Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer.

PURPOSE: Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease. METHODS: This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype-specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS. RESULTS: With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% v 51%, P = .03; 82% v 15%, P < .001; and 82% v 24%, P < .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS. CONCLUSION: Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.

Comparing dosimetry of locally advanced cervical cancer patients treated with 3 versus 4 fractions of MRI-guided brachytherapy.

PURPOSE: To demonstrate the feasibility of treating cervical cancer patients with MRI-guided brachytherapy (MRgBT) using 24 Gy in 3 fractions (F) versus a standard, more resource-intensive regimen of 28 Gy in 4F, and its ability to meet EMBRACE II planning aims. METHODS AND MATERIALS: A retrospective review of 224 patients with FIGO Stage IB-IVA cervical cancer treated with 28 Gy/4F (n = 91) and 24 Gy/3F (n = 133) MRgBT between 2016-2021 was conducted. Multivariable linear regression models were fitted to compare dosimetric parameters between the two groups, adjusting for CTVHR and T stage. RESULTS: Most patients had squamous cell carcinoma, T2b disease, and were treated with intracavitary applicator plus interstitial needles (96%). The 28 Gy/4F group had higher CTVHR (median 28 vs. 26 cm3, p = 0.04), CTVIR D98% (mean 65.5 vs. 64.5 Gy, p = 0.03), rectum D2cm3 (mean 61.7 vs. 59.2 Gy, p = 0.04) and bladder D2cm3 (81.3 vs. 77.9 Gy, p = 0.03). There were no significant differences in the proportion of patients meeting the EMBRACE II OAR dose constraints and planning aims, except fewer patients treated with 28 Gy/4F met rectum D2cm3 < 65 Gy (73 vs. 85%, p = 0.027) and ICRU rectovaginal point < 65 Gy (65 vs. 84%, p = 0.005). CONCLUSIONS: Cervical cancer patients treated with 24 Gy/3F MRgBT had comparable target doses and lower OAR doses compared to those treated with 28 Gy/4F. A less-resource intense fractionation schedule of 24 Gy/3F is an alternative to 28 Gy/4F in cervix MRgBT.

Quality-of-Life Outcomes and Toxic Effects Among Patients With Cancers of the Uterus Treated With Stereotactic Pelvic Adjuvant Radiation Therapy: The SPARTACUS Phase 1/2 Nonrandomized Controlled Trial.

Importance: Adjuvant radiation plays an important role in reducing locoregional recurrence in patients with uterine cancer. Although hypofractionated radiotherapy may benefit health care systems and the global community while decreasing treatment burden for patients traveling for daily radiotherapy, it has not been studied prospectively nor in randomized trials for treatment of uterine cancers, and the associated toxic effects and patient quality of life are unknown. Objective: To evaluate acute genitourinary and bowel toxic effects and patient-reported outcomes following stereotactic hypofractionated adjuvant radiation to the pelvis for treatment of uterine cancer. Design, Setting, and Participants: The Stereotactic Pelvic Adjuvant Radiation Therapy in Cancers of the Uterus (SPARTACUS) phase 1/2 nonrandomized controlled trial of patients accrued between May 2019 and August 2021 was conducted as a multicenter trial at 2 cancer centers in Ontario, Canada. In total, 61 patients with uterine cancer stages I through III after surgery entered the study. Interventions: Stereotactic adjuvant pelvic radiation to a dose of 30 Gy in 5 fractions administered every other day or once weekly. Main Outcomes and Measures: Assessments of toxic effects and patient-reported quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and endometrial EN24) were collected at baseline, fractions 3 and 5, and at 6 weeks and 3 months of follow-up. Descriptive analysis was conducted, calculating means, SDs, medians, IQRs, and ranges for continuous variables and proportions for categorical variables. Univariate generalized linear mixed models were generated for repeated measurements on the quality-of-life scales. Results: A total of 61 patients were enrolled (median age, 66 years; range, 51-88 years). Tumor histologic results included 39 endometrioid adenocarcinoma, 15 serous or clear cell, 3 carcinosarcoma, and 4 dedifferentiated. Sixteen patients received sequential chemotherapy, and 9 received additional vault brachytherapy. Median follow-up was 9 months (IQR, 3-15 months). Of 61 patients, worst acute gastrointestinal tract toxic effects of grade 1 were observed in 33 patients (54%) and of grade 2 in 8 patients (13%). For genitourinary worst toxic effects, grade 1 was observed in 25 patients (41%) and grade 2 in 2 patients (3%). One patient (1.6%) had an acute grade 3 gastrointestinal tract toxic effect of diarrhea at fraction 5 that resolved at follow-up. Only patient-reported diarrhea scores were both clinically (scores ≥10) and statistically significantly worse at fraction 5 (mean [SD] score, 35.76 [26.34]) compared with baseline (mean [SD] score, 6.56 [13.36]; P < .001), but this symptom improved at follow-up. Conclusions and Relevance: Results of this phase 1/2 nonrandomized controlled trial suggest that stereotactic hypofractionated radiation was well tolerated at short-term follow-up for treatment of uterine cancer. Longer follow-up and future randomized studies are needed to further evaluate this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04866394.

Implications of Oncoplastic Breast Surgery on Radiation Boost Delivery in Localized Breast Cancer.

Background Oncoplastic partial mastectomy (OPM) is a technique utilized to improve aesthetic and survivorship outcomes in patients with localized breast cancer. This technique leads to breast tissue rearrangement, which can have an impact on target definition for boost radiotherapy (BRT). The aim of this study was to determine if the choice of surgical technique independently affected the decision to deliver a radiation boost. Materials and methods This was a retrospective study of patients treated between January 2017 and December 2018. We selected consecutive patients based on surgical procedure: 50 undergoing standard breast-conserving surgery and 50 having had an OPM. The primary outcome was average treatment effect (ATE) of surgery type on reception of BRT. Secondary outcomes included ATE of surgery type on the time to reception of radiotherapy and incidence of ipsilateral breast tumor recurrence (IBTR). The ratio of boost clinical target volume (CTV) to pathologic tumor size was also compared between the two groups. Treatment effects regression adjustment and inverse-probability weighted analysis was used to estimate ATEs for both primary and secondary outcomes. Results For the entire cohort, the median age was 64 years (range: 37-88 years). The median tumor size was 1.5 cm (range: 0.1-6.5 cm). The majority of patients were with ≤ stage IIA (78%), invasive ductal subtype (80%), negative lymphovascular space invasion (78%), negative margin (90%), and positive ER/PR (estrogen receptor/progesterone receptor) (69%). Overall, surgical technique was not associated with differences in the proportion of patients receiving BRT (ATE: 6.0% [95% CI: -4.5 to 16.0]). There were no differences in delays to radiation treatment between the two groups (ATE: 32.8 days [95% CI: -22.1 to 87.7]). With a median follow-up time of 419 days (range: 30-793 days), there were only five recurrences, with one case of IBTR in each group. There was no difference in the ratio of CTV volume to tumor size between the two groups (p=0.38). Conclusions OPM did not affect the decision to offer localized BRT following standard whole breast radiotherapy or significantly affect treatment times or radiation volumes. The decision to offer OPM should include a multi-disciplinary approach.

Clinical Evaluation of Deep Learning and Atlas-Based Auto-Contouring of Bladder and Rectum for Prostate Radiation Therapy.

PURPOSE: Auto-contouring may reduce workload, interobserver variation, and time associated with manual contouring of organs at risk. Manual contouring remains the standard due in part to uncertainty around the time and workload savings after accounting for the review and editing of auto-contours. This preliminary study compares a standard manual contouring workflow with 2 auto-contouring workflows (atlas and deep learning) for contouring the bladder and rectum in patients with prostate cancer. METHODS AND MATERIALS: Three contouring workflows were defined based on the initial contour-generation method including manual (MAN), atlas-based auto-contour (ATLAS), and deep-learning auto-contour (DEEP). For each workflow, initial contour generation was retrospectively performed on 15 patients with prostate cancer. Then, radiation oncologists (ROs) edited each contour while blinded to the manner in which the initial contour was generated. Workflows were compared by time (both in initial contour generation and in RO editing), contour similarity, and dosimetric evaluation. RESULTS: Mean durations for initial contour generation were 10.9 min, 1.4 min, and 1.2 min for MAN, DEEP, and ATLAS, respectively. Initial DEEP contours were more geometrically similar to initial MAN contours. Mean durations of the RO editing steps for MAN, DEEP, and ATLAS contours were 4.1 min, 4.7 min, and 10.2 min, respectively. The geometric extent of RO edits was consistently larger for ATLAS contours compared with MAN and DEEP. No differences in clinically relevant dose-volume metrics were observed between workflows. CONCLUSION: Auto-contouring software affords time savings for initial contour generation; however, it is important to also quantify workload changes at the RO editing step. Using deep-learning auto-contouring for bladder and rectum contour generation reduced contouring time without negatively affecting RO editing times, contour geometry, or clinically relevant dose-volume metrics. This work contributes to growing evidence that deep-learning methods are a clinically viable solution for organ-at-risk contouring in radiation therapy.

Sensitivity of radiomic features to inter-observer variability and image pre-processing in Apparent Diffusion Coefficient (ADC) maps of cervix cancer patients.

PURPOSE: The aims of this study are to evaluate the stability of radiomic features from Apparent Diffusion Coefficient (ADC) maps of cervical cancer with respect to: (1) reproducibility in inter-observer delineation, and (2) image pre-processing (normalization/quantization) prior to feature extraction. MATERIALS AND METHODS: Two observers manually delineated the tumor on ADC maps derived from pre-treatment diffusion-weighted Magnetic Resonance imaging of 81 patients with FIGO stage IB-IVA cervical cancer. First-order, shape, and texture features were extracted from the original and filtered images considering 5 different normalizations (four taken from the available literature, and one based on urine ADC) and two different quantization techniques (fixed-bin widths from 0.05 to 25, and fixed-bin count). Stability of radiomic features was assessed using intraclass correlation coefficient (ICC): poor (ICC < 0.75); good (0.75 ≤ ICC ≤ 0.89), and excellent (ICC ≥ 0.90). Dependencies of the features with tumor volume were assessed using Spearman's correlation coefficient (ρ). RESULTS: The approach using urine-normalized values together with a smaller bin width (0.05) was the most reproducible (428/552, 78% features with ICC ≥ 0.75); the fixed-bin count approach was the least (215/552, 39% with ICC ≥ 0.75). Without normalization, using a fixed bin width of 25, 348/552 (63%) of features had an ICC ≥ 0.75. Overall, 26% (range 25-30%) of the features were volume-dependent (ρ ≥ 0.6). None of the volume-independent shape features were found to be reproducible. CONCLUSION: Applying normalization prior to features extraction increases the reproducibility of ADC-based radiomics features. When normalization is applied, a fixed-bin width approach with smaller widths is suggested.

5-Year Outcomes of a Prospective Phase 1/2 Study of Accelerated Hypofractionated Radiation Therapy to the Prostate Bed.

PURPOSE: To report the 5-year outcomes from a single institution, prospective, phase 1/2 study on hypofractionated, accelerated radiation therapy to the prostate bed after radical prostatectomy. METHODS AND MATERIALS: Patients enrolled in this study were all eligible for postoperative radiation therapy and received a prescribed dose of 51 Gy in 17 fractions to the prostate bed. On follow-up, gastrointestinal (GI) and genitourinary (GU) toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0; prostate-specific antigen (PSA) was evaluated and quality of life was assessed using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. RESULTS: A total of 30 patients were enrolled between 2008 and 2011. Median age was 65 (52-75) years. Median pretreatment PSA was 0.12 ng/mL (0.01-1.42). Twenty-six (93%) patients had Gleason ≤7 disease, 13 (43%) had pT3 disease, and 20 (67%) had positive margins. Twenty-six patients (87%) underwent radiation therapy as salvage treatment. After a median follow-up of 6.4 (2.1-8.1) years, no patient experienced Common Terminology Criteria for Adverse Events grade 3/4 toxicity. Eleven patients (37%) had grade 2 genitourinary and 2 (7%) had grade 2 gastrointestinal toxicity. At baseline and 5 years after radiation therapy, mean EPIC urinary domain score was 80% (standard deviation, 18%) and 82% (17%). Mean EPIC bowel domain score was 93% (13%) and 93% (15%). One patient (4%) had a minimally clinically important change in urinary domain score and 1 patient (4%) had a minimally clinically important change in bowel domain score. Nelson-Aalen estimated cumulative incidence of biochemical failure was 31% (nadir +0.2) and 18% (nadir +2.0) at 5 years. Four-year PSA ≥0.4 was predictive of subsequent androgen deprivation therapy use (Nelson-Aalen cumulative incidence: 1.45; P < .0001). Five patients (17%) received hormonal therapy for biochemical failure. Nelson-Aalen estimated cumulative incidence of hormone therapy use was 14% at 5 years. All patients who received hormone therapy had PSA >0.4 at 4 years. CONCLUSIONS: In this phase 1/2 study, hypofractionated postoperative radiation therapy seems to have good clinical efficacy without significant late toxicity. Phase 3 studies are warranted.

A prospective analysis of catheter complications for gynecological cancers treated with interstitial brachytherapy in the 3D era.

PURPOSE: Perineal interstitial brachytherapy (P-ISBT) is an important component in the treatment of locally advanced gynecological cancers. However, there are concerns about potential acute complications from catheter needles. The goal is to evaluate the safety of P-ISBT by studying acute complications and radiological organ needle intrusions. MATERIALS AND METHODS: Forty-eight patients with gynecological cancers treated with P-ISBT at a single institution from September 2014 to April 2016 were included in a prospective registry trial. Postoperative adverse events were recorded during inpatient stay and at 6-week followup. Postprocedure CT and MRI images were reviewed by two physicians to record the number of needles intruded into organs. Discrepancies were resolved by a radiologist. RESULTS: Median followup time was at least 3 months. Forty-two patients were initially treated with external beam radiation therapy, median dose of 45 Gy. A total of 73 insertions were performed. The median number of needles for first and second insertions was 17 and 19, respectively. Twenty-eight patients had radiological evidence of needle intrusion(s) into at least one pelvic organ. The most commonly intruded organs were large bowel (18 cases) and bladder (18), followed by rectum (12). A total of nine acute toxicities from needle intrusions were found: four hematuria (1 G1, 3 G2); four perineal infections (3 G2, 1 G3); and one vaginal bleeding (G3). No gastrointestinal complications were found. CONCLUSIONS: Perineal ISBT is an effective treatment for gynecological cancers. Despite occasional radiological catheter intrusions, there are low rates of organ complications. Concern of needle complications from P-ISBT should not be a barrier to adopting this technique for effective treatment.

Characterizing the impact of adaptive planning on image-guided perineal interstitial brachytherapy for gynecologic malignancies.

PURPOSE: To determine the dosimetric impact of organ and implant motion/deformation in the context of adaptive planning in image-guided gynecologic brachytherapy using a 3-fraction transperineal approach. METHODS AND MATERIALS: Twenty-six patients were analyzed. Each patient was treated with three fractions given over a 24-h period using a single insertion. A planning CT scan (±MRI) was acquired before the first fraction. A verification scan was taken within 1 h following the second fraction. A single plan was delivered for Fractions 1 and 2 with an adaptive plan delivered for Fraction 3. Two evaluation frameworks were established. Framework 1 investigated the effects of motion/deformation from both implant and organs. Framework 2 investigated the impact of implant motion/deformation alone. Differences in high-risk clinical target volume (HRCTV) D90%, V100%, and bladder/rectum D2cc were assessed. RESULTS: From implant to verification, the HRCTV D90% and V100% decreased significantly (5.0%, p < 0.01; 3.1%, p < 0.01) and rectal D2cc was significantly higher (12.2%, p = 0.02). Adaptive planning recouped these changes. Implant changes resulted in a reduction in HRCTV dose and coverage, but no significant effect was seen in the bladder or rectum. CONCLUSIONS: Adaptive planning represents an important aspect of perineal-based interstitial image-guided brachytherapy given in three fractions; its absence would result in plan degradation.

Association of Apparent Diffusion Coefficient with Disease Recurrence in Patients with Locally Advanced Cervical Cancer Treated with Radical Chemotherapy and Radiation Therapy.

PURPOSE: To investigate whether volumetrically derived apparent diffusion coefficient (ADC) from pretreatment diffusion-weighted (DW) magnetic resonance (MR) imaging is associated with disease recurrence in women with locally advanced cervical cancer treated with chemotherapy and radiation therapy. MATERIALS AND METHODS: An ethics board-approved, retrospective study was conducted in 85 women with stage IB-IVA cervical cancer treated with chemo- and radiation therapy in 2009-2013. All patients underwent MR imaging for staging, including T2-weighted and DW MR imaging series, by using a 1.5- or 3.0-T imager. The mean, median, 75th, 90th, and 95th percentile ADCs (ADCmean, ADC50, ADC75, ADC90, and ADC95, respectively) of all voxels that comprised each tumor were extracted and normalized to the mean urine ADC (nADCmean, nADC50, nADC75, nADC90, and nADC95, respectively) to reduce variability. The primary outcome was disease-free survival (DFS). Uni- and multivariable Cox regression analyses were used to evaluate the association of ADC parameters and relevant clinical variables with DFS. RESULTS: Of the 85 women included, 62 were free of disease at last follow-up. Median follow-up was 37 months (range, 5-68 months). Significant variables at univariable analysis included T2-weighted derived tumor diameter, para-aortic nodal involvement, advanced stage, ADC90 and ADC95, nADC75, nADC90, and nADC95. Normalized parameters were more highly associated (hazard ratio per 0.01 increase in normalized ADC, 0.91-0.94; P < .04). Because nADC75, nADC90, and nADC95 were highly correlated, only nADC95 (which had the lowest P value) was included in multivariable analysis. At multivariable analysis, absolute and normalized ADC95 remained associated with DFS (hazard ratio, 0.90-0.98; P < .05). CONCLUSION: The volumetric ADC95 may be a useful imaging metric to predict treatment failure in patients with locally advanced cervical cancer treated with chemo- and radiation therapy.

Variation in apparent diffusion coefficient measurements among women with locally advanced cervical cancer.

ADC variability from mixed data sets acquired from women with locally advanced cervical cancer appears to be predominantly of biologic origin. Intra-histology ADC variance was similar when pooled across technical factors. Inter-histology pooling increased ADC variance. Normalization to urine ADC improved intra-histology variance and receiver-operator curve test performance.

Prostatic displacement during extreme hypofractionated radiotherapy using volumetric modulated arc therapy (VMAT).

BACKGROUND: To determine prostate displacement during extreme hypofractionated volume modulated arc radiotherapy (VMAT) using pre- and post-treatment orthogonal images with three implanted gold seed fiducial markers. METHODS: A total of 150 image pairs were obtained from 30 patients who underwent extreme hypofractionated radiotherapy to a dose of 40 Gy in five fractions on standard linear accelerators. Position verification was obtained with orthogonal x-rays before and after treatment and were used to determine intra-fraction prostate displacement. RESULTS: The mean prostate displacements were 0.03 ± 1.23 mm (1SD), 0.18 ± 1.55 mm, and 0.37 ± 1.95 mm in the left-right, superior-inferior, and anterior-posterior directions, respectively. The mean 3D displacement was 2.32 ± 1.55 mm. Only 6 (4%) fractions had a 3D displacement of >5 mm. The average time of treatment delivery for a given fraction was 195 ± 59 seconds. CONCLUSIONS: The mean intra-fraction prostate displacement during a course of extreme hypofractionated radiotherapy delivered via VMAT, continues to be small. Clinical margins typically used in a similar fixed-angle IMRT treatment are adequate. The use of VMAT in further extreme hypofractionation may limit prostatic motion uncertainties that would be otherwise be associated with longer treatment times.

Evaluation of early imaging response criteria in glioblastoma multiforme.

BACKGROUND: Early and accurate prediction of response to cancer treatment through imaging criteria is particularly important in rapidly progressive malignancies such as Glioblastoma Multiforme (GBM). We sought to assess the predictive value of structural imaging response criteria one month after concurrent chemotherapy and radiotherapy (RT) in patients with GBM. METHODS: Thirty patients were enrolled from 2005 to 2007 (median follow-up 22 months). Tumor volumes were delineated at the boundary of abnormal contrast enhancement on T1-weighted images prior to and 1 month after RT. Clinical Progression [CP] occurred when clinical and/or radiological events led to a change in chemotherapy management. Early Radiologic Progression [ERP] was defined as the qualitative interpretation of radiological progression one month post-RT. Patients with ERP were determined pseudoprogressors if clinically stable for ≥6 months. Receiver-operator characteristics were calculated for RECIST and MacDonald criteria, along with alternative thresholds against 1 year CP-free survival and 2 year overall survival (OS). RESULTS: 13 patients (52%) were found to have ERP, of whom 5 (38.5%) were pseudoprogressors. Patients with ERP had a lower median OS (11.2 mo) than those without (not reached) (p < 0.001). True progressors fared worse than pseudoprogressors (median survival 7.2 mo vs. 19.0 mo, p < 0.001). Volume thresholds performed slightly better compared to area and diameter thresholds in ROC analysis. Responses of > 25% in volume or > 15% in area were most predictive of OS. CONCLUSIONS: We show that while a subjective interpretation of early radiological progression from baseline is generally associated with poor outcome, true progressors cannot be distinguished from pseudoprogressors. In contrast, the magnitude of early imaging volumetric response may be a predictive and quantitative metric of favorable outcome.

Spontaneous regression in advanced non-small cell lung cancer.

Locally advanced lung cancer, if untreated, typically progresses although the rapidity of progression may vary. The authors report the case of an 84-year-old woman who presented with radiologically progressive, biopsy proven stage IIIB (T2N3) squamous cell carcinoma in the left lower lobe of the lung. Her disease was too advanced for curative treatment and in view of the lack of symptoms to palliate, she received no anticancer treatment. In follow-up, her tumour was noted to spontaneously regress in size on serial chest x-rays. Eight months after biopsy, restaging CT showed complete resolution of the enlarged biopsy proven mediastinal and hilar lymph nodes and significant regression of the primary tumour. She remains clinically well.

Experimental measurements and Monte Carlo simulations for dosimetric evaluations of intrafraction motion for gated and ungated intensity modulated arc therapy deliveries.

Respiratory gated radiation therapy allows for a smaller margin expansion for the planning target volume (PTV) to account for respiratory induced motion and is emerging as a common method to treat lung and liver tumors. We investigated the dosimetric effect of free motion and gated delivery for intensity modulated arc therapy (IMAT) with experimental measurements and Monte Carlo simulations. The impact of PTV margin and duty cycle for gated delivery is studied with Monte Carlo simulations. A motion phantom is used for this study. Two sets of contours were drawn on the mid-inspiration CT scan of this motion phantom. For each set of contours, an IMAT plan to be delivered with constant dose rate was created. The plans were generated on a CT scan of the phantom in the static condition with 3 mm PTV margin and applied to the motion phantom under four conditions: static, full superior-inferior (SI) motion (A = 1 cm, T = 4 s) and gating conditions (25% and 50% duty cycles) with full SI motion. A 6 by 15 cm piece of radiographic film was placed in the sagittal plane of the phantom and then irradiated under all measurement conditions. Film calibration was performed with a step-wedge method to convert optical density to dose. Gated IMAT delivery was first validated in 2D by comparing static film with that from gating and full motion. A previously verified simulation tool for IMRT that takes the log files from the multileaf collimator (MLC) controller and the gating system were adapted to simulate the delivered IMAT treatment for full 3D dosimetric analysis. The IMAT simulations were validated against the 2D film measurements. The resultant IMAT simulations were evaluated with dose criteria, dose-volume histograms and 3D gamma analysis. We validated gated IMAT deliveries when we compared the static film with the one from gating using 25% duty cycle using 2D gamma analysis. Within experimental and setup uncertainties, film measurements agreed with their corresponding simulated plans using 2D gamma analysis. Finally, when planning with margins designed for gating with 25% duty cycle and applying 50% or no gating during treatment, the dose differences in D(min,) D(99%) and D(95%) of the clinical target volume can be up to 27 cGy, 20 cGy and 18 cGy, respectively, for a plan with 200 cGy prescription dose. We have experimentally delivered gated IMAT with constant dose rate to a motion phantom and assessed their accuracies with film dosimetry and Monte Carlo simulations. Film dosimetry demonstrated that 25% gating and static plans are within 2%, 2 mm. The Monte Carlo simulation method was employed to generate dose delivered in 3D to a motion phantom, and the dosimetric results were reported. Since our film measurements agreed well with Monte Carlo simulations, we can reliably use this simulation tool to further study the dosimetric effects of target motion and effectiveness of gating for IMAT deliveries.

Commissioning a fast Monte Carlo dose calculation algorithm for lung cancer treatment planning.

A commercial Monte Carlo simulation package, NXEGS 1.12 (NumeriX LLC, New York, NY), was commissioned for photon-beam dose calculations. The same sets of measured data from 6-MV and 18-MV beams were used to commission NXEGS and Pinnacle 6.2b (Philips Medical Systems, Andover, MA). Accuracy and efficiency were compared against the collapsed cone convolution algorithm implemented in Pinnacle 6.2b, together with BEAM simulation (BEAMnrc 2001: National Research Council of Canada, Ottawa, ON). We investigated a number of options in NXEGS: the accuracy of fast Monte Carlo, the re-implementation of EGS4, post-processing technique (dose de-noising algorithm), and dose calculation time. Dose distributions were calculated with NXEGS, Pinnacle, and BEAM in water, lung-slab, and air-cylinder phantoms and in a lung patient plan. We compared the dose distributions calculated by NXEGS, Pinnacle, and BEAM. In a selected region of interest (7725 voxels) in the lung phantom, all but 1 voxel had a gamma (3% and 3 mm thresholds) of 1 or less for the dose difference between the NXEGS re-implementation of EGS4 and BEAM, and 99% of the voxels had a gamma of 1 or less for the dose difference between NXEGS fast Monte Carlo and BEAM. Fast Monte Carlo with post-processing was up to 100 times faster than the NXEGS re-implementation of EGS4, while maintaining +/- 2% statistical uncertainty. With air inhomogeneities larger than 1 cm, post-processing preserves the dose perturbations from the air cylinder. When 3 or more beams were used, fast Monte Carlo with post-processing was comparable to or faster than Pinnacle 6.2b collapsed cone convolution.

Incorporating geometric ray tracing to generate initial conditions for intensity modulated arc therapy optimization.

PURPOSE AND BACKGROUND: Intensity modulated arc therapy (IMAT) is a rotational variant of Intensity modulated radiation therapy (IMRT) that is achieved by allowing the multileaf collimator (MLC) positions to vary as the gantry rotates around the patient. This work describes a method to generate an IMAT plan through the use of a fast ray tracing technique based on dosimetric and geometric information for setting initial MLC leaf positions prior to final IMAT optimization. METHODS AND MATERIALS: Three steps were used to generate an IMAT plan. The first step was to generate arcs based on anatomical contours. The second step was to generate ray importance factor (RIF) maps by ray tracing the dose distribution inside the planning target volume (PTV) to modify the MLC leaf positions of the anatomical arcs to reduce the maximum dose inside the PTV. The RIF maps were also segmented to create a new set of arcs to improve the dose to low dose voxels within the PTV. In the third step, the MLC leaf positions from all arcs were put through a leaf position optimization (LPO) algorithm and brought into a fast Monte Carlo dose calculation engine for a final dose calculation. The method was applied to two phantom cases, a clinical prostate case and the Radiological Physics Center (RPC)'s head and neck phantom. The authors assessed the plan improvements achieved by each step and compared plans with and without using RIF. They also compared the IMAT plan with an IMRT plan for the RPC phantom. RESULTS: All plans that incorporated RIF and LPO had lower objective function values than those that incorporated LPO only. The objective function value was reduced by about 15% after the generation of RIF arcs and 52% after generation of RIF arcs and leaf position optimization. The IMAT plan for the RPC phantom had similar dose coverage for PTV1 and PTV2 (the same dose volume histogram curves), however, slightly lower dose to the normal tissues compared to a six-field IMRT plan. CONCLUSION: The use of a ray importance factor can generate initial IMAT arcs efficiently for further MLC leaf position optimization to obtain more favorable IMAT plan.

Monte Carlo dose calculation of segmental IMRT delivery to a moving phantom using dynamic MLC and gating log files.

Respiratory gating is emerging as a tool to limit the effect of motion for liver and lung tumors. In order to study the impact of target motion and gated intensity modulated radiation therapy (IMRT) delivery, a computer program was developed to simulate segmental IMRT delivery to a moving phantom. Two distinct plans were delivered to a rigid-motion phantom with a film insert in place under four conditions: static, sinusoidal motion, gated sinusoidal motion with a duty cycle of 25% and gated sinusoidal motion with duty cycle of 50% under motion conditions of a typical patient (A = 1 cm, T = 4 s). The MLC controller log files and gating log files were retained to perform a retrospective Monte Carlo dose calculation of the plans. Comparison of the 2D planar dose distributions between simulation and measurement demonstrated that our technique had at least 94% of the points passing gamma criteria of 3% for dose difference and 3 mm as the distance to agreement. This note demonstrates that the use of dynamic multi-leaf collimator and respiratory monitoring system log files together with a fast Monte Carlo dose calculation algorithm is an accurate and efficient way to study the dosimetric effect of motion for gated or non-gated IMRT delivery on a rigidly-moving body.

Segmentation and leaf sequencing for intensity modulated arc therapy.

A common method in generating intensity modulated radiation therapy (IMRT) plans consists of a three step process: an optimized fluence intensity map (IM) for each beam is generated via inverse planning, this IM is then segmented into discrete levels, and finally, the segmented map is translated into a set of MLC apertures via a leaf sequencing algorithm. To date, limited work has been done on this approach as it pertains to intensity modulated arc therapy (IMAT), specifically in regards to the latter two steps. There are two determining factors that separate IMAT segmentation and leaf sequencing from their IMRT equivalents: (1) the intrinsic 3D nature of the intensity maps (standard 2D maps plus the angular component), and (2) that the dynamic multileaf collimator (MLC) constraints be met using a minimum number of arcs. In this work, we illustrate a technique to create an IMAT plan that replicates Tomotherapy deliveries by applying IMAT specific segmentation and leaf-sequencing algorithms to Tomotherapy output sinograms. We propose and compare two alternative segmentation techniques, a clustering method, and a bottom-up segmentation method (BUS). We also introduce a novel IMAT leaf-sequencing algorithm that explicitly takes leaf movement constraints into consideration. These algorithms were tested with 51 angular projections of the output leaf-open sinograms generated on the Hi-ART II treatment planning system (Tomotherapy Inc.). We present two geometric phantoms and 2 clinical scenarios as sample test cases. In each case 12 IMAT plans were created, ranging from 2 to 7 intensity levels. Half were generated using the BUS segmentation and half with the clustering method. We report on the number of arcs produced as well as differences between Tomotherapy output sinograms and segmented IMAT intensity maps. For each case one plan for each segmentation method is chosen for full Monte Carlo dose calculation (NumeriX LLC) and dose volume histograms (DVH) are calculated. In all cases, the BUS method outperformed the clustering, method. We recommend using the BUS algorithm and discuss potential improvements to the clustering algorithms.

Asymmetric fan beams (AFB) for improvement of the craniocaudal dose distribution in helical tomotherapy delivery.

Helical tomotherapy (HT) is a novel radiotherapy technique that utilizes intensity modulated fan beams that deliver highly conformal dose distributions in a helical beam trajectory. The most significant limitation in dose delivery with a constant fan beam thickness (FBT) is the penumbra width of the dose distribution in the craniocaudal direction, which is equivalent to the FBT. We propose to employ a half-blocked fan beam at start and stop location to reduce the penumbra width by half. By opening the jaw slowly during the helical delivery until the desired FBT is achieved it is possible to create a sharper edge in the superior and inferior direction from the target. The technique was studied using a tomotherapy beam model implemented on a commercial treatment planning system (Theraplan Plus V3.0). It was demonstrated that the dose distribution delivered using a 25 mm fan beam can be improved significantly, to reduce the dose to normal structures located superiorly and inferiorly of the target. Dosimetry for this technique is straightforward down to a FBT of 15 mm and implementation should be simple as no changes in couch movement are required compared to a standard HT delivery. We conclude that the use of asymmetric collimated fan beams for the start and stop of the helical tomotherapeutic dose delivery has the potential of significantly improving the dose distribution in helical tomotherapy.