Brain tumors in infants (defined as children younger. Resection of infantile brain tumors after neoadjuvant chemotherapy: the St.

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1 J Neurosurg Pediatrics 8: , 8: , 2011 Resection of infantile brain tumors after neoadjuvant chemotherapy: the St. Jude experience Clinical article Mark Van Poppel, M.D., 1 Paul Klimo Jr., M.D., M.P.H., 1 Mariko Dewire, M.D., 2 Robert A. Sanford, M.D., 1 Frederick Boop, M.D., 1 Alberto Broniscer, M.D., 2 Karen Wright, M.D., 2 and Amar J. Gajjar, M.D. 2 1 Division of Pediatric Neurosurgery, University of Tennessee College of Medicine; and 2 Department of Oncology, Division of Neurooncology, St. Jude Children s Research Hospital, Memphis, Tennessee Object. Brain tumors in infants are often large, high grade, and vascular, making complete resection difficult and placing children at risk for neurological complications and excessive blood loss. Neoadjuvant chemotherapy may reduce tumor vascularity and volume, which can facilitate resection. The authors evaluated how an ongoing institutional prospective chemotherapy trial would affect patients who did not have a gross-total resection (GTR) immediately and who therefore required further surgical intervention to achieve definitive tumor resection. Methods. Thirteen infants (4 girls and 9 boys) who were enrolled in an institutional protocol in which they were treated with multiagent chemotherapy (methotrexate, vincristine, cisplatin, and cyclophosphamide with vinblastine for high-risk patients) subsequently underwent second-look surgery. The primary outcome was extent of resection achieved in postchemotherapy surgery. Secondary outcomes included intraoperative blood loss, radiographic response to the chemotherapy, complications during chemotherapy, and survival. Results. Three infants underwent biopsy, 9 underwent subtotal resection, and 1 patient did not undergo surgery prior to chemotherapy. On subsequent second-look surgery, 11 of 13 patients had a GTR, 1 had a near-total resection, and 1 had a subtotal resection. In each case, a marked reduction in tumor vascularity was observed intraoperatively. The average blood loss was 19% of estimated blood volume, and 6 (46%) of 13 patients required a blood transfusion. Radiographically, chemotherapy induced a reduction in tumor volume in 9 (69%) of 13 patients. Emergency surgery was required in 2 patients during chemotherapy, 1 for intratumoral hemorrhage and 1 for worsening peritumoral edema. The average follow-up period for this cohort was 16.5 months, and at last follow-up, 4 patients (31%) had died, 1 patient had progressive metastatic spinal disease, and the rest had either no evidence of disease or stable disease. Conclusions. A GTR of pediatric brain tumors is one of the most important predictors of outcome. The application of the authors neoadjuvant induction chemotherapy protocol in a variety of tumor types resulted in devascularization of all tumors and volume regression in the majority, and subsequently facilitated resection, with acceptable intraoperative blood loss. Intracranial complications may occur during chemotherapy, ranging from incidental and asymptomatic to life threatening, necessitating close monitoring of these children. (DOI: / PEDS11158) Key Words neoadjuvant chemotherapy pediatric brain tumor infant blood loss surgery oncology Abbreviations used in this paper: ATRT = atypical teratoid/ rhabdoid tumor; CPC = choroid plexus carcinoma; EBL = estimated blood loss; GBM = glioblastoma multiforme; GTR = gross-total resection; HGG = high-grade glioma; NTR = near-total resection; PNET = primitive neuroectodermal tumor; STR = subtotal resection. J Neurosurg: Pediatrics / Volume 8 / September 2011 Brain tumors in infants (defined as children younger than 36 months of age) are rare, and they constitute a challenge from many perspectives. Tumors are often malignant, and radiation, a major component in the management of brain tumors in older children, is delayed or avoided if possible because of the well-known adverse late complications of this therapy, including growth impairment, endocrinopathies, neurocognitive decline, and secondary radiation-induced malignancies. 15 The therapeutic limitations of chemotherapy and irradiation render resection of infantile brain tumors highly essential when feasible. Maximal cytoreductive surgery is the goal with many infantile brain tumors because it has been shown to have a high correlation with improved outcomes. 6,12,15 However, this may not be possible if the tumor is large or hypervascular, because resection of such a tumor can result in the loss of an unacceptably high proportion of the total blood volume. In these patients, a combination of treatment regimens may provide the best opportunity for a successful outcome. 251

2 M. Van Poppel et al. In 2007, a prospective study was initiated at St. Jude Children s Research Hospital to evaluate the effectiveness of a chemotherapeutic regimen for children younger than 3 years of age in whom a brain tumor was diagnosed. The impetus for this protocol was to see whether this risk-stratified regimen would provide the same or better outcomes as prior chemotherapy regimens, but with less toxicity. The patients in the current report represent a subset of children enrolled in this trial in whom neoadjuvant chemotherapy was followed by surgery to resect the tumor. The chemotherapy is expected to reduce the tumor size sufficiently to allow definitive resection in these patients. We reviewed the surgical outcomes of infants with malignant brain tumors who had either no surgical intervention, a biopsy, or an STR followed by induction chemotherapy and then second-look surgery for definitive resection. Methods Study Design and Outcomes The St. Jude Hospital infant protocol, SJYC07, is a multiinstitutional, institutional review board approved study for children younger than 36 months of age with a CNS tumor. The protocol includes a risk-stratified approach. All patients receive similar induction chemotherapy that comprises high-dose methotrexate (5 g/m 2 ), cisplatin (75 mg/m 2 ), vincristine (1 mg/m 2 ), and cyclophosphamide (1.5 g/m 2 ), with vinblastine (1 mg/m 2 ) added for patients with high-risk disease (that is, those with metastatic disease at diagnosis). The patients reported in this series represent only those who either had no surgery or who did not have a GTR with their initial surgery, and who were thought to be candidates for additional surgery after their induction chemotherapy. Most of the initial surgeries were performed at other institutions. Secondlook or postchemotherapy surgery was performed after it was determined that the patient s response to the induction chemotherapy was maximized, usually during a weekly multidisciplinary brain tumor meeting. The indication to proceed with postchemotherapy surgery was either a regrowth of tumor after initial regression, no further reduction in tumor volume with repeated cycles of chemotherapy, or new emergency or urgent radiographic changes (for example, intratumoral hemorrhage). Typical descriptive statistics, such as patient age, sex, weight at the time of each surgery, estimated blood volume, use of initial surgery (biopsy or STR), and tumor type were collected. Perioperative data included the number of rounds of induction chemotherapy given, chemotherapyrelated systemic complications, and drugs administered. The primary outcome was the extent of resection performed after chemotherapy, categorized as GTR (no radiographically evident residual lesion on postoperative MR imaging); NTR (defined as < 1.5 cm 3 of residual tumor); or STR (defined as > 1.5 cm 3 of residual tumor). Secondary outcomes were intraoperative blood loss (both as an absolute volume and as a percentage of the child s estimated blood volume), the need for a blood transfusion at any time during the child s immediate postoperative hospital stay, radiographic response to chemotherapy, neurological complications during neoadjuvant chemotherapy, and survival. Results Patient Characteristics Between December 2007 and February 2011, almost 90 patients have been enrolled in the SJYC07 protocol. Of these, 13 patients underwent a postchemotherapy, secondlook surgery, and they make up the cohort in this report (Table 1). There were 9 boys and 4 girls, with an average age of 22.5 months (range 1 34 months). No child had metastatic craniospinal disease at the time of enrollment into the study. All patients except 1 underwent an initial surgery at an outside facility before enrollment in the protocol. Prechemotherapy surgery consisted of an STR in 9 patients and a biopsy in 3. One patient, a 1-month-old boy who had a large hemispheric tumor with imaging characteristics consistent with a high-grade neoplasm that was subsequently diagnosed as an HGG (GBM), received chemotherapy as the initial treatment (see Case 5 below) prior to any surgical intervention. The patients had various tumor types: ependymoma (5 patients); supratentorial PNET (3); ATRT (2); HGG (2); and CPC (1). All patients underwent at least 1 cycle of induction chemotherapy, as follows: 3 patients received 1 cycle; 3 underwent 2 cycles; 3 received 3 cycles; and 4 underwent 4 cycles of chemotherapy. Primary and Secondary Outcomes The average time between the initial prechemotherapy and postchemotherapy surgery was 14.9 weeks, with a range of 7 22 weeks. Eight surgeries were supratentorial, whereas 5 were infratentorial. A GTR was achieved in 11 (85%) of 13 patients, NTR in 1 patient, and STR in 1 patient (7.5% each). One of the patients who had a GTR achieved this with a planned, 2-stage operation. In all cases, even in the patient who required emergency resection because of intratumoral hemorrhage, the senior surgeons (F.B. and R.S.) noted a marked reduction in tumor vascularity and enhanced resectability. One patient required a repeat operation 3 days after a gross-total removal of a CPC for evacuation of a hematoma in his resection cavity (see Case 9 below). The average blood loss during the postchemotherapy surgery was 140 ml (range ml), and as a percentage of the patient s estimated preoperative blood volume, it averaged 19.4% (5.4% 79.4%). One outlier the same 1-month-old infant with a hemispheric HGG mentioned earlier lost 79.4% (250 ml) of his blood volume. Excluding this patient, the range of blood loss was 5.4% 28.2%, with an average of 13.3%. Six (46%) of 13 patients required a transfusion, either intra- or postoperatively, without any complications. Radiographically, 9 (69%) of 13 patients exhibited a decrease in the tumor size during induction chemotherapy. Of the 4 patients who did not exhibit a radiographic response to the chemotherapy, 3 had ependymomas, and the fourth was the infant with a hemispheric GBM. This 1-month-old infant was 2 weeks into his induction chemotherapy when he developed an intratumoral hemorrhage that required urgent surgery. Three patients (23%) developed radiographically evident changes that required surgical intervention sooner than anticipated, 2 of them on an emergency basis: intratumoral hemorrhage, malignant 252 J Neurosurg: Pediatrics / Volume 8 / September 2011

3 Brain tumor resection in infants after neoadjuvant chemotherapy TABLE 1: Summary of treatment and outcome in 13 infants who underwent second-look surgery after induction chemotherapy* Case No. Age at Dx (mos), Sex Dx Initial Op No. of Courses of Induction Chemo Time From Prechemo to Postchemo Op (days) Postchemo Op EBL (ml) EBL as % of Total Blood Vol Current Status, FU (mos) 1 34, M anaplastic ependymoma biopsy 1 49 GTR alive, NED, , F ATRT biopsy GTR dead, , F ependymoma STR GTR alive, SD, , F HGG biopsy 1 55 NTR alive, SD, , M HGG NA 1 NA GTR alive, NED, , F spnet STR 2 87 GTR dead, , M ependymoma STR 4 54 GTR alive, SD, , M ependymoma STR STR alive, PMD, , M CPC STR 2 75 GTR alive, NED, , M ATRT STR GTR dead, , M spnet STR GTR alive, NED, , M ependymoma STR GTR alive, NED, , M spnet STR 2 94 GTR dead, 20.6 * Chemo = chemotherapy; FU = follow-up; NA = not applicable; NED = no evidence of disease; PMD = progressive metastatic disease; SD = stable disease; spnet = supratentorial PNET. peritumoral edema, and the development of an interhemispheric cyst with mass effect. Three other patients had 4 notable radiographically confirmed changes during chemotherapy that were managed nonoperatively. These consisted of spontaneous thrombosis of the transverse sinus in 2 patients, a small hemorrhage within a chronic subdural collection, and marked cystic degeneration of a CPC. The average follow-up duration for the cohort was 16.5 months, calculated from the date at which pathological diagnosis was made until the last follow-up date or death (Table 1). Four patients (31%) have died of their disease. One patient recently underwent surgery for progressive metastatic spinal disease 14.5 months after his posterior fossa ependymoma was diagnosed. The other 8 patients have either no evidence of disease (5 patients) or stable local disease (3). Illustrative Cases Case 5 In this boy a large hemispheric tumor was diagnosed at 1 month of age as a result of a workup for macrocephaly. His imaging raised concerns about a malignant neoplasm, and he was enrolled in the SJYC07 protocol without prior biopsy or attempted resection (Fig. 1A). Two weeks into induction chemotherapy his neurological status declined, and a CT scan demonstrated an intratumoral hemorrhage (Fig. 1B). The child was severely pancytopenic because of his chemotherapy. An emergency frontotemporoparietal craniotomy was performed, with GTR. Pathological analysis of the tissue was consistent with GBM. The patient lost 250 ml of blood, which was 79% of his estimated total blood volume, and he required an intraoperative blood and platelet transfusion. The child recovered well from surgery and has finished all planned therapy. His scans show no evidence of disease recurrence (Fig. 1C). J Neurosurg: Pediatrics / Volume 8 / September 2011 Case 9 This 26-month-old boy presented with emesis and ataxic gait. Imaging revealed a large complex mass centered in the atrium of the right lateral ventricle (Fig. 2A). He underwent a limited STR at an outside institution and a CPC was diagnosed. This surgery had to be terminated because the child lost the equivalent of 2 blood volumes with a minimal resection. He was then referred to St. Jude Hospital for further evaluation and treatment. After 2 courses of induction chemotherapy, there was a significant reduction in the solid component of the tumor with marked cystic degeneration (Fig. 2B). Seventy-five days after the start of chemotherapy, repeat imaging showed some increase in both the solid and cystic components. The patient then underwent a craniotomy, and a GTR was achieved. He lost 300 ml, or 28%, of his estimated blood volume and received a blood transfusion intraoperatively. He required a repeat craniotomy on postoperative Day 3 for evacuation of a hematoma in the resection cavity. The patient is currently on maintenance chemotherapy and is doing well 13.1 months postoperatively without evidence of recurrent tumor (Fig. 2C). Discussion Our study evaluated the effectiveness of neoadjuvant chemotherapy in 13 infants with brain tumors of various types, with a focus on its effect on surgical intervention, specifically the ability to perform a safe and successful GTR, the amount of intraoperative blood loss, and the need for perioperative blood transfusion. Infants with brain tumors not only have a significantly worse survival overall than older children with similar tumors, but they are at risk for developing treatment-induced complications, the most worrisome being neurotoxicity and its long-term effects. 6,7 From a surgical standpoint, the ability to achieve a GTR is 253

4 M. Van Poppel et al. Fig. 1. Case 5. This 1-month-old boy received a diagnosis of a large, heterogeneous mass occupying almost his entire left hemisphere, as seen on the axial T2-weighted image (A). Soon after starting chemotherapy, he had a sudden clinical decline, and a CT scan revealed that a portion of the tumor had hemorrhaged (B), necessitating emergency surgery. After a GTR, the patient is disease free, as shown on the T1-weighted image with contrast enhancement (C), and remains on maintenance chemotherapy. limited by the tumor size, its location, and its vascularity. Infants often harbor large, vascular tumors, and their relatively small blood volume limits how much blood loss can be tolerated with attempted resection. Our experience with the use of chemotherapy consisting of methotrexate, cisplatin, vincristine, and cyclophosphamide with vinblastine for high-risk disease prior to attempted definitive resection in this series of infants has been favorable thus far. A GTR was achieved in 11 (85%) of our 13 patients. One patient had an NTR, and another patient, a 28-month-old boy with a posterior fossa ependymoma, had an STR. A GTR continues to be the goal because, as in older children, aggressive resection portends better infant survival in all the major tumor types: medulloblastomas, ependymomas, choroid plexus tumors, supratentorial PNETs, ATRTs, and HGGs. 15 The degree of tumor vascularity is often difficult to assess, but it can be predicted to some degree based on tumor type (for example, CPC) or the presence of intratumoral flow voids on the preoperative MR imaging studies. We used intraoperative blood loss, and more specifically, the amount of blood loss calculated as a percentage of the child s circulating blood volume, as a variable representative of tumor vascularity, assuming that most but certainly not all of the blood loss occurs during the resection of the tumor. The average EBL was 19%, with 1 patient having a blood loss of 79%, as previously discussed. This average blood loss compares favorably with a previous report on CPC resection after chemotherapy, in which the average EBL was 15%. 5 Nearly half of the patients in our cohort (6 of 13) required blood transfusion either intra- or postoperatively, but there were no adverse events related to the transfusions. Additionally, we evaluated whether there was a response to the chemotherapy, which was defined as a reduction in the solid component of a tumor as seen on MR imaging. Nine patients (69%) demonstrated a decrease in tumor volume during chemotherapy. Of the 4 nonresponders, 3 were patients with ependymomas and 1 was the child who suffered an intratumoral hemorrhage 2 weeks after chemotherapy was initiated. We observed that the patients with ependymomas had either no response or a mild response to chemotherapy, compared with the more robust results we saw with the malignant, more proliferative tumor types such as PNET or CPC. Nonetheless, all ependymomas were significantly devascularized intraoperatively. In summary, although our chemotherapy protocol resulted in varying degrees of tumor shrinkage due to what we believe is a direct oncolytic effect, it appeared to devascularize all of the tumors temporarily, which greatly facilitated our ability to resect them. The developing nervous system in infants is at risk Fig. 2. Case 9. This 24-month-old boy underwent an STR of a CPC prior to induction chemotherapy. A: Axial T2-weighted MR imaging study obtained before the patient underwent chemotherapy, showing postoperative changes in addition to the large heterogeneous mass occupying the region of the right atrium of the lateral ventricle. B: After chemotherapy, there was a substantial decrease in the tumor, with cystic changes. C: A T1-weighted, contrast-enhanced image showing no evidence of recurrent disease after surgery. 254 J Neurosurg: Pediatrics / Volume 8 / September 2011

5 Brain tumor resection in infants after neoadjuvant chemotherapy for permanent injury as a result of treatment-induced toxicities, with craniospinal radiation in particular being strongly associated with deleterious late effects. 5,9,17,24 This has led to the development of innovative chemotherapeutic regimens in the hopes of delaying, minimizing, or eliminating radiation therapy. 19 Alkylating and irreversible DNA cross-linking drugs, such as cyclophosphamide and cisplatin, have been the mainstay chemotherapeutic agents for these patients since the mid-1980s, but are associated with side effects such as oto- and nephrotoxicity. 7 A recent report found that a carboplatin-based regimen had a similar response and outcome profile compared with the cisplatin regimen, but with a more favorable toxicity profile, the primary toxicity being myelosuppression. 10 Rutkowski et al. 19 demonstrated that infants with desmoplastic medulloblastomas and no metastatic disease can be successfully treated with surgery and chemotherapy alone. Their chemotherapy regimen consisted of intravenous high-dose methotrexate and intrathecal methotrexate, but the latter can cause radiographic leukoencephalopathy and a decrease in IQ score. Surgery is an important part of the treatment armamentarium for infants with brain tumors, but it has its challenges, primarily because of the small circulating blood volume. As chemotherapy became the primary therapy for infants in the late 1980s, this led some to use it in a limited fashion preoperatively to facilitate surgical extirpation. In 1989, Sanford et al. 20 published their series of 6 children (3 of them infants) with various high- and low-grade tumor types who underwent preoperative chemotherapy followed by complete tumor resection as determined by postoperative CT scans. The observations made by the authors of this paper 20 years ago mirror our experience today: when the tumor responds to chemotherapy, a gliotic interface develops between tumor and normal cerebral tissue that facilitates surgical dissection. The subarachnoid space is preserved and the vascularity of the tumor is significantly reduced. Radiotherapy facilitates surgery by reducing the vascularity of brain tumors but the tissue reaction obliterates the subarachnoid spaces and obscures the margin between normal brain and tumor. 20 Shortly after that publication, the group at The Hospital for Sick Children in Toronto reported their experience with treating CPCs. 22 A report from the same group only a few years earlier had concluded that because of size, vascularity, and invasiveness, the outcome with this tumor was dismal. 13 In their subsequent report, however, 4 of 11 patients had been treated in a neoadjuvant chemotherapy program involving VP16, ifosfamide, and carboplatinum. Under this treatment protocol, there was a reduced tumor volume and vascularity, which allowed a safer and more complete resection. The authors concluded that it would seem that consistent gross total removal may be an initial step toward better overall management and prognosis in this tumor type. Since these early reports, multiple other small series and case reports have demonstrated a benefit to neoadjuvant chemotherapy in a variety of tumors such as PNETs, pleomorphic xanthoastrocytoma, low-grade gliomas and HGGs, medulloblastoma, and, of course, CPCs. 1 4,7,11,12,14,18,20,21,23 Despite these reports, preoperative chemotherapy is not generally J Neurosurg: Pediatrics / Volume 8 / September 2011 considered a common approach to pediatric brain tumors, with the possible exception of choroid plexus tumors. A recent report, again by the Toronto group, demonstrated that second-look surgery after neoadjuvant chemotherapy (ifosfamide, carboplatin, etoposide [ICE]) resulted in complete resection in 9 of 10 patients with CPC. 14 However, despite the avoidance of radiation in their patients, the majority of survivors still suffered neurocognitive impairment. Our experience treating patients with ependymoma, on the other hand, has been particularly favorable. Posterior fossa ependymomas are notoriously difficult to excise completely, and patients are at high risk of neurological injury because of the tumor s proximity and adherence to the brainstem or cranial nerves. Surgery is the most important prognostic factor for survival. 16 Neoadjuvant chemotherapy resulted in devascularization of these tumors and significantly improved our ability to resect them, despite having mild to no actual tumor shrinkage. This finding could significantly change the way neurosurgeons and oncologists view the utility of chemotherapy in the management of ependymomas. To our knowledge, only one other group has previously reported on the use of preoperative chemotherapy in patients with ependymoma. Foreman et al. 8 reported on 4 patients who received various chemotherapy regimens between the initial surgery and the subsequent secondlook surgery. Three patients had complete resection, and all of these patients were alive at the time of publication. The authors stated that use of chemotherapy may prevent tumor progression during the interval between the first and second surgery, allows the patient to recover from the initial surgery, and may result in the tumor being more circumscribed and amenable to resection. We observed a number of unfavorable radiographic changes during chemotherapy. Some of these complications are attributable to the chemotherapy, whereas others may be more related to the disease itself. Three patients required tumor resection sooner than expected as a result of radiographic complications, 2 of them on an emergency basis. The intratumoral hemorrhage in our opinion was due to the combination of a large malignant tumor with areas of necrosis precipitated by chemotherapy-induced thrombocytopenia, as detailed in Case 5. The patient with the worsening peritumoral edema was a 34-month-old boy with a large supratentorial anaplastic ependymoma. He completed 1 round of induction chemotherapy, and shortly thereafter had a precipitous neurological decline, with a CT scan demonstrating malignant peritumoral edema. The exacerbation of the edema could certainly be due to the oncolytic effects of the chemotherapy. The patient with the interhemispheric cyst was a 2-month-old girl with a hemispheric HGG who developed a loculated interhemispheric CSF collection, away from the site of her tumor. We did have 2 patients who developed spontaneous asymptomatic transverse sinus thrombosis during chemotherapy, in one of whom a prothrombotic disorder was subsequently diagnosed. The marked cystic degeneration of the CPC in the 26-monthold patient (Case 9) is also attributed to the chemotherapy. There were no nonneurological, systemic complications due to chemotherapy in our patient population. 255

6 M. Van Poppel et al. The major limitation of this study is the small number of patients. Still, it represents the largest collection of children treated with neoadjuvant chemotherapy who then went on to undergo second-look surgery. We focused on the impact that neoadjuvant chemotherapy had on surgery, but long-term outcomes, including survival as well as neurocognitive and functional outcomes, are needed. We hope that the results of this study will generate interest in the use of neoadjuvant chemotherapy at other pediatric cancer centers and ultimately lead to collaborative studies, which is the most productive way of evaluating treatments in a population with such a rare condition. Conclusions Neoadjuvant chemotherapy effectively devascularized all tumors and reduced the volume of most tumors in our population of infants with brain malignancies. This had the effect of greatly enhancing our ability to achieve a complete surgical extirpation. Our protocol seems to be effective in a variety of tumor types, but patients must be closely monitored with serial imaging because the impact of chemotherapy on tumor size reduction can be temporary. Several of our patients experienced deleterious intracranial changes during chemotherapy, some of which were thought to be directly due to the chemotherapy. Although the use of neoadjuvant chemotherapy has been sporadically published over the past 20 years, we hope that our experience will rejuvenate it as a viable treatment option for infants, and possibly for older children, with brain tumors. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Sanford, Boop, Broniscer, Wright, Gajjar. Acquisition of data: Klimo, Van Poppel, Dewire. Analysis and interpretation of data: Klimo, Van Poppel, Dewire. Drafting the article: Klimo, Van Poppel. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Klimo. Study supervision: Sanford, Boop, Broniscer, Wright, Gajjar. Formulated related trial: Broniscer, Wright, Gajjar. Acknowledgment The authors thank Kristin Kraus for her assistance in preparing this manuscript. References 1. Allen J, Wisoff J, Helson L, Pearce J, Arenson E: Choroid plexus carcinoma responses to chemotherapy alone in newly diagnosed young children. J Neurooncol 12:69 74, Cartmill M, Hewitt M, Walker D, Lowe J, Jaspan T, Punt J: The use of chemotherapy to facilitate surgical resection in pleomorphic xanthoastrocytoma: experience in a single case. Childs Nerv Syst 17: , Chow E, Reardon DA, Shah AB, Jenkins JJ, Langston J, Heideman RL, et al: Pediatric choroid plexus neoplasms. Int J Radiat Oncol Biol Phys 44: , Di Rocco C, Iannelli A, La Marca F, Tornesello A, Mastrangelo S, Riccardi R: Preoperative chemotherapy with carboplatin alone in high risk medulloblastoma. Childs Nerv Syst 11: , Duffner PK, Cohen ME: Long-term consequences of CNS treatment for childhood cancer, Part II: Clinical consequences. Pediatr Neurol 7: , Duffner PK, Horowitz ME, Krischer JP, Burger PC, Cohen ME, Sanford RA, et al: The treatment of malignant brain tumors in infants and very young children: an update of the Pediatric Oncology Group experience. Neuro Oncol 1: , Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, et al: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328: , Foreman NK, Love S, Gill SS, Coakham HB: Second-look surgery for incompletely resected fourth ventricle ependymomas: technical case report. 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N Engl J Med 352: , Sanford RA, Horowitz ME, Kun LE, Jenkins JJ III, Simmons JCH, Kovnar EH: Preoperative chemotherapy to facilitate the total resection of pediatric brain tumors. Concepts Pediatr Neurosurg 9: , Souweidane MM, Johnson JH Jr, Lis E: Volumetric reduction of a choroid plexus carcinoma using preoperative chemotherapy. J Neurooncol 43: , St Clair SK, Humphreys RP, Pillay PK, Hoffman HJ, Blaser SI, Becker LE: Current management of choroid plexus carcinoma in children. Pediatr Neurosurg 17: , Valera ET, Serafini LN, Machado HR, Tone LG: Complete surgical resection in children with low-grade astrocytomas after neoadjuvant chemotherapy. Childs Nerv Syst 19:86 90, Walter AW, Mulhern RK, Gajjar A, Heideman RL, Reardon D, Sanford RA, et al: Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children s Research Hospital. J Clin Oncol 17: , 1999 Manuscript submitted April 20, Accepted June 7, Address correspondence to: Paul Klimo Jr., M.D., M.P.H., Semmes-Murphey Neurologic & Spine Clinic, 6325 Humphreys Boulevard, Memphis, Tennessee pklimo@semmesmurphey.com. 256 J Neurosurg: Pediatrics / Volume 8 / September 2011