on this study was 20 patients, of which 14 were evaluable for
response. In the very small sub-group of 3 neuroblastoma patients there was one mixed
response (MR) and one stable disease (SD) lasting for four or more courses (49).
AT9283 is administered intravenously over 72 hours at the start of each 21 day cycle. Patients
can receive up to 6 cycles in the absence of disease progression or unacceptable toxicity. Details
of the trial can be found by following these links to the ClinicalTrials.gov and UKCRN websites
(50,51).
Future Trials
BEACON: A randomized phase IIb trial of bevacizumab added to temozolomide ± irinotecan for
children with refractory/relapsed neuroblastoma. At SIOP 2012, Professor Andy Pearson
presented plans for new randomised two-part trial to be run at Innovative Therapies for
Children with Cancer (ITCC) and SIOPEN centres.
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In the first part of the trial patients will be randomised to receive one of four experimental
treatment arms; (1) temozolomide only, (2) temozolomide + bevacizumab, (3) temozolomide +
irinotecan, or (4) temozolomide + irinotecan + bevacizumab. The results will determine which
of these is selected as the backbone to be used for the second part of the trial.
In the second part molecular targeted drugs will be added to the common backbone, to form a
personalised treatment plan dependant upon predictive biomarkers for each individual patient.
Tumor biology, Dynamic Contrast Enhanced MRI (DCE-MRI), mRNA expression and other
techniques will be used to select agents, and monitor responses. For example, a patient whose
neuroblastoma tests positive for an ALK mutation may be treating using an ALK-inhibitor such
as crizotinib (Xalkori) in addition to, say, temozolomide and irinotecan if that was the most
effective ‘standard’ treatment to emerge from part one of the study.
There are a number of questions about this trial that, until more details emerge, we do not have
answers to:-

The large COG randomised trial of topotecan plus cyclophosphamide vs topotecan alone
(20) took a total of five years to enrol 123 patients. It will be interesting to see what the
expected accrual rate is for part one of the BEACON trial, and how many patients it’s
anticipated will be needed on each of the four arms for it to produce a meaningful result.

Bevacizumab (on two of the comparator arms) in part one of the study is a noteworthy
inclusion. Whilst it is currently being studied in a number of ongoing trials in patients
with relapsed (and refractory) neuroblastoma (14,21,52), it’s not immediately obvious
what the rationale, or clinical evidence, is for including it as a candidate for forming part
of a standard treatment backbone.

As with so much research into neuroblastoma, and pretty much all early phase clinical
trials, children who are resistant to frontline therapies i.e. refractory patients, and those
who respond initially but later experience disease recurrence i.e. relapse patients, are all
bundled together as a homogeneous group. In reality, of course, they aren’t and so the
question arises as to what effect, if any, the distribution of patients between different
trial arms might have.
Treatment Abroad
It’s impossible to discuss relapse treatments in the UK without at least saying something about
the option of travelling abroad for treatment. Many families now have charitable appeals
running to raise funds for this purpose should their child relapse, and some are even being
established within weeks of diagnosis.
CNS Relapse
There is one specific type of neuroblastoma relapse that deserves a particular mention. It is well
known that neuroblastoma cells can spread to the central nervous system (CNS), putting them
beyond reach of most conventional therapeutic agents used to treat the disease. The incidence of
CNS disease in children with relapsed neuroblastoma is 6-8% (53,54), of which a subset have
disease that is detected only within the CNS.
Historically CNS relapses were almost always fatal, with a median survival of around 6 months.
However, MSKCC have developed a treatment specifically designed to treat CNS disease using
compartmental intrathecal antibody-based radioimmunotherapy (cRIT). 8H9, a mouse IgG1
antibody, is radiolabelled to deliver therapeutic doses of radiation direct to disseminated tumor
cells within the CNS. It forms part of an overall plan that comprises craniospinal irradiation,
chemotherapy, intrathecal radioimmunotherapy (8H9), anti-GD2 monoclonal antibody 3F8,
and 13-cisRA (55). Treatment for CNS relapse can be ongoing for more than two years,
depending on the individual patient. Initial results reported in 2009 speak for themselves.
“Seventeen of 21 cRIT-salvage patients are alive 7–74 months (median 33 months) since CNS
relapse, with all 17 remaining free of CNS neuroblastoma. …. This is significantly improved to
published results with non-cRIT based where relapsed CNS NB has a median time to death of
approximately 6 months. The cRIT-salvage regimen for CNS metastases was well tolerated by
young patients, despite their prior history of intensive cytotoxic therapies. It has the potential to
increase survival with better than expected quality of life.” (55)
8H9 treatment for CNS relapse is only available at MSKCC. It costs $350,000 USD as a basic
minimum, but in most cases the all-in cost will be significantly more.
General Relapse
For general, or systemic, neuroblastoma relapse it’s patently obvious that there are many more
options abroad than there are in the UK. There can be no debate about this. However, these are
almost universally early phase clinical trials; some of which may already have shown promise,
some of which may go on to form part of the future standard-of-care for treating neuroblastoma,
15
and some of which may prove to have little or no effectiveness once results of the research are
known. If there is one undeniable truth it’s that no therapy is suitable for all, so being able to
navigate sites like ClinicalTrials.gov, NANT, NMTRC, MSKCC, and others is vital in trying to
find a list of possible trials. A search on ClinicalTrials.gov returns a total of 37 studies open in
the United States on which patients with relapsed neuroblastoma are eligible to enrol. Some of
these are neuroblastoma specific trials, and others are open to multiple different tumor types.
When choosing a study there are many factors to take into account. What pre-clinical evidence
exists for the therapy? Have there been any other trials, or pilot studies, of the same or similar
therapies? If so, what were the results? Is there any relevant information that might exist about
children who did or didn’t respond in earlier studies; disease and treatment history, disease
status prior to enrolment? What are the eligibility criteria? What are the potential toxicities and
side-effects? Where is the study available? How long might treatment last? Will it involve being
away from home the entire time? How much will it cost?
There is a popular misconception regarding the cost of treatment abroad. Appeals may have a
target of £300,000 or £500,000, but this isn’t a price tag attached to any particular therapy.
Often, the experimental component of a study is covered by the trial funding grant. Supporting
medications, adjunct chemotherapy, etc. must be paid for. Where things become quite
uncertain, and costs can very quickly escalate dramatically is unplanned in-patient stays, visits
to the Emergency Room, etc. Staying in a Hospitality House like Ronald MacDonald might only
cost around $50 USD per night, but having to spend a night on an oncology ward can cost
around several thousand dollars or more per night, depending on the hospital involved. There is
simply no way to predict how events will unfold, except to say that it’s very much the exception
when everything works out precisely as planned. Costs can vary between institutions, and
receiving the same therapy on the same clinical trial at two different hospitals can result in two
very different bills.
Whilst most of the clinical trials are being conducted in North America, there is also some very
promising research taking place across Europe. Sometimes, even though it’s closer to home, this
can be more difficult to discover except by word-of-mouth; RIST, and Haploidentical Stem Cell
Transplantation are two such examples.
RIST
RIST is a combination therapy of chemotherapy drugs temozolomide and irinotecan together
with the mTOR inhibitor rapamycin and multi-kinase inhibitor dasatanib (Sprycel). It’s
currently the subject of an ongoing randomised clinical trial in which the full 4-drug
combination is being compared to treatment with temozolomide and irinotecan alone (16).
In the RIST design, temozolomide and irinotecan are given at higher doses than in previous
trials conducted by COG and MSKCC. Treatment begins with alternating weeks of
rapamycin/Sprycel (R/S) and temozolomide/irinotecan (T/I), and involves a number of phases
each decreasing in intensity,
A number of UK children have received RIST under the care of Universitätsmedizin Greifswald,
starting treatment at the hospital in Germany and continuing back home in the UK.
In a study of RIST used in a compassionate setting, 20 patients (18 relapsed, 2 refractory)
received a median of 16 courses of R/S and 7 courses of T/I. 18 patients (90%) showed an initial
response after a median of 12 weeks with CR in 12 (60%), PR in 2 (10%), and SD in 4 (20%). The
median progression-free survival (PFS) was 40% at 76 weeks, with 5 patients (25%) remaining
in CR. In a cohort of predominantly relapsed patients (11 after 1st relapse, and 7 after 2nd or 3rd
relapse) such results are very notable.
Haploidentical Stem Cell Transplantation
This post started with reference to the results of a German study on intensive relapse treatment
involving salvage chemotherapy and second autologous stem cell transplant (ASCT). Building
on the premise that children can go on to achieve long-term survival after relapse, a new
strategy has formed involving intensive second-line therapy e.g. RIST,
131I-MIBG
Therapy,
Haploidentical Stem Cell Transplantation (halplo-HSCT), and ch14.18 anti-GD2 monoclonal
antibody therapy with IL-2.
This aggressive treatment approach has already achieved some encouraging results, but only
time and further research will tell whether or not it can fulfil its promise of lasting remissions.
Combination therapy after relapse is given in the hope of securing a good initial response i.e.
complete or partial remission.
131I-MIBG
therapy is then received to further improve or
consolidate the response. Even in patients already in complete remission MIBG therapy is
normally used, both on the basis that MIBG imaging can underestimate the amount of disease
(simply because of the lower radiation dose of
conditioning for the subsequent haplo-HSCT.
17
123I-MIBG
used in scans), and as part of pre-
Haplo-HSCT involves taking stem cells from a parent and transplanting them into the patient
following myeloablative chemotherapy to completely destroy the existing bone marrow system.
The transplant process effectively equips the patient with a new immune system, which it’s
hoped will be able to target any remaining cancer cells in a way the patient’s own immune
system was unable to. The ‘graft’ of donor stem cells is engineered in such a way that ‘T’ and ‘B’
cells are depleted, but large numbers of Natural Killer (NK) cells are infused. Too many ‘T’ cells
can cause graft-versus-host disease (GvHD), and too many ‘B’ cells (relative to ‘T’ cells) may
result other serious complications. Optimisation of the graft composition has been the focus of
much research.
After an earlier study in which relapsed neuroblastoma patients were treated with haplo-HSCT
alone, the present German study is looking at the additive effect of giving ch14.18 anti-GD2
antibody therapy to patients starting at around 100 days post-transplant, with the introduction
of IL-2 in later rounds. The rationale is once again to use antibodies to detect minimal residual
disease (MRD) and present it as a target for the patient’s (new) immune system. An appealing
aspect of this approach is that the new donor-derived immune system will not have had previous
exposure to anti-GD2 antibody therapy, and so the treatment is applicable even in patients who
have received ch14.18 before and then gone on to relapse.
Universitätsklinikum Tübingen, near Stuttgart in Germany, is at the very forefront of haploHSCT for the treatment of relapsed neuroblastoma.
Conclusion
Unlike at initial diagnosis there is no standard-of-care protocol for relapsed neuroblastoma;
each patient has their own history, and their own presentation. In the United Kingdom options
beyond traditional treatments of chemotherapy and radiotherapy are limited. There is hope for
new developments in the area of radionuclide therapy with
research into optimising delivery of
131I-MIBG.
177Lu-DOTATATE,
and continuing
It remains to be seen what difference the
upcoming BEACON trial will have, but we must wait for the more exciting aspect of that when
biomarkers will be used to target specific agents at specific patients. In the meantime options
abroad, in places like Germany and the United States, may continue to offer the best hope for
some, and the only hope for others.
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