To determine the feasibility and toxicity of radiation therapy, delivered either as definitive tr... more To determine the feasibility and toxicity of radiation therapy, delivered either as definitive treatment or following surgery, following neo-adjuvant immune checkpoint inhibition for locally advanced NSCLC sixteen patients who received neo-adjuvant chemotherapy including ipilimumab as part of a phase II study were identified. Patients were analyzed by intent of radiation and toxicity graded based on CTCAE 4.0. There were seven patients identified who received definitive radiation and nine who received post-operative radiation. There was no grade 3 or greater toxicity in the definitive treatment group although one patient stopped treatment early due to back pain secondary to progression outside of the treatment field. In the post-operative treatment group, one patient required a one week break due to grade 2 odynophagia and no grade 3 or greater toxicity was observed. In this study of radiation as definitive or post-operative treatment following neo-adjuvant chemotherapy including ipilimumab for locally advanced NSCLC was feasible and well tolerated with limited toxicity.
International Journal of Radiation Oncology*Biology*Physics, 2015
Hypofractionated radiation therapy (RT) has promising long-term biochemical relapse-free survival... more Hypofractionated radiation therapy (RT) has promising long-term biochemical relapse-free survival (bRFS) with comparable toxicity for definitive treatment of prostate cancer. However, data reporting outcomes after adjuvant and salvage postprostatectomy hypofractionated RT are sparse. Therefore, we report the toxicity and clinical outcomes after postprostatectomy hypofractionated RT. From a prospectively maintained database, men receiving image guided hypofractionated intensity modulated RT (HIMRT) with 2.5-Gy fractions constituted our study population. Androgen deprivation therapy was used at the discretion of the radiation oncologist. Acute toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.0. Late toxicities were scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. Biochemical recurrence was defined as an increase of 0.1 in prostate-specific antigen (PSA) from posttreatment nadir or an increase in PSA despite treatment. The Kaplan-Meier method was used for the time-to-event outcomes. Between April 2008 and April 2012, 56 men received postoperative HIMRT. The median follow-up time was 48 months (range, 21-67 months). Thirty percent had pre-RT PSA <0.1; the median pre-RT detectable PSA was 0.32 ng/mL. The median RT dose was 65 Gy (range, 57.5-65 Gy). Ten patients received neoadjuvant and concurrent hormone therapy. Posttreatment acute urinary toxicity was limited. There was no acute grade 3 toxicity. Late genitourinary (GU) toxicity of any grade was noted in 52% of patients, 40% of whom had pre-RT urinary incontinence. The 4-year actuarial rate of late grade 3 GU toxicity (exclusively gross hematuria) was 28% (95% confidence interval [CI], 16%-41%). Most grade 3 GU toxicity resolved; only 7% had persistent grade ≥3 toxicity at the last follow-up visit. Fourteen patients experienced biochemical recurrence at a median of 20 months after radiation. The 4-year bPFS rate was 75% (95% CI, 63%-87%). The biochemical control in this series appears promising, although relatively short follow-up may lead to overestimation. Late grade 3 GU toxicity was higher than anticipated with hypofractionated radiation of 65 Gy to the prostate bed, although most resolved.
International journal of radiation oncology, biology, physics, 2014
To generate a population-averaged arterial input function (PA-AIF) for quantitative analysis of d... more To generate a population-averaged arterial input function (PA-AIF) for quantitative analysis of dynamic contrast-enhanced MRI data in head and neck cancer patients. Twenty patients underwent dynamic contrast-enhanced MRI during concurrent chemoradiation therapy. Imaging consisted of 2 baseline scans 1 week apart (B1/B2) and 1 scan after 1 week of chemoradiation therapy (Wk1). Regions of interest (ROIs) in the right and left carotid arteries were drawn on coronal images. Plasma concentration curves of all ROIs were averaged and fit to a biexponential decay function to obtain the final PA-AIF (AvgAll). Right-sided and left-sided ROI plasma concentration curves were averaged separately to obtain side-specific AIFs (AvgRight/AvgLeft). Regions of interest were divided by time point to obtain time-point-specific AIFs (AvgB1/AvgB2/AvgWk1). The vascular transfer constant (Ktrans) and the fractional extravascular, extracellular space volume (Ve) for primaries and nodes were calculated using ...
BACKGROUND: Our objective was to identify an optimal margin for SRS of brain metastases, minimizi... more BACKGROUND: Our objective was to identify an optimal margin for SRS of brain metastases, minimizing toxicity and local recurrence. METHODS: Adult patients with 1-3 brain metastases, no previous brain radiotherapy and KPS .70 were eligible for this IRB-approved trial. Individual lesions were randomized to 1 or 3mm uniform expansion of the gross tumor
Metastatic non-small cell lung cancer (NSCLC) carries a dismal prognosis. Clinical evidence sugge... more Metastatic non-small cell lung cancer (NSCLC) carries a dismal prognosis. Clinical evidence suggests the existence of an intermediate, or oligometastatic, state when metastases are limited in number and/or location. In addition, following initial curative therapy, many patients present with limited metastatic disease, or oligo-recurrence. Metastasis-directed, anti-cancer therapies may benefit these patients. A growing evidence-base supports the use of hypofractionated, image-guided radiotherapy (HIGRT) for a variety of malignant conditions including inoperable stage I NSCLC and many metastatic sites. When surgical resection is not possible, HIGRT offers an effective alternative for local treatment of limited metastatic disease. Early studies have produced promising results when HIGRT was delivered to all known sites of disease in patients with oligometastatic/oligorecurrent NSCLC. In a population of patients formerly considered rapidly terminal, these studies report five year overall survival rates of 13-22%. HIGRT for metastatic NSCLC warrants further study. We call for large, intergroup, and even international randomized trials incorporating HIGRT and other metastasis-directed therapies into the treatment of patients with oligometastatic/oligo-recurrent NSCLC.
Radiotherapy plays an integral role in the management of most patients with cancers of the head a... more Radiotherapy plays an integral role in the management of most patients with cancers of the head and neck. Better understanding of radiobiology and radiation physics has allowed radiation oncologists to enhance the tumoricidal effects of radiation and reduce the severity of normal tissue toxicities. This article reviews the biologic foundation of head and neck radiotherapy, the physical principles and technological innovations that enable delivery of highly conformal radiation, the acute and late complications of radiation-based treatments, and the clinical evidence supporting contemporary practice.
Journal of Bronchology & Interventional Pulmonology, 2013
Optimal treatment for unresectable central airway tumors is not well established. Stereotactic bo... more Optimal treatment for unresectable central airway tumors is not well established. Stereotactic body radiation therapy has shown efficacy for both peripheral and central lung lesions. However, the treatment of central tumors has been limited because of associated radiation toxicity. We report the use of an endobronchial fiducial to localize hypofractionated stereotactic body radiation therapy treatment of a limited central airways disease in a patient with recurrent metastatic squamous cell lung cancer. The fiducial was instrumental in designing the treatment field and minimizing related treatment toxicity. Future studies may take advantage of this technique in patients with unresectable central airways non-small cell lung cancers.
The purpose of this study was to define baseline variability of apparent diffusion coefficient (A... more The purpose of this study was to define baseline variability of apparent diffusion coefficient (ADC) on diffusion-weighted MR imaging (DWI) in patients with head and neck squamous cell carcinoma (HNSCC) and to compare it with early treatment-induced ADC change. Patients with American Joint Committee on Cancer stages III and IV HNSCC were imaged with two baseline DWI examinations 1 week apart and a third DWI examination during the 2nd week of curative-intent chemoradiation therapy. Mean ADC was measured in the primary tumor and largest lymph node for each patient on the three DWI scans. Mean baseline percentage differences (%∆ADC) were compared with intratreatment change. The repeatability coefficient for baseline %∆ADC was calculated and compared with intratreatment %∆ADC. Repeatability was also assessed with Bland-Altman plots and the intraclass correlation coefficient (ICC). Sixteen patients underwent double baseline imaging, with 14 also undergoing intratreatment imaging. Baseline nodal disease ADC could be measured in 16 patients, but ADC in primary tumors could only be measured in five patients. The nodal mean (SD) baseline %∆ADC was 8% (± 7%), which was significantly different compared with intratreatment changes of 32% (± 31%) (p = 0.01). Baseline ICC was 0.86 for nodal disease and 0.99 for primary tumor (excellent correlation). The calculated repeatability coefficient for baseline nodal ADC was 15%. No patients had decreases in intratreatment ADC of more than 15%. Baseline ADC variability for HNSCC is less than intratreatment ADC change for nodal disease. Assessment of response should consider intrinsic baseline variability.
Recent in vitro and in vivo evidence has suggested that statin medications may have anticancer ac... more Recent in vitro and in vivo evidence has suggested that statin medications may have anticancer activity. We sought to determine whether statin use was associated with improved clinical outcome in men treated with brachytherapy for prostate cancer. A database of men with prostate cancer treated with permanent Iodine-125 brachytherapy between January 1999 and February 2009 was retrospectively analyzed. Standard guidelines (i.e., American Brachytherapy Society selection criteria) were used for selecting patients for brachytherapy. Biochemical failure was defined using the Phoenix definition. From a total of 247 men with prostate adenocarcinoma treated with brachytherapy, 174 patients (70 %) were identified as using statin medications, either during initial visit or during follow-up. Median PSA follow-up was 51 months after date of implant (range 9.4-140.35). Overall biochemical failure rate was 7.3 % (18 patients). On univariate analysis, statin use was associated with significantly im...
International Journal of Radiation Oncology*Biology*Physics, 2015
To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (... more To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed. SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate.
Purpose: Calculation of the precontrast longitudinal relaxation times ͑T 10 ͒ is an integral part... more Purpose: Calculation of the precontrast longitudinal relaxation times ͑T 10 ͒ is an integral part of the Tofts-based pharmacokinetic ͑PK͒ analysis of dynamic contrast enhanced-magnetic resonance images. The purpose of this study was to investigate the interpatient and over time variability of T 10 in head and neck primary tumors and involved nodes and to determine the median T 10 for primary and nodes ͑T 10 p,n ͒. The authors also looked at the implication of using voxel-based T 10 values versus region of interest ͑ROI͒-based T 10 on the calculated values for vascular permeability ͑K trans ͒ and extracellular volume fraction ͑v e ͒. Methods: Twenty head and neck cancer patients receiving concurrent chemoradiation and molecularly targeted agents on a prospective trial comprised the study population. Voxel-based T 10 's were generated using a gradient echo sequence on a 1.5 T MR scanner using the variable flip angle method with two flip angles ͓J. A. Brookes et al., "Measurement of spin-lattice relaxation times with FLASH for dynamic MRI of the breast," Br. J. Radiol. 69, 206-214 ͑1996͔͒. The voxel-based T 10 , K trans , and v e were calculated using iCAD's ® ͑Nashua, NH͒ software. The mean T 10 's in muscle and fat ROIs were calculated ͑T 10 m,f ͒. To assess reliability of ROI drawing, T 10 p,n values from ROIs delineated by 2 users ͑A and B͒ were calculated as the average of the T 10 's for 14 patients. For a subset of three patients, the T 10 variability from baseline to end of treatment was also investigated. The K trans and v e from primary and node ROIs were calculated using voxel-based T 10 values and T 10 p,n and differences reported. Results: The calculated T 10 values for fat and muscle are within the range of values reported in literature for 1.5 T, i.e., T 10 m = 0.958 s and T 10 f = 0.303 s. The average over 14 patients of the T 10 's based on drawings by users A and B were T 10 pA = 0.804 s, T 10 nA = 0.760 s, T 10 pB = 0.849 s, and T 10 nB = 0.810 s. The absolute percentage difference between K trans and v e calculated with voxelbased T 10 versus T 10 p,n ranged from 6% to 81% and from 2% to 24%, respectively. Conclusions: There is a certain amount of variability in the median T 10 values between patients, but the differences are not significant. There were also no statistically significant differences between the T 10 values for primary and nodes at baseline and the subsequent time points ͑p = 0.94 Friedman test͒. Voxel-based T 10 calculations are essential when quantitative Tofts-based PK analysis in heterogeneous tumors is needed. In the absence of T 10 mapping capability, when a relative, qualitative analysis is deemed sufficient, a value of T 10 p,n = 0.800 s can be used as an estimate for T 10 for both the primary tumor and the affected nodes in head and neck cancers at all the time points considered.
To evaluate how well the tumor, node, metastasis (TNM) 6 and TNM 7 staging systems predict rates ... more To evaluate how well the tumor, node, metastasis (TNM) 6 and TNM 7 staging systems predict rates of local/regional recurrence (LRR) after surgery alone for non-small cell lung cancer. All patients who underwent surgery for non-small cell lung cancer at Duke between 1995 and 2005 were reviewed. Those undergoing sublobar resections, with positive margins or involvement of the chest wall, or those who received any chemotherapy or radiation therapy (RT) were excluded. Disease recurrence at the surgical margin, or within ipsilateral hilar and/or mediastinal lymph nodes, was considered as a LRR. Stage was assigned based on both TNM 6 and TNM 7. Rates of LRR were estimated using the Kaplan-Meier method. A Cox regression analysis evaluated the hazard ratio of LRR by stage within TNM 6 and TNM 7. A total of 709 patients were eligible for the analysis. Median follow-up was 32 months. For all patients, the 5-year actuarial risk of LRR was 23%. Conversion from TNM 6 to TNM 7 resulted in 21% stage migration (upstaging in 13%; downstaging in 8%). Five-year rates of LRR for stages IA, IB, IIA, IIB, and IIIA disease using TNM 6 were 16%, 26%, 43%, 35%, and 40%, respectively. Using TNM 7, corresponding rates were 16%, 23%, 37%, 39%, and 30%, respectively. The hazard ratios for LRR were statistically different for IA and IB in both TNM 6 and 7 but were also different for IB and IIA in TNM 7. LRR risk increases monotonically for stages IA to IIB in the new TNM 7 system. This information might be valuable when designing future studies of postoperative RT.
International Journal of Radiation Oncology*Biology*Physics, 2011
To evaluate actuarial rates of local failure in patients with pathologic N1 non-small-cell lung c... more To evaluate actuarial rates of local failure in patients with pathologic N1 non-small-cell lung cancer and to identify clinical and pathologic factors associated with an increased risk of local failure after resection. All patients who underwent surgery for non-small-cell lung cancer with pathologically confirmed N1 disease at Duke University Medical Center from 1995-2008 were identified. Patients receiving any preoperative therapy or postoperative radiotherapy or with positive surgical margins were excluded. Local failure was defined as disease recurrence within the ipsilateral hilum, mediastinum, or bronchial stump/staple line. Actuarial rates of local failure were calculated with the Kaplan-Meier method. A Cox multivariate analysis was used to identify factors independently associated with a higher risk of local recurrence. Among 1,559 patients who underwent surgery during the time interval, 198 met the inclusion criteria. Of these patients, 50 (25%) received adjuvant chemotherapy. Actuarial (5-year) rates of local failure, distant failure, and overall survival were 40%, 55%, and 33%, respectively. On multivariate analysis, factors associated with an increased risk of local failure included a video-assisted thoracoscopic surgery approach (hazard ratio [HR], 2.5; p = 0.01), visceral pleural invasion (HR, 2.1; p = 0.04), and increasing number of positive N1 lymph nodes (HR, 1.3 per involved lymph node; p = 0.02). Chemotherapy was associated with a trend toward decreased risk of local failure that was not statistically significant (HR, 0.61; p = 0.2). Actuarial rates of local failure in pN1 disease are high. Further investigation of conformal postoperative radiotherapy may be warranted.
International Journal of Radiation Oncology*Biology*Physics, 2012
Thirteen patients had at least three usable beams and were analyzed. The mean of R m was 0.87 (ra... more Thirteen patients had at least three usable beams and were analyzed. The mean of R m was 0.87 (range, 0.84e0.95). The mean of A m was 3.18 mm (range, 0.46e7.80 mm). R m was found to decrease as A m increases following an equation of R m Z 0.17e À0.9Am þ 0.84. R m also decreased slightly throughout the course of treatments. Intersubject CV of R m (0.05) was comparable to intrasubject CVof R m (range, 0.02e0.09); intersubject CVof A m (0.73) was significantly greater than intrasubject CV of A m (range, 0.09e0.24). Conclusions: Tumor motion PDF can be determined using cine MV images acquired during the treatments. The reproducibility of lung tumor motion PDF decreased exponentially as the tumor motion range increased and decreased slightly throughout the course of the treatments.
International Journal of Radiation Oncology*Biology*Physics, 2012
Dynamic contrast-enhanced (DCE) MRI-extracted parameters measure tumor microvascular physiology a... more Dynamic contrast-enhanced (DCE) MRI-extracted parameters measure tumor microvascular physiology and are usually calculated from an intratumor region of interest (ROI). Optimal ROI delineation is not established. The valid clinical use of DCE-MRI requires that the variation for any given parameter measured within a tumor be less than that observed between tumors in different patients. This work evaluates the impact of tumor ROI selection on the assessment of intra- and interpatient variability. Head and neck cancer patients received initial targeted therapy (TT) treatment with erlotinib and/or bevacizumab, followed by radiotherapy and concurrent cisplatin with synchronous TT. DCE-MRI data from Baseline and the end of the TT regimen (Lead-In) were analyzed to generate the vascular transfer function (K(trans)), the extracellular volume fraction (v(e)), and the initial area under the concentration time curve (iAUC(1 min)). Four ROI sampling strategies were used: whole tumor or lymph node (Whole), the slice containing the most enhancing voxels (SliceMax), three slices centered in SliceMax (Partial), and the 5% most enhancing contiguous voxels within SliceMax (95Max). The average coefficient of variation (aCV) was calculated to establish intrapatient variability among ROI sets and interpatient variability for each ROI type. The average ratio between each intrapatient CV and the interpatient CV was calculated (aRCV). Baseline primary/nodes aRCVs for different ROIs not including 95Max were, for all three MR parameters, in the range of 0.14-0.24, with Lead-In values between 0.09 and 0.2, meaning a low intrapatient vs. interpatient variation. For 95Max, intrapatient CVs approximated interpatient CVs, meaning similar data dispersion and higher aRCVs (0.6-1.27 for baseline) and 0.54-0.95 for Lead-In. Distinction between different patient's primary tumors and/or nodes cannot be made using 95Max ROIs. The other three strategies are viable and equivalent for using DCE-MRI to measure head and neck cancer physiology.
International Journal of Radiation Oncology*Biology*Physics, 2009
Purpose-To describe our experience and clinical strategy for stereotactic body radiotherapy (SBRT... more Purpose-To describe our experience and clinical strategy for stereotactic body radiotherapy (SBRT) of spinal lesions.
International Journal of Radiation Oncology*Biology*Physics, 2009
inverse orientation was cloned (pHR'SIN-GULS). The human lymphoblastoid TK6 cell line (p53 wild-t... more inverse orientation was cloned (pHR'SIN-GULS). The human lymphoblastoid TK6 cell line (p53 wild-type) was transduced with the viral supernatants. The FACS was used to sort the EGFP-positive cells to get completely transduced cell pools. The SLUG expression was determined by Western blot. Radioprotection was analyzed by a proliferation assay, an MTT cytotoxicity assay, and a clonogenic assay. The effect of SLUG on the rate of apoptosis was determined by measuring the amount of sub-G1 cells. Results: After 2-8 hours irradiation of TK6 cells with 2 Gy, a three to fourfold increase of PUMA transcription was detected by quantitative real-time PCR. An increase of PUMA expression could be verified also at the protein level. The TK6 cells showed no endogenous SLUG expression, whereas SLUG protein was demonstrated by Western blot in lysates of TK6-SLUG cells. In a first radioprotection assay, the amount of EGFP-positive cells was determined 48 hours after irradiation of transduced TK6 cells: 2 Gy resulted in a twofold, and 6 Gy in an up to fourfold increase in SLUG-overexpressing cells. After FACS sorting, a pool of nearly 100% transduced cells was irradiated with 0-5 Gy. In the MTT assay, a significant survival advantage by SLUG overexpression could be demonstrated. The EGFP-expression was not responsible for this radioprotective effect since SLUGexpressing cells were also radioresistant after removal of the IRES-EGFP-cassette by CRE-recombinase. Determination of the amount of sub-G1 cells in TK6-SLUG cells revealed an approximately 50% reduction in apoptosis as compared with both control entities. Additionally, TK6-SLUG compared to TK6-GULS cells showed a survival advantage in the clonogenic assay after irradiation with 0-3 Gy. Conclusions: We established a lentiviral vector for expression of a transgene (without the possibility to select on its expression) in a bicistronic expression cassette with floxed EGFP as selection marker. Using this vector, we could show that SLUG-expression functions radioprotective in TK6 cells demonstrating its potential as candidate for gene therapeutic radioprotection of normal tissues.
To determine the feasibility and toxicity of radiation therapy, delivered either as definitive tr... more To determine the feasibility and toxicity of radiation therapy, delivered either as definitive treatment or following surgery, following neo-adjuvant immune checkpoint inhibition for locally advanced NSCLC sixteen patients who received neo-adjuvant chemotherapy including ipilimumab as part of a phase II study were identified. Patients were analyzed by intent of radiation and toxicity graded based on CTCAE 4.0. There were seven patients identified who received definitive radiation and nine who received post-operative radiation. There was no grade 3 or greater toxicity in the definitive treatment group although one patient stopped treatment early due to back pain secondary to progression outside of the treatment field. In the post-operative treatment group, one patient required a one week break due to grade 2 odynophagia and no grade 3 or greater toxicity was observed. In this study of radiation as definitive or post-operative treatment following neo-adjuvant chemotherapy including ipilimumab for locally advanced NSCLC was feasible and well tolerated with limited toxicity.
International Journal of Radiation Oncology*Biology*Physics, 2015
Hypofractionated radiation therapy (RT) has promising long-term biochemical relapse-free survival... more Hypofractionated radiation therapy (RT) has promising long-term biochemical relapse-free survival (bRFS) with comparable toxicity for definitive treatment of prostate cancer. However, data reporting outcomes after adjuvant and salvage postprostatectomy hypofractionated RT are sparse. Therefore, we report the toxicity and clinical outcomes after postprostatectomy hypofractionated RT. From a prospectively maintained database, men receiving image guided hypofractionated intensity modulated RT (HIMRT) with 2.5-Gy fractions constituted our study population. Androgen deprivation therapy was used at the discretion of the radiation oncologist. Acute toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.0. Late toxicities were scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. Biochemical recurrence was defined as an increase of 0.1 in prostate-specific antigen (PSA) from posttreatment nadir or an increase in PSA despite treatment. The Kaplan-Meier method was used for the time-to-event outcomes. Between April 2008 and April 2012, 56 men received postoperative HIMRT. The median follow-up time was 48 months (range, 21-67 months). Thirty percent had pre-RT PSA <0.1; the median pre-RT detectable PSA was 0.32 ng/mL. The median RT dose was 65 Gy (range, 57.5-65 Gy). Ten patients received neoadjuvant and concurrent hormone therapy. Posttreatment acute urinary toxicity was limited. There was no acute grade 3 toxicity. Late genitourinary (GU) toxicity of any grade was noted in 52% of patients, 40% of whom had pre-RT urinary incontinence. The 4-year actuarial rate of late grade 3 GU toxicity (exclusively gross hematuria) was 28% (95% confidence interval [CI], 16%-41%). Most grade 3 GU toxicity resolved; only 7% had persistent grade ≥3 toxicity at the last follow-up visit. Fourteen patients experienced biochemical recurrence at a median of 20 months after radiation. The 4-year bPFS rate was 75% (95% CI, 63%-87%). The biochemical control in this series appears promising, although relatively short follow-up may lead to overestimation. Late grade 3 GU toxicity was higher than anticipated with hypofractionated radiation of 65 Gy to the prostate bed, although most resolved.
International journal of radiation oncology, biology, physics, 2014
To generate a population-averaged arterial input function (PA-AIF) for quantitative analysis of d... more To generate a population-averaged arterial input function (PA-AIF) for quantitative analysis of dynamic contrast-enhanced MRI data in head and neck cancer patients. Twenty patients underwent dynamic contrast-enhanced MRI during concurrent chemoradiation therapy. Imaging consisted of 2 baseline scans 1 week apart (B1/B2) and 1 scan after 1 week of chemoradiation therapy (Wk1). Regions of interest (ROIs) in the right and left carotid arteries were drawn on coronal images. Plasma concentration curves of all ROIs were averaged and fit to a biexponential decay function to obtain the final PA-AIF (AvgAll). Right-sided and left-sided ROI plasma concentration curves were averaged separately to obtain side-specific AIFs (AvgRight/AvgLeft). Regions of interest were divided by time point to obtain time-point-specific AIFs (AvgB1/AvgB2/AvgWk1). The vascular transfer constant (Ktrans) and the fractional extravascular, extracellular space volume (Ve) for primaries and nodes were calculated using ...
BACKGROUND: Our objective was to identify an optimal margin for SRS of brain metastases, minimizi... more BACKGROUND: Our objective was to identify an optimal margin for SRS of brain metastases, minimizing toxicity and local recurrence. METHODS: Adult patients with 1-3 brain metastases, no previous brain radiotherapy and KPS .70 were eligible for this IRB-approved trial. Individual lesions were randomized to 1 or 3mm uniform expansion of the gross tumor
Metastatic non-small cell lung cancer (NSCLC) carries a dismal prognosis. Clinical evidence sugge... more Metastatic non-small cell lung cancer (NSCLC) carries a dismal prognosis. Clinical evidence suggests the existence of an intermediate, or oligometastatic, state when metastases are limited in number and/or location. In addition, following initial curative therapy, many patients present with limited metastatic disease, or oligo-recurrence. Metastasis-directed, anti-cancer therapies may benefit these patients. A growing evidence-base supports the use of hypofractionated, image-guided radiotherapy (HIGRT) for a variety of malignant conditions including inoperable stage I NSCLC and many metastatic sites. When surgical resection is not possible, HIGRT offers an effective alternative for local treatment of limited metastatic disease. Early studies have produced promising results when HIGRT was delivered to all known sites of disease in patients with oligometastatic/oligorecurrent NSCLC. In a population of patients formerly considered rapidly terminal, these studies report five year overall survival rates of 13-22%. HIGRT for metastatic NSCLC warrants further study. We call for large, intergroup, and even international randomized trials incorporating HIGRT and other metastasis-directed therapies into the treatment of patients with oligometastatic/oligo-recurrent NSCLC.
Radiotherapy plays an integral role in the management of most patients with cancers of the head a... more Radiotherapy plays an integral role in the management of most patients with cancers of the head and neck. Better understanding of radiobiology and radiation physics has allowed radiation oncologists to enhance the tumoricidal effects of radiation and reduce the severity of normal tissue toxicities. This article reviews the biologic foundation of head and neck radiotherapy, the physical principles and technological innovations that enable delivery of highly conformal radiation, the acute and late complications of radiation-based treatments, and the clinical evidence supporting contemporary practice.
Journal of Bronchology & Interventional Pulmonology, 2013
Optimal treatment for unresectable central airway tumors is not well established. Stereotactic bo... more Optimal treatment for unresectable central airway tumors is not well established. Stereotactic body radiation therapy has shown efficacy for both peripheral and central lung lesions. However, the treatment of central tumors has been limited because of associated radiation toxicity. We report the use of an endobronchial fiducial to localize hypofractionated stereotactic body radiation therapy treatment of a limited central airways disease in a patient with recurrent metastatic squamous cell lung cancer. The fiducial was instrumental in designing the treatment field and minimizing related treatment toxicity. Future studies may take advantage of this technique in patients with unresectable central airways non-small cell lung cancers.
The purpose of this study was to define baseline variability of apparent diffusion coefficient (A... more The purpose of this study was to define baseline variability of apparent diffusion coefficient (ADC) on diffusion-weighted MR imaging (DWI) in patients with head and neck squamous cell carcinoma (HNSCC) and to compare it with early treatment-induced ADC change. Patients with American Joint Committee on Cancer stages III and IV HNSCC were imaged with two baseline DWI examinations 1 week apart and a third DWI examination during the 2nd week of curative-intent chemoradiation therapy. Mean ADC was measured in the primary tumor and largest lymph node for each patient on the three DWI scans. Mean baseline percentage differences (%∆ADC) were compared with intratreatment change. The repeatability coefficient for baseline %∆ADC was calculated and compared with intratreatment %∆ADC. Repeatability was also assessed with Bland-Altman plots and the intraclass correlation coefficient (ICC). Sixteen patients underwent double baseline imaging, with 14 also undergoing intratreatment imaging. Baseline nodal disease ADC could be measured in 16 patients, but ADC in primary tumors could only be measured in five patients. The nodal mean (SD) baseline %∆ADC was 8% (± 7%), which was significantly different compared with intratreatment changes of 32% (± 31%) (p = 0.01). Baseline ICC was 0.86 for nodal disease and 0.99 for primary tumor (excellent correlation). The calculated repeatability coefficient for baseline nodal ADC was 15%. No patients had decreases in intratreatment ADC of more than 15%. Baseline ADC variability for HNSCC is less than intratreatment ADC change for nodal disease. Assessment of response should consider intrinsic baseline variability.
Recent in vitro and in vivo evidence has suggested that statin medications may have anticancer ac... more Recent in vitro and in vivo evidence has suggested that statin medications may have anticancer activity. We sought to determine whether statin use was associated with improved clinical outcome in men treated with brachytherapy for prostate cancer. A database of men with prostate cancer treated with permanent Iodine-125 brachytherapy between January 1999 and February 2009 was retrospectively analyzed. Standard guidelines (i.e., American Brachytherapy Society selection criteria) were used for selecting patients for brachytherapy. Biochemical failure was defined using the Phoenix definition. From a total of 247 men with prostate adenocarcinoma treated with brachytherapy, 174 patients (70 %) were identified as using statin medications, either during initial visit or during follow-up. Median PSA follow-up was 51 months after date of implant (range 9.4-140.35). Overall biochemical failure rate was 7.3 % (18 patients). On univariate analysis, statin use was associated with significantly im...
International Journal of Radiation Oncology*Biology*Physics, 2015
To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (... more To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed. SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate.
Purpose: Calculation of the precontrast longitudinal relaxation times ͑T 10 ͒ is an integral part... more Purpose: Calculation of the precontrast longitudinal relaxation times ͑T 10 ͒ is an integral part of the Tofts-based pharmacokinetic ͑PK͒ analysis of dynamic contrast enhanced-magnetic resonance images. The purpose of this study was to investigate the interpatient and over time variability of T 10 in head and neck primary tumors and involved nodes and to determine the median T 10 for primary and nodes ͑T 10 p,n ͒. The authors also looked at the implication of using voxel-based T 10 values versus region of interest ͑ROI͒-based T 10 on the calculated values for vascular permeability ͑K trans ͒ and extracellular volume fraction ͑v e ͒. Methods: Twenty head and neck cancer patients receiving concurrent chemoradiation and molecularly targeted agents on a prospective trial comprised the study population. Voxel-based T 10 's were generated using a gradient echo sequence on a 1.5 T MR scanner using the variable flip angle method with two flip angles ͓J. A. Brookes et al., "Measurement of spin-lattice relaxation times with FLASH for dynamic MRI of the breast," Br. J. Radiol. 69, 206-214 ͑1996͔͒. The voxel-based T 10 , K trans , and v e were calculated using iCAD's ® ͑Nashua, NH͒ software. The mean T 10 's in muscle and fat ROIs were calculated ͑T 10 m,f ͒. To assess reliability of ROI drawing, T 10 p,n values from ROIs delineated by 2 users ͑A and B͒ were calculated as the average of the T 10 's for 14 patients. For a subset of three patients, the T 10 variability from baseline to end of treatment was also investigated. The K trans and v e from primary and node ROIs were calculated using voxel-based T 10 values and T 10 p,n and differences reported. Results: The calculated T 10 values for fat and muscle are within the range of values reported in literature for 1.5 T, i.e., T 10 m = 0.958 s and T 10 f = 0.303 s. The average over 14 patients of the T 10 's based on drawings by users A and B were T 10 pA = 0.804 s, T 10 nA = 0.760 s, T 10 pB = 0.849 s, and T 10 nB = 0.810 s. The absolute percentage difference between K trans and v e calculated with voxelbased T 10 versus T 10 p,n ranged from 6% to 81% and from 2% to 24%, respectively. Conclusions: There is a certain amount of variability in the median T 10 values between patients, but the differences are not significant. There were also no statistically significant differences between the T 10 values for primary and nodes at baseline and the subsequent time points ͑p = 0.94 Friedman test͒. Voxel-based T 10 calculations are essential when quantitative Tofts-based PK analysis in heterogeneous tumors is needed. In the absence of T 10 mapping capability, when a relative, qualitative analysis is deemed sufficient, a value of T 10 p,n = 0.800 s can be used as an estimate for T 10 for both the primary tumor and the affected nodes in head and neck cancers at all the time points considered.
To evaluate how well the tumor, node, metastasis (TNM) 6 and TNM 7 staging systems predict rates ... more To evaluate how well the tumor, node, metastasis (TNM) 6 and TNM 7 staging systems predict rates of local/regional recurrence (LRR) after surgery alone for non-small cell lung cancer. All patients who underwent surgery for non-small cell lung cancer at Duke between 1995 and 2005 were reviewed. Those undergoing sublobar resections, with positive margins or involvement of the chest wall, or those who received any chemotherapy or radiation therapy (RT) were excluded. Disease recurrence at the surgical margin, or within ipsilateral hilar and/or mediastinal lymph nodes, was considered as a LRR. Stage was assigned based on both TNM 6 and TNM 7. Rates of LRR were estimated using the Kaplan-Meier method. A Cox regression analysis evaluated the hazard ratio of LRR by stage within TNM 6 and TNM 7. A total of 709 patients were eligible for the analysis. Median follow-up was 32 months. For all patients, the 5-year actuarial risk of LRR was 23%. Conversion from TNM 6 to TNM 7 resulted in 21% stage migration (upstaging in 13%; downstaging in 8%). Five-year rates of LRR for stages IA, IB, IIA, IIB, and IIIA disease using TNM 6 were 16%, 26%, 43%, 35%, and 40%, respectively. Using TNM 7, corresponding rates were 16%, 23%, 37%, 39%, and 30%, respectively. The hazard ratios for LRR were statistically different for IA and IB in both TNM 6 and 7 but were also different for IB and IIA in TNM 7. LRR risk increases monotonically for stages IA to IIB in the new TNM 7 system. This information might be valuable when designing future studies of postoperative RT.
International Journal of Radiation Oncology*Biology*Physics, 2011
To evaluate actuarial rates of local failure in patients with pathologic N1 non-small-cell lung c... more To evaluate actuarial rates of local failure in patients with pathologic N1 non-small-cell lung cancer and to identify clinical and pathologic factors associated with an increased risk of local failure after resection. All patients who underwent surgery for non-small-cell lung cancer with pathologically confirmed N1 disease at Duke University Medical Center from 1995-2008 were identified. Patients receiving any preoperative therapy or postoperative radiotherapy or with positive surgical margins were excluded. Local failure was defined as disease recurrence within the ipsilateral hilum, mediastinum, or bronchial stump/staple line. Actuarial rates of local failure were calculated with the Kaplan-Meier method. A Cox multivariate analysis was used to identify factors independently associated with a higher risk of local recurrence. Among 1,559 patients who underwent surgery during the time interval, 198 met the inclusion criteria. Of these patients, 50 (25%) received adjuvant chemotherapy. Actuarial (5-year) rates of local failure, distant failure, and overall survival were 40%, 55%, and 33%, respectively. On multivariate analysis, factors associated with an increased risk of local failure included a video-assisted thoracoscopic surgery approach (hazard ratio [HR], 2.5; p = 0.01), visceral pleural invasion (HR, 2.1; p = 0.04), and increasing number of positive N1 lymph nodes (HR, 1.3 per involved lymph node; p = 0.02). Chemotherapy was associated with a trend toward decreased risk of local failure that was not statistically significant (HR, 0.61; p = 0.2). Actuarial rates of local failure in pN1 disease are high. Further investigation of conformal postoperative radiotherapy may be warranted.
International Journal of Radiation Oncology*Biology*Physics, 2012
Thirteen patients had at least three usable beams and were analyzed. The mean of R m was 0.87 (ra... more Thirteen patients had at least three usable beams and were analyzed. The mean of R m was 0.87 (range, 0.84e0.95). The mean of A m was 3.18 mm (range, 0.46e7.80 mm). R m was found to decrease as A m increases following an equation of R m Z 0.17e À0.9Am þ 0.84. R m also decreased slightly throughout the course of treatments. Intersubject CV of R m (0.05) was comparable to intrasubject CVof R m (range, 0.02e0.09); intersubject CVof A m (0.73) was significantly greater than intrasubject CV of A m (range, 0.09e0.24). Conclusions: Tumor motion PDF can be determined using cine MV images acquired during the treatments. The reproducibility of lung tumor motion PDF decreased exponentially as the tumor motion range increased and decreased slightly throughout the course of the treatments.
International Journal of Radiation Oncology*Biology*Physics, 2012
Dynamic contrast-enhanced (DCE) MRI-extracted parameters measure tumor microvascular physiology a... more Dynamic contrast-enhanced (DCE) MRI-extracted parameters measure tumor microvascular physiology and are usually calculated from an intratumor region of interest (ROI). Optimal ROI delineation is not established. The valid clinical use of DCE-MRI requires that the variation for any given parameter measured within a tumor be less than that observed between tumors in different patients. This work evaluates the impact of tumor ROI selection on the assessment of intra- and interpatient variability. Head and neck cancer patients received initial targeted therapy (TT) treatment with erlotinib and/or bevacizumab, followed by radiotherapy and concurrent cisplatin with synchronous TT. DCE-MRI data from Baseline and the end of the TT regimen (Lead-In) were analyzed to generate the vascular transfer function (K(trans)), the extracellular volume fraction (v(e)), and the initial area under the concentration time curve (iAUC(1 min)). Four ROI sampling strategies were used: whole tumor or lymph node (Whole), the slice containing the most enhancing voxels (SliceMax), three slices centered in SliceMax (Partial), and the 5% most enhancing contiguous voxels within SliceMax (95Max). The average coefficient of variation (aCV) was calculated to establish intrapatient variability among ROI sets and interpatient variability for each ROI type. The average ratio between each intrapatient CV and the interpatient CV was calculated (aRCV). Baseline primary/nodes aRCVs for different ROIs not including 95Max were, for all three MR parameters, in the range of 0.14-0.24, with Lead-In values between 0.09 and 0.2, meaning a low intrapatient vs. interpatient variation. For 95Max, intrapatient CVs approximated interpatient CVs, meaning similar data dispersion and higher aRCVs (0.6-1.27 for baseline) and 0.54-0.95 for Lead-In. Distinction between different patient's primary tumors and/or nodes cannot be made using 95Max ROIs. The other three strategies are viable and equivalent for using DCE-MRI to measure head and neck cancer physiology.
International Journal of Radiation Oncology*Biology*Physics, 2009
Purpose-To describe our experience and clinical strategy for stereotactic body radiotherapy (SBRT... more Purpose-To describe our experience and clinical strategy for stereotactic body radiotherapy (SBRT) of spinal lesions.
International Journal of Radiation Oncology*Biology*Physics, 2009
inverse orientation was cloned (pHR'SIN-GULS). The human lymphoblastoid TK6 cell line (p53 wild-t... more inverse orientation was cloned (pHR'SIN-GULS). The human lymphoblastoid TK6 cell line (p53 wild-type) was transduced with the viral supernatants. The FACS was used to sort the EGFP-positive cells to get completely transduced cell pools. The SLUG expression was determined by Western blot. Radioprotection was analyzed by a proliferation assay, an MTT cytotoxicity assay, and a clonogenic assay. The effect of SLUG on the rate of apoptosis was determined by measuring the amount of sub-G1 cells. Results: After 2-8 hours irradiation of TK6 cells with 2 Gy, a three to fourfold increase of PUMA transcription was detected by quantitative real-time PCR. An increase of PUMA expression could be verified also at the protein level. The TK6 cells showed no endogenous SLUG expression, whereas SLUG protein was demonstrated by Western blot in lysates of TK6-SLUG cells. In a first radioprotection assay, the amount of EGFP-positive cells was determined 48 hours after irradiation of transduced TK6 cells: 2 Gy resulted in a twofold, and 6 Gy in an up to fourfold increase in SLUG-overexpressing cells. After FACS sorting, a pool of nearly 100% transduced cells was irradiated with 0-5 Gy. In the MTT assay, a significant survival advantage by SLUG overexpression could be demonstrated. The EGFP-expression was not responsible for this radioprotective effect since SLUGexpressing cells were also radioresistant after removal of the IRES-EGFP-cassette by CRE-recombinase. Determination of the amount of sub-G1 cells in TK6-SLUG cells revealed an approximately 50% reduction in apoptosis as compared with both control entities. Additionally, TK6-SLUG compared to TK6-GULS cells showed a survival advantage in the clonogenic assay after irradiation with 0-3 Gy. Conclusions: We established a lentiviral vector for expression of a transgene (without the possibility to select on its expression) in a bicistronic expression cassette with floxed EGFP as selection marker. Using this vector, we could show that SLUG-expression functions radioprotective in TK6 cells demonstrating its potential as candidate for gene therapeutic radioprotection of normal tissues.
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Papers by David Yoo