Chemotherapy and DIPG

The cure rate for children with cancer has improved dramatically over the past few decades, rising from less than 50% in the 1960s to close to 80% today. This is a remarkable story of laboratory research, which has given us a better understanding of how children’s cancers work. It is the story of unprecedented collaboration between hundreds of pediatric cancer centers around the country and the world. It is the story of pediatric oncologists, radiation oncologists, and surgeons working together to improve the lives of children with cancer. And it is the story of strength, heartbreak, resilience, inspiration, and advocacy on the part of children with cancer and their families, who have contributed more than anyone in moving this field of medicine forward.

Yet the successes in curing children with cancer have been unequal. Remarkable strides have been made in treating some types of childhood cancers, but cure rates for others remain stagnant. Such is the case for children with brainstem glioma, for whom success has sadly eluded us. Surgical removal of this tumor is not possible. In fact, these children rarely undergo a biopsy, so tumor samples are not available to help researchers understand this disease. Radiation has proven to be quite effective, but only for a short time. This leaves chemotherapy and biologics. It would seem that for a tumor that cannot be removed surgically and that responds only temporarily to radiation treatment, chemotherapy might be the best approach to this challenging disease. But this has not been the case. Despite decades of research and clinical trials, researchers have yet to find a chemotherapeutic or biologic agent that improves the survival of children with brainstem glioma. But this does not mean we never will. In fact, it could be a new drug or some sort of targeted therapy based on a better understanding of the biology of brainstem gliomas that will lead to future success in treating children with this disease. That day has not yet come, but it will. This reviews what chemotherapy is, why it has not worked for children with brainstem glioma, what has been tried, and what holds promise. Also discussed are biologic therapies (i.e., treatment that more specifically targets some of the mechanisms tumor cells use to grow).

Chemotherapy

What is Chemotherapy?

Chemotherapy is simply any medication that kills cancer cells. Just as “antibiotic” refers to the broad class of drugs used to treat infections, chemotherapy refers to the broad class of drugs used to treat cancer. Chemotherapy can be given intravenously (IV), through an injection into the skin or muscle, orally, or even injected directly into a body cavity (e.g., injection of chemotherapy into the spinal fluid via a spinal tap [lumbar puncture]). Most chemotherapy is given by IV or orally. Chemotherapy works by targeting cells that are actively dividing thereby stopping the cancer cells from reproducing. Many different types of chemotherapy drugs exist, and each one targets one of the many different aspects of tumor cell division.

For many pediatric cancers, it has been shown that by using combination chemotherapy—two, three, or more drugs together—the child’s survival is improved. This is because several drugs together work better to kill cancer cells than any one drug alone. In addition, if a tumor is resistant to one drug, it may be killed by one of the others given.  

A disadvantage of chemotherapy (particularly in treating children with brain tumors) is that it circulates everywhere in the child’s body, and therefore has the potential to kill or damage normally dividing cells. This fact accounts for many of the side effects of chemotherapy, such as low blood counts, risk of infection, bleeding, fatigue, mouth sores, and nausea and vomiting.

Challenges of Using Chemotherapy for Children with Brainstem Glioma

Finding effective chemotherapy for children with brain tumors is more challenging than finding effective chemotherapy for children with other malignancies. A major challenge with brain tumors is the blood-brain barrier. Blood vessels in the brain are unique; they are designed to be very selective about what can penetrate them to get into brain cells. They selectively allow nutrients to reach brain cells, but block many unrecognizable, potentially toxic substances including many types of chemotherapy. From an evolutionary standpoint, this makes perfect sense (i.e., protecting our brains from toxins), but when it comes to getting chemotherapy into brain tumors, it is a problem. Therefore chemotherapy must be designed to penetrate the blood-brain barrier. The list of drugs that can do this is small, leaving us with fewer weapons to use for children with brain tumors. It is thought (but not proven) that the blood vessels in brainstem gliomas are particularly restrictive and allow very few substances to penetrate them.

Another challenge is the tumor itself. For reasons that are unclear (and still not definitely proven), it appears that the tumor cells that make up brainstem gliomas are extremely resistant to chemotherapy. That is, even if the chemotherapy gets into the tumor, it cannot kill the tumor cells.