Publications by authors named "Bernadine Donahue"

32 Publications

Hippocampal sparing in patients receiving radiosurgery for ≥25 brain metastases.

Radiother Oncol 2021 08 27;161:65-71. Epub 2021 May 27.

Department of Neurosurgery, NYU Grossman School of Medicine, New York, USA; Brain and Spine Tumor Center, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, USA; Department of Radiation Oncology, NYU Grossman School of Medicine, New York, USA.

Purpose/objectives: To report our dosimetric analysis of the hippocampi (HC) and the incidence of perihippocampal tumor location in patients with ≥25 brain metastases who received stereotactic radiosurgery (SRS) in single or multiple sessions.

Materials/methods: Analysis of our prospective registry identified 89 patients treated with SRS for ≥25 brain metastases. HC avoidance regions (HA-region) were created on treatment planning MRIs by 5 mm expansion of HC. Doses from each session were summed to calculate HC dose. The distribution of metastases relative to the HA-region and the HC was analyzed.

Results: Median number of tumors irradiated per patient was 33 (range 25-116) in a median of 3 (range1-12) sessions. Median bilateral HC D (D), D, D, D, and D (Gy) was 1.88, 3.94, 3.62, 16.6, and 3.97 for all patients, and 1.43, 2.99, 2.88, 5.64, and 3.07 for patients with tumors outside the HA-region. Multivariate linear regression showed that the median HC D, D, and D were significantly correlated with the tumor number and tumor volume (p < 0.001). Of the total 3059 treated tumors, 83 (2.7%) were located in the HA-region in 57% evaluable patients; 38 tumors (1.2%) abutted or involved the HC itself.

Conclusions: Hippocampal dose is higher in patients with tumors in the HA-region; however, even for patients with a high burden of intracranial disease and tumors located in the HA-regions, SRS affords hippocampal sparing. This is particularly relevant in light of our finding of eventual perihippocampal metastases in more than half of our patients.
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http://dx.doi.org/10.1016/j.radonc.2021.05.019DOI Listing
August 2021

Clinical Determinants Differentiating the Severity of SARS-CoV-2 Infection in Cancer Patients: Hospital Care or Home Recovery.

Front Med (Lausanne) 2021 16;8:604221. Epub 2021 Feb 16.

Department of Medicine, Division of Hematology/Oncology, Maimonides Medical Center, Brooklyn, NY, United States.

Cancer patients may carry a worse prognosis with SARS-CoV-2 infection. Most of the previous studies described the outcomes of hospitalized cancer patients. We aimed to study the clinical factors differentiating patients requiring hospital care vs. home recovery, and the trajectory of their anti-cancer treatment. This study was conducted in a community cancer center in New York City. Eligible patients were those who had cancer history and were diagnosed of SARS-CoV-2 infection between March 1 and May 30, 2020, with confirmatory SARs-CoV-2 virus test or antibody test. Four groups were constructed: (A) hospitalized and survived, (B) hospitalized requiring intubation and/or deceased, (C) non-hospitalized, asymptomatic, with suspicious CT image findings, close exposure, or positive antibody test, and (D) non-hospitalized and symptomatic. One hundred and six patients were included in the analysis. Thirty-five patients (33.0%) required hospitalization and 13 (12.3%) died. Thirty (28.3%) patients were asymptomatic and 41 (38.7%) were symptomatic and recovered at home. Comparing to patients who recovered at home, hospitalized patients were composed of older patients (median age 71 vs. 63 years old, = 0.000299), more who received negative impact treatment (62.9 vs. 32.4%, = 0.0036) that mostly represented myelosuppressive chemotherapy (45.7 vs. 23.9%, = 0.0275), and more patients with poorer baseline performance status (PS ≥ 2 25.7 vs. 2.8%, = 0.0007). Hypoxemia (35% in group A vs. 73.3% in group B, = 0.0271) at presentation was significant to predict mortality in hospitalized patients. The median cumulative hospital stay for discharged patients was 16 days (range 5-60). The median duration of persistent positivity of SARS-CoV-2 RNA was 28 days (range 10-86). About 52.9% of patients who survived hospitalization and required anti-cancer treatment reinitiated therapy. Ninety-two percent of the asymptomatic patients and 51.7% of the symptomatic patients who recovered at home continued treatment on schedule and almost all reinitiated treatment after recovery. Cancer patients may have a more severe status of SARS-CoV-2 infection after receiving myelosuppressive chemotherapy. Avoidance should be considered in older patients with poor performance status. More than two thirds of patients exhibit minimal to moderate symptoms, and many of them can continue or restart their anti-cancer treatment upon recovery.
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http://dx.doi.org/10.3389/fmed.2021.604221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921307PMC
February 2021

Primum Non Nocere: Not All Targetable Lesions Should Be Targeted.

Int J Radiat Oncol Biol Phys 2021 03;109(3):654-655

Maimonides Cancer Center, Brooklyn, New York; New York University Langone Medical Center, New York City, New York.

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http://dx.doi.org/10.1016/j.ijrobp.2020.08.016DOI Listing
March 2021

Covert COVID-19: Cone Beam Computed Tomography Lung Changes in an Asymptomatic Patient Receiving Radiation Therapy.

Adv Radiat Oncol 2020 Jul-Aug;5(4):715-721. Epub 2020 May 19.

Department of Radiation Oncology, Maimonides Cancer Center, Brooklyn, New York.

Purpose: COVID-19 profoundly affected the United States, with New York City rapidly becoming the epicenter of the disease. Patients with cancer represent a vulnerable population in this pandemic, with data suggesting a higher risk for severe events and unfavorable outcomes. Timely identification of COVID-19 in patients with cancer has been thwarted by the limited availability of outpatient testing for SARS-CoV-2. Chest computed tomography (CT) plays a major role in the identification of COVID-19 pneumonia, with radiologic hallmarks including bilateral, peripheral ground-glass opacities (GGOs) and consolidation. Patients with cancer undergoing radiation therapy (RT) commonly have daily cone beam computed tomography (CBCT) obtained for image-guided RT, and such imaging frequently includes the chest.

Methods And Materials: We retrospectively reviewed the CBCT scans of an initially asymptomatic patient undergoing image-guided RT for breast cancer who developed COVID-19 symptoms during the second week of RT. Lung windows of daily CBCT scans were reviewed with diagnostic radiology to survey for changes consistent with COVID-19. Diagnostic CT scans at the time of recovery were obtained and compared with the CBCTs.

Results: Five consecutive CBCT scans were retrospectively reviewed. Bilateral, peripheral GGOs were noted on the fourth and fifth CBCT scans in the 2 days before symptom onset. CBCT on the day of RT resumption demonstrated substantial worsening of the GGO compared with scans obtained during the asymptomatic phase. Diagnostic CTs demonstrated bilateral, peripheral GGOs and mediastinal lymphadenopathy, findings suggesting COVID-19 pneumonitis. Repeat diagnostic CT 3 days later showed improved pulmonary findings, and the patient resumed RT without incident.

Conclusions: Familiarity with typical CT changes of COVID-19 pneumonitis may allow for early detection in cancer patients undergoing CBCT for RT treatment. Prompt review of the lung windows is recommended to identify such changes, with the hope that presymptomatic diagnosis leads to expedited patient management, improved outcomes, and a reduction of inadvertent COVID-19 dissemination.
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http://dx.doi.org/10.1016/j.adro.2020.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235566PMC
May 2020

Stereotactic radiosurgery for focal leptomeningeal disease in patients with brain metastases.

J Neurooncol 2017 Aug 23;134(1):139-143. Epub 2017 May 23.

Department of Neurosurgery, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York University, Suite 8R, 530 First Avenue, New York, NY, 10016, USA.

Leptomeningeal disease (LMD) is well described in patients with brain metastases, presenting symptomatically in approximately 5% of patients. Conventionally, the presence of LMD is an indication for whole brain radiation therapy (WBRT) and not suitable for stereotactic radiosurgery (SRS). The purpose of the study was to evaluate the local control and overall survival of patients who underwent SRS to focal LMD. We reviewed our prospective registry and identified 32 brain metastases patients with LMD, from a total of 465 patients who underwent SRS between 2013 and 2015. Focal LMD was targeted with SRS in 16 patients. The median imaging follow-up time was 7 months. The median volume of LMD was 372 mm and the median margin dose was 16 Gy. Five patients underwent prior WBRT. Histology included non-small cell lung (8), breast (5), melanoma (1), gastrointestinal (1) and ovarian cancer (1). Follow-up MR imaging was available for 14 patients. LMD was stable in 5 and partially regressed in 8 patients at follow-up. One patient had progression of LMD with hemorrhage 5 months after SRS. Seven patients developed distant LMD at a median time of 7 months. The median actuarial overall survival from SRS for LMD was 10.0 months. The 6-month and 1-year actuarial overall survival was 60% and 26% respectively. Six patients underwent WBRT after SRS for focal LMD at a median time of 6 months. Overall, focal LMD may be may be treated successfully with radiosurgery, potentially delaying WBRT in some patients.
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http://dx.doi.org/10.1007/s11060-017-2497-6DOI Listing
August 2017

Delayed Cytoreductive Nephrectomy Following Three Years of Targeted Therapy for Metastatic Renal Cell Carcinoma.

Curr Urol 2017 Jan 26;9(4):202-208. Epub 2016 Dec 26.

Division of Urologic Oncology, Maimonides Medical Center, Brooklyn, N.Y., USA.

We present a 55-year-old male, with good performance status who was diagnosed with a case of metastatic renal cell carcinoma following a pathologic femur fracture. Despite good performance status, multifocal metastases and poor-prognostic features portended a grim prognosis with predicted overall survival of less than nine months. On initial presentation, he was excluded from cytoreductive nephrectomy based on brain metastasis and interleukin-2 was not pursued as the primary tumor was to be left . The patient was reconsidered for cytoreductive nephrectomy after sustained response to fifth line targeted therapies with shrinkage of tumor burden. The post-operative course was uneventful and the patient was discharged home on postoperative day one. Temsirolimus was resumed one week after surgery and the patient reported returning to his normal activities at the two week follow-up visit. We highlight important clinical features of metastatic renal cell carcinoma, the surgical considerations for cytoreductive nephrectomy and the detailed multidisciplinary care the patient received throughout this case report.
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http://dx.doi.org/10.1159/000447141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385451PMC
January 2017

Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery.

J Neurosurg 2018 01 17;128(1):23-31. Epub 2017 Feb 17.

Departments of1Neurosurgery.

OBJECTIVE The incidence of brain metastases is increasing with improved systemic therapies, many of which have a limited impact on intracranial disease. Stereotactic radiosurgery (SRS) is a first-line management option for brain metastases. The purpose of this study was to determine if there is a threshold tumor size below which local control (LC) rates approach 100%, and to relate these findings to the use of routine surveillance brain imaging. METHODS From a prospective registry, 200 patients with 1237 brain metastases were identified who underwent SRS between December 2012 and May 2015. The median imaging follow-up duration was 7.9 months, and the median margin dose was 18 Gy. The maximal diameter and volume of tumors were measured. Histological analysis included 96 patients with non-small cell lung cancers (NSCLCs), 40 with melanoma, 35 with breast cancer, and 29 with other histologies. RESULTS Almost 50% of brain metastases were NSCLCs and commonly measured less than 6 mm in maximal diameter or 70 mm in volume. Thirty-three of 1237 tumors had local progression at a median of 8.8 months. The 1- and 2-year actuarial LC rates were 97% and 93%, respectively. LC of 100% was achieved for all intracranial metastases less than 100 mm in volume or 6 mm in diameter. Patients whose tumors at first SRS were less than 10 mm maximal diameter or a volume of 250 mm had improved overall survival. CONCLUSIONS SRS can achieve LC rates approaching 100% for subcentimeter metastases. The earlier initial detection and prompt treatment of small intracranial metastases may prevent the development of neurological symptoms and the need for resection, and improve overall survival. To identify tumors when they are small, routine surveillance brain imaging should be considered as part of the standard of care for lung, breast, and melanoma metastases. ■ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort; evidence: Class II.
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http://dx.doi.org/10.3171/2016.10.JNS161036DOI Listing
January 2018

Traumatic brain injury and subsequent glioblastoma development: Review of the literature and case reports.

Surg Neurol Int 2016 26;7:78. Epub 2016 Aug 26.

Department of Neurosurgery, NYU School of Medicine, Brooklyn, New York, USA; Kimmel Center for Stem Cell Biology, NYU School of Medicine, Brooklyn, New York, USA; Brain Tumor Center, NYU School of Medicine, Brooklyn, New York, USA.

Background: Previous reports have proposed an association between traumatic brain injury (TBI) and subsequent glioblastoma (GBM) formation.

Methods: We used literature searches and radiographic evidence from two patients to assess the possibility of a link between TBI and GBM.

Results: Epidemiological studies are equivocal on a possible link between brain trauma and increased risk of malignant glioma formation. We present two case reports of patients with GBM arising at the site of prior brain injury.

Conclusion: The hypothesis that TBI may predispose to gliomagenesis is disputed by several large-scale epidemiological studies, but supported by some. Radiographic evidence from two cases presented here suggest that GBM formed at the site of brain injury. We propose a putative pathogenesis model that connects post-traumatic inflammation, stem and progenitor cell transformation, and gliomagenesis.
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http://dx.doi.org/10.4103/2152-7806.189296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009580PMC
September 2016

Dose-Response Relationships for Meningioma Radiosurgery.

Am J Clin Oncol 2015 Dec;38(6):600-4

*Department of Radiation Oncology, University of California San Francisco, San Francisco, CA Departments of †Radiation Oncology ‡Neurosurgery, New York University School of Medicine, New York ∥Department of Radiation Oncology, Maimonides Medical Center, Brooklyn, NY §Department of Environmental Science, Alaska Pacific University, Anchorage, AK.

Objective: Dose-response relationships for meningioma radiosurgery are poorly characterized. We evaluated determinants of local recurrence for meningiomas treated with Gamma Knife radiosurgery (GKRS), to guide future treatment approaches to optimize tumor control.

Materials And Methods: A total of 101 consecutive patients (108 tumors) who underwent GKRS for benign, atypical, or malignant meningiomas between 1998 and 2011 were studied. Local recurrence was assessed. Cox proportional hazards and logistic regression analyses were used to determine the association of patient-related, tumor-related, and treatment-related characteristics with local recurrence. Acute and late toxicity was evaluated.

Results: World Health Organization (2007 classification) tumor grade was I (82%), II (11%), or III (7%). Median dose was 14 Gy (range, 10 to 18 Gy) for grade I tumors and 16 Gy (range, 12 to 20 Gy) for grade II and III tumors. Median follow-up was 25 months (maximum, 17 y). Two- /5-year actuarial local control rates were 100%/98% for grade I tumors and 76%/56% for grade II/III tumors. Higher tumor grade and lower GKRS dose were associated with local failure. In this cohort, there was a 42% relative reduction in local recurrence for each 1 Gy of dose escalation.

Conclusions: Treatment was well tolerated with no moderate or severe toxicity. Tumor control was excellent in benign tumors and suboptimal in higher grade tumors. Because the main determinant of local recurrence was GKRS dose, we recommend dose escalation for atypical or malignant tumors to doses between 16 and 20 Gy where critical structures allow.
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http://dx.doi.org/10.1097/COC.0000000000000008DOI Listing
December 2015

Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery.

J Neurooncol 2016 Feb 31;126(3):483-91. Epub 2015 Oct 31.

Department of Neurosurgery, New York University Langone Medical Center, Suite 8R, 530 First Avenue, New York, NY, 10016, USA.

We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7%, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.
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http://dx.doi.org/10.1007/s11060-015-1986-8DOI Listing
February 2016

Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study.

J Clin Oncol 2015 Aug 22;33(22):2464-71. Epub 2015 Jun 22.

Stewart Goldman, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Eric Bouffet, The Hospital for Sick Children, Toronto, ON, Canada; Paul G. Fisher, Lucile Packard Children's Hospital Stanford, Palo Alto; Cynthia S. Kretschmar, Children's Hospital Los Angeles, Los Angeles; Tianni Zhou, California State University, Long Beach; Allen B. Buxton, Children's Oncology Group, Monrovia, CA; Jeffrey C. Allen and Bernadine Donahue, New York University Langone Medical Center, New York, NY; Patricia L. Robertson, University of Michigan C.S. Mott Children's Hospital, Ann Arbor; Paul J. Chuba, St. John Hospital and Medical Center, Grosse Pointe, MI; and Ian F. Pollack, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA.

Purpose: This phase II trial evaluated the effect of neoadjuvant chemotherapy with or without second-look surgery before craniospinal irradiation on response rates and survival outcomes in children with newly diagnosed non-germinomatous germ cell tumors.

Patients And Methods: Induction chemotherapy consisted of six cycles of carboplatin/etoposide alternating with ifosfamide/etoposide. Patients demonstrating less than complete response after induction chemotherapy were encouraged to undergo second-look surgery. Patients who did not achieve complete response or partial response after chemotherapy with or without second-look surgery proceeded to high-dose chemotherapy with thiotepa and etoposide and autologous peripheral blood stem-cell rescue before craniospinal irradiation.

Results: The study included 102 patients treated between January 2004 and July 2008. Median age was 12 years, and 76% were male; 53.9% had pineal region masses, and 23.5% had suprasellar lesions. Sixty-nine percent of patients achieved complete response or partial response with neoadjuvant chemotherapy. At 5 years, event-free survival was 84% ± 4% (SE) and overall survival was 93% ± 3%. During the median follow-up of 5.1 years, 16 patients recurred or progressed, with seven deaths after relapse. No deaths were attributed to therapy-related toxicity. Relapse occurred at the site of primary disease in 10 patients, at a distant site in three patients, or both in one patient. In two patients, progression was detected by marker increase alone. Increased serum α-fetoprotein was a negative prognostic variable. Histologic subtype and increase of beta-human chorionic gonadotropin were not significantly correlated with worse outcomes.

Conclusion: Neoadjuvant chemotherapy with or without second-look surgery achieved high response rates contributing to excellent survival outcomes in children with newly diagnosed non-germinomatous germ cell tumors. This regimen should be included as a backbone for further studies.
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http://dx.doi.org/10.1200/JCO.2014.59.5132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507465PMC
August 2015

Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery.

Melanoma Res 2013 Jun;23(3):191-5

Department of Radiation Oncology, New York University Langone Medical Center, New York, New York 10016, USA.

The anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab has been shown to improve survival in patients with metastatic non-CNS melanoma. The purpose of this study was to investigate the efficacy of CTLA-4 inhibitors in the treatment of metastatic melanoma with limited brain metastases treated with stereotactic radiosurgery (SRS). Between January 2008 and June 2011, 58 patients with limited brain metastases from melanoma were treated with SRS with a median dose of 20 Gy delivered to the 50% isodose line (range, 15-20 Gy). In 25 patients, ipilimumab was administered intravenously at a dose of 3 mg/kg over 90 min every 3 weeks for a median of four doses (range, 1-8). Local control (LC), freedom from new brain metastases, and overall survival (OS) were assessed from the date of the SRS procedure. The median LC, freedom from new brain metastases, and OS for the entire group were 8.7, 4.3, and 5.9 months, respectively. The cause of death was CNS progression in all but eight patients. Six-month LC, freedom from new brain metastases, and OS were 65, 35, and 56%, respectively, for those who received ipilimumab and 63, 47, and 46% for those who did not (P=NS). Intracranial hemorrhage was noted in seven patients who received ipilimumab compared with 10 patients who received SRS alone (P=NS). In this retrospective study, administration of ipilimumab neither increased toxicity nor improved intracerebral disease control in patients with limited brain metastases who received SRS.
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http://dx.doi.org/10.1097/CMR.0b013e32835f3d90DOI Listing
June 2013

Radiation therapy quality in CCG/POG intergroup 9961: implications for craniospinal irradiation and the posterior fossa boost in future medulloblastoma trials.

Front Oncol 2012 11;2:185. Epub 2012 Dec 11.

New York University School of Medicine New York, NY, USA.

Purpose: Associations of radiation therapy (RT) deviations and outcomes in medulloblastoma have not been defined well, particularly in the era of reduced-dose craniospinal irradiation and chemotherapy. The aim of this study is to evaluate the quality of RT on Children's Cancer Group/Pediatric Oncology Group 9961 and analyze associations of RT deviations with outcome.

Materials And Methods: Major volume deviations were assessed based on the distance from specified anatomical region to field edge. We investigated associations of RT deviations with progression-free survival (PFS), overall survival (OS), and explored associations with demographics and clinical variables.

Results: Of the 308 patients who were evaluable for volume deviations, 101 patients (33%) did not have any. Of the remaining 207 patients, 50% had only minor deviations, 29% had only major deviations, and 21% had both minor and major deviations. Of the patients with major deviations, 73% had a single major deviation. The most common major deviation was in the cribriform plate region, followed by the posterior fossa (PF); PF deviations resulted from treating less than whole PF. There were no significant differences in PFS or OS between patients with deviations and those without. There was no evidence of associations of deviations with patient age.

Conclusions: Approximately one-third of patients had major volume deviations. There was no evidence of a significant association between these and outcome. This lack of correlation likely reflects the current high quality of RT delivered in Children's Oncology Group institutions, our strict definition of volume deviations, and the relatively few instances of multiple major deviations in individual patients. In is noteworthy that the types of PF volume deviations observed in this study were not adversely associated with outcome. As we move forward, quality assurance will continue to play an important role to ensure that deviations on study do not influence study outcome.
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http://dx.doi.org/10.3389/fonc.2012.00185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540930PMC
January 2013

A phase II study of conventional radiation therapy and thalidomide for supratentorial, newly-diagnosed glioblastoma (RTOG 9806).

J Neurooncol 2013 Jan 20;111(1):33-9. Epub 2012 Oct 20.

Dana-Farber/Brigham and Women's Cancer Center, 75 Francis Street, ASB1-L2, Boston, MA 02115, USA.

The Radiation Therapy Oncology Group (RTOG) initiated the single-arm, phase II study 9806 to determine the safety and efficacy of daily thalidomide with radiation therapy in patients with newly diagnosed glioblastoma. Patients were treated with thalidomide (200 mg daily) from day one of radiation therapy, increasing by 100-200 to 1,200 mg every 1-2 weeks until tumor progression or unacceptable toxicity. The median survival time (MST) of all 89 evaluable patients was 10 months. When compared with the historical database stratified by recursive partitioning analysis (RPA) class, this end point was not different [hazard ratio (HR) = 1.18; 95 % CI: 0.95-1.46; P = 0.93]. The MST of RPA class III and IV patients was 13.9 versus 12.5 months in controls (HR = 0.99; 95 % CI: 0.73-1.36; P = 0.48), and 4.3 versus 8.6 months in RPA class V controls (HR = 1.63, 95 % CI: 1.17-2.27; P = 0.99). In all, 34 % of patients discontinued thalidomide because of adverse events or refusal. The most common grade 3-4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy. In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.
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http://dx.doi.org/10.1007/s11060-012-0987-0DOI Listing
January 2013

Long-term outcomes after staged-volume stereotactic radiosurgery for large arteriovenous malformations.

Neurosurgery 2012 Sep;71(3):632-43; discussion 643-4

Department of Neurosurgery, NYU Langone Medical Center, New York, New York, USA.

Background: Stereotactic radiosurgery is an effective treatment modality for small arteriovenous malformations (AVMs) of the brain. For larger AVMs, the treatment dose is often lowered to reduce potential complications, but this decreases the likelihood of cure. One strategy is to divide large AVMs into smaller anatomic volumes and treat each volume separately.

Objective: To prospectively assess the long-term efficacy and complications associated with staged-volume radiosurgical treatment of large, symptomatic AVMs.

Methods: Eighteen patients with AVMs larger than 15 mL underwent prospective staged-volume radiosurgery over a 13-year period. The median AVM volume was 22.9 mL (range, 15.7-50 mL). Separate anatomic volumes were irradiated at 3- to 9-month intervals (median volume, 10.9 mL; range, 5.3-13.4 mL; median marginal dose, 15 Gy; range, 15-17 Gy). The AVM was divided into 2 volumes in 10 patients, 3 volumes in 5 patients, and 4 volumes in 3 patients. Seven patients underwent retreatment for residual disease.

Results: Actuarial rates of complete angiographic occlusion were 29% and 89% at 5 and 10 years. Five patients (27.8%) had a hemorrhage after radiosurgery. Kaplan-Meier analysis of cumulative hemorrhage rates after treatment were 12%, 18%, 31%, and 31% at 2, 3, 5, and 10 years, respectively. One patient died after a hemorrhage (5.6%).

Conclusion: Staged-volume radiosurgery for AVMs larger than 15 mL is a viable treatment strategy. The long-term occlusion rate is high, whereas the radiation-related complication rate is low. Hemorrhage during the lag period remains the greatest source of morbidity and mortality.
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http://dx.doi.org/10.1227/NEU.0b013e31825fd247DOI Listing
September 2012

Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma.

Pediatr Blood Cancer 2012 Dec 2;59(7):1180-2. Epub 2012 Feb 2.

NYU Langone Medical Center, New York, NY 10016, USA.

Background: Marked elevations of AFP and bHCG in serum or CSF may serve as surrogate diagnostic markers in lieu of histology for primary CNS mixed, malignant germ cell tumors. There is less information on the diagnostic sensitivity of bHCG assays in germinoma.

Procedure: We report baseline serum and lumbar CSF bHCG values in 58 newly diagnosed, histologically confirmed germinoma patients gathered from two prospective clinical trials which required that patients have a normal AFP and bHCG ≤50 mIU/ml in serum and lumbar CSF.

Results: The location of the primary tumors was: suprasellar(23); pineal(20); suprasellar/pineal(9); and other sites(6). The mean age of the study population was 13.5 (4.3-25.9) years. A total of 23(40%) patients had elevations of bHCG in either serum or CSF, 20(34.5%) of whom had only bHCG elevations in CSF. The patients' bHCG profiles were divided into four categories: I (normal serum and lumbar CSF bHCG), 35(60%); II (normal serum and elevated CSF bHCG), 20(34.5%); III (elevated serum and CSF bHCG), 2(3.5%); and IV (elevated serum and normal CSF bHCG), 1(2%). The median CSF bHCG level was 7.7(2.5-16) in the 22 patients with abnormal CSF values and the lumbar value was higher than the serum value in 20 of 23(87%) patients with bHCG elevations.

Conclusions: Lumbar CSF was a more informative screen for bHCG than serum but the majority of patients (60%) had normal bHCG values at diagnosis. Until a more sensitive tumor marker for germinoma is devised, histologic confirmation remains the standard of care. Pediatr Blood Cancer 2012; 59: 1180-1182. © 2012 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/pbc.24097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356788PMC
December 2012

Efficacy of gamma knife radiosurgery for small-volume recurrent malignant gliomas after initial radical resection.

World Neurosurg 2011 Jul-Aug;76(1-2):128-40; discussion 61-2

Department of Neurosurgery, New York University Langone Medical Center, New York, New York, USA.

Objective: To review the authors' experience with Gamma Knife radiosurgery (GKR) for small recurrent high-grade gliomas (HGGs) following prior radical resection, external-beam radiation therapy (EBRT), and chemotherapy with temozolomide (TMZ).

Methods: The authors retrospectively analyzed 26 consecutive adults (9 women and 17 men; median age 60.4 years; Karnofsky Performance Status [KPS]≥70) who underwent GKR for recurrent HGGs from 2004-2009. Median lesion volume was 1.22 cc, and median treatment dose was 15 Gy. Pathology included glioblastoma multiforme (GBM; n=16), anaplastic astrocytoma (AA; n=5), and anaplastic mixed oligoastrocytoma (AMOA; n=5). Two patients lost to follow-up were excluded from radiographic outcome analyses.

Results: Median overall survival (OS) for the entire cohort from the time of GKR was 13.5 months. Values for 12-month actuarial survival from time of GKR for GBM, AMOA, and AA were 37%, 20% and 80%. Local failure occurred in 9 patients (37.5%) at a median time of 5.8 months, and 18 patients (75%) experienced distant progression at a median of 4.8 months. Complications included radiation necrosis in two patients and transient worsening of hemiparesis in one patient. Multivariate hazard ratio (HR) analysis showed KPS 90 or greater, smaller tumor volumes, and increased time to recurrence after resection to be associated with longer OS following GKR.

Conclusions: GKR provided good local tumor control in this group of clinically stable and predominantly high-functioning patients with small recurrent HGGs after radical resection. Meaningful survival times after GKR were seen. GKR can be considered for selected patients with recurrent HGGs.
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http://dx.doi.org/10.1016/j.wneu.2010.12.053DOI Listing
October 2011

Postoperative intraperitoneal 5-fluoro-2'-deoxyuridine added to chemoradiation in patients curatively resected (R0) for locally advanced gastric and gastroesophageal junction adenocarcinoma.

Ann Surg Oncol 2012 Feb 19;19(2):478-85. Epub 2011 Jul 19.

Division of Medical Oncology, New York University Cancer Center, NYU Medical Center, New York, NY, USA.

Purpose: Chemoradiation after surgery for locally advanced gastric cancer improves overall and relapse-free survival compared with observation. However, locoregional recurrences remain high. Accordingly, we instituted this pilot/feasibility study, including intraperitoneal 5-fluoro-2'-deoxyuridine (IP FUDR) as part of the treatment.

Methods: Gastric/gastroesophageal junction adenocarcinoma stage Ib-IV (M0) patients who underwent R(0) resection were eligible and had IP catheters inserted at time of surgery. IP FUDR (3 g/dose/day) was given during study days 1-3 and 15-17 before combined 5-fluorouracil, leucovorin, and external beam radiation (45 Gy). Endpoints included toxicity, completion rate, locoregional recurrence, and survival.

Results: Twenty-eight patients (22 men) were enrolled from 2002-2006 at two institutions; their median age was 59.5 years. After R(0) resection, a median 22 (range, 8-102) lymph nodes were examined, and 22 patients had positive nodes. AJCC stages were IB (n = 8), II (n = 10), IIIA (n = 5), IIIB (n = 1), and IV (n = 4). Full-dose IP FUDR and chemoradiation treatment was completed in 20 and 25 patients, respectively. At nearly 4-year median follow-up, 11 patients were disease-free, 5 were alive with disease, 7 were dead of disease, and 1 was dead from other cause; 4 have been lost to follow-up. Recurrences were local in one, intra-abdominal in six, distant in two, multiple sites in two, and unknown in one. The median relapse-free survival is 65.3 months, and the median overall survival has not yet been reached.

Conclusions: IP FUDR before chemoradiation after R(0) gastric cancer resection is well tolerated without compromising completion of postoperative adjuvant treatment. Larger randomized trials studying IP FUDR as part of gastric cancer multidisciplinary treatment are needed to prove efficacy in reducing regional recurrence and improving survival.
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http://dx.doi.org/10.1245/s10434-011-1940-8DOI Listing
February 2012

Incidence, timing, and treatment of new brain metastases after Gamma Knife surgery for limited brain disease: the case for reducing the use of whole-brain radiation therapy.

J Neurosurg 2011 Jul 18;115(1):37-48. Epub 2011 Mar 18.

Department of Radiation Oncology, New York University Langone Medical Center, 530 First Ave, Suite 8R, New York, New York 10016, USA.

Object: In this paper, the authors' goal was to analyze the incidence, timing, and treatment of new metastases following initial treatment with 20-Gy Gamma Knife surgery (GKS) alone in patients with limited brain metastases without whole-brain radiation therapy (WBRT).

Methods: A retrospective analysis of 114 consecutive adults (75 women and 34 men; median age 61 years) with KPS scores of 60 or higher who received GKS for 1-3 brain metastases ≤ 2 cm was performed (median lesion volume 0.35 cm(3)). Five patients lacking follow-up data were excluded from analysis. After treatment, patients underwent MR imaging at 6 weeks and every 3 months thereafter. New metastases were preferentially treated with additional GKS. Indications for WBRT included development of numerous metastases, leptomeningeal disease, or diffuse surgical-site recurrence.

Results: The median overall survival from GKS was 13.8 months. Excluding the 3 patients who died before follow-up imaging, 12 patients (11.3%) experienced local failure at a median of 7.4 months. Fifty-three patients (50%) developed new metastases at a median of 5 months. Six (7%) of 86 instances of new lesions were symptomatic. Most patients (67%) with distant failures were successfully treated using salvage GKS alone. Whole-brain radiotherapy was indicated in 20 patients (18.3%). Thirteen patients (11.9%) died of neurological disease.

Conclusions: For patients with limited brain metastases and functional independence, 20-Gy GKS provides excellent disease control and high-functioning survival with minimal morbidity. New metastases developed in almost 50% of patients, but additional GKS was extremely effective in controlling disease. Using our algorithm, fewer than 20% of patients required WBRT, and only 12% died of progressive intracranial disease.
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http://dx.doi.org/10.3171/2011.2.JNS101724DOI Listing
July 2011

Local control of newly diagnosed and distally recurrent, low-volume brain metastases with fixed-dose (20 gy) gamma knife radiosurgery.

Neurosurgery 2011 Apr;68(4):921-31; discussion 931

Department of Neurosurgery, New York University Langone Medical Center, New York, New York 10016, USA.

Background: Metastases to the brain occur in 20% to 30% of patients with cancer and have been identified on autopsy in as many as 50% of patients.

Objective: To analyze the efficacy of 20-Gy Gamma Knife radiosurgery (GKR) as initial treatment in patients with 1 to 3 brain metastases ≤ 2 cm in greatest diameter.

Methods: A retrospective analysis of 114 consecutive adults with Karnofsky performance status ≥ 60 who received GKR for 1 to 3 brain metastases ≤ 2 cm in size was performed. Five patients lacked detailed follow-up and were excluded, leaving 109 for outcome analysis (34 men and 75 women; median age, 61.2 years). All metastases received 20 Gy to the 50% isodose line.

Results: One hundred nine patients underwent treatment of 164 metastases at initial GKR. Twenty-six patients (23.9%) were alive at last follow-up (median time, 29.9 months; range, 6.6 months to 7.8 years). The median overall survival was 13.8 months (range, 1 day to 7.6 years). Among the 52 patients with distant failure, 33 patients received 20 Gy to 95 new lesions. A total of 259 metastases received 20 Gy, and 4 patients lacked imaging follow-up secondary to death before posttreatment imaging. Local failure occurred in 17 of 255 treated lesions (6.7%), yielding an overall local control rate of 93.3%. Actuarial local control at 6, 12, 24, and 36 months was 96%, 93%, 89%, and 88%, respectively. Permanent neurological complications occurred in 3 patients (2.8%).

Conclusion: Among patients with 1 to 3 brain metastases ≤ 2 cm in size who have not received whole-brain radiation therapy, GKR with 20 Gy provides high rates of local control with low morbidity and excellent neurological symptom-free survival.
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http://dx.doi.org/10.1227/NEU.0b013e318208f58eDOI Listing
April 2011

Neurological complications and symptom resolution following Gamma Knife surgery for brain metastases 2 cm or smaller in relation to eloquent cortices.

J Neurosurg 2010 Dec;113 Suppl:53-64

Department of Neurosurgery, New York University Langone Medical Center, New York, New York 10016, USA.

Object: Reports on resection of tumors in or near eloquent cortices have noted neurological complications in up to 30% of patients. This paper contains an analysis of symptom resolution and neurological morbidity following 20-Gy Gamma Knife surgery (GKS) for supratentorial brain metastases < or = 2 cm in greatest diameter.

Methods: The authors performed a retrospective analysis of 98 consecutively treated adults (33 men and 65 women with a median age of 61.4 years at the time of GKS) with Karnofsky Performance Scale score > or = 60, who underwent GKS for supratentorial brain metastases < or = 2 cm in diameter. Lesion location was classified as noneloquent (Grade I), near eloquent (Grade II), or eloquent (Grade III), in accordance with the grading system developed by the group at M. D. Anderson Cancer Center. Following treatment, the patients underwent MR imaging and clinical examinations at 6 weeks and every 3 months thereafter.

Results: Ninety-eight patients underwent 20-Gy GKS for 131 metastases at initial presentation and 31 patients underwent salvage 20-Gy GKS for 76 new lesions, for a total of 207 lesions (mean lesion volume 0.44 cm3). Lesions were classified as follows: Grade I, 96 (46.4%); Grade II, 51 (24.6%); and Grade III, 60 (29%). Fifteen patients (2 with Grade II and 13 with Grade III lesions) presented with deficits referable to their lesions, yielding pre-GKS deficit rates of 7.2% per lesion and 15.3% per patient. The pre-GKS deficits improved or resolved in 10 patients (66.7%) at a median time of 2.8 months and remained stable in 3 patients (20%). Two patients (13.3%) experienced worsened neurological deficits. One patient who was neurologically intact prior to treatment developed a new hemiparesis (1 of 83 patients [1.2%]). The rates of permanent neurological deterioration following GKS for Grades I, II, and III lesions were 0% (0 of 96 tumors), 2% (1 of 51), and 3.3% (2 of 60), respectively. The pre-GKS neurological deficits and larger lesions were the most significant risk factors for post-GKS neurological deterioration.

Conclusions: Gamma Knife surgery performed using a 20-Gy dose provides amelioration of neurological deficits from brain metastases that are < or = 2 cm in diameter and located in or near eloquent cortices in nearly two-thirds of patients with a low incidence of morbidity. Consistent with the surgical literature, higher rates of neurological complications were observed as proximity to eloquent regions and lesion size increased. There was no neurological deterioration in patients harboring metastases in noneloquent areas.
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December 2010

Prospective neuraxis MRI surveillance reveals a high risk of leptomeningeal dissemination in diffuse intrinsic pontine glioma.

J Neurooncol 2011 Mar 10;102(1):121-7. Epub 2010 Jul 10.

Department of Radiation Oncology, New York University Langone Medical Center, 566 First Avenue, New York, NY 10014, USA.

Prognosis of diffuse intrinsic pontine gliomas (DIPGs) remains poor. Failure has been predominantly local, with leptomeningeal dissemination (LD) occurring in 4-33% of patients in pre-MRI era series. Routine craniospinal imaging after initial treatment may reveal other relapse patterns relapse. Sixteen consecutive pediatric patients with DIPG treated between 2006 and 2009 were retrospectively reviewed. Treatment regimens, recurrence patterns, survival, and pathologic diagnosis were recorded. Fourteen patients received involved-field radiotherapy to 54 Gy, and two patients received craniospinal irradiation for LD at presentation. Neuraxis MRI was performed at diagnosis and at 4 month intervals following radiotherapy. Fifteen patients have had progression of disease (median progression-free survival 5.0 ± 1.2 months), and 13 patients have died (median survival 9.0 ± 1.4 months). Local failure occurred in 12 patients (75%). LD occurred in nine patients (56%). LD was present at diagnosis in three patients, after initial staging and treatment in six patients, and during autopsy in two patients. Median overall survival was 12.0 ± 3.3 months without LD and 8.0 ± 2.1 months with LD (P = 0.059, log rank test). Median progression-free survival was 9.5 ± 3.9 months without LD and 3.0 ± 2.1 months with LD (P = 0.012, log rank test). The high incidence of LD probably reflects liberal use of spine MRI surveillance. All patients should undergo routine craniospinal imaging at diagnosis and follow-up. Central nervous system prophylaxis should be considered in future clinical trials.
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http://dx.doi.org/10.1007/s11060-010-0301-yDOI Listing
March 2011

Clinical outcomes in extracranial tumor sites and unusual toxicities with concurrent whole brain radiation (WBRT) and Erlotinib treatment in patients with non-small cell lung cancer (NSCLC) with brain metastasis.

Lung Cancer 2010 Nov 6;70(2):174-9. Epub 2010 Mar 6.

Department of Pediatrics, Maimonides Medical Center, 4802 Tenth Avenue, Brooklyn, NY 11219, USA.

Background: Thirty percent of newly diagnosed NSCLC patients present with synchronous brain metastases, most of whom are treated with whole brain radiation. Systemic chemotherapy is usually avoided during WBRT due to concerns regarding toxicity. However, concurrent administration of targeted agents, such as Erlotinib, during WBRT may address systemic disease without causing toxicity. We report our institutional data on outcomes and toxicities with this treatment approach.

Materials And Methods: Medical records of patients with newly diagnosed NSCLC and brain metastases receiving concurrent WBRT and Erlotinib treatment were reviewed. Radiographic response to therapy and toxicities were analyzed.

Result: Eight patients were identified and 7 were evaluable for response. All patients had intracranial disease control. In the extracranial sites, 3 (37.5%, intent-to-treat) showed partial response (PR), 2 (25%) had stable disease (SD), 1 (12.5%) had progression (PD) and 1 (12.5%) had new air space disease obscuring tumor response assessment. Among the three responders, two were female never smokers, while one was a female current smoker. Unanticipated grade 3 hepatotoxitity, hyponatremia, mental status changes, grade 3 and 4 thrombocytopenia, and grade 4 neutropenia with sepsis were observed. Three deaths occurred without clear signs of disease progression: one from neutropenic sepsis, one from wide spread air space disease, and one from neurologic deterioration.

Conclusion: Our data demonstrates a high percentage of extracranial tumor response rates with first line Erlotinib in selected NSCLC patients. We observed unexpected serious complications and postulate possible mechanisms. We recommend caution to be exercised when considering Erlotinib treatment during WBRT, particularly in regard to drug-drug interactions and infection control. Data from prospective trials are needed to determine the benefits and toxicities of Erlotinib during WBRT.
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http://dx.doi.org/10.1016/j.lungcan.2010.01.018DOI Listing
November 2010

A phase II study of preradiotherapy chemotherapy followed by hyperfractionated radiotherapy for newly diagnosed high-risk medulloblastoma/primitive neuroectodermal tumor: a report from the Children's Oncology Group (CCG 9931).

Int J Radiat Oncol Biol Phys 2009 Jul 7;74(4):1006-11. Epub 2009 Apr 7.

Departments of Pediatrics and Pathology, New York University Medical Center, New York, NY 10016, USA.

Purpose: To verify feasibility and monitor progression-free survival and overall survival in children with high-risk medulloblastoma and noncerebellar primitive neuroectodermal tumors (PNETs) treated in a Phase II study with preradiotherapy chemotherapy (CHT) followed by high-dose, hyperfractionated craniospinal radiotherapy (CSRT).

Methods And Materials: Eligibility criteria included age >3 years at diagnosis, medulloblastoma with either high M stage and/or >1.5 cm(2) postoperative residual disease, and all patients with noncerebellar PNET. Treatment was initiated with five alternating monthly cycles of CHT (A [cisplatin, cyclophosphamide, etoposide, and vincristine], B [carboplatin and etoposide], A, B, and A) followed by hyperfractionated CSRT (40 Gy) with a boost to the primary tumor (72 Gy) given in twice-daily 1-Gy fractions.

Results: The valid study group consisted of 124 patients whose median age at diagnosis was 7.8 years. Eighty-four patients (68%) completed the entire protocol according to study guidelines (within 9 months), and the median time to complete CSRT was 1.6 months. Major reasons for failure to complete CHT included progressive disease (17%) and toxic death (2.4%). The 5-year progression-free survival and overall survival rates were 43% +/- 5% and 52% +/- 5%, respectively. No significant differences were detected in subset analysis related to response to CHT, site of primary tumor, postoperative residual disease, or M stage.

Conclusions: The feasibility of this intensive multimodality protocol was confirmed, and response to pre-RT CHT did not impact on survival. Survival data from this protocol can not be compared with data from other studies, given the protocol design.
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http://dx.doi.org/10.1016/j.ijrobp.2008.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739055PMC
July 2009

Phase I/II trial of induction chemotherapy followed by concurrent chemoradiotherapy and surgery for locoregionally advanced pancreatic cancer.

Ann Surg Oncol 2008 Dec 2;15(12):3521-31. Epub 2008 Oct 2.

Department of Surgery, Division of Surgical Oncology, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.

Background: We used a novel combination of induction chemotherapy with gemcitabine (GEM) and cisplatin (CDDP), followed by concurrent chemoradiotherapy (CCRT) with the same agents in patients with locoregionally advanced pancreatic cancer. Surgery or additional chemotherapy followed on the basis of response.

Methods: Patients with borderline resectable or locally advanced pancreatic cancer received induction weekly with GEM (1000 mg/m(2)) or CDDP (30 g/m(2)). Patients without progression of disease then underwent surgery or CCRT, including four cohorts of escalating GEM/CDDP doses combined with full-dose radiotherapy. After CCRT, patients deemed resectable underwent surgery; patients with disease that remained unresectable and that did not progress received additional GEM/CDDP for 2 months.

Results: A mean 76% of intended GEM dose and 75% of CDDP dose was delivered during induction (n = 26). There were three incidences of grade 4 toxicity (fever or neutropenia). After induction, five patients progressed and one patient underwent resection. Eighteen patients received CCRT, and three patients underwent resection. After CCRT, disease of 10 patients progressed, and in 5 patients, it remained unresectable without progression, and the patient received additional GEM/CDDP. Dose-limiting toxicity was at dose level IV (thrombocytopenia). Median overall and disease-specific survival was 13 months.

Conclusion: GEM/CDDP induction chemotherapy followed by CCRT is well tolerated and rendered the disease of 4 of 26 patients resectable in this study. The recommended phase II dose for GEM and CDDP in combination with full-dose radiotherapy (5040 cGy) is 300 mg/m(2) and 10 mg/m(2) weekly for 5 weeks. Median survival in this group was 13 months. This neoadjuvant combined modality approach is both feasible and active; further studies are warranted.
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http://dx.doi.org/10.1245/s10434-008-0152-3DOI Listing
December 2008

Chapter resident education.

J Am Coll Radiol 2004 Oct;1(10):788

New York University Medical Center, Department of Radiation Oncology, New York, NY 10016, USA.

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http://dx.doi.org/10.1016/j.jacr.2004.05.024DOI Listing
October 2004

Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma.

J Clin Oncol 2006 Sep;24(25):4202-8

Division of Neurology, Children's National Medical Center, Washington, DC 20010, USA.

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.
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http://dx.doi.org/10.1200/JCO.2006.06.4980DOI Listing
September 2006

Results of surgical resection for progression of brain metastases previously treated by gamma knife radiosurgery.

Neurosurgery 2006 Jul;59(1):86-97; discussion 86-97

Department of Radiation Oncology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Objective: To determine treatment outcome after surgical resection for progressive brain metastases after gamma knife radiosurgery (GKR) and to explore the role of dynamic contrast agent-enhanced perfusion magnetic resonance imaging (MRI) and proton spectroscopic MRI studies (MRS/P) in predicting pathological findings.

Methods: Between 1997 and 2002, 32 patients underwent surgical resection for suspected progression of brain metastases from a cohort of 245 patients with brain metastases treated with GKR. Postradiosurgery MRI surveillance was performed at 6 and 12 weeks, and then every 12 weeks after GKR. In some cases, additional MRI scanning with spectroscopy or perfusion (MRS/P) was used to aid differentiation of radiation change from tumor progression. The decision to perform neurosurgical resection was based on MRI or clinical evidence of lesion progression among patients with a Karnofsky performance score of 60 or more and absent or stable systemic disease.

Results: Thirteen percent (32 out of 245) of patients and 6% (38 out of 611) of lesions required surgical resection after GKR. The median time from GKR to surgical resection was 8.6 months (range, 1.7-27.1 mo). The 6-, 12-, and 24-month actuarial survival from time of GKR was 97, 78, and 47% for the resected patients and 65, 40, and 19% for the nonresected patients (P < 0.0001). The two-year survival rate of patients requiring two resections after GKR was 100% compared with 39% for patients undergoing one resection (P = 0.02). The median survival of resected patients was 27.2 months (range, 7.0-72.5 mo) from the diagnosis of brain metastases, 19.9 months (range, 5.0-60.7 mo) from GKR, and 8.9 months (range, 0.2-53.1 mo) from surgical resection. Tumor was found in 90% of resected specimens and necrosis alone in 10%. MRS/P studies were performed in 15 resected patients. Overall, MRS/P predicted tumor in 11 lesions, confirmed pathologically in nine lesions, and necrosis alone was found in two. The MRS/P predicted necrosis alone in three, whereas pathology revealed viable tumor in two and necrosis in one lesion.

Conclusion: Surgical intervention of progressive brain metastases after GKR in selected patients leads to a meaningful improvement in survival rates. Further studies are necessary to determine the role of MRS/P in the postradiosurgery surveillance of brain metastases.
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http://dx.doi.org/10.1227/01.NEU.0000219858.80351.38DOI Listing
July 2006

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

J Clin Oncol 2005 Oct;23(30):7621-31

Children's Hospital and Regional Medical Center, Department of Pediatric Hematology-Oncology, Seattle, WA 98105, USA.

Purpose: To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis.

Patients And Methods: Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed.

Results: Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy.

Conclusion: Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.
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http://dx.doi.org/10.1200/JCO.2005.09.095DOI Listing
October 2005

Patterns of treatment failure in infants with primitive neuroectodermal tumors who were treated on CCG-921: a phase III combined modality study.

Pediatr Blood Cancer 2005 Oct;45(5):676-82

Department of Human Oncology, School of Medicine, University of Wisconsin, Madison, WI 53792, USA.

Purpose: To analyze patterns of treatment failure in infants with primitive neuroectodermal tumors (PNETs) who were treated primarily with chemotherapy in a large multi-institutional study.

Materials And Methods: Sixty-five prospectively staged patients with PNET confirmed by central pathology review, who were 18 months or younger were treated on Children's Cancer Group Study 921 (CCG-921) primarily with chemotherapy. Forty-six patients had posterior fossa (PF) primary tumors and 19 patients had supratentorial (ST) primaries. Patterns of sites of initial treatment failure were analyzed and compared to failure patterns of 180 older children who had PF-PNETs, and 44 older children with ST-PNETs who were treated on the same protocol.

Results: The entire cohort of younger patients fared much worse than those older than 18 months. Cumulative 5-year relapse incidence (+/-SE) for younger patients with PF-PNETs was 64.5 +/- 8.9% for patients without metastases (M0) compared to 71.4 +/- 13.4% for patients with metastases (M+). The cumulative 5-year relapse incidences for younger patients with ST-PNETs were 64.3 +/- 13.7% for M0 patients compared to 100 +/- 33.3% for M+ patients. Relapses in these patients occurred within 2 years. The overall treatment failure rate was significantly higher for younger compared to older patients with PF-PNET and ST-PNET. There was no statistically significant difference in relapse patterns between patients with PF primary tumors and ST primaries when stratified by stage. There was no statistically significant difference in relapse patterns between M0 and M+ patients. All patients had a high risk of recurrence at primary tumor site. Younger patients who had PF primary tumors without metastasis at presentation were significantly more likely to relapse in PF than older patients. Younger patients were at significant risk of relapse in the spine, but none had it as the sole site of first relapse.

Conclusions: Despite aggressive chemotherapy, younger children with PNETs have high rates of treatment failure and fare worse than high-risk, older patients with PF-PNETs, indicating the need to maximize local, regional, and systemic therapies.
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http://dx.doi.org/10.1002/pbc.20184DOI Listing
October 2005
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