Sean S. Park

Adaptive Image-Guided Radiotherapy (IGRT) Eliminates the Risk of Biochemical Failure Caused by the Bias of Rectal Distension in Prostate Cancer Treatment Planning: Clinical Evidence

PURPOSE Rectal distension has been shown to decrease the probability of biochemical control. Adaptive image-guided radiotherapy (IGRT) corrects for target position and volume variations, reducing the risk of biochemical failure while yielding acceptable rates of gastrointestinal (GI)/genitourinary (GU) toxicities. METHODS AND MATERIALS Between 1998 and 2006, 962 patients were treated with computed tomography (CT)-based offline adaptive IGRT. Patients were stratified into low (n = 400) vs. intermediate/high (n = 562) National Comprehensive Cancer Network (NCCN) risk groups. Target motion was assessed with daily CT during the first week. Electronic portal imaging device (EPID) was used to measure daily setup error. Patient-specific confidence-limited planning target volumes (cl-PTV) were then constructed, reducing the standard PTV and compensating for geometric variation of the target and setup errors. Rectal volume (RV), cross-sectional area (CSA), and rectal volume from the seminal vesicles to the inferior prostate (SVP) were assessed on the planning CT. The impact of these volumetric parameters on 5-year biochemical control (BC) and chronic Grades ≥2 and 3 GU and GI toxicity were examined. RESULTS Median follow-up was 5.5 years. Median minimum dose covering cl-PTV was 75.6 Gy. Median values for RV, CSA, and SVP were 82.8 cm(3), 5.6 cm(2), and 53.3 cm(3), respectively. The 5-year BC was 89% for the entire group: 96% for low risk and 83% for intermediate/high risk (p < 0.001). No statistically significant differences in BC were seen with stratification by RV, CSA, and SVP in quartiles. Maximum chronic Grades ≥2 and 3 GI toxicities were 21.2% and 2.9%, respectively. Respective values for GU toxicities were 15.5% and 4.3%. No differences in GI or GU toxicities were noted when patients were stratified by RV. CONCLUSIONS Incorporation of adaptive IGRT reduces the risk of geometric miss and results in excellent biochemical control that is independent of rectal volume/distension while maintaining very low rates of chronic GI toxicity.

Accelerated Partial Breast Irradiation for Pure Ductal Carcinoma in Situ

PURPOSE To report outcomes for ductal carcinoma in situ (DCIS) treated with breast-conserving therapy using accelerated partial breast irradiation (APBI). METHODS AND MATERIALS From March 2001 to February 2009, 53 patients with Stage 0 breast cancer were treated with breast conserving surgery and adjuvant APBI. Median age was 62 years. All patients underwent excision with margins negative by ≥1 mm before adjuvant radiotherapy (RT). A total of 39 MammoSite brachytherapy (MS) patients and 14 three-dimensional conformal external beam RT (3DCRT) patients were treated to the lumpectomy bed alone with 34 Gy and 38.5 Gy, respectively. Of the DCIS cases, 94% were mammographically detected. All patients with calcifications had either specimen radiography or postsurgical mammography confirmation of clearance. Median tumor size was 6 mm, and median margin distance was 5 mm. There were no statistically significant differences according to APBI method for race/ethnicity, tumor detection method, tumor grade, estrogen receptor (ER) status, or use of tamoxifen (p = NS). Recurrence and survival were calculated using the Kaplan-Meier method. Cosmesis was scored by the Harvard criteria. RESULTS With a median follow-up of 3.6 years (range, 0.4-6.3 years), the overall and cause-specific survival rates were 98% and 100%, respectively. Three-year actuarial ipsilateral breast tumor recurrence was 2%. One failure was observed at the resection bed 11 months post-RT. No other elsewhere breast failures, regional recurrences, or distant metastases were noted. Cosmesis was excellent or good in 92.4% of cases, with no statistically significant differences according to the APBI method (92.3% with MammoSite and 92.8% with 3DCRT; p = 0.649). CONCLUSIONS APBI as part of breast-conserving therapy for pure DCIS was associated with excellent local control and survival rates, with the vast majority of patients having good to excellent cosmesis. This finding supports the recent analysis by the American Society of Breast Surgeons on a subset of DCIS patients treated efficaciously with APBI.

MicroPET/CT Imaging of an Orthotopic Model of Human Glioblastoma Multiforme and Evaluation of Pulsed Low-Dose Irradiation

PURPOSE Glioblastoma multiforme (GBM) is an aggressive tumor that typically causes death due to local progression. To assess a novel low-dose radiotherapy regimen for treating GBM, we developed an orthotopic murine model of human GBM and evaluated in vivo treatment efficacy using micro-positron-emission tomography/computed tomography (microPET/CT) tumor imaging. METHODS Orthotopic GBM xenografts were established in nude mice and treated with standard 2-Gy fractionation or 10 0.2-Gy pulses with 3-min interpulse intervals, for 7 consecutive days, for a total dose of 14 Gy. Tumor growth was quantified weekly using the Flex Triumph (GE Healthcare/Gamma Medica-Ideas, Waukesha, WI) combined PET-single-photon emission CT (SPECT)-CT imaging system and necropsy histopathology. Normal tissue damage was assessed by counting dead neural cells in tissue sections from irradiated fields. RESULTS Tumor engraftment efficiency for U87MG cells was 86%. Implanting 0.5 × 10(6) cells produced a 50- to 70-mm(3) tumor in 10 to 14 days. A significant correlation was seen between CT-derived tumor volume and histopathology-measured volume (p = 0.018). The low-dose 0.2-Gy pulsed regimen produced a significantly longer tumor growth delay than standard 2-Gy fractionation (p = 0.045). Less normal neuronal cell death was observed after the pulsed delivery method (p = 0.004). CONCLUSION This study successfully demonstrated the feasibility of in vivo brain tumor imaging and longitudinal assessment of tumor growth and treatment response with microPET/CT. Pulsed radiation treatment was more efficacious than the standard fractionated treatment and was associated with less normal tissue damage.

Pulsed Versus Conventional Radiation Therapy in Combination With Temozolomide in a Murine Orthotopic Model of Glioblastoma Multiforme

PURPOSE To evaluate the efficacy of pulsed low-dose radiation therapy (PLRT) combined with temozolomide (TMZ) as a novel treatment approach for radioresistant glioblastoma multiforme (GBM) in a murine model. METHODS AND MATERIALS Orthotopic U87MG hGBM tumors were established in Nu-Foxn1(nu) mice and imaged weekly using a small-animal micropositron emission tomography (PET)/computed tomography (CT) system. Tumor volume was determined from contrast-enhanced microCT images and tumor metabolic activity (SUVmax) from the F18-FDG microPET scan. Tumors were irradiated 7 to 10 days after implantation with a total dose of 14 Gy in 7 consecutive days. The daily treatment was given as a single continuous 2-Gy dose (RT) or 10 pulses of 0.2 Gy using an interpulse interval of 3 minutes (PLRT). TMZ (10 mg/kg) was given daily by oral gavage 1 hour before RT. Tumor vascularity and normal brain damage were assessed by immunohistochemistry. RESULTS Radiation therapy with TMZ resulted in a significant 3- to 4-week tumor growth delay compared with controls, with PLRT+TMZ the most effective. PLRT+TMZ resulted in a larger decline in SUVmax than RT+TMZ. Significant differences in survival were evident. Treatment after PLRT+TMZ was associated with increased vascularization compared with RT+TMZ. Significantly fewer degenerating neurons were seen in normal brain after PLRT+TMZ compared with RT+TMZ. CONCLUSIONS PLRT+TMZ produced superior tumor growth delay and less normal brain damage when compared with RT+TMZ. The differential effect of PLRT on vascularization may confirm new treatment avenues for GBM.

Longitudinal assessment of quality of life and audiometric test outcomes in vestibular schwannoma patients treated with gamma knife surgery.

Objective: To prospectively assess the quality of life (QOL) and hearing acuity in vestibular schwannoma (VS) patients after gamma knife surgery (GKS). Patients: Fifty-nine VS patients. Intervention: GKS. Main Outcome Measures: Prospective follow-up algorithm included 36-item Short Form Health Survey (SF-36), Hearing Handicap Inventory (HHI), Dizziness Handicap Inventory (DHI), Tinnitus Handicap Inventory (THI), pure-tone average, and speech discrimination hearing scores (Gardner-Robertson and American Academy of Otolaryngology), performed before and after GKS at 1-, 3-, 6-, 12-, and 18-month posttreatment intervals. Results: From December 2006 to November 2008, 59 VS patients were treated with a median follow-up of 15 months. At baseline, mean scores for SF-36, HHI, DHI, and THI were 73, 37, 17, and 23, respectively. Median baseline Gardner-Robertson and American Academy of Otolaryngology hearing acuity scores were 2 and B, respectively. No significant decline in SF-36 health survey was noted after GKS. Mean SF-36 score at baseline was 73, compared with a range of 70 to 77 at predetermined posttreatment intervals. Similarly, no significant changes in DHI, HHI, and THI were noted. Approximately 47% of patients with baseline serviceable hearing maintained serviceable hearing at 12 months. Significant acute and chronic worsening in hearing acuity were noted at 1 and 18 months, respectively. No correlative decline in QOL was noted as assessed by SF-36 or HHI. Conclusion: No significant decline in global QOL occurred after GKS with relatively short follow-up and approximately 50% survey completion. When discussing therapy options with VS patients, anticipated treatment-related QOL outcomes should be considered.

External beam pulsed low dose radiotherapy using volumetric modulated arc therapy: Planning and delivery

PURPOSE To evaluate the feasibility of planning and delivering pulsed low dose radiotherapy (PLRT) using volumetric modulated arc therapy (VMAT) on Elektalinacs. METHODS Ten patients previously treated for glioblastomamultiforme (GBM) were replanned using PLRT VMAT to deliver ten 0.2 Gy pulses separated by 3 min intervals with an effective dose rate of 0.067 Gy∕min. VMAT parameters such as leaf speed and arc length were investigated to deliver 2 Gy∕fraction to a total of 60 Gy to the target volume in ten subfractions or pulses. Plan quality was assessed using conformity and homogeneity indices. Absolute dose distribution for individual pulses was measured using ArcCHECK diode array. Individual pulses were analyzed for reproducibility and stability using machine log files. Machine characteristics at low monitor units and low dose rate were also investigated. RESULTS An optimal arc length of 140°-160° and a leaf speed of 0.18-0.25 cm∕° were sufficient to provide equivalent plan coverage and stable delivery. The average time and dose rate required to deliver a single 0.2 Gy pulse was 39.5 ± 2.3 s and 49 ± 32.3 cGy∕min. Average reductions in MUs for the VMAT PLRT plan compared to IMRT for PTV was 16% (Range: -5.5%-36.1%) and 10.9% (Range: -18.4%-32.3%) for the initial and boost plan. A significant improvement was seen in maximum doses to all sensitive structures when planned with VMAT PLRT. The average absolute dose gamma passing rate for the 10 pulses combined and 2 Gy plan were 91.6 ± 2.5% and 97.3 ± 1.2%, respectively. Cumulative monitor units, dose rate, gantry angles, and leaf positions evaluated using machine log files were within 2% for all pulses. CONCLUSIONS Elekta linacs are capable of delivering reproducible and stable PLRT plans. A prospective clinical study employing PLRT is currently in development.