Early recurrence in standard-risk medulloblastoma patients with the common idic(17)(p11.2) rearrangement

Medulloblastoma is diagnosed histologically; treatment depends on staging and age of onset. Whereas clinical factors identify a standard- and a high-risk population, these findings cannot differentiate which standard-risk patients will relapse and die. Outcome is thought to be influenced by tumor subtype and molecular alterations. Poor prognosis has been associated with isochromosome (i)17q in some but not all studies. In most instances, molecular investigations document that i17q is not a true isochromosome but rather an isodicentric chromosome, idic(17)(p11.2), with rearrangement breakpoints mapping within the REPA/REPB region on 17p11.2. This study explores the clinical utility of testing for idic(17)(p11.2) rearrangements using an assay based on fluorescent in situ hybridization (FISH). This test was applied to 58 consecutive standard- and high-risk medulloblastomas with a 5-year minimum of clinical follow-up. The presence of i17q (ie, including cases not involving the common breakpoint), idic(17)(p11.2), and histologic subtype was correlated with clinical outcome. Overall survival (OS) and disease-free survival (DFS) were consistent with literature reports. Fourteen patients (25%) had i17q, with 10 (18%) involving the common isodicentric rearrangement. The presence of i17q was associated with a poor prognosis. OS and DFS were poor in all cases with anaplasia (4), unresectable disease (7), and metastases at presentation (10); however, patients with standard-risk tumors fared better. Of these 44 cases, tumors with idic(17)(p11.2) were associated with significantly worse patient outcomes and shorter mean DFS. FISH detection of idic(17)(p11.2) may be useful for risk stratification in standard-risk patients. The presence of this abnormal chromosome is associated with early recurrence of medulloblastoma.     

Radiotherapy Advances in Paediatric Medulloblastoma Treatment

Radiotherapy is an essential element in the multidisciplinary management of children with medulloblastoma and postoperative craniospinal axis radiotherapy is considered to be the cornerstone of curative treatment. With modern multidisciplinary management, more than 80% of children with standard-risk medulloblastoma and up to 70% of children with high-risk medulloblastoma are long-term survivors. Current clinical trials are evaluating risk-adapted radiotherapy in standard-risk medulloblastoma to reduce long-term sequelae, whereas the research approach in high-risk medulloblastoma is to improve clinical outcome with dose-intensification of chemotherapy and the use of hyperfractionated radiotherapy regimens. Technological advances, such as tomotherapy, volumetric modulated arc therapy and proton therapy, may further improve the therapeutic ratio by reducing radiotherapy toxicities. A selected group of children with recurrent disease after treatment for standard-risk medulloblastoma may be considered for re-irradiation.     

Molecular risk stratification of medulloblastoma patients based on immunohistochemical analysis of MYC, LDHB, and CCNB1 expression.

PURPOSE: Medulloblastoma is the most common malignant embryonal brain tumor in children. The current clinical risk stratification to select treatment modalities is not optimal because it does not identify the standard-risk patients with resistant disease or the unknown number of high-risk patients who might be overtreated with current protocols. The aim of this study is to improve the risk stratification of medulloblastoma patients by using the expression of multiple prognostic markers in combination with current clinical parameters. EXPERIMENTAL DESIGN: Candidate prognostic markers were selected from literature or from medulloblastoma expression data. Selected genes were immunohistochemically analyzed for their prognostic value using medulloblastoma tissue arrays containing 124 well-characterized patient samples. RESULTS: Protein expression analyses showed that the combined expression of three genes was able to predict survival in medulloblastoma patients. Low MYC expression identified medulloblastoma patients with a very good outcome. In contrast, concomitant expression of LDHB and CCNB1 characterized patients with a very poor outcome. Multivariate analyses showed that both expression of MYC and the LDHB/CCNB1 gene signature were strong prognostic markers independent of the clinical parameters metastasis and residual disease. Combined analysis of clinical and molecular markers enabled greater resolution of disease risk than clinical factors alone. CONCLUSIONS: A molecular risk stratification model for medulloblastoma patients is proposed based on the signature of MYC, LDHB, and CCNB1 expression. Combined with clinical variables, the model may provide a more accurate basis for targeting therapy in children with this disease.     

Medulloblastomas and central nervous system primitive neuroectodermal tumors

Opinion statement Significant advances in the treatment of medulloblastoma and primitive neuroectodermal tumors have been made in the past three decades. Maximal surgical resection is a mainstay of therapy. However, unlike many other central nervous system neoplasms, medulloblastoma and primitive neuroectodermal tumors are radiation and chemotherapy responsive. Despite this response, the prognosis for patients with these tumors remains variable and is relatively poor in infants and patients with metastatic disease. These tumors most commonly arise in children, thus most clinical trials emphasize the reduction of long-term sequelae, in addition to improving survival. All newly diagnosed patients who are eligible should be offered participation in a clinical trial. If a patient is ineligible or declines consent/ assent for a clinical trial, the best current treatment approach is surgical resection, followed by radiation therapy (except for children younger than 3 years) with weekly vincristine. For high-risk patients, 36 Gy of craniospinal irradiation should be delivered plus a boost of 19.8 Gy to the posterior fossa/primary tumor bed and sites of bulk metastatic disease. For average-risk patients, the craniospinal irradiation dose may be lowered to 23.4 Gy plus 32.4 Gy to the posterior fossa/tumor bed. After radiation therapy, intensive multimodal chemotherapy should be used for all patients.     

Minimal Residual Disease Negativity Does Not Overcome Poor Prognosis in High-Risk Multiple Myeloma: A Single-Center Retrospective Study

BackgroundMinimal residual disease (MRD) is a standard measurement for response assessment in multiple myeloma (MM). Despite new treatments, high-risk MM patients continue to have poor prognosis. We evaluated the effect of MRD negativity in high-risk versus standard-risk patients.Patients and MethodsWe retrospectively evaluated all consecutive MM patients who underwent routine MRD testing by 1-tube 8-color advanced flow cytometry with 2,000,000 events and sensitivity level 10⁻⁵ at our center from 2015 to 2018 after initial therapy. Kaplan-Meier and log-rank test were used to assess survival estimates and differences between study groups.ResultsOne hundred thirty-six patients with MRD testing after initial therapy or autologous stem-cell transplantation were identified. At a median follow-up of 14 months (range, 1-36 months), progression-free survival and overall survival were significantly worse in high-risk versus standard-risk patients. During the study period, 50% of high-risk group had experienced disease progression (relapse and/or death) versus 20% in the standard-risk group (P = .0006). No patients with standard-risk died, but 4 (14%) in the high-risk group did (P = .0007). Regardless of MRD status, high-risk patients had statistically significant worse progression-free survival than standard-risk patients. At median follow-up, those with disease 10% standard-risk/MRD negative; 20% standard-risk/MRD positive; 40% high-risk/MRD negative; and 45% high-risk/MRD positive had either experienced relapse or died (P = .0041). MRD status did not significantly affect overall survival in either group (P = .0914); however, longer follow-up is needed to assess survival.ConclusionGenetic abnormalities remain a powerful prognostic indicator for MM, regardless of MRD status. For newly diagnosed MM patients treated with novel triple-drug initial therapy and frontline autologous stem-cell transplantation, MRD-negative status did not mitigate the poor-prognosis outcomes of high-risk MM patients.     

Survival and recurrence factors in adult medulloblastoma: the M.D. Anderson Cancer Center experience from 1978 to 1998

Medulloblastoma is a rare adult primary brain tumor for which limited retrospective studies are available to elucidate natural history or to guide therapy. A retrospective chart and imaging review of adult patients (aged >18 years) with medulloblastoma was performed to identify survival and prognostic factors. Fifty-seven patients were evaluated at the University of Texas M.D. Anderson Cancer Center from 1978-1998. Statistical analysis of prognostic factors and overall survival was performed for a subgroup of 28 patients who were followed exclusively at our institution from the time of diagnosis until death or last follow-up. These 28 patients had an overall survival of 91% at 3 years and 84% at 5 years, whereas median survival was not reached after a median follow-up of 168 weeks (range, 9-602 weeks). Progression-free survival for all patients was 68% at 3 years and 62% at 5 years, and was not statistically different between poor- and standard-risk patients. Univariate analysis of clinical features, such as age, sex, extent of local disease, extent of resection, and use of adjuvant chemotherapy, did not identify any prognostic variables for survival among the 28 patients. Patterns of recurrence revealed that the posterior fossa was the most common site (56%), followed by bone marrow (25%). Adult medulloblastoma appears to have a favorable prognosis after treatment with maximally surgically feasible resection followed by craniospinal irradiation. Optimal treatment remains to be clarified, as both standard-risk and poor-risk patients have prolonged disease-free survival. The marked difference between survival and progression-free survival suggests that salvage therapy, usually with combination chemotherapy in this cohort of patients, is of benefit. More formal analysis of the survival benefit was not possible, however, because of the small number of patients treated at recurrence with any one therapeutic regimen.     

The Therapy of Infantile Malignant Brain Tumors: Current Status?

Malignant brain tumors are not uncommon in infants as their occurrence before the age of three represents 20-25% of all malignant brain tumors in childhood [1]. Genetic predisposition to infantile malignant brain tumors are known in Gorlin syndrome for example who present with desmoplastic medulloblastoma in about 5% of the affected patients. In addition, sequelae from tumor and its treatment are more severe at this age [2]. Thus, malignant brain tumors represent a true therapeutic challenge in neuro-oncology. Before the era of modern imaging and modern neurosurgery these malignant brain tumors were misdiagnosed or could not benefit of the surgical procedures as well as older children because of increased risks in this age group. Since the end of the 80s, noninvasive imaging procedures produce accurate diagnosis of brain tumors and improvement in neurosurgery, neuroanesthesia and perioperative intensive care permit safe tumor resections or at least biopsies. Consequently, the pediatric oncologists are more often confronted with very young children who need a complementary treatment. Before the development of specific approaches for this age group, these children received the same kind of treatment than the older children did, but their survival and quality of life were significantly worse. The reasons of these poor results were probably due in part to the fear of late effects induced by radiation therapy, leading to decrease the necessary doses of irradiation which increased treatment failures without avoiding treatment related complications [3]. At the end of the 80s, pilot studies were performed using postoperative chemotherapy in young medulloblastoma patients. Van Eys treated 12 selected children with medulloblastoma with MOPP regimen and without irradiation; 8 of them were reported to be long term survivors [4]. Subsequently, the pediatric oncology cooperative groups studies have designed therapeutic trials for very young children with malignant brain tumors. Different approaches have been explored: * Prolonged postoperative chemotherapy and delayed irradiation as designed in the POG (Pediatric Oncology Group). * Postoperative chemotherapy without irradiation in the SFOP (Société Fran?aise d'Oncologie Pédiatrique) and in the GPO (German Pediatric Oncology) studies. * The role of high-dose chemotherapy with autologous stem cells transplantation was explored in different ways: High-dose chemotherapy given in all patients as proposed in the Head Start protocol. High-dose chemotherapy given in relapsing patients as salvage treatment in the French strategy. In the earliest trials, the same therapy was applied to all histological types of malignant brain tumors and whatever the initial extension of the disease. This attitude was justified by the complexity of the classification of all brain tumors that has evolved over the past few decades leading to discrepancy between the diagnosis of different pathologists for a same tumor specimen. Furthermore, it has become increasingly obvious that the biology of brain tumors in very young children is different from that seen in older children. However, in the analysis of these trials an effort was made to give the results for each histological groups, according to the WHO classification and after a central review of the tumor specimens. All these collected data have brought to an increased knowledge of infantile malignant brain tumors in terms of diagnosis, prognostic factors and response to chemotherapy. Furthermore a large effort was made to study long term side effects as endocrinopathies, cognitive deficits, cosmetic alterations and finally quality of life in long term survivors. Prospective study of sequelae can bring information on the impact of the different factors as hydrocephalus, location of the tumor, surgical complications, chemotherapy toxicity and irradiation modalities. With these informations it is now possible to design therapeutic trials devoted to each histological types, adapted to pronostic factors and more accurate treatment to decrease long term sequelae.     

Adjuvant chemotherapy for brain tumor

Adjuvant systemic chemotherapy, in addition to surgical resection and cranial RT, modestly improves survival in children and adults with malignant astrocytoma or glioblastoma, and produces sustained major responses in patients with anaplastic oligodendroglioma. Chemotherapy alone can produce prolonged tumor control in children with optic pathway gliomas, delaying the need for RT. Adjuvant chemotherapy has also shown a clear benefit in the treatment of other tumors such as medulloblastoma, ^53–55 pineal region germ-cell tumors,⁵⁶ and primary CNS lymphoma.⁵⁷ Although overall the gains to date have been modest, the development of new chemotherapeutic agents and combinations, and improvements in our knowledge of brain tumor biology and drug pharmacology should improve substantially the benefits of adjuvant chemotherapy for brain tumor in the future.     

Advances in the diagnosis,molecular genetics,and treatment of pediatric embryonal CNS tumors

Embryonal central nervous system (CNS) tumors are the most common group of malignant brain tumors in children. The diagnosis and classification of tumors belonging to this family have been controversial; however, utilization of molecular genetics is helping to refine traditional histopathologic and clinical classification schemes. Currently, this group of tumors includes medulloblastomas, supratentorial primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, ependymoblastomas, and medulloepitheliomas. While the survival of older children with nonmetastatic medulloblastomas has improved considerably within the past two decades, the outcomes for infants and for those with metastatic medulloblastomas or other high-risk embryonal CNS tumors remain poor. It is anticipated that the emerging field of molecular biology will greatly aid in the future stratification and therapy for pediatric patients with malignant embryonal tumors. In this review, recent advances in the diagnosis, molecular genetics, and treatment of the most common pediatric embryonal CNS tumors are discussed.     

Molecular analysis of pediatric brain tumors

The identification of molecular genetic abnormalities in specific types of pediatric brain tumors is beginning to play a role in the stratification of patients into treatment groups. The finding of an INI1 alteration in an atypical teratoid/ rhabdoid tumor or malignant neoplasm with overlapping histologic features will be required for entry onto diseasespecific protocols within the Children’s Oncology Group. Refinement in the classification of medulloblastoma and malignant glioma patients will likely depend on the genetic and signaling pathways that characterize these tumors. Advances in this area will depend on the ability to identify new disease genes, validate prognostic markers, and develop biologically based therapeutic strategies to tailor treatment.     

A cell kinetic study on medulloblastomas

The cell kinetics of medulloblastoma were studied to define characteristic proliferation for comparison with other neuroectodermal tumors. Four patients with cerebellar medulloblastoma received 3H-thymidine intravenously 1 to 2 days before surgery. Biopsy specimens from each tumor were processed for autoradiography. The respective average labeling indices were 14.4%, 14.1%, and 11.2% in the three mid-cerebellar medulloblastomas and 8.0% in the cerebellar hemispheric medulloblastoma. The mean survival time with various treatments including radiation therapy before or after the study in these four patients was 6 years (range, 3-9 years). In contrast, patients with malignant gliomas that had a labeling index greater than 5% died within 1 year. This difference in survival was attributed to the greater sensitivity of medulloblastoma to radiation therapy.     

Preirradiation cisplatin and etoposide in the treatment of high-risk medulloblastoma and other malignant embryonal tumors of the central nervous system: a phase II study

Medulloblastoma, pineoblastoma, and cerebral neuroblastoma are malignant embryonal tumors of the CNS that may demonstrate similar histologic features, a propensity for neuraxis dissemination and sensitivity to radiation therapy and, in certain cases, chemotherapy. To evaluate the activity of preirradiation chemotherapy in such tumors, 11 newly diagnosed children with measurable residual disease and characteristics indicative of poor prognosis were treated postoperatively with cisplatin (CDDP) and etoposide (VP-16). Responses graded on the basis of radiographic findings in areas of either macroscopic residual tumor or metastatic disease included two complete responses (CRs), eight partial responses (PRs), and one stable disease (SD). Acute and subacute toxicity consisted of high-frequency hearing loss in four patients, reversible signs and symptoms of increased intracranial pressure in two patients, and transient neutropenia. Seven of eight patients with high-risk medulloblastoma and two of two with pineoblastoma remain free of tumor progression following neuraxis irradiation at 8 to 48 months postdiagnosis (median, 18 months). CDDP and VP-16 is a highly active drug combination when given before irradiation in children with high-risk medulloblastoma and other malignant embryonal tumors of the CNS, producing objective responses in at least one site of measurable disease in 10 of 11 newly diagnosed patients, including all of five with gross neuraxis dissemination.     

Common strategy for adult and pediatric medulloblastoma: a multicenter series of 253 adults

PURPOSE: To assess prognostic factors for adults with medulloblastoma in a multicenter, retrospective study. METHODS AND MATERIALS: Data were collected by file review or mail inquiry for 253 adults treated between 1975 to 2004. Radiologists or surgeons assessed disease characteristics, such as volume and extension. Patients were classified as having either high- or standard-risk disease. Prognostic factors were analyzed. RESULTS: Median patient age was 29 years. Median follow-up was 7 years. Radiotherapy was delivered in 246 patients and radiochemotherapy in 142. Seventy-four patients relapsed. Respective 5- and 10-year overall survival rates were 72% and 55%. Univariate analysis showed that survival significantly correlated with metastasis, postsurgical performance status, brainstem involvement, involvement of the floor of the fourth ventricle (V4), and radiation dose to the spine and to the posterior cerebral fossa (PCF). By multivariate analysis, brainstem, V4 involvement, and dose to the PCF were negative prognostic factors. In the standard-risk subgroup there was no overall survival difference between patients treated with axial doses of >or=34 Gy and patients treated with craniospinal doses <34 Gy plus chemotherapy. CONCLUSION: We report the largest series of medulloblastoma in adults. Prognostic factors were similar to those observed in children. Results suggest that patients with standard-risk disease could be treated with radiochemotherapy, reducing doses to the craniospinal area, maintaining at least 50 Gy to the PCF. The role of chemotherapy for this group is still unclear. A randomized study should be performed to confirm these results, but because frequency is very low, such a study would be difficult.     

Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study.

OBJECTIVE: The primary objective of this study was to decrease the late effects of prophylactic radiation without reducing survival in standard-risk childhood medulloblastoma. PATIENTS AND METHODS: Inclusion criteria were as follows: children between the ages of 3 and 18 years with total or subtotal tumor resection, no metastasis, and negative postoperative lumbar puncture CSF cytology. Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin (500 and 800 mg/m(2) per course, respectively) were administered after surgery. Radiation therapy had to begin 90 days after surgery. Delivered doses were 55 Gy to the posterior fossa and 25 Gy to the brain and spinal canal. RESULTS: Between November 1991 and June 1998, 136 patients (median age, 8 years; median follow-up, 6.5 years) were included. The overall survival rate and 5-year recurrence-free survival rate were 73.8% +/- 7.6% and 64.8% +/- 8.1%, respectively. Radiologic review showed that 4% of patients were wrongly included. Review of radiotherapy technical files demonstrated a correlation between the presence of a major protocol deviation and treatment failure. The 5-year recurrence-free survival rate of patients included in this study with all optimal quality controls of histology, radiology, and radiotherapy was 71.8% +/- 10.5%. In terms of sequelae, 31% of patients required growth hormone replacement therapy and 25% required special schooling. CONCLUSION: Reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma provided staging and radiation therapy are performed under optimal conditions.     

Patterns of failure using a conformal radiation therapy tumor bed boost for medulloblastoma.

PURPOSE: To assess the patterns of failure for patients with medulloblastoma receiving a conformal tumor bed boost rather than a boost to the entire posterior fossa. PATIENTS AND METHODS: From 1994 to 2002, 32 consecutive patients with newly diagnosed medulloblastoma treated at Memorial Sloan-Kettering Cancer Center (New York, NY) received a conformal boost to the tumor bed in conjunction with craniospinal radiation therapy. Twenty-eight patients also received chemotherapy. The median age was 9 years (range, 3 to 34 years), and the male to female ratio was 3:1. Twenty-seven patients had standard-risk disease, and five patients had high-risk disease. Craniospinal doses ranged from 23.4 to 39.6 Gy, and total tumor bed doses ranged from 54 to 59.4 Gy. RESULTS: With a median follow-up of 56 months, six patients have relapsed; five relapsed outside of the posterior fossa, and one failed within the posterior fossa, outside of the high-dose boost volume. Five-year actuarial disease-free and overall survival rates were 84% and 85%, respectively. Freedom from posterior fossa failure was 100% and 86% at 5 and 10 years, respectively. Freedom from distant failure was 84% at 5 years, with a trend for improvement when full-dose craniospinal radiation (36 to 39.6 Gy) was used compared with a reduced dose (23.4 Gy) of radiation (100% v 63%, respectively; P =.06). No other predictive variables were identified. CONCLUSION: Conformal treatment to the tumor bed allows for significant sparing of critical structures. The posterior fossa failure rate in this series is similar to that reported when the entire posterior fossa is treated. This approach should be investigated further in a phase III trial.     

Evaluation of polyamine levels in cerebrospinal fluid of children with brain tumors

Summary Cerebrospinal fluid (CSF) polyamine levels were analyzed retrospectively in 21 pediatric patients with different types of intracranial malignant tumors to determine the benefit of following these markers during the clinical management of brain tumors. The tumors included 16 medulloblastomas and 1 each of germinoma, ependymoma, primitive neuroectodermal tumor, astrocytoma, and malignant teratoma. The clinical course of each patient was followed by neurologic examination, cranial computed tomography, CSF cell count, and cytology after cytocentrifugation. The correlation of CSF putrescine and spermidine levels with the clinical course of the brain tumors was analyzed. The following results were obtained: (1) A significant increase in CSF putrescine levels was observed in children with medulloblastoma when there was recurrent or metastatic disease in the sites close to the CSF pathway compared with the children whose disease status was stable after successful treatment (P < 0.005). (2) The increase of CSF putrescine levels was the earliest predictor of recurrence or metastasis near the CSF pathway. (3) In tumors other than medulloblastoma, the levels of polyamines were not predictive of disease activity with the possible exception of germinoma. (4) Spermidine levels in the CSF were of limited clinical importance for patients with brain tumors.CSF putrescine levels may be the earliest and most sensitive quantitative marker of the progression of medulloblastoma, and their evaluation should be included in the diagnostic work-up and follow-up examination of children with medulloblastoma.     

Current chemotherapeutic approaches for hepatoblastoma

Cisplatin-based chemotherapy has markedly improved the survival of patients with standard-risk hepatoblastoma (HB). However, treatment results for patients with metastatic disease remain unsatisfactory. As a result, the current therapeutic strategy for HB is to decrease dose intensity for standard-risk tumors in order to reduce chemotherapy-related toxicity and to intensify chemotherapy in combination with new drugs to develop new therapies and improve the outcome of patients with metastatic disease. Results from various trials of The North American Cooperative Study demonstrated that patients with localized disease achieved long-term survival following treatment with a combination of cisplatin, 5-fluorouracil, and vincristine (C5V). In the ongoing Children’s Oncology Group (COG) trial, AHEP0731, patients with stage I pure fetal histology are classified as very low risk and treated with resection only, and patients with any stage IV disease or any stage plus an alpha-fetoprotein level at diagnosis of <100 ng/ml are classified as high risk and receive up-front window therapy followed by C5V + doxorubicin in an attempt to discover novel efficacious agents. The early International Childhood Liver Tumors Strategy Group (SIOPEL) trial, SIOPEL-1, demonstrated that a combination of cisplatin + doxorubicin (PLADO) is effective. In the SIOPEL-3SR trial, cisplatin alone was proved to be non-inferior to PLADO for standard-risk HB. In the SIOPEL-4 trial, intensified preoperative cisplatin was administered on a weekly basis, and this approach achieved the highest survival rate ever reported for patients, even those with metastatic disease. SIOPEL, COG, and the Japanese Study Group for Pediatric Liver Tumor (JPLT) have established the Children’s Hepatoma International Collaboration (CHIC) to create a common risk classification and initiate international clinical trials in order to further improve the outcome of children with HB.