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1.  Chemoirradiation for Glioblastoma Multiforme: The National Cancer Institute Experience 
PLoS ONE  2013;8(8):e70745.
Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established.
Experimental Design
The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging.
At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005.
Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients.
PMCID: PMC3733728  PMID: 23940635
To identify, within the framework of a current Phase I trial, whether factors related to intraprostatic cancer lesions (IPLs) or individual patients predict the feasibility of high-dose intraprostatic irradiation.
Methods and Materials
Endorectal coil MRI scans of the prostate from 42 men were evaluated for dominant IPLs. The IPLs, prostate, and critical normal tissues were contoured. Intensity-modulated radiotherapy plans were generated with the goal of delivering 75.6 Gy in 1.8-Gy fractions to the prostate, with IPLs receiving a simultaneous integrated boost of 3.6 Gy per fraction to a total dose of 151.2 Gy, 200% of the prescribed dose and the highest dose cohort in our trial. Rectal and bladder dose constraints were consistent with those outlined in current Radiation Therapy Oncology Group protocols.
Dominant IPLs were identified in 24 patients (57.1%). Simultaneous integrated boosts (SIB) to 200% of the prescribed dose were achieved in 12 of the 24 patients without violating dose constraints. Both the distance between the IPL and rectum and the hip-to-hip patient width on planning CT scans were associated with the feasibility to plan an SIB (p = 0.002 and p = 0.0137, respectively).
On the basis of this small cohort, the distance between an intraprostatic lesion and the rectum most strongly predicted the ability to plan high-dose radiation to a dominant intraprostatic lesion. High-dose SIB planning seems possible for select intraprostatic lesions.
PMCID: PMC3580994  PMID: 20932672
IMRT; Prostate cancer; Dose escalation; Radiotherapy; Treatment planning
3.  Comparison of Intensity-modulated Radiotherapy, Adaptive Radiotherapy, Proton Radiotherapy, and Adaptive Proton Radiotherapy for Treatment of Locally Advanced Head and Neck Cancer 
Background and Purpose
Various radiotherapy planning methods for locally advanced squamous cell carcinoma of the head and neck (SCCHN) have been proposed to decrease normal tissue toxicity. We compare IMRT, adaptive IMRT, proton therapy (IMPT), and adaptive IMPT for SCCHN.
Materials and Methods
Initial and re-simulation CT images from 10 consecutive patients with SCCHN were used to quantify dosimetric differences between photon and proton therapy. Contouring was performed on both CTs, and plans (n=40 plans) and dose volume histograms were generated.
The mean GTV volume decreased 53.4% with re-simulation. All plans provided comparable PTV coverage. Compared with IMRT, adaptive IMRT significantly reduced the maximum dose to the mandible (p=0.020) and mean doses to the contralateral parotid gland (p=0.049) and larynx (p=0.049). Compared with IMRT and adaptive IMRT, IMPT significantly lower the maximum doses to the spinal cord (p<0.002 for both) and brainstem (p<0.002 for both) and mean doses to the larynx (p<0.002 for both) and ipsilateral (p=0.004 IMRT, p=0.050 adaptive) and contralateral (p<0.002 IMRT, p=0.010 adaptive) parotid glands. Adaptive IMPT significantly reduced doses to all critical structures compared with IMRT and adaptive IMRT and several critical structures compared with non-adaptive IMPT.
Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, non-adaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning. Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage.
PMCID: PMC3174314  PMID: 21663988
head and neck cancer; proton therapy; adaptive radiotherapy; IMRT; treatment planning
4.  Comparison of T2 and FLAIR imaging for target delineation in high grade gliomas 
FLAIR and T2 weighted MRIs are used based on institutional preference to delineate high grade gliomas and surrounding edema for radiation treatment planning. Although these sequences have inherent physical differences there is limited data on the clinical and dosimetric impact of using either or both sequences.
40 patients with high grade gliomas consecutively treated between 2002 and 2008 of which 32 had pretreatment MRIs with T1, T2 and FLAIR available for review were selected for this study. These MRIs were fused with the treatment planning CT. Normal structures, clinical tumor volume (CTV) and planning tumor volume (PTV) were then defined on the T2 and FLAIR sequences. A Venn diagram analysis was performed for each pair of tumor volumes as well as a fractional component analysis to assess the contribution of each sequence to the union volume. For each patient the tumor volumes were compared in terms of total volume in cubic centimeters as well as anatomic location using a discordance index. The overlap of the tumor volumes with critical structures was calculated as a measure of predicted toxicity. For patients with MRI documented failures, the tumor volumes obtained using the different sequences were compared with the recurrent gross tumor volume (rGTV).
The FLAIR CTVs and PTVs were significantly larger than the T2 CTVs and PTVs (p < 0.0001 and p = 0.0001 respectively). Based on the discordance index, the abnormality identified using the different sequences also differed in location. Fractional component analysis showed that the intersection of the tumor volumes as defined on both T2 and FLAIR defined the majority of the union volume contributing 63.6% to the CTV union and 82.1% to the PTV union. T2 alone uniquely identified 12.9% and 5.2% of the CTV and PTV unions respectively while FLAIR alone uniquely identified 25.7% and 12% of the CTV and PTV unions respectively. There was no difference in predicted toxicity to normal structures using T2 or FLAIR. At the time of analysis, 26 failures had occurred of which 19 patients had MRIs documenting the recurrence. The rGTV correlated best with the FLAIR CTV but the percentage overlap was not significantly different from that with T2. There was no statistical difference in the percentage overlap with the rGTV and the PTVs generated using either T2 or FLAIR.
Although both T2 and FLAIR MRI sequences are used to define high grade glial neoplasm and surrounding edema, our results show that the volumes generated using these techniques are different and not interchangeable. These differences have bearing on the use of intensity modulated radiation therapy (IMRT) and highly conformal treatment as well as on future clinical trials where the bias of using one technique over the other may influence the study outcome.
PMCID: PMC2827477  PMID: 20109218
5.  A dosimetric comparison of four treatment planning methods for high grade glioma 
High grade gliomas (HGG) are typically treated with a combination of surgery, radiotherapy and chemotherapy. Three dimensional (3D) conformal radiotherapy treatment planning is still the main stay of treatment for these patients. New treatment planning methods suggest better dose distributions and organ sparing but their clinical benefit is unclear. The purpose of the current study was to compare normal tissue sparing and tumor coverage using four different radiotherapy planning methods in patients with high grade glioma.
Three dimensional conformal (3D), sequential boost IMRT, integrated boost (IB) IMRT and Tomotherapy (TOMO) treatment plans were generated for 20 high grade glioma patients. T1 and T2 MRI abnormalities were used to define GTV and CTV with 2 and 2.5 cm margins to define PTV1 and PTV2 respectively.
The mean dose to PTV2 but not to PTV1 was less then 95% of the prescribed dose with IB and IMRT plans. The mean doses to the optic chiasm and the ipsilateral globe were highest with 3D plans and least with IB plans. The mean dose to the contralateral globe was highest with TOMO plans. The mean of the integral dose (ID) to the brain was least with the IB plan and was lower with IMRT compared to 3D plans. The TOMO plans had the least mean D10 to the normal brain but higher mean D50 and D90 compared to IB and IMRT plans. The mean D10 and D50 but not D90 were significantly lower with the IMRT plans compared to the 3D plans.
No single treatment planning method was found to be superior to all others and a personalized approach is advised for planning and treating high-grade glioma patients with radiotherapy. Integral dose did not reflect accurately the dose volume histogram (DVH) of the normal brain and may not be a good indicator of delayed radiation toxicity.
PMCID: PMC2774332  PMID: 19845946
6.  Craniospinal Irradiation with Spinal IMRT to Improve Target Homogeneity 
To report a new technique for the spinal component of craniospinal irradiation (CSI) in the supine position, to describe a verification procedure for this method, and to compare this technique to conventional plans.
Methods and Materials
Twelve patients were treated between 1998 and 2006 with CSI using a novel technique. Sixteen children were treated with a conventional field arrangement. All patients were followed for outcomes and toxicity. CSI was delivered using a posterior-to-anterior (PA) intensity-modulated radiation therapy (IMRT) spinal field matched to conventional, opposed lateral cranial fields. Treatment plans were generated for each patient using the IMRT technique and a standard PA field technique. The resulting dosimetry was compared to determine target homogeneity, maximum dose to normal tissues, and total monitor units delivered.
Evaluation of the spinal IMRT technique compared to a standard PA technique reveals a 7% reduction in the target volume receiving ≥110% of the prescribed dose and an 8 % increase in the target volume receiving ≥ 95% of the prescribed dose. While target homogeneity was improved, the maximum dose delivered in the paraspinal muscles was increased by approximately 8.5 % with spinal IMRT compared to the PA technique. Follow-up evaluations revealed no unexpected toxicity associated with the IMRT technique.
A new technique of spine IMRT is presented in combination with a quality assurance method. This method improves target dose uniformity compared to the conventional CSI technique. Longer follow-up will be required to determine any benefit with regard to toxicity and disease control.
PMCID: PMC1994073  PMID: 17467921
IMRT; craniospinal; homogeneity; pediatric; supine
Magnetic resonance imaging (MRI) provides superior visualization of the prostate and surrounding anatomy, making it the modality of choice for imaging the prostate gland. This pilot study was performed to determine the feasibility and dosimetric quality achieved when placing high-dose-rate prostate brachytherapy catheters under MRI guidance in a standard “closed-bore” 1.5T scanner.
Methods and Materials:
Patients with intermediate-risk and high-risk localized prostate cancer received MRI-guided high-dose-rate brachytherapy boosts before and after a course of external beam radiotherapy. Using a custom visualization and targeting program, the brachytherapy catheters were placed and adjusted under MRI guidance until satisfactory implant geometry was achieved. Inverse treatment planning was performed using high-resolution T2-weighted MRI.
Ten brachytherapy procedures were performed on 5 patients. The median percentage of volume receiving 100% of prescribed minimal peripheral dose (V100) achieved was 94% (mean, 92%; 95% confidence interval, 89–95%). The urethral V125 ranged from 0% to 18% (median, 5%), and the rectal V75 ranged from 0% to 3.1% (median, 0.3%). In all cases, lesions highly suspicious for malignancy could be visualized on the procedural MRI, and extracapsular disease was identified in 2 patients.
High-dose-rate prostate brachytherapy in a standard 1.5T MRI scanner is feasible and achieves favorable dosimetry within a reasonable period with high-quality image guidance. Although the procedure was well tolerated in the acute setting, additional follow-up is required to determine the long-term safety and efficacy of this approach.
PMCID: PMC2396328  PMID: 15275727
Prostate cancer; Brachytherapy; MRI; Image guidance
8.  System for Prostate Brachytherapy and Biopsy in a Standard 1.5 T MRI Scanner 
A technique for transperineal high-dose-rate (HDR) prostate brachytherapy and needle biopsy in a standard 1.5 T MRI scanner is demonstrated. In each of eight procedures (in four patients with intermediate to high risk localized prostate cancer), four MRI-guided transperineal prostate biopsies were obtained followed by placement of 14–15 hollow transperineal catheters for HDR brachytherapy. Mean needle-placement accuracy was 2.1 mm, 95% of needle-placement errors were less than 4.0 mm, and the maximum needle-placement error was 4.4 mm. In addition to guiding the placement of biopsy needles and brachytherapy catheters, MR images were also used for brachytherapy treatment planning and optimization. Because 1.5 T MR images are directly acquired during the interventional procedure, dependence on deformable registration is reduced and online image quality is maximized.
PMCID: PMC2396258  PMID: 15334592
MRI; brachytherapy; prostate; prostatic neoplasms; biopsy; interventional MRI
9.  Simultaneous integrated boost of biopsy proven, MRI defined dominant intra-prostatic lesions to 95 Gray with IMRT: early results of a phase I NCI study 
To assess the feasibility and early toxicity of selective, IMRT-based dose escalation (simultaneous integrated boost) to biopsy proven dominant intra-prostatic lesions visible on MRI.
Patients with localized prostate cancer and an abnormality within the prostate on endorectal coil MRI were eligible. All patients underwent a MRI-guided transrectal biopsy at the location of the MRI abnormality. Gold fiducial markers were also placed. Several days later patients underwent another MRI scan for fusion with the treatment planning CT scan. This fused MRI scan was used to delineate the region of the biopsy proven intra-prostatic lesion. A 3 mm expansion was performed on the intra-prostatic lesions, defined as a separate volume within the prostate. The lesion + 3 mm and the remainder of the prostate + 7 mm received 94.5/75.6 Gray (Gy) respectively in 42 fractions. Daily seed position was verified to be within 3 mm.
Three patients were treated. Follow-up was 18, 6, and 3 months respectively. Two patients had a single intra-prostatic lesion. One patient had 2 intra-prostatic lesions. All four intra-prostatic lesions, with margin, were successfully targeted and treated to 94.5 Gy. Two patients experienced acute RTOG grade 2 genitourinary (GU) toxicity. One had grade 1 gastrointestinal (GI) toxicity. All symptoms completely resolved by 3 months. One patient had no acute toxicity.
These early results demonstrate the feasibility of using IMRT for simultaneous integrated boost to biopsy proven dominant intra-prostatic lesions visible on MRI. The treatment was well tolerated.
PMCID: PMC2075521  PMID: 17877821
10.  Early observed transient prostate-specific antigen elevations on a pilot study of external beam radiation therapy and fractionated MRI guided High Dose Rate brachytherapy boost 
To report early observation of transient PSA elevations on this pilot study of external beam radiation therapy and magnetic resonance imaging (MRI) guided high dose rate (HDR) brachytherapy boost.
Materials and methods
Eleven patients with intermediate-risk and high-risk localized prostate cancer received MRI guided HDR brachytherapy (10.5 Gy each fraction) before and after a course of external beam radiotherapy (46 Gy). Two patients continued on hormones during follow-up and were censored for this analysis. Four patients discontinued hormone therapy after RT. Five patients did not receive hormones. PSA bounce is defined as a rise in PSA values with a subsequent fall below the nadir value or to below 20% of the maximum PSA level. Six previously published definitions of biochemical failure to distinguish true failure from were tested: definition 1, rise >0.2 ng/mL; definition 2, rise >0.4 ng/mL; definition 3, rise >35% of previous value; definition 4, ASTRO defined guidelines, definition 5 nadir + 2 ng/ml, and definition 6, nadir + 3 ng/ml.
Median follow-up was 24 months (range 18–36 mo). During follow-up, the incidence of transient PSA elevation was: 55% for definition 1, 44% for definition 2, 55% for definition 3, 33% for definition 4, 11% for definition 5, and 11% for definition 6.
We observed a substantial incidence of transient elevations in PSA following combined external beam radiation and HDR brachytherapy for prostate cancer. Such elevations seem to be self-limited and should not trigger initiation of salvage therapies. No definition of failure was completely predictive.
PMCID: PMC1564026  PMID: 16914054
11.  Intra- and inter-radiation therapist reproducibility of daily isocenter verification using prostatic fiducial markers 
We sought to determine the intra- and inter-radiation therapist reproducibility of a previously established matching technique for daily verification and correction of isocenter position relative to intraprostatic fiducial markers (FM).
Materials and methods
With the patient in the treatment position, anterior-posterior and left lateral electronic images are acquired on an amorphous silicon flat panel electronic portal imaging device. After each portal image is acquired, the therapist manually translates and aligns the fiducial markers in the image to the marker contours on the digitally reconstructed radiograph. The distances between the planned and actual isocenter location is displayed. In order to determine the reproducibility of this technique, four therapists repeated and recorded this operation two separate times on 20 previously acquired portal image datasets from two patients. The data were analyzed to obtain the mean variability in the distances measured between and within observers.
The mean and median intra-observer variability ranged from 0.4 to 0.7 mm and 0.3 to 0.6 mm respectively with a standard deviation of 0.4 to 1.0 mm. Inter-observer results were similar with a mean variability of 0.9 mm, a median of 0.6 mm, and a standard deviation of 0.7 mm. When using a 5 mm threshold, only 0.5% of treatments will undergo a table shift due to intra or inter-observer error, increasing to an error rate of 2.4% if this threshold were reduced to 3 mm.
We have found high reproducibility with a previously established method for daily verification and correction of isocenter position relative to prostatic fiducial markers using electronic portal imaging.
PMCID: PMC1436003  PMID: 16722575

Results 1-11 (11)