David S. Yoo

STEREOTACTIC BODY RADIOTHERAPY FOR LESIONS OF THE SPINE AND PARASPINAL REGIONS

PURPOSE To describe our experience and clinical strategy for stereotactic body radiotherapy (SBRT) of spinal lesions. METHODS AND MATERIALS Thirty-two patients with 33 spinal lesions underwent computed tomography-based simulation while free breathing. Gross/clinical target volumes included involved portions of the vertebral body and paravertebral/epidural tumor. Planning target volume (PTV) expansion was 6 mm axially and 3 mm radially; the cord was excluded from the PTV. Biologic equivalent dose was calculated using the linear quadratic model with alpha/beta = 3 Gy. Treatment was linear accelerator based with on-board imaging; dose was adjusted to maintain cord dose within tolerance. Survival, local control, pain, and neurologic status were monitored. RESULTS Twenty-one patients are alive at 1 year (median survival, 14 months). Median follow-up is 6 months for all patients (7 months for survivors). Mean previous radiotherapy dose to 22 patients was 35 Gy, and median interval was 17 months. Renal (31%), breast, and lung (19% each) were the most common histologic sites. Three SBRT fractions (range, one to four fractions) of 7 Gy (range, 5-16 Gy) were delivered. Median cord and target biologic equivalent doses were 70 Gy(3) and 34.3 Gy(10), respectively. Thirteen patients reported complete and 17 patients reported partial pain relief at 1 month. There were four failures (mean, 5.8 months) with magnetic resonance imaging evidence of in-field progression. No dosimetric parameters predictive of failure were identified. No treatment-related toxicity was seen. CONCLUSIONS Spinal SBRT is effective in the palliative/re-treatment setting. Volume expansion must ensure optimal PTV coverage while avoiding spinal cord toxicity. The long-term safety of spinal SBRT and the applicability of the linear-quadratic model in this setting remain to be determined, particularly the time-adjusted impact of prior radiotherapy.

Analysis of Pretreatment FDG-PET SUV Parameters in Head-and-Neck Cancer: Tumor SUVmean Has Superior Prognostic Value

PURPOSE To evaluate the prognostic significance of different descriptive parameters in head-and-neck cancer patients undergoing pretreatment [F-18] fluoro-D-glucose-positron emission tomography (FDG-PET) imaging. PATIENTS AND METHODS Head-and-neck cancer patients who underwent FDG-PET before a course of curative intent radiotherapy were retrospectively analyzed. FDG-PET imaging parameters included maximum (SUV(max)), and mean (SUV(mean)) standard uptake values, and total lesion glycolysis (TLG). Tumors and lymph nodes were defined on co-registered axial computed tomography (CT) slices. SUV(max) and SUV(mean) were measured within these anatomic regions. The relationships between pretreatment SUV(max), SUV(mean), and TLG for the primary site and lymph nodes were assessed using a univariate analysis for disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS). Kaplan-Meier survival curves were generated and compared via the log-rank method. SUV data were analyzed as continuous variables. RESULTS A total of 88 patients was assessed. Two-year OS, LRC, DMFS, and DFS for the entire cohort were 85%, 78%, 81%, and 70%, respectively. Median SUV(max) for the primary tumor and lymph nodes was 15.4 and 12.2, respectively. Median SUV(mean) for the primary tumor and lymph nodes was 7 and 5.2, respectively. Median TLG was 770. Increasing pretreatment SUV(mean) of the primary tumor was associated with decreased disease-free survival (p = 0.01). Neither SUV(max) in the primary tumor or lymph nodes nor TLG was prognostic for any of the clinical endpoints. Patients with pretreatment tumor SUV(mean) that exceeded the median value (7) of the cohort demonstrated inferior 2-year DFS relative to patients with SUV(mean) ≤ the median value of the cohort, 58% vs. 82%, respectively, p = 0.03. CONCLUSION Increasing SUV(mean) in the primary tumor was associated with inferior DFS. Although not routinely reported, pretreatment SUV(mean) may be a useful prognostic FDG-PET parameter and should be further evaluated prospectively.

Prospective Trial of Synchronous Bevacizumab, Erlotinib, and Concurrent Chemoradiation in Locally Advanced Head and Neck Cancer

Purpose: We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC). Experimental Design: Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT. Results: Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%–100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median Ktrans values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median Ktrans values that decreased during therapy. Conclusions: Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure. Clin Cancer Res; 18(5); 1404–14. ©2012 AACR.

Defining the Optimal Planning Target Volume in Image-Guided Stereotactic Radiosurgery of Brain Metastases: Results of a Randomized Trial

PURPOSE To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. METHODS AND MATERIALS 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). RESULTS 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. CONCLUSIONS 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.

Dosimetric comparison of treatment plans based on free breathing, maximum, and average intensity projection CTs for lung cancer SBRT

PURPOSE To determine whether there is a CT dataset may be more favorable for planning and dose calculation by comparing dosimetric characteristics between treatment plans calculated using free breathing (FB), maximum and average intensity projection (MIP and AIP, respectively) CTs for lung cancer patients receiving stereotactic body radiation therapy (SBRT). METHODS Twenty lung cancer SBRT patients, treated on a linac with 2.5 mm width multileaf-collimator (MLC), were analyzed retrospectively. Both FB helical and four-dimensional CT scans were acquired for each patient. Internal target volume (ITV) was delineated based on MIP CTs and modified based on both ten-phase datasets and FB CTs. Planning target volume (PTV) was then determined by adding additional setup margin to ITV. The PTVs and beams in the optimized treatment plan based on FB CTs were copied to MIP and AIP CTs, with the same isocenters, MLC patterns and monitor units. Mean effective depth (MED) of beams, and some dosimetric parameters for both PTVs and most important organ at risk (OAR), lung minus PTV, were compared between any two datasets using two-tail paired t test. RESULTS The MEDs in FB and AIP plans were similar but significantly smaller (Ps < 0.001) than that in MIP plans. Minimum dose, mean dose, dose covering at least 90% and 95% of PTVs in MIP plans were slightly higher than two other plans (Ps < 0.008). The absolute volume of lung minus PTV receiving greater than 5, 10, and 20 Gy in MIP plans were significantly smaller than those in both FB and AIP plans (Ps < 0.008). Conformity index for FB plans showed a small but statistically significantly higher. CONCLUSIONS Dosimetric characteristics of AIP plans are similar to those of FB plans. Slightly better target volume coverage and significantly lower low-dose region (≤30 Gy) in lung was observed in MIP plans. The decrease in low-dose region in lung was mainly caused by the change of lung volume contoured on two datasets rather than the differences of dose distribution between AIP and MIP plans. Compare with AIP datasets, FB datasets were more prone to significant image artifacts and MIP datasets may overestimate or underestimate the target volume when the target is closer to the denser tissue, so AIP seems favorable for planning and dose calculation for lung SBRT.

How Well Does the New Lung Cancer Staging System Predict for Local/Regional Recurrence After Surgery?: A Comparison of the TNM 6 and 7 Systems

Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.

Dynamic Contrast-Enhanced MRI in Head-and-Neck Cancer: The Impact of Region of Interest Selection on the Intra- and Interpatient Variability of Pharmacokinetic Parameters

PURPOSE 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. METHOD AND MATERIALS 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). RESULTS 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. CONCLUSION Distinction between different patients 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.

Using FDG-PET to Measure Early Treatment Response in Head and Neck Squamous Cell Carcinoma: Quantifying Intrinsic Variability in Order to Understand Treatment-Induced Change

BACKGROUND AND PURPOSE: Quantification of both baseline variability and intratreatment change is necessary to optimally incorporate functional imaging into adaptive therapy strategies for HNSCC. Our aim was to define the baseline variability of SUV on FDG-PET scans in patients with head and neck squamous cell carcinoma and to compare it with early treatment-induced SUV change. MATERIALS AND METHODS: Patients with American Joint Committee on Cancer stages III-IV HNSCC were imaged with 2 baseline PET/CT scans and a third scan after 1–2 weeks of curative-intent chemoradiation. SUVmax and SUVmean were measured in the primary tumor and most metabolically active nodal metastasis. Repeatability was assessed with Bland-Altman plots. Mean percentage differences (%ΔSUV) in baseline SUVs were compared with intratreatment %ΔSUV. The repeatability coefficient for baseline %ΔSUV was compared with intratreatment %ΔSUV. RESULTS: Seventeen patients had double-baseline imaging, and 15 of these patients also had intratreatment scans. Bland-Altman plots showed excellent baseline agreement for nodal metastases SUVmax and SUVmean, but not primary tumor SUVs. The mean baseline %ΔSUV was lowest for SUVmax in nodes (7.6% ± 5.2%) and highest for SUVmax in primary tumor (12.6% ± 9.2%). Corresponding mean intratreatment %ΔSUVmax was 14.5% ± 21.6% for nodes and 15.2% ± 22.4% for primary tumor. The calculated RC for baseline nodal SUVmax and SUVmean were 10% and 16%, respectively. The only patient with intratreatment %ΔSUV above these RCs was 1 of 2 patients with residual disease after CRT. CONCLUSIONS: Baseline SUV variability for HNSCC is less than intratreatment change for SUV in nodal disease. Evaluation of early treatment response should be measured quantitatively in nodal disease rather than the primary tumor, and assessment of response should consider intrinsic baseline variability.

Diffusion-Weighted Imaging for Head and Neck Squamous Cell Carcinoma: Quantifying Repeatability to Understand Early Treatment-Induced Change

OBJECTIVE 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. SUBJECTS AND METHODS 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). RESULTS 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%. CONCLUSION Baseline ADC variability for HNSCC is less than intratreatment ADC change for nodal disease. Assessment of response should consider intrinsic baseline variability.

MultiModality Surgical and Hyperbaric Management of Mandibular Osteoradionecrosis

PURPOSE To elucidate long-term outcomes in 65 consecutive patients meeting a uniform definition of mandibular osteoradionecrosis (ORN) treated with multimodality therapy including hyperbaric oxygen (HBO). METHODS AND MATERIALS Pretreatment, post-treatment and long-term follow-up of mandibular lesions with exposed bone were ranked by a systematic review of medical records and patient telephone calls. The ranking system was based on lesion diameter and number plus disease progression. Changes from pretreatment to post-treatment and follow-up were analyzed by Wilcoxon signed-rank tests. Improved wound survival, measured by time to relapse, defined as any less favorable rank after HBO treatment, was assessed by Kaplan-Meier analysis. RESULTS In all, 57 cases (88%) resolved or improved by lesion grade or progression and evolution criteria after HBO (p < 0.001). Four patients healed before surgery after HBO alone. Of 57 patients who experienced improvement, 41 had failed previous nonmultimodality therapy for 3 months and 26 for 6 months or more. A total of 43 patients were eligible for time-to-relapse survival analysis. Healing or improvement lasted a mean duration of 86.1 months (95% confidence interval [95% CI], 64.0-108.2) in nonsmokers (n = 20) vs. 15.8 months (95% CI, 8.4-23.2) in smokers (n = 14) versus 24.2 months (95% CI, 15.2-33.2) in patients with recurrent cancer (n = 9) (p = 0.002 by the log-rank method). CONCLUSIONS Multimodality therapy using HBO is effective for ORN when less intensive therapies have failed. Although the healing rate in similarly affected patients not treated with HBO is unknown, the improvements seen with peri-operative HBO were durable provided that the patients remained cancer free and abstained from smoking.