Adjuvant Therapies for Pineal Region Tumors in Children

Radiation

Germ cell tumors

Teratomas (mature or immature) require surgical extirpation due to their lack of response to adjuvant therapy.   In contrast, germinomas and NGGCTs demonstrate sensitivity to radiation and chemotherapy, which have become the primary forms of treatment for these tumors. In the past, due to this significant radiosensitivity coupled with the high preponderance of germinoma and significant operative morbidity rate of surgical resection, pineal region tumors were typically managed with diagnostic irradiation of 200 cGy (1, 97).  If tumors demonstrated response on follow-up imaging, a diagnosis of germinoma was presumed, and radiation therapy would continue with a total dose up to 5500 cGy, achieving a 5-year survival rate of up to 83% after completion (19, 63, 74). Diagnostic radiation is no longer used for pineal region tumors due to the lower surgical complications associated with modern microneurosurgical techniques, the availability of tumor marker testing, and an awareness of the heterogeneity of pineal region tumors.  In addition, the neurotoxic effect of radiation to the developing CNS, even at doses as low as 2000 cGy, is not insignificant.

• Germinomas: Presently, the dose and field of irradiation for pineal germinomas is controversial.  Conventional recommendations are for 4800–5500 cGy to the tumor (18, 42, 81). Poor long-term control has been reported with doses of 3000–4000 cGy (5). The appropriate field of irradiation for germinomas is also under debate, with doses applied to whole brain, entire craniospinal axis,or limited to the primary tumor site (18, 19, 27, 42, 59, 61, 85). However, most of the current protocols for germinoma recommend a whole ventricle irradiation. Stereotactic irradiation and brachytherapy are being employed in an attempt to minimize radiation-induced side effects and damage to the developing CNS (59). Most authors advocate for craniospinal irradiation only in cases with evidence of CSF dissemination, which occurs at a rate of 10–52% in patients with intracranial germinomas (18, 29, 80).
• NGGCTs: In contrast to germinomas, NGGCTs respond poorly to radiotherapy alone.  The 5-year survival rate after radiation ranges from 10–45.5%with reports rates of CSF dissemination of up to 45% among patients with NGGCTs (36, 61).  There is also literature to suggest a variable response of malignant germ cell tumors to radiotherapy (33, 48).

Pineal parenchymal tumors

Pineocytomas are considered benign lesions, and surgical excision can lead to a cure.  In contrast, pineoblastomas typically affect infants and young children and tend to recur and disseminate without appropriate therapy. 

• Pineoblastomas: Rates of CSF dissemination in pineoblastomas are as high as 50% at initial diagnosis in some studies and are near 100% at the terminal stage of the disease (13, 21, 32, 62).  As such, radiation and chemotherapy are important tools in the management of patients with pineoblastomas, who may be treated with radiation therapy alone, radiation therapy and chemotherapy, or chemotherapy alone.

Astrocytomas

Astrocytomas of the pineal region typically arise in the quadrigeminal plate, splenium of the corpus callosum, or posterior thalamus.  These tumors typically do not have an obvious tumor capsule with many being intrinsic with a significant risk of postoperative morbidity when radical resection is attempted.  Astrocytic tumors of the pineal region are most often low grade and usually demonstrate only indolent progression.  Patients are typically managed first with a CSF diversion procedure in cases of aqueductal obstruction and are monitored over time. 

• Radiotherapy for progression: Disease progression with tumor enlargement is reported in 25% of patients (10, 68).  In cases of progression, open or stereotactic biopsy followed by local irradiation provides long-term survival (68).   Patients may also be managed with stereotactic radiosurgery or open surgical resection when anatomically favorable (47, 65, 83).

Chemotherapy

Germ cell tumors

Because of the lack of a blood-brain barrier in the pineal gland, chemotherapy has been widely adopted for the management of malignant germ cell tumors, achieving decreased tumor size on radiographic imaging and decreased tumor marker expression.  Authors have reported significant response rates and progression-free survival rates in patients receiving neoadjuvant chemotherapy with a variety of agents (3, 4, 12, 49, 79, 98). 

• Germinomas: A prospective international cooperative study of chemotherapy without radiation therapy for newly diagnosed CNS germ cell tumors demonstrated complete response rates of 84% in patients with germinomas (6). 50% of those who did not subsequently receive radiotherapy experienced disease recurrence (6). A similar study by the Japanese Pediatric Brain Tumor Study Group demonstrated complete responses in 83.6% of patients with germinomas (60). 78% of those with syncytiotrophoblastic cells had a similar response rate in the Japanese study (60). Clinical outcome was not influenced by patient age, tumor location, CSF dissemination, extent of tumor resection, histological cell subtype, or tumor marker positivity (6, 60).  
• NGGCTs: 78% of patients with NGGCTs experienced a complete response to chemotherapy in the prospective international cooperative study mentioned above (6).  50% of those who did not subsequently receive radiotherapy experienced disease recurrence(6). In the Japanese study no patients with NGGCTs demonstrated a clinical response to chemotherapy alone (60). Clinical outcome was not influenced by patient age, tumor location, CSF dissemination, extent of tumor resection, histological cell subtype, or tumor marker positivity (6, 60). 
• Use as a neoadjuvant: Extremely vascular NGGCTs can be treated initially with chemotherapy to reduce tumor mass and vascularity.  The use of neoadjuvant chemotherapy can also reduce the dose and field of irradiation needed (36, 61).  A combination of chemotherapy and reduced doses of irradiation with local field showed increased cure rates and reduced radiation-induced side effects (14, 61).
• Second-look surgery: Second-look surgery after neoadjuvant chemotherapy is strongly recommended before further chemotherapy or radiation treatment is used, since these modalities can induce paradoxical acceleration of teratomatous components in a malignant germ cell tumor (28). Because residual tumor is likely to be mature teratoma, these lesions are best managed with resection in a second-look surgery.  Furthermore, histological evaluation after second-look surgery often reveals necrotic tissue without viable tumor cells, negating the need for further medical treatment. 

Pineal parenchymal tumors

• Pineoblastomas: Patients treated with high-dose cyclophosphamide followed by craniospinal radiation and autologous marrow or stem-cell rescue exhibit 3-yearsurvival rates of about 60%.
• Pineocytomas with nests of anaplasia: Pineocytomas with a pineoblastic component are considered malignant and are managed with multimodal therapy.  Some authors advocate the application of radiation to the tumor bedand craniospinal axis, citing the high propensity of leptomeningeal dissemination (28, 64, 78).  Others advocate the addition of adjuvant chemotherapy, citing the relative lack of radioresponsiveness of these tumors (9, 93). 

Astrocytomas of the pineal region

• Anaplastic astrocytomas: These tumors are commonly treated with multimodal treatments that include chemotherapy.