Diffuse intrinsic pontine glioma

A diffuse intrinsic pontine glioma (DIPG) is a tumour located in the pons (middle) of the brain stem. The brain stem is the bottommost portion of the brain, connecting the cerebrum with the spinal cord. The majority of brain stem tumours occur in the pons and are diffusely infiltrating (they grow amidst the nerves), and therefore cannot be surgically removed. Glioma is a general name for any tumour that arises from the supportive tissue called glia, which help keep the neurons in place and functioning well. The brain stem contains all of the afferent (incoming) neurons within the spinal cord, as well as important structures involved in eye movements and in face and throat muscle control and sensation.^[1][2]

Prognosis

DIPG has a 0% survival rate. The median overall survival of children diagnosed with DIPG is approximately 9 months. The 1- and 2-year survival rates are approximately 30% and less than 10%, respectively. These statistics make DIPG one of the most devastating pediatric cancers.^[3] Although 75–85% of patients show some improvement in their symptoms after radiation therapy, DIPGs almost always begin to grow again (called recurrence, relapse, or progression). Clinical trials have reported that the median time between radiation therapy and progression is 5–8.8 months.^[4] Patients whose tumours begin to grow again may be eligible for Pilot, Phase I, or Phase II clinical trials. These trials use experimental drugs or other experimental therapeutic approaches to try to slow or stop the growth of the tumour. However, clinical trials have not shown any significant benefit from experimental DIPG therapies so far.^[4]

DIPGs that progress usually grow quickly and affect important parts of the brain. The median time from tumour progression to death is usually very short, between 1 and 4.5 months. During this time, doctors focus on palliative care: controlling symptoms and making the patient as comfortable as possible.^[4]

Treatment

The standard treatment for DIPG is 6 weeks of radiation therapy, which often dramatically improves symptoms. However, symptoms usually recur after 6 to 9 months and progress rapidly.^[5]

Neurosurgery

Surgery to attempt tumour removal is usually not possible or advisable for DIPG. By nature, these tumours invade diffusely throughout the brain stem, growing between normal nerve cells. Aggressive surgery would cause severe damage to neural structures vital for arm and leg movement, eye movement, swallowing, breathing, and even consciousness.

Surgery with less than total removal can be performed for many focal brain stem gliomas. Such surgery often results in quality long-term survival, without administering chemotherapy or radiotherapy immediately after surgery, even when a child has residual tumour. Surgery is particularly useful for tumours that grow out (exophytic) from the brain stem.

Focal brain stem tumours that arise at the top back of the midbrain (tectal gliomas) are managed conservatively, without surgical removal. Nevertheless, shunt placement or ventriculostomy for hydrocephalus (see below) is frequently necessary. These tumours have been reported as stable for many years or decades without any intervention other than shunting.

Radiotherapy

Conventional radiotherapy, limited to the involved area of tumour, is the mainstay of treatment for DIPG. A total radiation dosage ranging from 5400 to 6000 cGy, administered in daily fractions of 150 to 200 cGy over 6 weeks, is standard. Hyperfractionated (twice-daily) radiotherapy was used previously to deliver higher radiation dosages, but did not lead to improved survival. Radiosurgery (e.g., gamma knife or cyberknife) has no role in the treatment of DIPG.

Chemotherapy and other drug therapies

The role of chemotherapy in DIPG remains unclear. Studies have shown little improvement in survival, although efforts (see below) through the Children's Oncology Group (COG), Paediatric Brain Tumour Consortium (PBTC), and others are underway to explore further the use of chemotherapy and other drugs. Drugs that increase the effect of radiotherapy (radiosensitizers) have shown no added benefit, but promising new agents are under investigation. Immunotherapy with beta-interferon and other drugs has also had little effect in trials. Intensive or high-dose chemotherapy with autologous bone marrow transplantation or peripheral blood stem cell rescue has not demonstrated any effectiveness in brain stem gliomas. Future clinical trials may involve medicines designed to interfere with cellular pathways (signal transfer inhibitors), or other approaches that alter the tumor or its environment.^[6][7][8]

Research

As is the case with most brain tumors, a major difficulty in treating DIPG is overcoming the blood–brain barrier.^[9][10]

In the brain—unlike in other areas of the body, where substances can pass freely from the blood into the tissue—there is some space between the cells lining the blood vessels. Thus, the movement of substances into the brain is significantly limited. This barrier is formed by the lining cells of the vessels as well as by projections from nearby astrocytes. These two types of cells are knitted together by proteins to form what are called "tight junctions". The entire structure is called the blood–brain barrier (BBB). It prevents chemicals, toxins, bacteria, and other substances from getting into the brain, and thus serves a daily protective function. However, with diseases such as brain tumors, the BBB can also prevent diagnostic and therapeutic agents from reaching their target.

Researchers and clinicians have tried several methods to overcome the blood–brain barrier:

• Intrathecal/intraventricular administration: Chemotherapy is injected directly into the cerebrospinal fluid, either through a lumbar puncture or a surgically implanted catheter.
• Intracerebral implants: A neurosurgeon creates a cavity within a tumor to allow the placement of dime-sized chemotherapy wafers, such as Gliadel wafers. Several of these wafers can be placed at the time of surgery and will release a chemotherapy agent (carmustine) slowly over time. This provides a much higher concentration of chemotherapy in the brain than can be obtained with intravenous administration, and it causes fewer systemic side effects. However, it is an option only for patients with surgically resectable tumours, so it cannot be used to treat DIPG.^[11]
• Osmotic blood–brain barrier disruption (BBBD): The cells of the blood–brain barrier are shrunk by a concentrated sugar solution (mannitol). This opens the barrier and allows 10 to 100 times more chemotherapy to enter the brain. A catheter is placed into a large artery (usually the one in the groin called the femoral artery) and threaded up to the carotid or vertebral artery. The hypertonic mannitol is injected, followed by a chemotherapeutic agent. Patients spend a few days in the hospital for each administration. This has been attempted with DIPG tumours.^[12]
• Convection-enhanced delivery: Chemotherapy is delivered to the tumour by a surgically implanted catheter under a pressure gradient to achieve more distribution than with diffusion alone. Limited experiments have been conducted with brain tumors, including one with a DIPG.^[13]
• Drug carriers: Carriers such as Trojan horses, liposomes, and nanoparticles might theoretically allow a therapeutic drug to enter the brain. Such tactics are mostly in the investigatory stages and are not yet clinically relevant to brain tumour treatment.^[10]

Prominent patients

Lauren Hill, a DIPG patient from Lawrenceburg, Indiana, made national news headlines in the United States for her performance in high school basketball, followed by college basketball at Mount St. Joseph University near Cincinnati. Shortly before she was incapacitated by the tumour, MSJ and Hiram College held a sold-out game for her at Xavier University's Cintas Center (see 2014 Hiram vs. Mount St. Joseph women's basketball game). NBA star LeBron James posted words of encouragement on Instagram, and Pat Summitt and the Indiana Pacers gave $5,000 to Hill's charity, The Cure Starts Now.^[14] Doctors said she could become the "face" of DIPG, much in the same way that Lou Gehrig was the public face of Amyotrophic lateral sclerosis. Hill said she "didn't want to be another local story that disappeared and just became another statistic on a paper", and that she would "do anything she could to be the voice for little kids".^[15] She died on April 10, 2015.^[15][16][17]

See also

• Brainstem glioma
• Glioma

References