Palliative radiotherapy in pediatrics

Spinal cord compression

Spinal cord compression (SCC) is a frequent complication in pediatric oncology patients. It is estimated that 3% to 25% of patients will develop SCC at some time during their disease course. SCC may be the presenting symptom, reported in 30% to 67% of cases, and may also occur in the terminal phases of disease. Soft tissue sarcomas account for approximately 43% to 65% of SCC cases in children. ^, Neuroblastoma may present with cord or nerve root compression in 7% to 15% of cases and is a common cause of SCC in patients under the age of 5 years. Other less frequently observed histologies include Hodgkin lymphoma, non-Hodgkin lymphoma, and renal tumors. ^{, ,}

Back pain and lower extremity weakness are the most common presenting symptoms. More advanced cases may present with sphincter dysfunction including urinary retention or constipation. Infants may present with more subtle symptoms including irritability, often leading to a delay in diagnosis. ^{, ,} These young patients may also have symptoms less frequently seen in adult patients with SCC including visible flank masses and respiratory compromise.

Steroids are generally initiated urgently for symptomatic control, although may be delayed for patients without a histologic diagnosis. ^, Magnetic resonance imaging (MRI) is the most sensitive diagnostic imaging and is recommended if it can be obtained emergently. For those patients without a tissue diagnosis, laminectomy may be required if there are no other sites of disease amenable to biopsy or resection. ^,

Treatment options for SCC in pediatric patients include decompressive surgery, systemic therapy, and RT. Decisions regarding optimal management are complex and depend on the patient’s stage, prior therapy, histology, degree of symptoms, and prognosis.

Cord compression at initial diagnosis.

For patients with potentially curable disease who present with cord compression at the time of diagnosis, future need for definitive RT and late toxicities of treatment should be considered ( Fig. 17.2 A). For chemosensitive histologies including Ewing sarcoma or rhabdomyosarcoma where radiation may be indicated in the future to therapeutic doses, it is important to avoid exceeding dose tolerances by delivering palliative treatment in the upfront management. In these cases, starting with chemotherapy often provides a therapeutic response and is recommended as first line therapy in newly diagnosed, responsive histologies.

For patients with high grade neurologic deficits and chemosensitive histologies laminectomy may be considered ( Table 17.4 ). ^, However, extensive surgery may result in significant late effects which should be considered for patients presenting with cord compression who have received no other therapy. In surgical series, 31% to 62% of patients experienced postoperative scoliosis, 26% to 34% had kyphosis, and severe deformities requiring spinal fusions were reported in 28%. More recent series demonstrate spine abnormalities in 52.9% of patients treated by neurosurgery compared to 23.5% in patients treated with chemotherapy alone.

TABLE 17.4

Grading of Neurologic Dysfunction

Data from Gilbert RW, Kim JH, Posner JB. Epidural spinal cord compression from metastatic tumor: diagnosis and treatment. Ann Neurol . 1978;3(1):40–51.

Grade 1	Ambulatory patient with or without hypotonia or ataxia of the legs
Grade 2	Nonambulatory patient, but able to raise the legs against the gravity force while laying down
Grade 3	Unable to raise the legs against the gravity force or paraplegia

In contrast, laminectomy in the upfront setting is indicated for resistant histologies such as non-rhabdomyosarcoma, non-Ewing soft tissue sarcoma or bone sarcoma. Klein et al. demonstrated that in patients with non-rhabdomyosarcoma, non-Ewing soft tissue sarcoma, surgically treated patients had a higher average posttreatment functional score compared to those treated medically. In this series, of 22 patients with a pretreatment symptomatic cord compression, 86% improved and 17% had a complete response. Pollono et al. evaluated 70 patients with cord compression, 17 with soft tissue sarcoma. They recommended laminectomy for all patients with paraplegia except in cases of complete paraplegia for greater than 24 to 96 hours, recurrent disease, or poor prognosis. Laminectomy was also recommended in cases with chemoradiotherapy non-responsive tumors. Improvement was noted in 57% of all cases after laminectomy for paraplegia.

If RT is required for refractory cord compression from the primary tumor at the time of diagnosis, it is reasonable to consider treating to a definitive dose when delivery of emergent radiation would compromise the ability to give the curative dose in the future. This is of greatest concern for histologies such as Ewing or rhabdomyosarcoa, where the definitive dose is at the tolerance of the spinal cord. For other histologies such as neuroblastoma where cord tolerance is of less concern at the definitive dose, low-dose palliative radiation prior to definitive local therapy may be considered.

Brain metastases

In pediatric patients, brain metastases from a solid extracranial primary tumor is uncommon, with reported frequencies of 1.5% to 10% from clinical series and 6% to 13% from autopsy reports. In contrast to superior vena cava syndrome (SVCS) and cord compression, brain metastases are typically not the initial presentation of disease and most often occur after extensive systemic metastasis and disease progression. ^{, , ,} Intracranial spread may arise from tumor in adjacent bony structures invading the meninges and brain parenchyma, more common in osteosarcoma or rhabdomyosarcoma, or by hematogenous spread from distant organs. There is a strong association of brain metastases following pulmonary metastases due to hematogenous spread. In a study from MD Anderson, 70% of patients had a lung metastasis at the time brain metastases were diagnosed.

The most common histologies include sarcomas, neuroblastoma, and germ cell tumors. Multiple series have suggested changes in epidemiology of pediatric brain metastases with the advent of modern chemotherapy regimens. Metastases from Wilms tumors were reported in up to 13% of patients dying of metastatic disease on autopsy but was clinically observed in no patients treated with modern systemic therapy. ^{, ,} While brain metastases are historically rare in patients with neuroblastoma, prolonged survival with chemotherapy has resulted in increasing numbers of reports describing CNS relapse. ^,

The most common presenting symptoms include headache, nausea, vomiting, and seizures. MRI is the most sensitive imaging modality for diagnosis of multiple lesions, although computed tomography (CT) may be obtained in the emergent setting. Neuroaxis spread has been reported in 26.7% to 36% of cases and cytologic evaluation with cerebral spinal fluid (CSF) is recommended to exclude or establish leptomeningeal disease (LMD) after imaging is obtained. ^, In general, upfront symptomatic management with steroids and anticonvulsives is indicated.

For patients with solitary brain metastases, controlled systemic disease, and good performance status, surgical management has been shown to be beneficial. Graus et al. reported that six patients with solitary brain metastases who underwent surgical resection followed by RT had a median survival of 7 months. In a report from Memorial Sloan Kettering, nine patients with neuroblastoma were treated with palliative radiation to doses from 1500 to 3000 cGy. The survival times for the four children treated with radiation alone ranged from one to five and a half months while survival for those treated with surgery followed by radiation ranged from 4.2 to 25 months. While craniotomy is typically offered only to select patients with good performance status and solitary lesions, these studies support use of surgical excision for single metastases when feasible.

Following surgical resection, postoperative RT is indicated. The importance was highlighted in a study by Bouffet et al., in which a patient treated with surgery alone had an early recurrence at the same site. Postoperative RT was subsequently recommended in all cases. Similarly, Paulino et al. found better freedom from neurologic progression in patients who received RT as compared to those who did not. In the postoperative setting in this series, patients were treated with whole brain RT to 2000 to 3000 cGy in 10 fractions.

Series reporting use of RT without surgical resection demonstrate a response based on histology. In a series of patients treated with whole brain RT alone to 3000 cGy in 10 fractions, a complete response was detected in four of five patients with germ cell tumors and only one of six patients with sarcoma. None of the patients with a complete response to radiation died of recurrent brain disease. For patients at initial diagnosis or with excellent prognosis, aggressive palliation with doses comparable to those used to control the primary tumor may be considered. Paulino et al. treated newly diagnosed metastatic Ewing and rhabdomyosarcoma with 2800 to 3000 cGy whole brain radiation followed by tumor boosts of 2800 to 5000 cGy. In contrast, Caussa et al. treated patients with a single metastasis from neuroblastoma to a median dose of 1500 cGy with a response rate of 44%. For patients with poor prognosis, doses as low as 900 cGy whole brain radiation may be considered for short-course palliation.

Long-term outcomes after treatment for brain metastases remain poor, with median survival reported from 4 to 9 months and 1 year survival rate from 11.5% to 38%. ^{, ,} Suki et al. reported median survival of 0.9 months in patients who did not receive treatment after a diagnosis of brain metastases compared to 8 months in those who initiated therapy. In cases of intracranial metastases, deaths are related to both progression of intracranial and systemic disease. ^, However, deaths due to neurologic causes have been reported in only 20% to 27% of patients who receive RT. ^,

Patients presenting with LMD from extracranial solid tumors have very poor outcomes, with median survival of 2 months reported in one series. For patients with poor performance status and uncontrolled extracranial disease supportive therapy alone is reasonable, while those with good clinical features may have improved survival with aggressive craniospinal irradiation (CSI). ^, Deutsch et al. reported on four patients with LMD from neuroendocrine carcinoma, squamous cell of the lung, retinoblastoma and rhabdomyosarcoma treated with CSI. Doses to the craniospinal axis ranged from 2200 to 3600 cGy. Patients survived between 4 days and 11 years. Given the limited number of patients and array of histologies associated with LMD, differentiation of outcomes between various therapies is limited. Optimal therapy must take into consideration the patient’s extent of extracranial disease, systemic therapy options, and patient and family preferences for aggressive treatment.