Childhood Solid Tumours: Brain, Neuroblastoma, Wilms, Bone

Most childhood solid tumours are curable when surgery, chemotherapy and radiotherapy are combined in the right order. Survival is around 70 to 80% for childhood brain tumours overall and around 80% even for stage 4 Wilms tumour in well-resourced centres, while limb salvage surgery now makes amputation a last resort for children with bone cancer. High-risk neuroblastoma and DIPG remain the hardest problems.

Dr. Arun Singh Danewa, Senior Consultant – Pediatric-Haemato-Oncology & Bone Marrow Transplant (Unit II), Artemis Hospitals, Gurugram, India, covered the main solid tumours of childhood: brain tumours, neuroblastoma, Wilms tumour, osteosarcoma and Ewing sarcoma, rhabdomyosarcoma and hepatoblastoma. His theme was the same one that transformed leukaemia: understand each tumour's biology, sequence the treatments correctly, and look for a target that a drug can hit. The complete guide to childhood cancer gives the overview, and the leukaemia and targeted therapy article covers the blood cancers and drug costs.

Brain tumours in children

Brain tumours are the most common solid tumours in children, and the second largest group of childhood cancers after leukaemia. The WHO classification recognises many distinct types, but a handful account for most cases:

• Gliomas, both low-grade and high-grade.
• Medulloblastoma, an embryonal tumour that usually arises in the cerebellum.
• Ependymoma.
• Germ cell tumours of the brain.

Taken together, survival is good: around 70 to 80%, in Dr. Danewa's figures, although it depends heavily on the type. The exception is diffuse intrinsic pontine glioma (DIPG), a tumour of the brainstem. Because it grows in the brain's vital centre, it cannot be removed surgically, and fewer than 2% of children survive five years. Dr. Danewa called it almost a death sentence.

Who decides the treatment

The surgeon and the radiation oncologist carry much of the definitive treatment of brain tumours. The paediatric oncologist's role, in Dr. Danewa's description, is to orchestrate: deciding whether chemotherapy is needed with radiotherapy, whether targeted therapy has a place, and when each treatment should come. High-risk medulloblastoma illustrates the stakes. In the group 3 subtype, adding carboplatin during radiotherapy raised five-year event-free survival by about 20 percentage points.

Genetics and targeted pills for gliomas

As in leukaemia, NGS is reshaping brain tumour care. Some tumours can be controlled with surgery or low-dose chemotherapy alone; others need intensive therapy, and genetic profiling helps tell them apart. Medulloblastoma, for instance, is not one disease but several genetic groups, and treatment doses can be reduced or increased according to the group's prognosis.

Profiling also finds targets. Many low-grade gliomas carry a BRAF alteration, and the combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor), taken as pills, can control tumours that recur after chemotherapy or do not respond to it. Dr. Danewa cited a trial published in the New England Journal of Medicine in which response to chemotherapy was around 11%, against roughly 40 to 50% with targeted therapy. That trial, in children with BRAF V600-mutant low-grade glioma, reported response rates of 47% with dabrafenib plus trametinib and 11% with standard chemotherapy. These drugs are expensive today, but Dr. Danewa expects generics to bring the cost down and widen access. Patient assistance programmes already exist for targeted brain tumour drugs.

His centre has built its own series of glioma NGS results, identifying a range of mutations, and uses targeted therapy when a tumour is refractory to primary chemotherapy or surgery, or when it recurs.

A case: a large tumour that almost disappeared

Dr. Danewa described a child with a very large tumour occupying much of the frontal and temporal lobes. Genetic testing found an NTRK gene alteration, and the child was started on targeted therapy against NTRK. About four years later, the tumour has almost disappeared. Treatment has been free of significant side effects; the child comes in every three months for a few blood tests and every six months for an MRI, and is doing well.

Liquid biopsy for DIPG

Because DIPG lies where surgery is not possible, it has usually been diagnosed on its MRI appearance. Liquid biopsy changes that. By analysing circulating tumour DNA in the cerebrospinal fluid, doctors can confirm the diagnosis and identify targets without operating. Dr. Danewa expects liquid biopsy to come up in a big way in brain tumours.

Neuroblastoma treatment and survival

Neuroblastoma arises from the adrenal gland or nerve tissue and is the most common tumour in the abdomen in children. Dr. Danewa calls it a monster tumour because of its extremes.

• Low-risk neuroblastoma may need surgery alone, with no chemotherapy or radiotherapy, and the child does well.
• High-risk neuroblastoma needs every weapon available: surgery, chemotherapy, autologous bone marrow transplant (using the child's own stem cells), radiotherapy and targeted therapy. Even so, survival is around 40 to 50%.

Three newer therapies are now part of the effort to improve those results.

1. MIBG therapy, a radionuclide treatment that delivers radiation directly to neuroblastoma cells.
2. Anti-GD2 therapy with dinutuximab, an antibody against GD2, a molecule on the surface of neuroblastoma cells. Dr. Danewa put its cost at around 70 to 80 lakh rupees and described it as one of the very costly targeted therapies.
3. ALK inhibitors. About 10 to 15% of neuroblastomas carry an ALK alteration, and ALK inhibitors such as crizotinib and lorlatinib are being studied in front-line trials for high-risk neuroblastoma.

Some of these therapies are expensive, but new molecules are coming and Dr. Danewa expects costs to fall. Anti-GD2 CAR T-cell therapy is also in development. Indicative costs for autologous stem cell transplant are published separately.

Wilms tumour: surgery first or chemotherapy first

Wilms tumour arises from the kidney and is the second most common abdominal tumour in children. There are two accepted approaches.

Either approach is acceptable. What matters, Dr. Danewa stressed, is the surgeon's confidence. If the tumour ruptures or spills during the operation, the disease is upstaged directly to stage 3, and stage 3 requires radiotherapy. So if the paediatric surgeon is not confident of removing the tumour intact, chemotherapy should come first to shrink it and make surgery safer. Chemotherapy and surgery are the core of treatment, and a subset of children also need radiotherapy.

Stage 4 does not mean the end of the story in children. Dr. Danewa described a child with metastatic Wilms tumour that had spread widely, who followed the chemotherapy and radiotherapy protocol rigorously and was free of visible tumour two years after treatment. In adults, he noted, stage 4 is often treated as the end. In well-resourced centres, overall survival in children with stage 4 Wilms tumour is around 80%.

Bone cancer: osteosarcoma, Ewing sarcoma and limb salvage

Osteosarcoma and Ewing sarcoma are the two most common malignant bone tumours in children. Both need chemotherapy, on established protocols. They differ in radiotherapy: osteosarcoma is relatively resistant to radiation, so radiotherapy has a limited role, mainly for tumours that cannot be removed surgically, while Ewing sarcoma responds to it.

The biopsy scar that decides the operation

Dr. Danewa's simplest teaching point concerns the biopsy. A longitudinal incision, running along the limb, is correct. A transverse incision forces the surgeon to remove far more muscle and tissue at the definitive operation, because the biopsy tract must be removed with the tumour, and it can compromise limb salvage. The direction of a single scar can change the outcome.

Amputation is the last resort

Where expertise in limb salvage is lacking, children with bone cancer are often given an amputation. Dr. Danewa asked doctors to imagine a child living a whole life without a limb. Limb salvage surgery, which removes the tumour and reconstructs the limb, is now available. It is not especially costly, he pointed out: there is no expensive targeted drug involved, and like other orthopaedic surgery the main additional cost is the implant. A patient from East Africa recently underwent limb salvage at his centre and is doing well. His principle is that amputation should be the last resort, used only when limb salvage is genuinely not possible.

Shorter intervals, better survival in Ewing sarcoma

Ewing sarcoma chemotherapy used to be given every three weeks. A randomised trial then gave the same drugs at a shorter interval. Five-year event-free survival rose from 65% to 73%, with no new drug involved. The trial compared cycles every two weeks with cycles every three weeks. The trade-off is that interval-compressed chemotherapy needs stronger supportive care, because fever and febrile neutropenia, a dangerous fall in infection-fighting white cells with fever, are more frequent.

Rhabdomyosarcoma and hepatoblastoma

Rhabdomyosarcoma, a tumour of muscle, can arise wherever there is muscle: the orbit, the abdominal wall, inside the abdomen or in a limb. Treatment follows protocols that vary with the risk group the tumour belongs to.

Hepatoblastoma, the childhood liver tumour, spans a similar range. Some children are cured with chemotherapy and surgery alone, while others need a liver transplant.

The common thread across childhood solid tumours

Across every solid tumour, Dr. Danewa's message was that evidence-based practice is the need of the hour. NGS is helping to find targets and define prognosis, the order of surgery, chemotherapy and radiotherapy is decided by a team led by the paediatric oncologist, and simple decisions, such as the direction of a biopsy scar or whether to operate before or after chemotherapy, carry consequences for life. Indicative costs for brain tumour surgery and radiotherapy are published separately, the neurosurgery and orthopaedics hubs cover the related surgical specialties, and the questions doctors asked in the session are answered in the Live Discussion.