How is it treated & managed?
Therapy after stem cell transplant
Overview
Treatment of children with Neuroblastoma will be at regional paediatric oncology principal treatment centres that may be some distance form the child’s home. Treatment will be based on the risk group the child is in. Types and duration of treatments described in this guidance are presented in the same format. If medical evidence does not say what risk group the child is in, follow the high risk guidance for children undergoing stem cell transplant, the intermediate risk guidance for children undergoing chemotherapy but no stem cell transplant and low risk for children who appear to be having surgery as their only treatment.
Low risk group treatment strategy
The low risk group of children consists of children with surgically removable tumours and most children with stage 4S or MS disease, note that 4S and MS refer to the same stage, it depends which staging system is reported in the medical evidence.
Children with surgically resectable tumours
These children are likely to undergo surgical removal of their tumour. Recovery from surgery will depend on the site of the tumour. Recovery in the typical case will be well within 6 months. In most cases adjuvant therapy (add-on treatment) is not required. Even if the disease recurs and chemotherapy is required to treat recurrence, survival is around 95%. Note that a small number of children with surgically resectable small tumours will be in the high risk group because they have amplified MYC – refer to the high risk section for details.
Babies with 4S or MS disease
Babies in this category tend to experience spontaneous regression; this means the tumour goes away without treatment. Many of these children will have no or minimal symptoms. Occasionally, the site of the tumour can cause difficulties, for example if the liver becomes very large due to tumour infiltration and impedes breathing. Such babies will require chemotherapy treatment. A typical treatment regimen would include 2-4 courses of intravenous chemotherapy given at 3 weekly intervals and each course would take 3-5 days to administer. Survival in babies who require treatment is around 80%. Treatment and recovery from treatment occur within 6 months and recovery with long term survival is the norm.
Intermediate risk group treatment strategy
Children in this group are likely to have stage 3 or 4 disease (by INSS) or stage L2 or M by INRGSS, this means that complete surgical removal is not possible. Treatment plans for these children begin with chemotherapy to reduce the size of the tumour, followed by surgery to remove as much of the tumour as possible. Some children then go on to have adjuvant chemotherapy. A minority have radiotherapy treatment to the tumour bed. It is not clear in this group of children how much chemotherapy is required and children may be entered in to clinical trials designed to answer this question. Children are likely to receive 2 to 6 cycles of chemotherapy over 6 to 18 weeks respectively. Chemotherapy is likely to consist of moderate doses of the following drugs -:
- Carboplatin
- Cyclophosphamide
- Doxorubicin
- Etoposide
- Vincristine
Rarely children may have radiotherapy to the affected organs. This is usually given once a day for 14 days under general anaesthetic.
Children under 1 have a greater than 80% cure rate in this group; older children have a 50 to 70% cure rate.
It is clear that duration of treatment and recovery are variable within the intermediate risk group. Some children will undergo surgery and complete chemotherapy within 4 months; others may complete treatment in 7-8 months and spend longer recovering having had more intensive more prolonged treatment. Total duration of treatment and recovery may be up to a year in this group.
High risk group treatment strategy
This group of children have MYCN amplification and/or metastatic disease. There is often widespread disease, affecting a number of organs. This group are likely to have larger tumours that are difficult or impossible to remove completely with surgery. They will undergo intensive treatment usually in the following order -:
- Intensive chemotherapy
- Surgery
- High dose chemotherapy and stem cell transplant.
- Radiotherapy to the tumour site
- Retinoic Acid and Immunotherapy
Total duration of treatment is variable depending on amount and type of chemotherapy treatment used. Treatment takes a minimum of 12 months, but could take up to 18 months with 6-12 months of recovery time afterwards. More details about the treatments used in this group are provided below:
Children are likely to begin treatment with high dose chemotherapy. The chemotherapy is given every 10 days for 8 cycles over 10 - 12 weeks with assessment of response during and at the end of treatment. A combination of the following drugs is likely to be used -:
- Vincristine
- Cyclophosphamide
- Cisplatin
- Etoposide
- Carboplatin
Significant side effects are likely. All chemotherapy will be given in hospital as intravenous infusions, with most cycles requiring at least one overnight stay. Children may be receiving daily subcutaneous injections of G-CSF, which is likely to be given at home by the parent/carer.
If children do not show sufficient response to this initial induction treatment then they will receive further chemotherapy with the following drugs -:
- Vincristine
- Doxorubicin
- Topotecan
Surgery is likely to follow induction chemotherapy, although it may be delayed for further chemotherapy (see above) if response is slow. Neuroblastoma can occur in various sites, although the abdomen is the most common. The aim of surgery is for complete tumour resection whenever possible. This can mean complex and extensive operations in some cases. Post-operative hospital stay is variable 1-3 weeks.
Children will undergo autologous stem cell transplant, which means the patient’s own cells are used. This is usually undertaken after surgery. Stem cell transplant involves high dose myeloablative chemotherapy to kill off the bone marrow and neuroblastoma cells remaining in the body. The risks and side effects of this treatment are significant.
Peripheral Blood Stem Cell Transplant (PBSCT) or Bone Marrow Transplant
Children usually have external beam radiotherapy after stem cell transplant. Radiotherapy is given daily for 14 days and patients usually require general anaesthetics on a daily basis for this part of the treatment.
Therapy after stem cell transplant
Children are likely to continue oral drug therapy for 6 months following their transplant. This consists of a tablet, 13-cis-retinoic acid (Accutane), taken twice daily for 14 days in 28 day cycles. Treatment with this drug improves survival in this group. It is a Vitamin A derivative that may cause liver enzyme dysfunction, muscle cramps, dry skin or neurological symptoms. It does not inhibit recovery from chemotherapy in terms of hair regrowth or return of energy.
Most patients will also receive immunotherapy at the same time as 13-cis-retinoic acid and this is given as part of the main European High Risk Neuroblastoma clinical trial. There are 2 components to the immunotherapy -:
- Anti-GD2 – this is a neuroblastoma antibody given for 5 days by intra-venous infusion as an in-patient. Five courses are given at 28 day intervals and therefore this treatment finishes one month prior to completing the 13-cis-retinoic acid treatment. This treatment causes significant pain and patients need to be on intra-venous morphine treatment at the same time.
- Interleukin-2 (Aldesleukin) - only 50% of patients receiving the anti-GD2 will also receive IL-2 and this is decided in a random fashion as part of the clinical trial protocol. This treatment involves a daily subcutaneous injection for 14 days every month and this will mean a daily visit to hospital. The treatment can cause significant fever. Five courses of the treatment are given and it will be complete at the same time as the anti-GD2.
