Melanie Davidson

Assessing the role of volumetric modulated arc therapy (VMAT) relative to IMRT and helical tomotherapy in the management of localized, locally advanced, and post-operative prostate cancer.

PURPOSE To quantify differences in treatment delivery efficiency and dosimetry between step-and-shoot intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT) for prostate treatment. METHODS AND MATERIALS Twenty-five prostate cancer patients were selected retrospectively for this planning study. Treatment plans were generated for: prostate alone (n = 5), prostate + seminal vesicles (n = 5), prostate + seminal vesicles + pelvic lymph nodes (n = 5), prostate bed (n = 5), and prostate bed + pelvic lymph nodes (n = 5). Target coverage, dose homogeneity, integral dose, monitor units (MU), and sparing of organs at risk (OAR) were compared across techniques. Time required to deliver each plan was measured. RESULTS The dosimetric quality of IMRT, VMAT, and HT plans were comparable for target coverage (planning target volume V95%, clinical target volume V100% all >98.7%) and sparing of organs at risk (OAR) for all treatment groups. Although HT resulted in a slightly higher integral dose and mean doses to the OAR, it yielded a lower maximum dose to all OAR examined. VMAT resulted in reductions in treatment times over IMRT (mean = 75%) and HT (mean = 70%). VMAT required 15-38% fewer monitor units than IMRT over all treatment volumes, with the reduction per fraction ranging from 100-423 MU from the smallest to largest volumes. CONCLUSIONS VMAT improves efficiency of delivery for equivalent dosimetric quality as IMRT and HT across various prostate cancer treatment volumes in the intact and postoperative settings.

Spine Stereotactic Body Radiotherapy Utilizing Cone-Beam CT Image-Guidance With a Robotic Couch: Intrafraction Motion Analysis Accounting for all Six Degrees of Freedom

PURPOSE To evaluate the residual setup error and intrafraction motion following kilovoltage cone-beam CT (CBCT) image guidance, for immobilized spine stereotactic body radiotherapy (SBRT) patients, with positioning corrected for in all six degrees of freedom. METHODS AND MATERIALS Analysis is based on 42 consecutive patients (48 thoracic and/or lumbar metastases) treated with a total of 106 fractions and 307 image registrations. Following initial setup, a CBCT was acquired for patient alignment and a pretreatment CBCT taken to verify shifts and determine the residual setup error, followed by a midtreatment and posttreatment CBCT image. For 13 single-fraction SBRT patients, two midtreatment CBCT images were obtained. Initially, a 1.5-mm and 1° tolerance was used to reposition the patient following couch shifts which was subsequently reduced to 1 mm and 1° degree after the first 10 patients. RESULTS Small positioning errors after the initial CBCT setup were observed, with 90% occurring within 1 mm and 97% within 1°. In analyzing the impact of the time interval for verification imaging (10 ± 3 min) and subsequent image acquisitions (17 ± 4 min), the residual setup error was not significantly different (p > 0.05). A significant difference (p = 0.04) in the average three-dimensional intrafraction positional deviations favoring a more strict tolerance in translation (1 mm vs. 1.5 mm) was observed. The absolute intrafraction motion averaged over all patients and all directions along x, y, and z axis (± SD) were 0.7 ± 0.5 mm and 0.5 ± 0.4 mm for the 1.5 mm and 1 mm tolerance, respectively. Based on a 1-mm and 1° correction threshold, the target was localized to within 1.2 mm and 0.9° with 95% confidence. CONCLUSION Near-rigid body immobilization, intrafraction CBCT imaging approximately every 15-20 min, and strict repositioning thresholds in six degrees of freedom yields minimal intrafraction motion allowing for safe spine SBRT delivery.

Bone-composition imaging using coherent-scatter computed tomography: Assessing bone health beyond bone mineral density

Quantitative analysis of bone composition is necessary for the accurate diagnosis and monitoring of metabolic bone diseases. Accurate assessment of the bone mineralization state is the first requirement for a comprehensive analysis. In diagnostic imaging, x-ray coherent scatter depends upon the molecular structure of tissues. Coherent-scatter computed tomography (CSCT) exploits this feature to identify tissue types in composite biological specimens. We have used CSCT to map the distributions of tissues relevant to bone disease (fat, soft tissue, collagen, and mineral) within bone-tissue phantoms and an excised cadaveric bone sample. Using a purpose-built scanner, we have measured hydroxyapatite (bone mineral) concentrations based on coherent-scatter patterns from a series of samples with varying hydroxyapatite content. The measured scatter intensity is proportional to mineral density in true g/cm3. Repeated measurements of the hydroxyapatite concentration in each sample were within, at most, 2% of each other, revealing an excellent precision in determining hydroxyapatite concentration. All measurements were also found to be accurate to within 3% of the known values. Phantoms simulating normal, over-, and under-mineralized bone were created by mixing known masses of pure collagen and hydroxyapatite. An analysis of the composite scatter patterns gave the density of each material. For each composite, the densities were within 2% of the known values. Collagen and hydroxyapatite concentrations were also examined in a bone-mimicking phantom, incorporating other bone constituents (fat, soft tissue). Tomographic maps of the coherent-scatter properties of each specimen were reconstructed, from which material-specific images were generated. Each tissue was clearly distinguished and the collagen-mineral ratio determined from this phantom was also within 2% of the known value. Existing bone analysis techniques cannot determine the collagen-mineral ratio in intact specimens. Finally, to demonstrate the in situ potential of this technique, the mineralization state of an excised normal cadaveric radius was examined. The average collagen-mineral ratio of the cortical bone derived from material-specific images of the radius was 0.53+/-0.04, which is in agreement with the expected value of 0.55 for healthy bones.

Patient outcome study of concurrent chemoradiation, external beam radiotherapy, and high-dose rate brachytherapy in locally advanced carcinoma of the cervix.

Introduction: A regimen of concurrent chemoradiation for definitive treatment of cervical cancer is widely used. This retrospective review has been conducted to determine the outcomes and late toxic effect associated with the specific regimen of whole-pelvic external beam radiotherapy of 45 Gy in 25 fractions with parametrial boosts of 5.4 or 9 Gy and HDR brachytherapy (BT) of 30 Gy in 5 fractions to point A delivered by tandem and ring. This protocol is accepted by the Gynecological Oncology Group and endorsed by the American Brachytherapy Society, but no late toxic effect data have been reported. Materials and Methods: The electronic records of sequential patients treated definitively at the Sunnybrook Odette Cancer Centre between January 2006 and December 2008 were reviewed. Patient-, tumor-, and treatment-related details (including external beam radiotherapy, BT, and chemotherapy) were obtained. Outcome measures included disease-free status, dates and sites of first recurrence, survival, and grade 3/4 late toxic effect results (Common Terminology Criteria Adverse Events 3.0 criteria). Exclusion criteria were no follow-up or a planned alternative regimen. Results: One hundred twenty-two patients (+11 excluded) were treated with a median follow-up of 18 months from diagnosis. The actuarial 2-year disease-free survival rate was 70%. The median time to recurrence was 8 months (range, 2-22 months). The median time to toxic effect was 10 months (range 4-27 months). Grade 3/4 toxic effect was observed in 13 patients (11%). The actuarial grade 3/4 toxic effect rate at 2 years was 14%. Conclusions: Despite a relatively short follow-up, the toxicity of this regimen seems high compared with other retrospective series, although pelvic control is good. Consideration should be given to a reduction in BT dose alternatively when feasible image-guided BT may allow maintenance of tumor dose with reduced dose to organs at risk.

Image-guided cervix high-dose-rate brachytherapy treatment planning: Does custom computed tomography planning for each insertion provide better conformal avoidance of organs at risk?

PURPOSE Intracavitary high-dose-rate (HDR) brachytherapy (BT) for cervical cancer involves multiple applicator insertions. Our study addresses whether customized three-dimensional plans generated for the first insertion (using computed tomography [CT] planning) can be applied to subsequent insertions without significant changes in dose distributions if identical applicators are used. METHODS AND MATERIALS Twenty-seven patients were treated with external-beam radiotherapy, platinum-based chemotherapy, and HDR BT. Either tandem and ovoids (TO, n=12) or tandem and ring (TR, n=15) applicators were used, based on clinical indications. Postimplant CT scans were acquired and custom plans generated for each insertion. Dose parameters for organs at risk (OARs) from the second insertion were retrospectively compared to those that would have been delivered using the initial plan. RESULTS Overall, we observed a significant increase (p<0.038) in dose to International Commission on Radiation Units and Measurement points and 2cm(3) volumes of bladder and rectum when a single plan was used. The sigmoid and small bowel exhibited a more variable increase in dose. Applicator-specific results revealed a significant increase (p<0.030) to dose points and volumes for the rectum and bladder for TR applicators. Conversely, dose values from the more flexible TO did not show any significant trend, exhibiting large interpatient variations. CONCLUSIONS A duplication of planned dwell times and positions from one insertion to the next does not duplicate dose distributions in HDR cervix applications. A single plan used for an entire course of BT can result in significant increases to OAR doses for TR and unpredictable OAR doses for TO applicators. Treatment plans should be tailored for each insertion to reflect current applicator and anatomical geometry.

Laboratory coherent-scatter analysis of intact urinary stones with crystalline composition: a tomographic approach

Knowledge of urinary stone composition and structure provides important insights in guiding treatment and preventing recurrence. No current method can successfully provide information relating structure and composition of intact stones. We are developing a tomographic technique that uses measures of coherently scattered diagnostic x-rays to yield stone composition. Coherent-scatter (CS) properties depend on molecular structure and are, therefore, sensitive to material composition. Powdered, amorphous or polycrystalline materials with no significant orientation produce circularly symmetric CS patterns. However, in materials with preferred crystallite orientation, like urinary stones, bright spots in CS patterns are observed. This compromises a composition analysis based on comparing CS measurements from calculi to a library of CS signatures from powdered chemicals. We show that a computed tomographic reconstruction of CS measurements using filtered backprojection (CSCT) effectively eliminates bright spots and yields CS patterns equivalent to powdered materials. This allows for direct comparison with a powdered chemical reference library to establish composition. Validation is achieved through a tomographic CS analysis of an aluminium (Al) rod phantom. Much like calculi, CS patterns from a solid polycrystalline Al rod exhibit diffraction spots, absent in the ring-like Al powder CS pattern. We show that the reconstructed Al CS cross-section is equivalent to its powdered counterpart and results in clearly defined composition images. The potential of CSCT to identify stone composition is demonstrated through images of intact stones deemed chemically pure by infrared spectroscopy. Computed tomographic reconstruction of CS signals allowed the generation of composition maps, showing the distribution of stone components. These images provide strong evidence that current laboratory techniques risk missing critical stone components due to inadequate sampling. This is of particular importance since follow-up treatments are based on these composition analyses. CS analysis can distinguish common stone components and can provide topographic composition maps of intact stones. Such details offer invaluable clinical information regarding stone formation, treatment and follow-up, and thus support the development of CS analysis as a laboratory stone analysis technique.

Predictive Parameters of Symptomatic Hematochezia Following 5-Fraction Gantry-Based SABR in Prostate Cancer

PURPOSE This study identified predictors of high-grade late hematochezia (HH) following 5-fraction gantry-based stereotactic ablative radiation therapy (SABR). METHODS AND MATERIALS Hematochezia data for 258 patients who received 35 to 40 Gy SABR in 5-fractions as part of sequential phase 2 prospective trials was retrieved. Grade 2 or higher late rectal bleeding was labeled HH. Hematochezia needing steroid suppositories, 4% formalin, or 1 to 2 sessions of argon plasma coagulation (APC) was labeled grade 2. More than 2 sessions of APC, blood transfusion, or a course of hyperbaric oxygen was grade 3 and development of visceral fistula, grade 4. Various dosimetric and clinical factors were analyzed using univariate and multivariate analyses. Receiver operating characteristic (ROC) curve analysis and recursive partitioning analysis were used to determine clinically valid cut-off points and identify risk groups, respectively. RESULTS HH was observed in 19.4%, grade ≥3 toxicity in 3.1%. Median follow-up was 29.7 months (interquartile range [IQR]: 20.6-61.7) Median time to develop HH was 11.7 months (IQR: 9.0-15.2) from the start of radiation. At 2 years, cumulative HH was 4.9%, 27.2%, and 42.1% in patients who received 35 Gy to prostate (4-mm planning target volume [PTV] margin), 40 Gy to prostate (5-mm PTV margin), and 40 Gy to prostate/seminal vesicles (5-mm PTV margin), respectively (P<.0001). In the ROC analysis, volume of rectum receiving radiation dose of 38 Gy (V38) was a strong predictor of HH with an area under the curve of 0.65. In multivariate analysis, rectal V38 (≥2.0 cm(3); odds ratio [OR]: 4.7); use of anticoagulants in the follow-up period (OR: 6.5) and presence of hemorrhoids (OR: 2.7) were the strongest predictors. Recursive partitioning analysis showed rectal V38 < 2.0 cm(3), and use of anticoagulants or rectal V38 ≥ 2.0 cm(3) plus 1 other risk factor resulted in an HH risk of >30%. CONCLUSIONS Rectal V38 and 2 clinical factors were strong predictors of HH following 5-fraction SABR. Planning constraints should keep rectal V38 below 2.0 cm(3).

Dose-escalation of five-fraction SABR in prostate cancer: Toxicity comparison of two prospective trials

PURPOSE To compare biochemical outcome and toxicities of two prospective 5-fraction stereotactic ablative radiotherapy (SABR) studies in prostate cancer. MATERIALS AND METHODS 84 patients in pHART3 received 35 Gy, 30 patients in pHART6 received 40 Gy in 5-fractions to the prostate alone, once weekly. 4mm and 5mm PTV margins were used, respectively. Biochemical outcome, acute, late and cumulative genitourinary (GU)/gastrointestinal (GI) toxicities were compared. RESULTS Median follow-up was 74 and 36 months, respectively. Median prostate specific antigen nadir was 0.4 ng/ml and 0.3 ng/ml. 2-, 4- and 6-year biochemical relapse-free survival (bRFS-2+nadir) was 100%, 98.7% and 95.9% in pHART3; 100%, 100% and not reached in pHART6 (p=0.91). There was one acute grade 3 GU (retention) and late grade 4 GI (fistula) toxicity in pHART3, none in pHART6. One patient in each study had persisting grade 2+ toxicity at the last follow-up. pHART6 patients had a greater grade 2+ cumulative GU (5% versus 24.2%) and GI (7.6% versus 26.2%) toxicities. CONCLUSIONS Patients receiving dose-escalated SABR had slightly lower PSA nadir and similar bRFS, longer follow-up is needed to better estimate biochemical outcomes. There was a greater risk of grade 2 toxicity in pHART6 but not grade 3+ toxicities. Persisting toxicity at the last follow-up is similar.

Analysis of urinary stone components by x-ray coherent scatter: characterizing composition beyond laboratory x-ray diffractometry.

Monoenergetic x-ray diffraction (XRD) analysis is an established standard for the assessment of urinary stone composition. The inherent low energy of x-rays used (8 keV), however, restricts penetration depth and imposes a requirement for small powdered samples. A technique capable of producing detailed information regarding component structural arrangements in calculi non-destructively would provide clearer insights into causes of formation and subsequent growth and allow the selection of more appropriate courses of therapy. We describe a new method based on the detection of coherent scatter (CS) in stone components using polyenergetic x-rays (70 kVp) from diagnostic equipment. While the higher energy allows the analysis of intact calculi, the polyenergetic source causes an angular broadening of measured CS patterns. We show that it is possible to relate the polyenergetic (CS) and monoenergetic (XRD) measurements through a superposition integral of the monoenergetic XRD cross-section with a function representative of the polyenergetic spectrum used in CS. Experimentally acquired diffractometry cross-sections of the seven major urinary stone components were subjected to this operation, revealing good agreement of diffraction features with CS. Therefore, our CS analysis is sensitive to stone component structure, similar to conventional XRD analysis. This indicates that CS analysis can be used as a basis to classify urinary calculi by composition. The potential of identifying stone components non-destructively was demonstrated from a tomographic CS analysis of a stone-mimicking phantom. Tomographic composition maps were generated from CS patterns, showing the structural arrangement of multiple stone components within the phantom. CS analysis has the ability to detect components in the presence of many others. The ability to perform CS measurements in intact calculi would allow for the identification of stone structures critical to patient metaprophylaxis.

Mathematical modeling of liver metastases tumour growth and control with radiotherapy

Generating an optimized radiation treatment plan requires understanding the factors affecting tumour control. Mathematical models of tumour dynamics may help in future studies of factors predicting tumour sensitivity to radiotherapy. In this study, a time-dependent differential model, incorporating biological cancer markers, is presented to describe pre-treatment tumour growth, response to radiation, and recurrence. The model uses Gompertzian-Exponential growth to model pre-treatment tumour growth. The effect of radiotherapy is handled by a realistic cell-kill term that includes a volume-dependent change in tumour sensitivity. Post-treatment, a Gompertzian, accelerated, delayed repopulation is employed. As proof of concept, we examined the fit of the models prediction using various liver enzyme levels as markers of metastatic liver tumour growth in a liver cancer patient. A tumour clonogen population model was formulated. Each enzyme was coupled to the same tumour population, and served as surrogates of the tumour. This dynamical model was solved numerically and compared to the measured enzyme levels. By minimizing the mean-squared error of the model enzyme predictions, we determined the following tumour model parameters: growth rate prior to treatment was 0.52% per day; the fractional radiation cell kill for the prescribed dose (60 Gy in 15 fractions) was 42% per day, and the tumour repopulation rate was 2.9% per day. These preliminary results provided the basis to test the model in a larger series of patients, to apply biological markers for improving the efficacy of radiotherapy by determining the underlying tumour dynamics.