Publications by authors named "James G Douglas"

28 Publications

  • Page 1 of 1

The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial.

Blood 2014 Mar 4;123(13):2017-25. Epub 2014 Feb 4.

Division of Hematology and Hematological Malignancies, Huntsman Cancer Institute/University of Utah School of Medicine, Primary Children's Hospital, Salt Lake City, UT;

Sirolimus has activity against acute lymphoblastic leukemia (ALL) in xenograft models and efficacy in preventing acute graft-versus-host disease (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children with ALL would decrease aGVHD and relapse. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 patients. Rate of Grade 2-4 aGVHD was 31% vs 18% (standard vs experimental, P = .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P = .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P = .05; 1% vs 10% TMA, P = .06). At 2 years, event free survival (EFS) and overall survival (OS) were 56% vs 46%, and 65% vs 55% (standard vs experimental), respectively (P = .28 and .23). Multivariate analysis showed increased relapse risk in children with ≥0.1% minimal residual disease (MRD) pretransplant, and decreased risk in patients with grades 1-3 aGVHD (P = .04). Grades 1-3 aGVHD were associated with improved EFS (P = .02), whereas grade 4 aGVHD and extramedullary disease at diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. This study is registered with ClinicalTrials.gov as #NCT00382109.
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http://dx.doi.org/10.1182/blood-2013-10-534297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968388PMC
March 2014

Pediatric CSI: are protons the only ethical approach?

Int J Radiat Oncol Biol Phys 2013 Oct;87(2):228-30

Melvin & Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

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http://dx.doi.org/10.1016/j.ijrobp.2013.05.037DOI Listing
October 2013

Neutron radiotherapy for adenoid cystic carcinoma of the lacrimal gland.

Ophthalmic Plast Reconstr Surg 2013 Jul-Aug;29(4):256-60

University of Washington Medical Center, Seattle, Washington 98195, USA.

Purpose: Lacrimal gland adenoid cystic carcinomas are rare, aggressive orbital tumors that share histopathologic similarities with salivary gland malignancies. Neutron radiotherapy may be useful for treatment due to its high biological effectiveness for salivary malignancies.

Methods: The authors retrospectively reviewed the outcomes for 11 lacrimal gland adenoid cystic carcinoma patients treated with neutrons from 1988 to 2011. Most had undergone surgery prior to radiation therapy. However, gross residual disease was present in 8 patients. The most common American Joint Committee on Cancer stage was T4cN0M0. Four patients with skull base involvement received a radiosurgery boost and 1 received a proton therapy boost.

Results: Median follow up was 6.2 years. Median overall survival was 11.1 years and median disease-free survival was 6.3 years. Five-year local control was estimated by the Kaplan-Meier method as 80%. Three patients had a local recurrence; 4 developed distant metastases. Six patients died. Seven patients had intact vision in the affected eye before neutron radiation. Two required enucleation for a painful dry eye. Of the 5 who avoided an enucleation, 3 had either severe visual impairment (20/400) or only light perception and 2 were without known vision compromise or complications at the time of their death. One patient developed asymptomatic frontal lobe radionecrosis after 2 courses of radiation therapy.

Conclusions: Neutron radiation therapy achieved excellent 5-year local control in this series of high-risk patients, with most cases having gross residual disease. Late recurrences and distant metastases remain a challenge. Meaningful ipsilateral vision preservation was not possible in most cases in the long term, although only 2 patients required an enucleation for treatment effects.
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http://dx.doi.org/10.1097/IOP.0b013e318295f99bDOI Listing
January 2014

Definitive treatment of leptomeningeal spinal metastases in children.

Pediatr Blood Cancer 2013 Nov 20;60(11):1839-41. Epub 2013 Jun 20.

Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana; IU Health Proton Therapy Center, Bloomington, Indiana.

Background: Uniquely in children, the existence of leptomeningeal spinal metastases does not confer a uniformly grave prognosis. Although the radiation tolerance of the spinal cord is of significant concern in these cases, the chemo- and radiosensitivity of these lesions argues for an aggressive approach where possible.

Methods: The records of the Indiana University Health Proton Therapy Center were reviewed for patients undergoing proton beam therapy with curative intent for LSM between January 1, 2004 and July 7, 2012. Patients with microscopic disease only on LP were not included. Particulars of therapy, including dose, field sizes, toxicities, and outcomes were collated.

Results: Twenty-two children received therapy as described, of median age 5 years (range 1.1-17.1). Patients had medulloblastoma (n = 9), ATRT (n = 4), ependymoma, and PNET (n = 3 each). Five lesions (23%) were chemo-recurrent, though no patient had prior radiation to the spine. Median follow-up was 14 months (range 4-33) for all living patients. Fifteen (68%) children continued to have local control at last follow-up visit. Median dose was 37.8 Gy (range 21.6-54 Gy). Eight patients with chemo-recurrent disease or diffuse cord seeding did poorly, with local control and overall survival achieved in four. The 12-month overall survival was 68% with grade 1 skin erythema as the most frequent toxicity.

Conclusions: We describe a cohort of LSM patients treated with RT with definitive intent, and the only available data from the proton environment. Durable response is possible for these children in over two-thirds of cases. Significant toxicity was infrequent using proton radiotherapy and these fractionation schemes.
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http://dx.doi.org/10.1002/pbc.24659DOI Listing
November 2013

Repetitive pediatric anesthesia in a non-hospital setting.

Int J Radiat Oncol Biol Phys 2013 Apr 1;85(5):1296-300. Epub 2012 Dec 1.

Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Purpose: Repetitive sedation/anesthesia (S/A) for children receiving fractionated radiation therapy requires induction and recovery daily for several weeks. In the vast majority of cases, this is accomplished in an academic center with direct access to pediatric faculty and facilities in case of an emergency. Proton radiation therapy centers are more frequently free-standing facilities at some distance from specialized pediatric care. This poses a potential dilemma in the case of children requiring anesthesia.

Methods And Materials: The records of the Indiana University Health Proton Therapy Center were reviewed for patients requiring anesthesia during proton beam therapy (PBT) between June 1, 2008, and April 12, 2012.

Results: A total of 138 children received daily anesthesia during this period. A median of 30 fractions (range, 1-49) was delivered over a median of 43 days (range, 1-74) for a total of 4045 sedation/anesthesia procedures. Three events (0.0074%) occurred, 1 fall from a gurney during anesthesia recovery and 2 aspiration events requiring emergency department evaluation. All 3 children did well. One aspiration patient needed admission to the hospital and mechanical ventilation support. The other patient returned the next day for treatment without issue. The patient who fell was not injured. No patient required cessation of therapy.

Conclusions: This is the largest reported series of repetitive pediatric anesthesia in radiation therapy, and the only available data from the proton environment. Strict adherence to rigorous protocols and a well-trained team can safely deliver daily sedation/anesthesia in free-standing proton centers.
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http://dx.doi.org/10.1016/j.ijrobp.2012.10.006DOI Listing
April 2013

A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain Tumor Consortium.

Neuro Oncol 2011 Mar 3;13(3):290-7. Epub 2011 Feb 3.

Department of Neurosurgery, Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.

This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provided patients had a characteristic clinical history and MRI findings. Treatment consisted of gefitinib, administered orally, 250 mg/m(2)/day, during standard external beam radiotherapy, continuing for up to 13 monthly courses in the absence of disease progression or unacceptable toxicity. Toxicities, particularly intratumoral hemorrhage, were monitored. Pharmacokinetics and investigational imaging studies were performed in consenting patients. Forty-three eligible patients were included in the study. Therapy was well tolerated; only 4 patients were withdrawn from the study for dose-limiting toxicity after receiving therapy for 6, 9, 17, and 24 weeks. The 12- and 24-month progression-free survival rates were 20.9 ±5.6 % and 9.3 ±4%, respectively. Overall survival rates were 56.4 ±7.6% and 19.6 ±5.9%, respectively, which appear nominally superior to other contemporaneous Pediatric Brain Tumor Consortium trials. Three patients remain progression-free survivors with ≥36 months follow-up. The observation that a subset of children with this generally fatal tumor experienced long-term progression-free survival, coupled with recent observations regarding the molecular features of brainstem gliomas, raises the possibility that prospective molecular characterization may allow enrichment of treatment responders and improvement in outcome results in future studies of biologically targeted agents.
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http://dx.doi.org/10.1093/neuonc/noq199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064605PMC
March 2011

A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas.

Eur J Cancer 2010 Dec 12;46(18):3287-93. Epub 2010 Aug 12.

Seattle Children's Hospital, Seattle, WA, USA.

Purpose: To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ⩽21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG.

Patients And Methods: Three strata were identified: stratum 1A--BSG; stratum IB--incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II--incompletely resected STMG receiving EIACD. Dose escalation using a modified 3+3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100mg/m(2)/d commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients.

Results: Of the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100mg/m(2)/d, 1 of 10 at 250 mg/m(2)/d and 3 of 12 at 375 mg/m(2)/d. Subsequently a second patient at 250 mg/m(2)/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage (p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples.

Conclusion: This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m(2)/d was selected for the phase II trial.
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http://dx.doi.org/10.1016/j.ejca.2010.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988095PMC
December 2010

Impact of cranial irradiation added to intrathecal conditioning in hematopoietic cell transplantation in adult acute myeloid leukemia with central nervous system involvement.

Int J Radiat Oncol Biol Phys 2011 May 30;80(1):193-8. Epub 2010 Jun 30.

Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA 98195-6043, USA.

Purpose: Neither the prognostic importance nor the appropriate management of central nervous system (CNS) involvement is known for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We examined the impact of a CNS irradiation boost to standard intrathecal chemotherapy (ITC).

Methods And Materials: From 1995 to 2005, a total of 648 adult AML patients received a myeloablative HCT: 577 patients were CNS negative (CNS-), and 71 were CNS positive (CNS+). Of the 71 CNS+ patients, 52 received intrathecal chemotherapy alone (CNS+ITC), and 19 received ITC plus an irradiation boost (CNS+RT).

Results: The CNS-, CNS+ITC, and CNS+RT patients had 1- and 5-year relapse-free survivals (RFS) of 43% and 35%, 15% and 6%, and 37% and 32%, respectively. CNS+ITC patients had a statistically significant worse RFS compared with CNS- patients (hazard ratio [HR], 2.65; 95% confidence interval [CI], 2.0-3.6; p < 0.0001). CNS+RT patients had improved relapse free survival over that of CNS+ITC patients (HR, 0.45; 95% CI, 0.2-0.8; p = 0.01). The 1- and 5-year overall survivals (OS) of patients with CNS-, CNS+ITC, and CNS+RT, were 50% and 38%, 21% and 6%, and 53% and 42%, respectively. The survival of CNS+RT were significantly better than CNS+ITC patients (p = 0.004). After adjusting for known risk factors, CNS+RT patients had a trend toward lower relapse rates and reduced nonrelapse mortality.

Conclusions: CNS+ AML is associated with a poor prognosis. The role of a cranial irradiation boost to intrathecal chemotherapy appears to mitigate the risk of CNS disease, and needs to be further investigated to define optimal treatment strategies.
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http://dx.doi.org/10.1016/j.ijrobp.2010.01.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297488PMC
May 2011

DTI fiber tracking to differentiate demyelinating diseases from diffuse brain stem glioma.

Neuroimage 2010 Aug 2;52(1):217-23. Epub 2010 Apr 2.

Department of Neurological Surgery, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.

Object: Intrinsic diffuse brainstem tumors and demyelinating diseases primarily affecting the brainstem can share common clinical and radiological features, sometimes making the diagnosis difficult especially at the time of first clinical presentation. To explore the potential usefulness of new MRI sequences in particular diffusion tensor imaging fiber tracking in differentiating these two pathological entities, we review a series of brainstem tumors and demyelinating diseases treated at our institution.

Material And Methods: The clinical history including signs and symptoms and MRI findings of three consecutive demyelinating diseases involving the brainstem that presented with diagnostic uncertainty and three diffuse intrinsic brainstem tumors were reviewed, along with a child with a supratentorial tumor for comparison. Fiber tracking of the pyramidal tracts was performed for each patient using a DTI study at the time of presentation. Additionally Fractional Anisotropy values were calculated for each patient in the pons and the medulla oblongata.

Results: Routine MR imaging was unhelpful in differentiating between intrinsic tumor and demyelination. In contrast, retrospective DTI fiber tracking clearly differentiated the pathology showing deflection of the pyramidal tracts posteriorly and laterally in the case of intrinsic brainstem tumors and, in the case of demyelinating disease, poorly represented and truncated fibers. Regionalized FA values were variable and of themselves were not predictive either pathology.

Conclusion: DTI fiber tracking of the pyramid tracts in patients with suspected intrinsic brainstem tumor or demyelinating disease presents two clearly different patterns that may help in differentiating between these two pathologies when conventional MRI and clinical data are inconclusive.
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http://dx.doi.org/10.1016/j.neuroimage.2010.03.079DOI Listing
August 2010

Thrombosis and hemorrhage in the acute period following Gamma Knife surgery for arteriovenous malformation. Case report.

J Neurosurg 2009 Jul;111(1):124-31

Department of Neurological Surgery, University of Washington, Seattle, WA 98104-2499, USA.

Bleeding of an arteriovenous malformation (AVM) following stereotactic radiosurgery (SRS) is a known risk during the latency interval, but hemorrhage in the 30-day period following radiosurgery rarely has been reported in the literature. The authors present the case of a 57-year-old man who underwent Gamma Knife surgery for a large AVM, and they provide radiographic documentation of a thrombus in the primary draining vein immediately preceding an AVM hemorrhage within 9 days after radiosurgery. They postulate that the pathophysiology of an AVM hemorrhage in the acute period following SRS is related to an association among tissue irradiation, acute inflammatory response, and vessel thrombosis. The authors also review the literature on risk factors for hemorrhage due to untreated and radiosurgically treated AVMs. Recent evidence on the role of inflammation in the pathogenesis of AVMs and the pathophysiology of AVM rupture is presented. Inflammatory markers have been demonstrated in brain AVM tissue, and the association between inflammation and AVM hemorrhage has been established. There is an acute inflammatory response following tissue irradiation, resulting in structural and functional vascular changes that can lead to vessel thrombosis. Early hemorrhage following radiosurgical treatment of AVMs may be related to the acute inflammatory response and associated vascular changes that occur in irradiated tissue. In the first stage of a planned 2-stage Gamma Knife treatment for a large AVM in the featured case, the superior posteromedial portion of the primary draining vein was included in the treatment field. The authors present the planning images and subsequent CT scans demonstrating a new venous thrombus in the primary draining vein. An acute inflammatory response following radiosurgery with resultant acute venous thrombus formation and venous obstruction is proposed as one mechanism of an AVM hemorrhage in this patient. Radiographic evidence of the time course of thrombosis and hemorrhage supports the hypothesis that acute venous obstruction is a cause of intracranial hemorrhage.
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http://dx.doi.org/10.3171/2009.1.JNS08784DOI Listing
July 2009

Treatment of arteriovenous malformations using Gamma Knife surgery: the experience at the University of Washington from 2000 to 2005.

J Neurosurg 2008 Dec;109 Suppl:51-6

Department of Radiation Oncology, University of Washington Cancer Center, Seattle, Washington 98195-6043, USA.

Object: The purpose of this study was to examine the efficacy and toxicity of treating arteriovenous malformations (AVMs) with the model 3C Gamma Knife at the University of Washington Medical Center.

Methods: Ninety-five evaluable patients with 99 treatable AVMs were treated at the University of Washington Medical Center from April 2000 through June 2005. The median patient age at the time of treatment was 40 years (range 6-68 years). The male to female patient ratio was 0.98:1. The median AVM volume treated was 3.8 cm(3) (range 0.12-32 cm(3)). Forty-four percent of the patients had hemorrhaged prior to treatment. The median peripheral Gamma Knife surgery dose was 20 Gy with a median of 12 isocenters treated. The median follow-up duration was 38 months (range 3-91 months). Eighty-one percent of the patients had no previous stereotactic radiosurgery (SRS), whereas the remaining 19% had previously been treated with linear accelerator-based SRS.

Results: The Kaplan-Meier estimated 6-year AVM obliteration rate for the entire cohort was 71.4%. The Kaplan-Meier estimated 6-year obliteration rate was 72% for patients having no prior SRS and 54.5% for those undergoing repeat SRS. The median time to AVM obliteration was 47 months, with 90% of the obliterations occurring between 24 and 58 months. Eight patients (7.4%) experienced late toxicities. There were 2 fatal bleeds and 13 (13.8%) nonfatal bleeds after Gamma Knife surgery.

Conclusions: Gamma Knife surgery is an effective treatment for AVMs, resulting in an excellent obliteration rate with acceptable toxicity.
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http://dx.doi.org/10.3171/JNS/2008/109/12/S9DOI Listing
December 2008

Treatment of locally advanced adenoid cystic carcinoma of the trachea with neutron radiotherapy.

Int J Radiat Oncol Biol Phys 2008 Oct 18;72(2):410-4. Epub 2008 Apr 18.

Department of Radiation Oncology, University of Washington Medical Center, Seattle, WA 98195, USA.

Purpose: To examine the efficacy of fast neutron radiotherapy in the treatment of locally advanced adenoid cystic carcinoma (ACC) of the trachea and to compare outcomes with and without high-dose-rate (HDR) endobronchial brachytherapy boost.

Methods And Materials: Between 1989 and 2005, a total of 20 patients with ACC of the trachea were treated with fast neutron radiotherapy at the University of Washington. Of these 20 patients, 19 were treated with curative intent. Neutron doses ranged from 10.7 to 19.95 Gy (median, 19.2 Gy). Six of these patients received an endobronchial brachytherapy boost using an HDR (192)Ir source (3.5 Gy x 2 fractions). Median duration of follow-up was 46 months (range, 10-121 months).

Results: The 5-year actuarial overall survival rate and median overall survival for the entire cohort were 89.4%, and 97 months, respectively. Overall survival was not statistically different among those patients receiving an endobronchial boost compared with those receiving neutron radiotherapy alone (100% vs. 68%, p = 0.36). The 5-year actuarial locoregional control rate for the entire cohort was 54.1%. The locoregional control rate was not statistically different among patients who received an endobronchial boost compared with those who received neutron radiotherapy alone (40% vs. 58%, p = 0.94). There were no cases of Grade > or =3 acute toxicity. There were 2 cases of Grade 3/4 chronic toxicity.

Conclusions: Fast neutron radiotherapy is an effective treatment for locally advanced adenoid cystic carcinoma of the trachea, with acceptable treatment-related toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2008.01.016DOI Listing
October 2008

Positron emission tomography-guided conformal fast neutron therapy for glioblastoma multiforme.

Neuro Oncol 2008 Feb 30;10(1):88-92. Epub 2007 Nov 30.

Celilo Radiation Therapy, Mid-Columbia Medical Center, Dalles, OR, USA.

Glioblastoma multiforme (GBM) continues to be a difficult therapeutic challenge. Our study was conducted to determine whether improved survival and tumor control could be achieved with modern delivery of fast neutron radiation using three-dimensional treatment planning. Ten patients were enrolled. Eligibility criteria included pathologic diagnosis of GBM, age >or=18 years, and KPS >or=60. Patients underwent MRI and (18)F-fluorodeoxyglucose PET (FDG PET) as part of initial three-dimensional treatment planning. Sequential targets were treated with noncoplanar fields to a total dose of 18 Gy in 16 fractions over 4 weeks. Median and 1-year overall survival were 55 weeks and 60%, respectively. One patient remains alive at last follow-up 255 weeks after diagnosis. Median progression-free survival was 16 weeks, and all patients had tumor progression by 39 weeks. Treatment was clinically well tolerated, but evidence of mild to moderate gliosis and microvascular sclerosis consistent with radiation injury was observed at autopsy in specimens taken from regions of contralateral brain that received approximately 6-10 Gy. Fast neutron radiation using modern imaging, treatment planning, and beam delivery was feasible to a total dose of 18 Gy, but tumor control probability was poor in comparison to that predicted from a dose-response model based on older studies. Steep dose-response curves for both tumor control and neurotoxicity continue to present a challenge to establishing a therapeutic window for fast neutron radiation in GBM, even with modern techniques.
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http://dx.doi.org/10.1215/15228517-2007-044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600842PMC
February 2008

Gamma knife stereotactic radiosurgery for salivary gland neoplasms with base of skull invasion following neutron radiotherapy.

Head Neck 2008 Apr;30(4):492-6

Department of Radiation Oncology, University of Washington Cancer Center, 1959 NE Pacific Street, Box 356043, Seattle, Washington 98195-6043, USA.

Background: Our aim was to examine the outcome of patients treated with a planned gamma knife boost after completion of neutron radiotherapy for salivary gland neoplasms involving the base of skull.

Methods: Thirty-four patients with salivary gland neoplasms involving the base of skull were treated from 2001 to 2005 at our institution. These results were compared with a similar historical group treated at our institution from 1984 to 2000. The patients had the following characteristics: median age: 54 years (range, 23-80); median follow-up period: 20.5 months (range, 4-55); women-to-men patient ratio: 1.1:1; histology: 29 adenoid cystic, 3 adenocarcinoma, 1 acinic cell, 1 mucoepidermoid; primary sites of disease: 6 nasopharyngeal, 14 paranasal sinuses, 4 parotid gland, 8 oral cavity, 1 lacrimal gland, and 1 auditory canal. All patients had gross residual disease at the time of treatment. The median neutron dose prescribed to isocenter was 19.2 nGy and the median dose to the effected temporal tip was 11.98 nGy. The median prescribed gamma knife dose was 12 Gy to the 50% isodose line. The median number of isocenters was 17. The median target volume treated was 12.4 cm3 (range, 1.9-28.9) with a median total volume treated of 18.3 cm3 (range, 5.9-53.9).

Results: The 24-month and 40-month Kaplan-Meier estimated local control was 82% versus 81% (24 months) and 82% versus 39% (40 months; p = .04) for the gamma knife treated group versus historical controls (n = 61). Two of the 4 failures in the gamma knife-treated group occurred outside the boosted area. Complications were no greater in the gamma knife-treated group than in those treated with neutron radiotherapy alone.

Conclusions: Patients with primary salivary gland neoplasms that involve the base of skull and are treated with neutron radiotherapy alone are at high risk of local recurrence. A gamma knife boost improves local control and adds little additional toxicity. These preliminary results suggest that all patients with salivary neoplasms and base of skull invasion should be considered for a gamma knife boost after primary treatment with neutron radiotherapy.
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http://dx.doi.org/10.1002/hed.20729DOI Listing
April 2008

Delayed radiotherapy following dose intensive chemotherapy for parameningeal rhabdomyosarcoma (PM-RMS) of childhood.

Eur J Cancer 2007 Apr;43(6):1045-50

Department of Radiation Oncology, University of Washington Affiliated Hospitals, Seattle, WA, United States.

Purpose: To evaluate the local control rates and survival rates of patients with Group III parameningeal rhabdomyosarcoma (PM-RMS) treated with a dose intensive chemotherapy regimen followed by irradiation.

Materials And Methods: Twenty-six patients with group III, PM-RMS were enrolled in a prospective pilot trial at the Mayo Clinic, Rochester, MN and Children's Hospital and Regional Medical Center Seattle, WA. The median age at diagnosis was 8.5 years (range 1.5-19 years). The male to female patient ratio was 1.6:1. Twenty-three patients had embryonal histology with the remaining three alveolar. Risk factors indicating high risk disease included intracranial extension (10 patients), base of skull erosion (12 patients), and cranial nerve palsy (10 patients). The median follow-up period for all patients was 82 months (range 17-148 months). Patients were treated with an intensified chemotherapy regimen followed by definitive local irradiation at week 12 following further chemotherapy. The median time from initiation of chemotherapy to irradiation was 16 weeks (range 6-23). The median dose delivered was 50.4Gy (50.4-66.6Gy).

Results: Response was assessed after the fourth course of chemotherapy. Three patients exhibited a complete response, 22 a partial response, and 1 patient had no response after two cycles of chemotherapy and proceeded to irradiation at week 6. The 5-year estimated event free survival was 81% (+/-15%, 95% CI). Two patients died from progressive metastatic disease; 1 patient died from secondary malignancy; and 2 patients died from locally progressive disease. The 5-year local control rate was 92% (+/-10.6%, 95% CI).

Conclusions: Treatment of group III PM-RMS patients with neo-adjuvant, intensive chemotherapy with a delay in irradiation resulted in excellent local-regional control rates and survival rates and may allow for a response-based radiotherapy approach.
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http://dx.doi.org/10.1016/j.ejca.2007.01.033DOI Listing
April 2007

Treatment of arteriovenous malformations with linear accelerator-based radiosurgery compared with Gamma Knife surgery.

J Neurosurg 2006 Dec;105 Suppl:58-63

Department of Radiation Oncology and Neurological Surgery, The University of Washington Gamma Knife Facility at Harborview Medical Center, Seattle, Washington, USA.

Object: The authors sought to compare the outcomes of patients with arteriovenous malformations (AVMs) treated by Gamma Knife surgery (GKS) with those of patients treated by linear accelerator-based (LINAC) radiosurgery.

Methods: One hundred and eighty-seven patients with AVMs were treated at our institution between 1992 and 2003. Ninety-one patients were treated with GKS and 96 patients were treated with LINAC radiosurgery. Patient and treatment characteristics in the two groups included the following. In the LINAC group, the median age was 33 years (range 9-66 years); the median dose was 16 Gy (70% isodose line); the median treated AVM volume was 5.5 cm3; and 46% of patients in this group were treated after hemorrhage. In the GKS group, the median age was 38 years (range 6-63 years); the median dose was 20 Gy (50% isodose line); the median treated AVM volume was 4.3 cm3; and 44% of patients in this group were treated after hemorrhage. Obliteration of AVMs was determined by performing computed tomography (CT) angiography and/or magnetic resonance (MR) angiography and angiography. Patient follow-up evaluation included obtaining an MR angiogram/MR image or CT angiogram at 6 months, at 1 year, and then annually thereafter. Angiography was performed to confirm obliteration when MR angiography and/or CT angiography no longer revealed evidence of an AVM. The 5-year estimated AVM obliteration rate was 66% in the entire patient group; the LINAC group was 60%; the GKS group was 72%; this difference was not statistically significant (p = 0.97). Twelve patients who underwent treatment with LINAC radiosurgery underwent retreatment with GKS and one was retreated with LINAC radiosurgery. The obliteration rate was 82%. Six patients treated with GKS were retreated with GKS, but the follow-up time is of short duration. Chronic toxicity occurred in 8% of both the GKS and the LINAC groups (p = 0.61). Posttreatment hemorrhage during the time of risk before AVM obliteration was 13% in the GKS group and 6.2% in the LINAC group (p = 0.05).

Conclusions: Treatment of patients with AVMs by using LINAC radiosurgery and GKS treatment produces high obliteration rates with acceptable long-term radiation toxicity in the patients treated.
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http://dx.doi.org/10.3171/sup.2006.105.7.58DOI Listing
December 2006

A simple treatment planning strategy for patients with multiple metastases treated with Gamma Knife surgery.

J Neurosurg 2006 Dec;105 Suppl:2-4

University of Washington Gamma Facility at Harborview, University of Washington, Seattle, Washington 89195-6043, USA.

Object: In a substantial number of patients treated at the authors' facility for brain metastases, additional lesions are identified at the time of Gamma Knife surgery (GKS). These lesions are often widely dispersed and may number over 10, which is the maximal number of matrices that can be currently placed for treatment with Leksell Gamma-Plan 4C. The authors describe a simple planning method for GKS in patients with multiple, widely dispersed central nervous system (CNS) metastases.

Methods: Two patients presented with three to five identified recurrent metastases from non-small cell lung carcinoma and breast carcinoma after having received whole-brain radiotherapy. At the time of treatment with GKS in each patient, spoiled-gradient Gd-enhanced magnetic resonance (MR) imaging revealed substantially more metastases than originally thought, which were widely scattered throughout all regions of the brain. The authors simplified the treatment planning approach by dividing the entire CNS contents into six contiguous, nonoverlapping matrices, which allowed for the planning, calculation, and treatment of all lesions. Two patients were successfully treated with GKS for more than 10 CNS metastases by using this simple planning method. Differing peripheral doses to varied-size lesions were delivered by prescribing to different isodose curves within any given matrix when required. Dose-volume histograms showed brain doses as follows: 10% of the total brain volume received 5 to 6.4 Gy; 25% received 3.8 to 4.8 Gy; 50% received 2.7 to 3.1 Gy; and 75% received 2.2 to 2.5 Gy.

Conclusions: The delineation of more metastases than appreciated on the diagnostic MR imaging is a common occurrence at the time of GKS at the authors' institution. The treatment of multiple (>10), widely dispersed CNS metastases can be simplified by the placement of multiple, contiguous, non-overlapping matrices, which can be employed to treat lesions in all areas of the brain when separate matrices cannot be utilized.
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http://dx.doi.org/10.3171/sup.2006.105.7.2DOI Listing
December 2006

Cisplatin-based chemotherapy followed by focal, reduced-dose irradiation for pediatric primary central nervous system germinomas.

J Pediatr Hematol Oncol 2006 Jan;28(1):36-9

Department of Radiation Oncology, University of Washington, Seattle, 98195, USA.

The objective of this study was to evaluate retrospectively one institution's experience treating pediatric central nervous system (CNS) pure germinomas with platinum-based chemotherapy followed by focal, reduced-dose irradiation. Eight patients were identified with localized, pure CNS germinomas from 1993 to 2004 at the authors' institution. The median age at diagnosis was 13 years (range 7-19). The median follow-up was 40 months (range 8-141). The tumor location was suprasellar in four, the pineal region in three, and the third ventricle in one. Irradiation was started a median of 20 weeks (range 17-22) from diagnosis and consisted of conformal fields to the primary site as determined by the initial diagnostic MR plus a 1.5- to 2-cm margin. Six of the eight patients received a dose of 3,060 cGy; two patients received 3,600 cGy. The 5-year actuarial event free survival was 71% (56-86%, 95% CI). Two patients suffered marginal (at field edge) failures and both were salvaged using reinduction platinum-based chemotherapy followed by cranial spinal irradiation and a boost to the primary tumor. The 5-year actuarial overall survival was 100%. There were no spinal failures. These data suggest that a reduction in both volume and dose (30.6-36 Gy) retains the excellent survival rates for patients with localized, pure germinomas of the CNS. A higher rate of ventricular relapse rate is observed, although salvage of those patients is feasible.
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January 2006

[F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: clinical outcomes and patterns of failure.

Int J Radiat Oncol Biol Phys 2006 Mar 19;64(3):886-91. Epub 2005 Oct 19.

Department of Radiation Oncology, University of Washington Medical Center, Seattle, WA 98195-6043, USA.

Purpose: [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for brain tumors has been shown to identify areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme may lead to improved disease control. Based on these premises, we initiated a prospective study of FDG-PET for the treatment planning of radiation dose escalation for the treatment of glioblastoma multiforme.

Methods And Materials: Forty patients were enrolled. Patients were treated with standard conformal fractionated radiotherapy with volumes defined by MRI imaging. When patients reached a dose of 45-50.4 Gy, they underwent FDG-PET imaging for boost target delineation, for an additional 20 Gy (2 Gy per fraction) to a total dose of 79.4 Gy (n = 30).

Results: The estimated 1-year and 2-year overall survival (OS) for the entire group was 70% and 17%, respectively, with a median overall survival of 70 weeks. The estimated 1-year and 2-year progression-free survival (PFS) was 18% and 3%, respectively, with a median of 24 weeks. No significant improvements in OS or PFS were observed for the study group in comparison to institutional historical controls.

Conclusions: Radiation dose escalation to 79.4 Gy based on FDG-PET imaging demonstrated no improvement in OS or PFS. This study establishes the feasibility of integrating PET metabolic imaging into radiotherapy treatment planning.
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http://dx.doi.org/10.1016/j.ijrobp.2005.08.013DOI Listing
March 2006

RE: A comparison of survival rates for treatment of melanoma metastatic to the brain.

Cancer Invest 2004 ;22(4):643-4

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http://dx.doi.org/10.1081/cnv-200027169DOI Listing
December 2004

Toxicity and efficacy of intensive chemotherapy for children with acute lymphoblastic leukemia (ALL) after first bone marrow or extramedullary relapse.

Pediatr Blood Cancer 2004 Oct;43(5):571-9

Seattle Children's Hospital and Regional Medical Center, Seattle, Washington, USA.

Background: Approximately 25% of children newly diagnosed with acute lymphoblastic leukemia (ALL) will eventually experience leukemic relapse, with bone marrow being the most common site of recurrence. The ability to achieve a durable second remission is complicated by toxicity and resistant disease. We report a novel combination of chemotherapy for relapsed pediatric ALL.

Procedure: Thirty pediatric patients with relapsed medullary (n = 18) and extra-medullary (n = 12) ALL were enrolled at three pediatric institutions. Following receipt of induction and the first Block A and Block B of intensification, each patient was evaluated for toxicity, efficacy in achieving remission, and long-term survival. Additionally, minimal residual disease (MRD) detection by multidimensional flow cytometry (MDF) was performed.

Results: During induction, the major non-hematopoeitic toxicities were mucositis (30% of patients) and bacteremia (50% of patients). Two patients (7%) died of toxicity during induction. Toxicity during intensification Block 1A and 1B was markedly reduced. Eight-nine percent of patients with marrow disease achieved a remission following induction and intensification. The event-free survival (EFS) for all patients at 2 and 4 years were 60% (95% CI: 42-78%) and 49% (95% CI: 30-68%), respectively.

Conclusions: This regimen for patients with relapsed ALL was successful in achieving a second remission for the majority of patients with acceptable toxicity.
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http://dx.doi.org/10.1002/pbc.20128DOI Listing
October 2004

Gamma knife stereotactic radiosurgical boost for patients treated primarily with neutron radiotherapy for salivary gland neoplasms.

Stereotact Funct Neurosurg 2004 25;82(2-3):84-9. Epub 2004 Mar 25.

Department of Radiation Oncology, University of Washington Affiliated Hospitals, University of Washington Cancer Center, Seattle 98195, USA.

Object: To determine the feasibility of utilizing a Gamma Knife stereotactic boost for patients at high risk of local recurrence from minor salivary gland tumors invading the base of skull.

Methods: Eight patients with minor salivary gland tumors invading the base of skull were treated with primary neutron radiotherapy followed by a Gamma Knife radiosurgical boost to the base of skull. Patients had the following characteristics: (1) primary site of disease: paranasal sinuses (n = 3), nasopharynx (n = 3), hard palate (n = 1), pterygopalatine fossa (n = 1); (2) median age 59 years (range 37-80); (3) interval from completion of neutron radiotherapy to Gamma Knife boost 4 weeks (range 2-8 weeks); (4) median stereotactic dose delivered 10 Gy (prescribed to 50% isodose line, range 8-12 Gy), and (5) median number of isocenters treated 16 (range 14-21). Dosimetry from the neutron radiotherapy was used to determine both the volume boosted and the dose utilized. The median follow-up interval from the time of Gamma Knife treatment was 21.5 months (range 16-23 months).

Results: All patients tolerated the procedure well. Acute side effects were minimal and included 1 patient with a delayed fatigue reaction at 2 months, 1 patient with vertigo of limited duration, and a third patient with prolonged nausea requiring steroid use. All patients were placed on a tapering dose of steroids after the procedure. One patient suffered a local relapse, with a 2-year actuarial disease-free survival rate of 80%.

Conclusions: Gamma Knife radiosurgical boost following primary neutron radiotherapy for patients with a high risk of local failure is feasible and well tolerated acutely. Careful attention must be given to the previously treated regions in regard to volume treated and dose delivered. Further follow-up will be necessary to determine the long-term effectiveness and complications of such a boost in these high-risk patients.
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http://dx.doi.org/10.1159/000077457DOI Listing
October 2004

Fractionated low-dose radiotherapy after myeloablative stem cell transplantation for local control in patients with high-risk neuroblastoma.

Cancer 2004 Mar;100(6):1268-75

Department of Pediatric Hematology/Oncology, Children's Hospital and Regional Medical Center, Seattle, Washington 98105-5371, USA.

Background: The optimal administration of radiotherapy for patients with high-risk neuroblastoma (NB) currently is undefined in the context of modern therapy using myeloablative chemotherapy with autologous stem cell rescue (hematopoietic stem cell transplantation [HSCT]).

Methods: The authors conducted a retrospective review of the records of 21 consecutive patients with high-risk NB to assess local control and toxicity of external beam radiotherapy (XRT). Therapy included multiagent induction chemotherapy and delayed surgical resection, consolidation of HSCT and local XRT, and 13-cis-retinoic acid maintenance therapy. XRT was delivered to the primary site, using postchemotherapy volumes, and to initial metastatic sites with 1-2 cm margins to 2100 centigrays (cGy) using 14 fractions administered once daily.

Results: Four of 21 patients did not receive XRT due to toxic death (n = 2), disease progression before XRT (n = 1), or parental refusal (n = 1). The median time to XRT post-HSCT was 54 days. Thirteen patients received a second peripheral blood stem cell infusion after completing XRT. Twelve of the 14 patients who received XRT post-HSCT and for whom toxicity data were available had Grade 3-4 acute toxicities, including gastrointestinal toxicity (n = 8), hematologic toxicity (n = 9), and infection (n = 1). Nonrecurrent long-term toxicities included prolonged nutritional deficiency (n = 9) and leg-length discrepancy (n = 1). Tumors recurred in 7 of 21 patients (5 of 17 patients who received radiotherapy), either within a radiation field (n = 1) or at distant nonirradiated sites (n = 6). The estimated local failure rate was 7% (95% confidence interval [95% CI], 0-14%), with a 2-year event-free survival rate of 48% (95% CI, 26-70%).

Conclusions: Post-HSCT, fractionated XRT to 2100 cGy was a tolerable and effective treatment for patients with high-risk NB, and minimal recurrences were observed at designated XRT sites.
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http://dx.doi.org/10.1002/cncr.20091DOI Listing
March 2004

Concurrent chemotherapy and reduced-dose cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for average-risk medulloblastoma: efficacy and patterns of failure.

Int J Radiat Oncol Biol Phys 2004 Mar;58(4):1161-4

Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA 98195, USA.

Purpose: To review the efficacy and patterns of failure in average-risk medulloblastoma patients treated with concurrent chemotherapy and reduced-dose cranial spinal irradiation and a conformal tumor bed boost.

Methods And Materials: Thirty-three patients with average risk (defined as < or =1.5 cm(2) of residual tumor after resection, age >3 years, and no involvement of the cerebrospinal fluid or spine [M0]) medulloblastoma were diagnosed at our institution between January 1994 and December 2001. They were enrolled in an institutional pilot protocol consisting of concurrent chemotherapy (vincristine), reduced-dose cranial spinal irradiation (2340 cGy), a conformal primary tumor bed boost (3240 cGy), followed by eight cycles of chemotherapy (vincristine, cisplatin, and lomustine or cyclophosphamide). The median age at diagnosis of the 33 patients was 7 years (range, 3-21 years). The male/female patient ratio was 2.4:1. The median follow-up of the entire group was 37 months (range, 6-96 months), and the median follow-up of the survivors was 44 months (range, 10-96 months).

Results: The 5-year estimated disease-free survival rate, as determined by Kaplan-Meier plots, was 86% (+/-12.6%, 95% confidence interval). The 5-year estimated disease-free posterior fossa control and primary tumor bed control rates were both 94% (+/-8.2%, 95% confidence interval). The patterns of failure included 2 patients with distant central nervous system failure only, 1 patient who developed local primary tumor bed failure, posterior fossa failure, and diffuse leptomeningeal spread simultaneously, and 1 patient with failure in the high-dose, primary tumor bed field. No patient experienced isolated posterior fossa failure outside the high-dose boost region.

Conclusion: The treatment of average-risk medulloblastoma with chemotherapy, reduced-dose cranial spinal irradiation, and a conformal tumor bed boost results in survival rates and local control rates comparable to those in contemporary studies. A reduction in the amount of posterior fossa treated to the high dose is possible. These results need to be corroborated in a large, cooperative group study.
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http://dx.doi.org/10.1016/j.ijrobp.2003.09.010DOI Listing
March 2004

Intensive induction chemotherapy and delayed irradiation in the management of parameningeal rhabdomyosarcoma.

J Pediatr Hematol Oncol 2003 Oct;25(10):774-9

University of Washington, Department of Radiation Oncology, Seattle, WA 98195-6043, USA.

Purpose: To evaluate local control, event-free survival, and overall survival for patients with parameningeal (PM) rhabdomyosarcoma (RMS) treated with intensive chemotherapy and delayed irradiation.

Patients And Methods: Thirteen consecutive patients with PM RMS were treated with an institutional protocol from 1992 to 1998 at the University of Washington/Children's Hospital and Regional Medical Center and Deaconess Medical Center. Patients received intensive chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide prior to radiotherapy. Irradiation was delayed, in contrast to current Intergroup Rhabdomyosarcoma Study Group (IRSG) recommendations.

Results: Median follow-up was 39 months. Eleven patients had high-risk features, including five with intracranial extension. All patients responded to the intensive chemotherapy, with 38% exhibiting a complete response and the remaining 62% a partial response. Radiation was administered a median of 21 weeks from initiation of chemotherapy. The Kaplan-Meier estimate of 5-year local control was 92%, with event-free survival and overall survival rates of 83%.

Conclusions: With intensive induction chemotherapy, delayed irradiation for PM RMS does not compromise local control. Event-free survival and overall survival rates compare favorably with recently IRSG trials employing early irradiation. Delaying irradiation allows for intensification of chemotherapy and could permit response-based radiation volume and/or dose modifications, which could decrease treatment-related morbidity.
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http://dx.doi.org/10.1097/00043426-200310000-00006DOI Listing
October 2003

Treatment of salivary gland neoplasms with fast neutron radiotherapy.

Arch Otolaryngol Head Neck Surg 2003 Sep;129(9):944-8

Department of Radiation Oncology, University of Washington Cancer Center, Seattle, USA.

Objective: To evaluate the efficacy of fast neutron radiotherapy for the treatment of salivary gland neoplasms.

Design: Retrospective analysis.

Setting: University of Washington Cancer Center, Neutron Facility, Seattle.

Patients: The medical records of 279 patients treated with curative intent using fast neutron radiotherapy at the University of Washington Cancer Center were reviewed. Of the 279 patients, 263 had evidence of gross residual disease at the time of treatment (16 had no evidence of gross residual disease), 141 had tumors of a major salivary gland, and 138 had tumors of minor salivary glands. The median follow-up period was 36 months (range, 1-142 months).

Main Outcome Measures: Local-regional control, cause-specific survival, and freedom from metastasis.

Results: The 6-year actuarial cause-specific survival rate was 67%. Multivariate analysis revealed that low group stage (I-II) disease, minor salivary sites, lack of skull base invasion, and primary disease were associated with a statistically significant improvement in cause-specific survival. The 6-year actuarial local-regional control rate was 59%. Multivariate analysis revealed size 4 cm or smaller, lack of base of skull invasion, prior surgical resection, and no previous radiotherapy to have a statistically significant improved local-regional control. Sixteen patients without evidence of gross residual disease had a 100% 6-year actuarial local-regional control. The 6-year actuarial freedom from metastasis rate was 64%. Factors associated with decreased development of systemic metastases included negative lymph nodes at the time of treatment and lack of base of skull involvement. The 6-year actuarial rate of development of grade 3 or 4 long-term toxicity (using the Radiation Therapy Oncology Group and European Organization for Research on the Treatment of Cancer criteria) was 10%. No patient experienced grade 5 toxic effects.

Conclusions: Neuron radiotherapy is an effective treatment for patients with salivary gland neoplasms who have gross residual disease and achieves excellent local-regional control in patients without evidence of gross disease.
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http://dx.doi.org/10.1001/archotol.129.9.944DOI Listing
September 2003

Volumetric analysis of 18F-FDG PET in glioblastoma multiforme: prognostic information and possible role in definition of target volumes in radiation dose escalation.

J Nucl Med 2002 Dec;43(12):1667-73

Department of Radiation Oncology, University of Washington Medical Center, Seattle, Washington, USA.

Unlabelled: The use of (18)F-FDG PET for brain tumors has been shown to be accurate in identifying areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme (GBM) may lead to improved disease control. On the basis of these premises, we initiated a pilot study to investigate the use of (18)F-FDG PET for the guidance of radiation dose escalation in the treatment of GBM.

Methods: Patients were considered eligible to participate in the study if they had a diagnosis of GBM, were at least 18 y old, and had a score of at least 60 on the Karnofsky Scale. Patients were treated with standard conformal fractionated radiotherapy (1.8 Gy per fraction, to 59.4 Gy), with volumes defined by MRI. At a dose of 45-50.4 Gy, patients underwent (18)F-FDG PET for boost target delineation. Final noncoplanar fields (3-4) were designed to treat the volume of abnormal (18)F-FDG uptake plus a 0.5-cm margin for an additional 20 Gy (2 Gy per fraction), to a total dose of 79.4 Gy. If no abnormal (18)F-FDG uptake was observed, treatment was stopped after the conventional course of 59.4 Gy. Age, Karnofsky score, MRI-based volumes, and (18)F-FDG PET volume were analyzed as prognostic variables for time to tumor progression (TTP) and overall survival. (18)F-FDG PET volumes and MRI-based volumes were compared to assess concordance.

Results: For the 27 patients who could be evaluated, median actuarial TTP was 43 wk, and median actuarial survival was 70 wk. On univariate analysis, (18)F-FDG PET, T1-weighted MRI gadolinium enhancement (excluding nonenhancing resection cavity), and T2-weighted MRI volumes were significantly predictive of TTP. On multivariate analysis, only (18)F-FDG PET volume retained significance for predicting TTP. Similar results were obtained on analysis of these variables as prognostic factors for survival. When (18)F-FDG PET-based volumes were compared with MRI-based volumes, a difference of at least 25% was detected in all patients, with all but 2 having smaller (18)F-FDG PET volumes. Of patients in whom (18)F-FDG uptake was initially present but treatment subsequently failed, 83% demonstrated the first tumor progression within the region of abnormal (18)F-FDG uptake.

Conclusion: In comparison with MRI, (18)F-FDG PET defined unique volumes for radiation dose escalation in the treatment of GBM. (18)F-FDG PET volumes were predictive of survival and time to tumor progression in the treatment of patients with GBM.
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December 2002

The treatment of brain metastases from malignant melanoma.

Semin Oncol 2002 Oct;29(5):518-24

Department of Radiation Oncology, University of Washington Cancer Center, Seattle, WA, USA.

Metastasis to the CNS develops in nearly half of patients with advanced melanoma; in 15% to 20% of these patients, the CNS is the first site of relapse. While systemic therapy for metastatic melanoma produces objective responses in 15% to 50% of patients, the available drugs do not penetrate well into the CNS, and these patients rarely benefit from systemic therapy. Although brain metastasis may be treated with surgery and/or stereotactic radiosurgery (SRS) when disease is limited to approximately one to three lesions, treatment for patients with large or multiple metastases is limited to whole brain irradiation (WBRT). While formal response and survival analyses of the impact of WBRT in melanoma have not been reported, the estimated median survival time for unselected patients with CNS metastases is only 2 to 4 months, with 1-year survival rates of less than 13%. In a selected population of patients with limited CNS involvement, surgical resection alone or in combination with WBRT appears to prolong median survival. More recently, SRS has been shown to be an effective local treatment for selected patients with brain metastases. In several retrospective reports of patients with melanoma CNS metastases, treatment with surgical resection alone or in combination with WBRT has been demonstrated to prolong median survival. More recently, SRS has been shown to be an effective local treatment for selected patients with brain metastases. In several retrospective reports, patients with CNS metastases from melanoma treated with a combination of WBRT plus SRS or SRS alone had median survivals and rates of control in the CNS superior to published reports for traditional WBRT. Most of these patients died from progressive extracranial disease with locally controlled CNS disease. Investigation of the contribution of newer systemic agents to the control of melanoma metastatic to the CNS has been based on the identification of drugs that have antitumor activity and the ability to cross the blood-brain barrier. Fotemustine is a nitrosourea that produced similar activity in CNS metastasis as in systemic disease, with a response rate of about 25%. Temozolomide (TMZ) is an oral alkylating agent that acts via the same mechanism as dacarbazine (DTIC), the most active single agent in melanoma. TMZ, which is highly active in brain tumors, has also been associated with activity in systemic and CNS metastases in melanoma patients, also in the 25% range. Efforts are underway to assess the additive benefit of TMZ and other drugs to WBRT or focused radiotherapy in this disease.
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http://dx.doi.org/10.1053/sonc.2002.35247DOI Listing
October 2002