Use of Steroids in DIPG Patients

Steroids play a major role in the management of patients with diffuse intrinsic pontine glioma (DIPG), particularly at the time of presentation. Corticosteroids have been used to control cerebral edema in various conditions, particularly in the context of aggressive brain tumors. Dexamethasone is generally considered the steroid of choice because of its superior brain penetration and longer half-life (time it takes for a drug to lose half of its pharmacologic activity). The role of steroids in the management of disease at the time of progression and during palliative care remains controversial. The aim of this section is to review the role of steroids during the care of patients with diffused pontine glioma.

Steroids During the Early Management of DIPG

At the time of diagnosis, steroids are usually the first treatment offered to patients with diffuse intrinsic pontine glioma. Although their role has never been properly assessed, most physicians prescribe steroids, and in particular dexamethasone, once the diagnosis of DIPG is established. The doses used may vary individually according to the clinical signs and symptoms of the child, but many physicians use large doses, up to 10 mg/m2/per day in two or three doses. The aim of the treatment is to a) improve neurological symptoms, b) reduce the edema surrounding the tumor that may sometimes impact the flow of the cerebral spinal fluid (CSF) and cause some degree of hydrocephalus, and c) prevent or minimize the edema induced by the initiation of the radiation treatment. Traditionally, physicians would keep the dose of dexamethasone unchanged during the first week of treatment, and would then gradually decrease the dose as neurological symptoms improve with the radiation treatment. Some physicians prefer to keep a high dose of steroids maintained throughout the 6 weeks of radiation therapy.

Steroids, however, are associated with significant side effects that may affect the quality of life of patients with diffused pontine glioma. One of the most significant side effects is hyperphagia—a feeling of extreme excessive hunger. As a result, children with DIPG often experience significant weight gain during the first weeks of treatment. The use of steroids is also associated with personality changes, such as mood swings, anxiety or sometime aggressiveness (see below). Cutaneous complications are not uncommon, particularly in teenagers who can develop severe acne and stretch marks (or striae). All of these side effects will improve within a few weeks of decreased or discontinued use of steroids. They will persist if the steroids are continued throughout treatment.

Steroids Following Radiation

Up to 50 percent of DIPG patients will present with symptoms of so called “somnolence” in the weeks following completion of radiation treatment. The onset of these symptoms is usually observed 2 to 4 weeks after the last session of radiation, but can occur earlier or later.

The somnolence syndrome consists of symptoms ranging from mild drowsiness to marked lethargy with prolonged periods of sleep, irritability, anorexia, low grade fever, nausea and vomiting, cerebellar ataxia, dysarthria, dysphagia, and headaches. For many parents who have not been informed of this complication, the somnolence syndrome is suggestive of the initial manifestations of the disease. The physiopathological mechanisms of this complication are not fully understood, but somnolence is thought to be related to radiation-induced disruption of myelination. The period of somnolence usually lasts 2 weeks, and symptoms usually subside spontaneously. However, some patients can experience symptoms for up to 4 to 6 weeks. When symptoms are significant, the use of steroids can be beneficial. The optimal dose of steroids needed in this context is unknown. However, spectacular improvement of both appetite and sleepiness can be observed with small doses of dexamethasone, in the range of 0.5 to 1 mg per day.

Steroids at the Time of Progression

Because of their beneficial effect at the time of initial diagnosis, steroids are often used at the time of recurrence of symptoms and during palliation of DIPG patients. They often provide a marked improvement of recurrent neurological symptoms and are usually prescribed with the short objective to relieve the symptoms of progression. Their efficacy, however, is generally transient, and progressive symptoms recur within one or two weeks following the prescription of the corticosteroids. At this stage, the dilemma is whether to further increase the dose to alleviate these symptoms or discontinue the steroids because of their potential adverse effects. The choice is not easy for physicians and families and the decision should be made with a clear understanding of the consequences of prolonged use of steroids during palliation.

Although they can provide a transient improvement of neurological symptoms, steroids have side effects that are of particular concern in the context of progressive DIPG. Increased appetite and the resulting hyperphagia can lead to massive weight gain and body transformation, in particular the cushingoid appearance with the classic moon face. These changes can have significant cosmetic and social implications leading to stigma and isolation. They can also affect parents, siblings and relatives at the time of bereavement when they remember the cosmetic consequences of steroid usage. In addition, specific aspects of palliative care and symptom progression of DIPG patients need to be taken into account when steroids are considered. Lower cranial nerve deficits lead to swallowing disturbances and a risk of choking. In this context, steroids can have an unwanted effect, as they increase the appetite and therefore the risk of choking of a permanently hungry patient. As swallowing disorders worsen, the effects of steroids on appetite can become a nuisance and an obsession for the child who is unable to eat or drink. In addition the combination of oro-pharyngeal stasis of secretions and immunosuppression often leads to the development of painful thrush that will require specific management with mouth wash and in some cases antimicrobial medications against Candida.

Other side effects of steroids can have a significant impact on the quality of palliative care. In particular the behavioural side effects can alter the quality of the interaction of the patient with his family.

Overall, the decision to use steroids at the time of progression should be made with a clear understanding of the potential consequences of this choice. This includes the risk of facing a vicious cycle as the progressive deterioration of the disease leads to increasing the dose of steroids and subsequently to increasing the side effects. Management of DIPG patients without steroids is possible, and some neuro-oncology teams prefer to avoid their use at the time of disease progression.

Side Effects of Corticosteroids

Steroids are associated with a number of potentially serious side effects. The onset and severity of these side effects usually correlate with the dose and duration of the treatment. In the context of a short duration of administration (2 to 3 weeks), most side effects will resolve after cessation of corticosteroid use. However, some children may require prolonged steroid treatment because of persistent or recurrent symptoms, or some physicians are reluctant to decrease steroids during radiation. In this context side effects may persist or even worsen over time and significantly affect the child’s quality of life. Using the lowest possible dose of steroids will reduce the risk of these complications.

Cosmetic side effects include cushingoid appearance, truncal obesity, hirsutism (excessive hair), acne, and stretch marks. Other side effects include increased appetite, immunosuppression, hypertension, glucose intolerance, electrolyte disturbance, fluid retention, peripheral edema, gastrointestinal side effects, osteoporosis, avascular necrosis, growth retardation and ocular problems. Among the common side effects of steroids, weight gain, steroid myopathy, Pneumocystis carinii pneumonia (PCP) and behavioral changes are of particular concern in DIPG patients.

Hyperphagia

The introduction of high dose dexamethasone at the time of initiation of radiotherapy is associated with an immediate increase in appetite. As a consequence, children can show a dramatic weight gain within days and attempts at controlling their appetite are often difficult because of the associated mood swings and behavioural changes. The use of calorie-free drinks may help limit the weight gain. When patients can be weaned off the steroids, the weight gain is transient and most children go back to their baseline weight within weeks. However, when steroids are continued, hyperphagia may lead to massive weight gain that will limit even further the mobility of an already neurologically handicapped patient.

Mood Disturbance

The neuropsychiatric effects of steroids are probably the most common and most stressful for parents and caregivers who often report that “their child is not the same.” Steroids can cause anxiety, insomnia and irritability. Sometimes, discrimination of these complications from manifestations of gliomas, cerebral irradiation or changing intracranial pressure can be difficult in clinical practice, and it is not uncommon that clinicians request a CT or MRI scan to rule out complications such as intratumoral hemorrhage. However, steroids given at a very high dose have without any doubt a significant impact on behavior in some children and negatively affect their quality of life. The management of these neuropsychiatric side effects involves discontinuing or reducing the steroids as much and as soon as possible. The use of neuroleptics can be considered on an individual basis when discontinuation of steroids appears impossible.

Myopathy

Steroid myopathy is a complication that may significantly impact the quality of life of DIPG patients. The clinical manifestation of steroid myopathy is a progressive weakness affecting mostly lower limbs that can have an impact on walking abilities. Some children may require a wheelchair as a result of steroid myopathy. Other consequences include the difficulty to go up and down stairs and an inability to run. Back pain is not exceptional and seems to be the result of both myopathy and osteoporosis. Steroid myopathy usually improves when the drug is discontinued or if the dose can be reduced. However, recovery can take several months after steroid discontinuation. Not all patients will develop steroid myopathy and the exact mechanism of this complication is unknown. Some patients will present with severe symptoms of myopathy after 2 or 3 weeks of steroid use, whereas other patients treated for months may have minimal or no symptoms. It seems that regular exercise or physiotherapy programs may help reduce the severity of myopathy.

Gastrointestinal Bleeding and Ulcers

Patients treated with corticosteroids are also usually treated with medications that reduce the risk of gastric ulcer and hemorrhage. Although no significant association between steroid usage and gastrointestinal bleeding or ulcers has been identified in children with brain tumors receiving steroids, it is prudent to use H2 antagonists (like Pepcid) in DIPG patients treated with corticosteroids for a prolonged duration, in particular when patients are treated with unusually high doses of corticosteroids. However, in most patients treated with 1 or 2 mg. per day of dexamethasone, the systematic use of H2 antagonists appears unfounded and twice-daily corticosteroid dosing during meals reduces the risk of stomach irritation and spares the risks of side effects and the expense of H2 antagonists.

Effects of Corticosteroids on the Immune System

Dexamethasone and other corticosteroids can cause immunosuppression by inhibiting immune and inflammatory responses and reducing the pool of lymphocytes. The use of glucocorticoids will therefore increase the risk of opportunistic infections. Pneumocystis carinii (PCP) is a fungal infection responsible for life-threatening lung infections in immunocompromised patients. There is increasing evidence that patients with brain tumors receiving high doses of steroids have an increased risk of PCP and in several DIPG studies, cases of PCP have been reported as a result of the exclusive use of steroids (without any concomitant chemotherapy). It is therefore recommended to consider PCP prophylaxis when steroids are used for prolonged periods of time, in particular when patients cannot be weaned off steroids.

In the context of progressive disease, swallowing disturbances can cause significant oro-pharyngeal stasis of secretions. The immunosuppressive effect of the steroids will increase the risk of oral thrush (fungal infection) that can be extremely painful and difficult to treat.

Alternatives to Corticosteroids

The large number of complications associated with prolonged or repeated use of corticosteroids has led to the search for alternative therapies for the management of peritumoral edema in brain tumors, and in particular in DIPG.

Xerecept® is a synthetic analog of the naturally occurring human peptide corticotropin-releasing factor (CRF). Several animal studies have indicated the ability of CRF to reduce the brain edema caused by brain tumors. Corticotropin-releasing factor appears to reduce peritumoral edema by a direct effect on blood vessels, independent of the release of adrenal steroids. Clinical trials have shown promising activity against peritumoral edema in adult brain tumors. A randomised trial has shown that Xerecept® benefits patients with symptoms of peritumoral edema associated with primary or metastatic cerebral tumors by allowing them to reduce/stop their dexamethasone treatment, thereby reducing the incidence of the steroid-related adverse effects of myopathy, cushingoid symptoms, and skin disorders.

Cyclooxygenase-2 inhibitors (like Celebrex) have been utilized by several physicians for the management of progressive DIPG, either alone or in combination with steroids. There was indeed some suggestion that they might be effective in treating cerebral edema. However, the cardiac complications of this class of drugs have significantly reduced the use of these agents in children.

Since VEGF plays an important role in the pathogenesis of peritumoral edema, the use of inhibitors of VEGF, such as VEGF antibodies (for example bevacizumab/tradename Avastin®) appears to be a logical option in the search for alternatives to corticosteroids. In the context of DIPG a small study described the efficacy of bevacizumab in children with DIPG with suspected radiation necrosis. Four symptomatic children received bevacizumab for a period of 3 weeks to 3 months following completion of radiation at a dose of 10 mg/kg every other week for a total of 3 to 6 infusions. Treatment was well tolerated without evidence of side effects. Three of the 4 children were able to discontinue steroids and had significant clinical improvement in neurologic symptoms. Further studies are planned to better delineate the role of this agent in the management of children with DIPG.

Summary

Steroids and in particular dexamethasone have a major role in the management of DIPG patients. However, due to the lack of prospective studies on the use of steroids in this condition, our knowledge on the optimal dosing and schedule of administration including weaning remains limited and most physicians rely on their own experience when prescribing steroids in this context. There is currently significant diversity in clinical practice and it is hoped that future studies will provide more insight into the optimal use of steroids in DIPG, as well as potential steroid alternatives.