PERIOPERATIVE MANAGEMENT

Use of glucocorticoids to reduce peritumoral edema, cerebrospinal fluid diversion to treat hydrocephalus, anticonvulsants to prevent seizures, and hormonal replacement for patients with tumors in the hypothalamic-pituitary region are essential components of the perioperative management. Since edema commonly exacerbates the neurologic impairment produced by the tumor, glucocorticoids (e.g., dexamethasone 0.1 mg/kg/6 hours) are generally started preoperatively, continued intraoperatively, and then discontinued within 5 to 7 days postoperatively. In patients with pineal region tumors, a third ventriculostomy is a useful alternative to external ventricular drainage or shunt insertion. In patients with hypothalamic tumors, high doses of corticosteroids (e.g., hydrocortisone) are administered in the perioperative period unless dexamethasone is being used.

SURGICAL THERAPY

For the majority of pediatric brain tumors, direct open biopsy coupled with tumor resection is preferred. Although complete tumor removal is often feasible only for well-circumscribed benign tumors, a “near-complete” resection can be achieved with many parenchymal tumors, affording substantial cytoreduction and relieving symptoms of mass effect. Transsphenoidal approach for hypothalamic-pituitary tumors is possible over the age of approximately 8 years. In younger children, this approach is not usually possible due to the small size of the nasal passages and the nonaeration of the sphenoid sinus.

CHEMOTHERAPY

A radiosensitizing effect of certain drugs is often postulated. Among patients with malignant brain tumors, infants and very young children have the worst prognosis and the most severe treatment-related neurotoxic effects. Chemotherapy appears to be an effective primary postoperative treatment for many malignant brain tumors in young children. Disease control for 1 or 2 years in a large minority of patients permits a delay in the delivery of radiation and, on the basis of preliminary results, a reduction in neurotoxicity. For patients who had undergone total surgical resection or who had a complete response to chemotherapy, the results are sufficiently encouraging to suggest that radiation therapy may not be needed in this subgroup of children after at least 1 year of chemotherapy.²² Also, a significant proportion of children with malignant brain tumors can avoid radiotherapy and prolonged maintenance chemotherapy yet still achieve durable remission by administering myeloablative consolidation chemotherapy with autologous bone marrow reconstitution after maximal surgical resection and conventional induction chemotherapy.²³ No long-term side effects on height, bone mineral density, body composition, and bone maturation were found in patients with leukemia treated with chemotherapy alone. It causes growth retardation, but catch-up growth occurs after cessation of treatment.²⁴ Gonadal damage after cyclophosphamide (dose related; may be reversible) and busulfan (the association may cause permanent ovarian failure) is well documented in adults; it seems that prepubertal and pubertal ovaries are more resistant than ovaries of adults. Ovaries are more resistant than testes, and seminiferous tubules are more sensitive.²⁵

RADIOTHERAPY

The indications for radiotherapy of pediatric intracranial tumors and the parameters for radiation delivery have evolved in several ways during the last decade. Tumors have conventionally been treated with 5000 to 6000 cGy in 180 to 200 cGy/day fractions using multiple portals. Newer approaches, such as hyperfractionated irradiation and interstitial irradiation (stereotactic radiosurgery and interstitial brachytherapy) attempt to improve therapeutic efficacy while minimizing irradiation of surrounding brain and correspondingly reduce toxicity. Nevertheless, because more children are surviving brain tumors following surgery and radiation therapy, the price of the successful therapy is being increasingly realized in terms of adverse effects, particularly in the very young child. Chemotherapy is increasingly used to delay or avoid using irradiation in children younger than 3 years of age with high-grade and incompletely resected low-grade tumors. Improvements in imaging and dose-delivery techniques have allowed radiotherapy administration to be tailored to the geometry of the tumor. Hyperfractionated irradiation technique is based on the premise that normal cells are better able than tumor cells to repair sublethal damage between doses and that multiple fractions are more likely to irradiate proliferating cells in a sensitive part of the cell cycle.²⁶ Finally, novel approaches for focal irradiation, such as stereotactic radiosurgery and interstitial brachytherapy, are increasingly being employed in selected unresectable lesions to provide high doses of radiation to the tumor while minimizing irradiation of surrounding brain.^27,28 Radiosurgery is ideally suited to the treatment of small foci of unresectable disease and has led to long-term disease control in well-circumscribed benign lesions. In addition, ongoing studies in older children with selected lesions, such as “standard-risk” medulloblastoma and germinoma, use reduced doses of radiotherapy in conjunction with chemotherapy to minimize radiation-induced neurotoxicity. For many low-grade gliomas that have been extensively resected, adjuvant therapy often is deferred because these tumors may remain quiescent for extended periods.

Sequelae of Treatment

The small increase in incidence noted over the past 2 decades most likely represents advancements in diagnostic technology rather than true changes in disease frequency, though this is controversial. Survivors of childhood intracranial tumors are 13 times more likely to die than healthy age- and sex-matched peers.²⁹ Disease recurrence remains the single most common cause of late deaths. The sequelae of surgical treatment are evident soon after the operation, but the sequelae of irradiation and chemotherapy become apparent over many decades. Neurologic, neurocognitive, and endocrine disturbances are the most prevalent disabilities observed among the long-term survivors of pediatric intracranial tumors. Maximum quality of life for the individual patient can only be achieved by long-term care and close cooperation of specialists in the different medical disciplines involved. It has been demonstrated that cranial irradiation has been implicated as the major cause for cognitive dysfunction. In that study, intellectual functioning was significantly lower in children whose treatment included cranial irradiation than in those treated without cranial irradiation, and this effect was more pronounced in nonverbal than in verbal intellectual abilities.³⁰ Some authors also showed that children younger than 7 years at diagnosis had a mean IQ loss of 27 points, whereas children older than 7 years at diagnosis showed no significant decrease in IQ. They also demonstrated that decline in IQ occurred between baseline and year 2 of follow-up; none could be documented between years 2 and 4. All children younger than 7 years at diagnosis were receiving special education at follow-up; 50% of the children older than 7 years at diagnosis were receiving supplemental educational services.³⁰ In Packer’s study, children demonstrated a wide range of dysfunction, including deficits in fine-motor, visual-motor, and visual-spatial skills and memory difficulties; although not retarded, they had a multitude of neurocognitive deficits that detrimentally affected school performance after 2 years from treatment. The younger the child is at the time of treatment, the greater is the likelihood and severity of damage.³¹ Reimers and colleagues tried to identify subgroups of children who are at increased risk for cognitive deficits; they showed that younger age at diagnosis, tumor site in the cerebral hemisphere, hydrocephalus treated with a shunt, and treatment with radiation therapy were found to be significant predictors of lower cognitive function. Radiation therapy was the most important risk factor for impaired intellectual outcome. The mean observed full-scale IQ was 97 for the nonirradiated patients and 79 for the irradiated patients. Verbal IQ, but not performance and full-scale IQ, had a significant negative correlation to biological effective dose of irradiation to the tumor site.³² Tumor involving the hypothalamic-pituitary area often produces a loss of endocrine function during a characteristic sequence in time, an evolving endocrinopathy. The risk of developing these adverse events is related to the underlying disease and its treatment with cytotoxic drugs and radiation therapy. The incidence and time course of disorders and the number of anterior pituitary hormones that are deficient depend on the sensitivity of the hormone itself to such therapy, on the dose, fractionation, and time elapsed since irradiation. Early detection and appropriate replacement therapy before clinical manifestations occur may carry important benefits in terms of normal pubertal and social development, growth, fertility, and bone mineralization.³³ The GH axis is the most sensitive and the adrenal axis the most resistant to the effects of direct irradiation to the hypothalamic-pituitary region. Patients who have received high doses (>30 Gy) of cranial, craniospinal, or total body irradiation are likely to develop GHD within 2 to 5 years from cessation of treatment.³⁴ Growth may be further impaired by spinal irradiation which directly interferes with spinal growth and is not due to an endocrinopathy.

In the rare syndrome of “growth without GH,” normal or accelerated growth continues despite the patient having GHD, and this occurs at the expense of hyperphagia and rapid weight gain. It is considered that the etiology of this condition is related to insulin and insulin-like peptides, which allow growth in the presence of GH insufficiency. This phenomenon usually occurs after craniopharyngioma surgery. Indeed, the first sign of a recurrence of a treated intracranial tumor while on GH therapy may be growth deceleration.³⁵ GHD newborns can have a length within the normal range, which suggests that other growth factors dominate longitudinal gain during gestation. Obese children grow at a normal rate despite their low serum GH levels and reduced response to pharmacologic stimulation tests. Children with hypopituitarism secondary to craniopharyngioma resection may continue to grow and may even show growth rate acceleration if their weight increases significantly. Several possible mechanisms might underlie the growth stimulation in obese children, such as elevated levels of insulin and reduced levels of insulin-like growth factor binding protein 11. Recently, elevated sex hormone levels and elevated leptin levels in obese children were found to affect epiphyseal growth, and it may be that leptin also participates in the growth without GH observed in obesity, especially after craniopharyngioma removal. In the absence of GH, the sex hormones stimulate growth through a direct GH-independent effect on the epiphyses. Leptin, insulin, and sex hormones locally activate the insulin-like growth factor system in the epiphyseal growth plate.³⁶

There is a correlation between the age at diagnosis (the immature hypothalamus may be more sensitive to irradiation), the dose of radiation given, different regimens, fractionation of irradiation, and pubertal development. Gonadal dysfunction can be induced by a direct injury to the gonads (hypergonadotropic hypogonadism) and less frequently by neuroendocrine injury to the hypothalamic-pituitary axis (hypogonadotropic hypogonadism).³⁷ Low doses of cranial irradiation (18 to 24 Gy) can cause precocious puberty, especially in girls, with a compromised growth spurt leading to a loss in final height, whereas delayed puberty has been reported after high doses (>40 Gy) used to treat solid tumors adjacent to the hypothalamus. Either low-dose cranial irradiation given as prophylaxis in the treatment of acute lymphoblastic leukemia, or high-dose irradiation for tumors distant from the hypothalamic-pituitary axis can cause hypogonadism.³⁸ The irradiation to the gonads from the spinal irradiation could potentially cause oligo/azoospermia with total doses of 6 Gy; the Leydig cell damage is common after total doses greater than 20 Gy.^39,40 Early menopause has been reported as well.⁴¹ The possibility of using gonadotropin-releasing hormone agonists to prevent ovarian damage has been proposed. A number of treatment options for preserving fertility are available for cancer survivors. Sperm banking should be offered even to young adolescent boys. Sperm are present in urine from the early teens onward and can be obtained and banked. Ovary banking will be a technique in the future as some centers develop the procedures. Concern that residual cancer cells are not also banked with the ovarian cells is an issue still to be addressed. Cryopreservation of embryos is part of current practice and is useful in cases when couples desire it.⁴² Further information on the ability of both ovary and uterus to sustain a pregnancy is crucial in deciding which treatment option to pursue. Pregnancy presents a cardiorespiratory stress; peripartum heart failure in women treated as children with anthracycline chemotherapy is a known complication.⁴³ Survivors who have been exposed to anthracycline therapy with or without radiation to the heart and those who received therapy known to induce pulmonary fibrosis or cardiopulmonary radiation therapy may benefit from a cardiac evaluation or pulmonary function test before pregnancy.⁴⁴ Delayed puberty development was reported in boys and girls after a total body irradiation (TBI) containing conditioning regimen, whereas patients given bone marrow transplantation for severe aplastic anemia (without total body irradiation) presented a normal puberty.⁴⁵ Other authors demonstrated that children who have been treated with a dose of 25 Gy for acute lymphoblastic leukemia at an early age (<7 years) had normal pubertal development. Girls who had a late presentation of acute lymphoblastic leukemia and a late treatment had delayed puberty.³⁷ Deficiency of thyroid-stimulating hormone, adrenocorticotropic hormone, and hyperprolactinemia can be seen following high-dose radiotherapy (>40 Gy) of the hypothalamic-pituitary axis, especially among young women.^46,47

Patients in whom the pituitary stalk is injured during surgery often manifest a triphasic response of impaired fluid regulation characterized by an initial period of vasopressin insufficiency lasting 1 to 2 days, a subsequent period of inappropriate antidiuretic hormone release lasting several days, and a final phase of persistent DI. In view of the rapid changes in vasopressin secretion in the perioperative period, careful attention to fluid replacement and cautious administration of synthetic vasopressin, if needed, are essential to avoid electrolyte and fluid imbalance. The presence of DI may be masked by cortisol insufficiency and not revealed until glucocorticoids have been administered. One of the most difficult hypothalamic diseases to treat during childhood is hypoadipsia combined with DI. This usually results in difficult management of DI and repeated episodes of hypernatremia or hyponatremia associated with intercurrent infections, especially with gastroenteritis. The condition is usually managed by training the child to take a fixed fluid intake by mouth every hour, and then titrate the dose of vasopressin that is required. Although it is relatively easy to achieve homoeostasis when the child is well, the predominant problems revolve around intercurrent illnesses, especially if the child has concurrent anterior pituitary failure and has seizures treated with carbamazepine and/or lamotrigine; both interfere with fluid secretion from the renal tubules. It is unusual for children with adipsia and DI to survive childhood.

The incidence of second malignancies ranges from 1% to more than 3%. The majority of second tumors are thyroid cancer, malignant gliomas, meningiomas, and sarcomas that occur within radiotherapy treatment fields 10 to 20 years after irradiation. An increased incidence of hematologic malignancies has been noted after chemotherapy.⁴⁸ Thyroid ultrasound scan should be performed once a year. Cranial radiation has also been associated with carotid occlusive disease, which often manifests as Moyamoya syndrome with progressive ischemic cerebrovascular symptoms. This syndrome is particularly common in patients irradiated for parasellar lesions such as chiasmatic-hypothalamic gliomas.⁴⁹