Patricia L. Robertson

Phase III Study of Craniospinal Radiation Therapy Followed by Adjuvant Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma

PURPOSE To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. METHODS Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. CONCLUSION This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.

Angiogenesis in developing rat brain: an in vivo and in vitro study.

Brain capillary proliferation in postnatal rats was measured in vivo by [3H]thymidine autoradiography. Maximal capillary proliferation occurred between 5 and 9 postnatal days, and was 40 times greater than in the adult. To test the hypothesis that soluble angiogenesis factors play a role in this developmental vascularization of brain, we prepared extracts from the brains of 6-day-old rats at the peak of proliferative activity, and from adults when it was lowest. We assayed them using an in vitro growth system measuring [3H]thymidine incorporation into cultured brain capillary endothelial cells. Extracts prepared from either 6-day or adult rats and containing 150 micrograms/ml protein caused more than a 4-fold stimulation of the endothelial cells, increasing to 8-fold at a concentration of 1500 micrograms/ml. The presence of growth-promoting activity in brain extracts from both adult and immature rats suggests that soluble angiogenesis factors may be present in the brain throughout life, but are unavailable for stimulation of in vivo capillary growth unless released or activated by an appropriate stimulus.

Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy

The 5 year survival for patients with malignant intracranial non-germinoma germ cell tumors (NGGCT) which include endodermalsinus tumors, embryonal carcinomas, choriocarcinomas and immatureteratomas is less than 25% following a small resection and radiotherapy. In an effort to improve the survival of these patients, an approach using an attempt at radical resection wherefeasible, followed by multi-modality ’sandwich‘ therapy (chemotherapy-radiation-chemotherapy) was used to treat 18 newly diagnosed patients between 1986 and 1994 in a multi-institution study. Fourteen patients had histologically proven NGGCT andfour were presumed NGGCT because of markedly elevated concentrations of serum and/or CSF alpha fetoprotein (AFP) and/or beta human chorionic gonadatrophin (b-HCG). The primary tumor was confined to thepineal region in 12 patients, the suprasellar region in five, and acerebral hemisphere in one. None of the patients had central nervoussystem metastases at diagnosis by MRI imaging of the spine and CSF cytology. Radical surgical resection was performedinitially in 11 patients (gross total — 6, subtotal — 5);four had a biopsy and three had no surgery. All patients then received3 or 4 cycles of neoadjuvant chemotherapy with cisplatin (100 mg/m2/cycle) and VP-16 (500 mg/m2/cycle)/cycle). Of the 12 patients with evaluabledisease there were 9 responses to the neoadjuvant chemotherapy (5 CR,4 PR); 2 patients had stable disease and 1 progressed duringchemotherapy. Six patients with no evaluable disease after a grosstotal resection had a continuous complete response. Seventeen patientsreceived radiation therapy (involved field — 11, involved field + craniospinal — 4, involved field+ whole brain — 2). Twelve patients received 4 cycles post-radiation chemotherapy with vinblastine (6.5 mg/m2/cycle), bleomycin (15 U/m2/cycle),VP-16 (300 mg/m2/cycle, carboplatin (450 mg/m2/cycle). A total of four patients have died (3 — progressive/recurrent disease, 1 — metabolic). Four year actuarialevent-free and total survival rates are 67% and 74%. This multi-modality adjuvant therapy approach appears to dramatically improve the outcome of malignant intracranialNGGCT.

Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth

IMPORTANCE Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging. OBJECTIVE To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer. DESIGN, SETTING, AND PARTICIPANTS Single-site, observational, consecutive case series (May 2012-October 2014) involving 102 children and young adults (mean age, 10.6 years; median age, 11.5 years, range, 0-22 years) with relapsed, refractory, or rare cancer. EXPOSURES Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians. MAIN OUTCOMES AND MEASURES Proportion of patients with potentially actionable findings, results of clinical actions based on integrative clinical sequencing, and estimated proportion of patients or their families at risk of future cancer. RESULTS Of the 104 screened patients, 102 enrolled with 91 (89%) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Forty-two patients (46%) had actionable findings that changed their cancer management: 15 of 28 (54%) with hematological malignancies and 27 of 63 (43%) with solid tumors. Individualized actions were taken in 23 of the 91 (25%) based on actionable integrative clinical sequencing findings, including change in treatment for 14 patients (15%) and genetic counseling for future risk for 9 patients (10%). Nine of 91 (10%) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening. CONCLUSIONS AND RELEVANCE In this single-center case series involving young patients with relapsed or refractory cancer, incorporation of integrative clinical sequencing data into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling for a small proportion of patients. The lack of a control group limited assessing whether better clinical outcomes resulted from this approach than outcomes that would have occurred with standard care.

Diffusion MRI: A new strategy for assessment of cancer therapeutic efficacy

The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular or physiologic level. This would provide an early indicator or treatment response/outcome in an individual patient before completion of therapy. Moreover, response of a tumor to therapeutic intervention may be heterogeneous. The use of imaging could assist in delineating therapeutic-induced spatial heterogeneity within a tumor mass by providing information related to specific regions that are resistant or responsive to treatment. Largely untapped potential resides in exploratory methods such as diffusion MRI, which is a nonvolumetric intravoxel measure of tumor response based upon water molecular mobility. Alterations in water mobility reflect changes in tissue structure at the cellular level. While the clinical utility of diffusion MRI for oncologic practice is still under active investigation, this overview on the use of diffusion MRI for the evaluation of brain tumors will serve to introduce how this approach may be applied in the future for the management of patients with solid tumors.

Patterns of failure following treatment for medulloblastoma: is it necessary to treat the entire posterior fossa?

PURPOSE Craniospinal radiation (CSRT) followed by a boost to the entire posterior fossa (PF) is standard postoperative therapy for patients with medulloblastoma. A large proportion of recurrences after treatment are local, with approximately 50-70% of recurrences occurring in the PF. It is unclear, however, whether these failures are occurring in the original tumor bed or outside the tumor bed, but still within the PF. With improved diagnostic imaging, better definition of tumor volumes, and the use of three-dimensional conformal therapy (3D CRT), we may be able to restrict the boost volume to the tumor bed plus a margin without compromising local control. This retrospective study analyzes the patterns of failure within the PF in a series of patients treated with radiation therapy (RT). METHODS From July 1986 through February 1996, 114 patients >18 months and <18 years with medulloblastoma were treated at the University of Michigan and Childrens Hospital of Philadelphia, with RT following surgical resection. Of 114, 27 (24%) were found to have a recurrence and form the basis for this study. RT consisted of CSRT followed by a boost to the entire posterior fossa. Some patients received adjuvant chemotherapy. Patients preoperative magnetic resonance imaging (MRI) and/or computerized tomography (CT) studies were used to compare the original tumor volume with the specific region of local relapse. Failure was defined as MRI or CT evidence of recurrence or positive cerebrospinal fluid cytology. Relapse was scored as local, if it was within the original tumor bed, and regional if it was outside of the tumor bed but still within the PF. RESULTS The median age of the 27 patients who relapsed was 8.6 years. Three patients were <3 years old. Of 27, 21 had disease localized to the PF. Of 26, 22 patients received chemotherapy during their treatment regimen; 1 patient did not have information on systemic treatment. The median dose of RT to the craniospinal axis was 32.5 Gy and to the PF was 55.2 Gy. The median time to recurrence was 19.5 months. Local failure within the tumor bed as any component of first failure occurred in 52% (14 of 27) of all failures, but as the solitary site of first failure in only 2 of 27 failures. Of 14 patients who failed in the tumor bed, 11 also failed in the spine, 8 of 14 also failed within the PF but outside the tumor bed, and 7 of 14 failed in all three locations. Local failure within the PF but outside the tumor bed as any component of first failure occurred in 41% (11 of 27) of all failures, but as the solitary site of first failure in only 1 of 27 failures. Of 11 patients who failed in the PF but outside the tumor bed, 9 also failed in the spine, 8 also failed within the tumor bed, and 7 failed in the all three locations. Of the failures outside the tumor bed but still within the PF, 7 of 11 failed in the leptomeninges, 1 in the brainstem parenchyma, and 3 in the PF parenchyma. Of 7 who failed in the PF leptomeninges, 6 also failed within the spine. Failure within the spine as any component of first failure occurred in 70% (19 of 27) of all failures and as the only site of first failure in 5 of 27 patients. Of 19 patients who failed in the spine, 11 also failed in the tumor bed, 9 also failed within the PF but outside the tumor bed, and 9 failed in the all three locations. CONCLUSIONS Leptomeningeal failure is a common component of failure and occurs in the leptomeninges of the PF, as well as the spine. Isolated tumor bed failure is a rarely observed event and occurred in only 2 of 27 failures described here. Similarly, parenchymal (nonleptomeningeal) failures in the PF but outside of the tumor bed were rare: 4 patients recurred in this manner, only 1 of whom was an isolated event without other sites of recurrence. Our data suggest that, when the entire PF is treated, very few failures develop in isolation in the PF outside the tumor bed. Further studies will be necessary to determine if RT to the tu

Pediatric Midbrain Tumors: A Benign Subgroup of Brainstem Gliomas

The presentation, radiographic findings and course of 17 children with MRI-documented intrinsic midbrain lesions are reviewed. The anatomic centers of all the lesions were tectal, peritectal, or tegmental. Lesions centered at the pineal gland were excluded. Signs of increased intracranial pressure from hydrocephalus requiring shunt placement were present in 14 patients. Histopathological diagnosis was confirmed in three tumors; these were low grade astrocytomas and all received focal irradiation, as did one unbiopsied tumor. The remaining 13 patients with no histopathological diagnosis received no therapy other than shunt placement in 11. All but one of the lesions have remained clinically and radiographically stable, with a 4-year progression-free and total survival of 94 and 100%, respectively. We conclude that mass lesions originating in the upper midbrain are a subset of intrinsic brainstem tumors with a relatively benign course, usually presenting with hydrocephalus after infancy. They may remain stable for considerable periods and may require no further therapy after treatment of hydrocephalus. Surgical biopsy and/or resection can usually be reserved for progressive or atypical lesions which may also require further adjuvant therapy.

Successful treatment of childhood pilocytic astrocytomas metastatic to the leptomeninges with high‐dose Cyclophosphamide

Leptomeningeal dissemination of childhood pilocytic astrocytoma (PA) is a rare event with little information available regarding therapy. We report here four children with disseminated PA whom we treated with high doses of cyclophosphamide with clinical benefit. The patients were aged 2.5 to 8 years. Three patients presented with PA localized in the posterior fossa, initially treated with surgical resection (n = 3) and radiotherapy (n = 1). Leptomeningeal dissemination occurred at 32, 44, and 8 months from diagnosis, respectively. The fourth patient presented with an optic pathway tumor with leptomeningeal dissemination at diagnosis. At commencement of cyclophosphamide therapy, disease was present in the subarachnoid space (intracranial, n = 2; spinal, n = 4), cerebral ventricles (n = 2), and primary site (n = 3). Histology was identical at diagnosis and recurrence in the two biopsied cases and cerebrospinal fluid was negative in all cases. Treatment was with cyclophosphamide 4-5 g/m2/cycle given every 4 weeks for a total of two cycles (n = 1) and four cycles (n = 3). One patient achieved disease stabilization (duration 27 months at the time of publication) and three patients experienced significant reductions in tumor burden. Subsequent intrathecal therapy was administered to two patients. Two patients developed disease progression at 10 and 9 months from cessation of chemotherapy. The one re-treated patient responded to further, lower dose, cyclophosphamide. This is the first report of the use of high dose cyclophosphamide for disseminated PA. The recurrence of disease in two cases with a further response to lower dose cyclophosphamide has implications for the optimal duration of therapy for these low grade, aggressive tumors.

Transforming growth factor beta stimulates phosphoinositol metabolism and translocation of protein kinase C in cultured astrocytes

Transforming growth factor beta (TGF-beta) is a regulatory peptide found in many normal and neoplastic tissues, including brain, with a diverse range of cellular effects. The transmembrane biochemical signals by which TGF-beta exerts these effects and the second messenger systems that may amplify them are unknown. We investigated the effects of TGF-beta upon membrane phosphoinositol metabolism and protein kinase C activity in cultured astrocytes. We found that exposure of astrocyte enriched cultures to TGF-beta resulted in the stimulation of phosphoinositol lipid turnover to inositol phosphates and in the apparent redistribution of protein kinase C from cytosol to membrane.

Outcomes of Multidisciplinary Management in Pediatric Low-grade Gliomas

PURPOSE To evaluate the outcomes in pediatric low-grade gliomas managed in a multidisciplinary setting. METHODS AND MATERIALS We conducted a single-institution retrospective study of 181 children with Grade I-II gliomas. Log-rank and stepwise Cox proportional hazards models were used to analyze freedom from progression (FFP) and overall survival (OS). RESULTS Median follow-up was 6.4 years. Thirty-four (19%) of patients had neurofibromatosis Type 1 (NF1) and because of their favorable prognosis were evaluated separately. In the 147 (81%) of patients without NF1, actuarial 7-year FFP and OS were 67 ± 4% (standard error) and 94 ± 2%, respectively. In this population, tumor location in the optic pathway/hypothalamus was associated with worse FFP (39% vs. 76%, p < 0.0003), but there was no difference in OS. Age ≤5 years was associated with worse FFP (52% vs. 75%, p < 0.02) but improved OS (97% vs. 92%, p < 0.05). In those with tissue diagnosis, gross total resection (GTR) was associated with improved 7-year FFP (81% vs. 56%, p < 0.02) and OS (100% vs. 90%, p < 0.03). In a multivariate model, only location in the optic pathway/hypothalamus predicted worse FFP (p < 0.01). Fifty patients received radiation therapy (RT). For those with less than GTR, adjuvant RT improved FFP (89% vs. 49%, p < 0.003) but not OS. There was no difference in OS between patient groups given RT as adjuvant vs. salvage therapy. In NF1 patients, 94% of tumors were located in the optic pathway/hypothalamus. With a conservative treatment strategy in this population, actuarial 7-year FFP and OS were 73 ± 9% and 100%, respectively. CONCLUSIONS Low-grade gliomas in children ≤5 years old with tumors in the optic pathway/hypothalamus are more likely to progress, but this does not confer worse OS because of the success of salvage therapy. When GTR is not achieved, adjuvant RT improves FFP but not OS. Routine adjuvant RT can be avoided and instead reserved as salvage.