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High-Risk Neuroblastoma in the UK

A parent's perspective on UK Neuroblastoma treatment ...

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Why do parents of UK children with neuroblastoma seek treatment abroad?

© Nicholas Bird, May-2012 [Click here for PDF]

The mainstream view of 'fundraising for cancer treatment abroad' is desperate parents whose children have no realistic hope of being successfully treated, or vulnerable parents lured by false promises from foreign institutions out solely to make money. Whilst in some instances this is no doubt true, for parents of children with neuroblastoma the reasons for seeking treatment abroad are entirely rational, and based upon clear objective reasoning.

1. UK participation in SIOPEN, the European collaborative research network, is unnecessarily putting the lives of children at risk. Ethical research gives children the best available treatments as baseline, and designs trials to seek improvement with no reasonable expectation of worse outcomes (though they do sometimes regrettably occur, such is the nature of clinical trials). This ethical approach is demonstrably not the case with the most recent SIOPEN high-risk neuroblastoma trial. Consequently, some parents have elected to take children in remission to the US, to receive the treatment statistically proven to give the best chance of a cure. SIOPEN's decision to put the interests of research ahead of those of the child should be investigated.

2. For children whom doctors say need to be treated elsewhere because setting up trials in the UK can take years, there are no standard procedures for obtaining funding support. Department of Health reliance upon local adjudications results in an inequitable system. With no certainty of funding approval, there is little option but to use charitable funds to secure treatment within necessary timeframes. The speed at which clinical trials are introduced must be reviewed, and a standardised process established for interim funding of equivalent treatment abroad.

3. For children who fail to reach remission after frontline therapy, or those who reach remission but experience disease recurrence, there are woefully few options available in the UK. There are orders of magnitude more in the US, and promising new research also from places like Germany. Whilst these are predominantly early phase clinical trials, it is a fact that such trials are the foundations from which the next generation of standard treatments will emerge. Expeditious work needs to be done to bring more treatment options for relapsed and refractory patients into UK hospitals.

4. In certain cases the UK simply does not have the best treatment available. An obvious example being proton beam radiotherapy, where for some time the NHS has paid for children to travel abroad as such facilities do not currently exist here. For neuroblastoma that has spread to the central nervous system (CNS) the only institution worldwide with a treatment protocol that has demonstrated curative potential is Memorial Sloan-Kettering Cancer Center (MSKCC) in New York. At present it costs between $500,000 and $1,000,000 for a UK child to undergo this special therapy. The efficacy of MSKCC protocol for CNS disease should be examined, and a decision taken whether it should be made accessible to qualifying UK children as a matter of healthcare policy.

In some quarters the views expressed in this document will be seen as controversial. They highlight inadequacies within our present system of care, and seek to challenge the status quo. It is natural that there will be pushback amongst those in positions of responsibility. The intention, however, is to try and stimulate constructive debate about how we can provide better treatments, and more options, for all UK children with high-risk neuroblastoma. For surely this must be the common goal for parents and healthcare professionals alike?

Background

The incidence of neuroblastoma (incl. ganglioneuroblastoma and ganglioneuroma) is around 100 cases per year in the UK [1], and 650 per year in the US [2]. It is the most common extra-cranial solid tumour in childhood, accounting for 6-10% of all childhood malignancies [1,2,3] of which about 90% occur by the age of five [1,2], making it the most common cancer in infancy [4]. Relative to incidence, neuroblastoma is responsible for a disproportionately high 15% of cancer deaths in children [3].

"Since 1971, survival rates from neuroblastoma have risen from 17 to 64 per cent and it is estimated that around 800 more children survived their disease for more than five years due to this increase." [5]

The excerpt is from a UK press release from Nov 2011, which was widely reported in the media. However, such blanket statistics mask the true picture, as neuroblastoma is an extremely heterogeneous disease capable of ultra-aggressive growth in one form, and spontaneous regression in another. It is stratified into three distinct risk classifications; low, intermediate, and high risk. High-risk patients either have tumours with specific biological features, or are above 18 months old with metastatic disease. Whilst low and intermediate risk groups have excellent 5-year survival rates of 95% and 80-90% respectively, the high-risk group has a dismal 5-year survival rate of just 30-40% [3,6]. Roughly half of all children diagnosed with neuroblastoma are high-risk, and the majority of them will not survive the disease.

There are three predominant groups involved in neuroblastoma treatment; Children's Oncology Group (COG) in America, Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) in Germany, and Société Internationale d'Oncologie Pédiatrique European Neuroblastoma (SIOPEN), a collaborative organisation of which the UK is a member. Additionally Memorial Sloan-Kettering Cancer Center in New York has its own protocols, and has historically treated more neuroblastoma patients each year than any other institution.

Monoclonal Antibody in America

Whilst there are differences in high-risk frontline therapy between COG, GPOH and SIOPEN all use intensive treatment regimens comprising chemotherapy, surgery, radiation therapy, myeloablative chemotherapy with autologous stem cell transplantation, and retinoid therapy. More recently a COG Phase III clinical trial proved that monoclonal antibody ch14.18 together with cytokines IL2 and GM-CSF significantly improves survival rates in high-risk neuroblastoma patients [7]. Whilst this combination therapy is still administered as part of a clinical trial in the US, the purpose is to gather sufficient safety data for the FDA rather than assess efficacy. All eligible children now receive all three drugs, as it was deemed unethical to continue randomisation. It's accepted that it will become standard treatment in due course, but despite this it has yet to be adopted by either GPOH or SIOPEN (and therefore UK). GPOH are planning to implement their own study using the American design with ch14.18, IL2 and GM-CSF. SIOPEN meanwhile, opened a study randomising patients to either ch14.18 and IL2, or ch14.18 on its own.

There has been much consternation about the failure of the UK to adopt all elements of the US trial design, and instead participate in a new study that may, or may not, be as effective. It has been questioned whether the SIOPEN trial is even ethical, especially considering an earlier GPOH study concluded that ch14.18 alone did not provide any improvement in survival outcomes.

"Consolidation treatment of stage 4 neuroblastoma with ch14.18 was associated with considerable but manageable side effects. Compared with oral maintenance chemotherapy and no consolidation treatment, ch14.18 had no clear impact on the outcome of patients." [8]

A review of the GPOH study, after publication of the US results, concluded that longer-term follow-up analysis suggested there might be some benefit in prevention of late relapses [9].

To date six families have been funded through charitable donations to take their children to the US for its proven monoclonal antibody therapy, at a cost of around £250,000 per child. In addition, in July 2011 a UK high court judge ruled that it was in the best interests of a child being voluntarily withdrawn from the SIOPEN study after randomisation to ch14.18 alone, to be treated with a combination of both ch14.18 and IL2 [10].

It has been stated that lack of availability of GM-CSF in Europe is the reason why it was not included in the SIOPEN trial design. So the argument goes, was it not better for children in the UK to get access to something rather than nothing? Let us concede that GM-CSF could not initially be obtained. Why not then give all children two of the three elements of the proven treatment? Why instead conduct an experiment in which half are given antibody alone? And has work continued in the background to secure a supply of GM-CSF to improve on the 'something is better than nothing' approach?

The US trial may have been an imperfect piece of research, it has been acknowledged as such. We have no idea whether all the three drugs are actually necessary in order to prevent relapse. US doctors have even stated publically that it would be unethical to try and answer this question now, as by definition they would have to give children a treatment that they know might not be as good. And yet, this is precisely the experiment SIOPEN are currently conducting.

Monoclonal Antibody in Germany

Immunotherapy apart, whilst there is some variation in long-term survival between COG, GPOH, and SIOPEN, efficacy of frontline treatments can be viewed as roughly equivalent across the piece. Sadly, despite the most brutal and intensive treatment regimens of all cancers the majority of children still go on to relapse, and for these patients the prognosis is dire. Until recently the UK did not offer any relapse treatment except palliative chemotherapy and radiotherapy. A path does now exist involving salvage chemotherapy, 2nd autologous stem cell transplant or targeted (MIBG) radiation therapy, and ch14.18 monoclonal antibody therapy in Germany.

Since mid-2010 slow responders who failed to meet the strict entry criteria for the main SIOPEN antibody study, and those children requiring antibodies as part of relapse treatment, have needed to travel over 700 miles to Greifswald in northeastern Germany for treatment. In March 2010, it was agreed, following the intervention of the Rt Hon Peter Bone MP, that a second wider UK study would be established to give all children who might benefit from monoclonal antibody therapy access to such treatment [11].

As of May 2012 this second UK trial has still not opened, and UK families continue to be required to travel to Germany. The Department of Health have been made aware of this on numerous occasions. In April 2011, they advised "the new trial .... is planning to run across England from the autumn." In July 2011 "a second UK trial ... with wider eligibility criteria does not start until November." By January 2012 the Department of Health were "disappointed to learn ... that the trial may not begin until the middle of this year" and in March 2012 the Minister for Care Services concluded "there is very little that my officials and I can do to ensure the trial is established any quicker than the now estimated time of April."

Two years after the first child travelled to Germany for a treatment that wasn't available in the UK, it is still not available in the UK.

To compound matters no provision was, or has since been, put in place to fund the treatment in Germany, except through individual funding requests to the relevant primary care trusts. This has resulted in decisions that are clearly not universally based upon medical need, clinical evidence, and assessment of circumstances. Without charitable donations some children would not have been able to receive this treatment at the time they needed it.

Relapsed & Refractory Neuroblastoma

For refractory children who fail to respond well to conventional therapy, and for those who respond well initially but go on to relapse, there are very few options available in the UK. As mentioned earlier there is a second time round-the-loop protocol for relapse that involves salvage chemotherapy, MIBG radiation therapy, and monoclonal antibodies. However, if this is not appropriate, or does not elicit a positive response, there is nothing else to try. The number of early phase clinical trials in the UK across all solid tumour types is in the low single digits, and there are none specifically targeting neuroblastoma.

GPOH have been aggressively trying to treat and cure relapsed neuroblastoma for many years. In 2011 they published the results of a study into relapsed high-risk neuroblastoma concluding:

"The potential of long-term survival justifies clinical trials on intensive second-line treatment." [12]

Germany has now begun studies that build on this principle. Treatment is based upon a targeted drug therapy known as RIST (Rapamycin, Irinotecan, Sprycel, Temozolomide), MIBG radiation therapy, haploidentical transplantation after reduced intensity conditioning (RIC), and ch14.18 monoclonal antibody therapy. Early results have shown much promise and some parents of UK children with relapsed high-risk neuroblastoma are now actively pursuing this as a preferred treatment option.

America has a large number of Phase I and II clinical trials for relapsed and refractory neuroblastoma. As well as the research programs of individual institutions such as Children's Hospital of Philadelphia, St Jude Children's Research Hospital, Memorial Sloan-Kettering Cancer Center, and Baylor College of Medicine, there are two predominant research consortia. New Approaches to Neuroblastoma Therapy (NANT) and Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) run their own research programmes, each offering a number of clinical trials at hospitals across the US.

For children having already received vast quantities of cytotoxic drugs during frontline treatment, new approaches are required offering better tolerability and lower toxicity. Trials are currently available involving engineered tumour vaccines, oncolytic viruses, humanized monoclonal antibodies, small molecule inhibitors and other targeted agents such as the ALK inhibitor crizotinib. For some relapsed and refractory patients it has been shown that it's possible to manage their neuroblastoma as a chronic condition. For these children there remains the prospect of prolonged survival accompanied by excellent quality of life. As Dr John Maris Chief of Oncology at Children's Hospital of Philadelphia (CHOP) and leader in neuroblastoma research writes:

"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." [13]

The problem with this approach in the UK is that there are simply not enough treatment options to make it an achievable goal. An institution such as CHOP has access to drug company sponsored trials, institutional trials, NANT trials, and national trials, as well as treatments that can be prescribed or offered to individual children on a compassionate basis.

The brutal truth is for parents of children with relapsed and refractory neuroblastoma there comes a point where they are faced with three choices; (1) seek treatment in Germany to attempt to cure their child's disease through intensive salvage therapy, MIBG therapy, haploidentical transplantation, and monoclonal antibodies, (2) enrol on clinical trials in America hoping to achieve stable disease or better, whilst also providing for an excellent quality of life, or (3) remain in the UK for palliative care.

Central Nervous System Disease

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% [14,15], of which a subset have disease that is detected only within the CNS. There is evidence that incidence of CNS neuroblastoma may be increasing, in particular as the sole site of disease recurrence [14].

Historically CNS relapses were almost always fatal, with a median survival of 5.3 months [14,15]. However, Memorial Sloan-Kettering Cancer Center (MSKCC) has developed a treatment plan specifically designed to treat CNS disease with intrathecal radioimmunotherapy using monoclonal antibody 8H9.

Monoclonal antibody 8H9 is a mouse IgG1 antibody that is highly reactive to a range of solid tumour types; brain tumours, childhood sarcomas, and neuroblastomas [16]. At MSKCC the antibody is radiolabelled to deliver therapeutic doses of radiation direct to disseminated tumour cells within the CNS. It forms part of an overall treatment plan that comprises craniospinal irradiation, chemotherapy, intrathecal radioimmunotherapy (8H9), monoclonal antibody 3F8, and 13-cis-retinoic acid consolidation therapy [17].

It should be understood that 8H9 is not a magic bullet; the overall treatment plan lasts for up to two years, depending on the individual patient. However, the results seen so far are extraordinarily promising, as evident from a report published in October 2009.

"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." [17]

CNS relapse treatment at MSKCC costs between $500,000 and $1,000,000. It is currently not available anywhere else in the world. However, one only has to reflect on the statistics to see why UK families have raised the money necessary to get this treatment. Around 80% of children alive and free of CNS disease at a median of 33 months, compared to historic median survival of just 5.3 months.

Conclusion

This document discusses four issues, one of which goes to the very heart of the problem here in the UK; there are simply too few options for high-risk neuroblastoma children who fail to achieve a lasting remission after frontline treatment. We know high-risk neuroblastoma is an incredibly difficult cancer to treat successfully, and no amount of money can secure a successful outcome. At present, however, parents see a system that gives up on their children too soon, whilst there should still be hope. Elsewhere such hope is supported by a system that continues to treat children long after the UK has nothing to offer but palliative care. Sadly for most the eventual outcome will be the same, but for some those extra options translate into extra years of near normal family life, and for the very fortunate few, with the right type of disease at the right time enlisting on the right trial, they can even lead to long-term remissions.

It is accepted that clinical trials are the best method for establishing efficacy of new treatments. Past Phase I, II, and III trials are today's standard treatment protocols. So there is no scientific argument here, it's not about whether enrolling a child with relapsed high-risk neuroblastoma on early clinical trials is a correct or appropriate thing to do. If it were not there would, by definition, be no advances in treatment. The sole reason these trials are not available to more UK children is because of the travel, cost, and enormous upheaval involved ... and that is why we need more of them open for enrolment within our own shores.

References