Vitali Moiseenko

Volumetric Modulated Arc Therapy for Delivery of Prostate Radiotherapy: Comparison With Intensity-Modulated Radiotherapy and Three-Dimensional Conformal Radiotherapy

PURPOSE Volumetric modulated arc therapy (VMAT) is a novel form of intensity-modulated radiotherapy (IMRT) optimization that allows the radiation dose to be delivered in a single gantry rotation of up to 360 degrees , using either a constant dose rate (cdr-VMAT) or variable dose rate (vdr-VMAT) during rotation. The goal of this study was to compare VMAT prostate RT plans with three-dimensional conformal RT (3D-CRT) and IMRT plans. PATIENTS AND METHODS The 3D-CRT, five-field IMRT, cdr-VMAT, and vdr-VMAT RT plans were created for 10 computed tomography data sets from patients undergoing RT for prostate cancer. The parameters evaluated included the doses to organs at risk, equivalent uniform doses, dose homogeneity and conformality, and monitor units required for delivery of a 2-Gy fraction. RESULTS The IMRT and both VMAT techniques resulted in lower doses to normal critical structures than 3D-CRT plans for nearly all dosimetric endpoints analyzed. The lowest doses to organs at risk and most favorable equivalent uniform doses were achieved with vdr-VMAT, which was significantly better than IMRT for the rectal and femoral head dosimetric endpoints (p < 0.05) and significantly better than cdr-VMAT for most bladder and rectal endpoints (p < 0.05). The vdr-VMAT and cdr-VMAT plans required fewer monitor units than did the IMRT plans (relative reduction of 42% and 38%, respectively; p = 0.005) but more than for the 3D-CRT plans (p = 0.005). CONCLUSION The IMRT and VMAT techniques achieved highly conformal treatment plans. The vdr-VMAT technique resulted in more favorable dose distributions than the IMRT or cdr-VMAT techniques, and reduced the monitor units required compared with IMRT.

Radiotherapy Dose–Volume Effects on Salivary Gland Function

Publications relating parotid dose-volume characteristics to radiotherapy-induced salivary toxicity were reviewed. Late salivary dysfunction has been correlated to the mean parotid gland dose, with recovery occurring with time. Severe xerostomia (defined as long-term salivary function of <25% of baseline) is usually avoided if at least one parotid gland is spared to a mean dose of less than approximately 20 Gy or if both glands are spared to less than approximately 25 Gy (mean dose). For complex, partial-volume RT patterns (e.g., intensity-modulated radiotherapy), each parotid mean dose should be kept as low as possible, consistent with the desired clinical target volume coverage. A lower parotid mean dose usually results in better function. Submandibular gland sparing also significantly decreases the risk of xerostomia. The currently available predictive models are imprecise, and additional study is required to identify more accurate models of xerostomia risk.

The use and QA of biologically related models for treatment planning: short report of the TG-166 of the therapy physics committee of the AAPM.

Treatment planning tools that use biologically related models for plan optimization and/or evaluation are being introduced for clinical use. A variety of dose-response models and quantities along with a series of organ-specific model parameters are included in these tools. However, due to various limitations, such as the limitations of models and available model parameters, the incomplete understanding of dose responses, and the inadequate clinical data, the use of biologically based treatment planning system (BBTPS) represents a paradigm shift and can be potentially dangerous. There will be a steep learning curve for most planners. The purpose of this task group is to address some of these relevant issues before the use of BBTPS becomes widely spread. In this report, the authors (1) discuss strategies, limitations, conditions, and cautions for using biologically based models and parameters in clinical treatment planning; (2) demonstrate the practical use of the three most commonly used commercially available BBTPS and potential dosimetric differences between biologically model based and dose-volume based treatment plan optimization and evaluation; (3) identify the desirable features and future directions in developing BBTPS; and (4) provide general guidelines and methodology for the acceptance testing, commissioning, and routine quality assurance (QA) of BBTPS.

In vitro study of cell survival following dynamic MLC intensity-modulated radiation therapy dose delivery.

The possibility of reduced cell kill following intensity-modulated radiation therapy (IMRT) compared to conventional radiation therapy has been debated in the literature. This potential reduction in cell kill relates to prolonged treatment times typical of IMRT dose delivery and consequently increased repair of sublethal lesions. While there is some theoretical support to this reduction in cell kill published in the literature, direct experimental evidence specific to IMRT dose delivery patterns is lacking. In this study we present cell survival data for three cell lines: Chinese hamster V79 fibroblasts, human cervical carcinoma, SiHa and colon adenocarcinoma, WiDr. Cell survival was obtained for 2.1 Gy delivered as acute dose with parallel-opposed pair (POP), irradiation time 75 s, which served as a reference; regular seven-field IMRT, irradiation time 5 min; and IMRT with a break for multiple leaf collimator (MLC) re-initialization after three fields were delivered, irradiation time 10 min. An actual seven-field dynamic MLC IMRT plan for a head and neck patient was used. The IMRT plan was generated for a Varian EX or iX linear accelerator with 120 leaf Millenium MLC. Survival data were also collected for doses 1X, 2X, 3X, 4X, and 5x 2.1 Gy to establish parameters of the linear-quadratic equation describing survival following acute dose delivery. Cells were irradiated inside an acrylic cylindrical phantom specifically designed for this study. Doses from both IMRT and POP were validated using ion chamber measurements. A reproducible increase in cell survival was observed following IMRT dose delivery. This increase varied from small for V79, with a surviving fraction of 0.8326 following POP vs 0.8420 following uninterrupted IMRT, to very pronounced for SiHa, with a surviving fraction of 0.3903 following POP vs 0.5330 for uninterrupted IMRT. When compared to IMRT or IMRT with a break for MLC initialization, cell survival following acute dose delivery was significantly different, p < 0.05, in three out of six cases. In contrast, when cell survival following IMRT was compared to that following IMRT with a break for MLC initialization the difference was always statistically insignificant. When projected to a 30 fraction treatment, dose deficit to bring cell survival to the same value as in POP was calculated as 4.1, 24.9, and 31.1 Gy for V79, WiDr, and SiHa cell lines, respectively. The dose deficit did not relate to the alpha/beta ratio obtained in this study for the three cell lines. Clinical data do not show reduction in local control following IMRT. Possible reasons for this are discussed. The obtained data set can serve as a test data set for models designed to explore the effect of dose delivery prolongation/fractionation in IMRT on radiation therapy outcome.

Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer

Avoiding irradiation of the region of the parotid gland containing stem cells reduces the risk of xerostomia (dry mouth). Preserving saliva flow after radiotherapy Radiotherapy for head and neck cancer may damage the salivary glands, resulting in reduced salivation with consequent xerostomia (dry mouth). Xerostomia affects the quality of life of patients with head and neck cancer. van Luijk and co-workers reported the location of salivary (parotid) gland stem cells in the mouse, rat, and human. Next, they showed in rat and human that irradiation of the salivary gland region containing the highest number of stem cells resulted in the greatest loss of saliva production after treatment. Finally, the authors showed that it is possible to avoid irradiation of this specific area during therapy, which may reduce the patient’s risk of developing post-radiotherapy xerostomia. Each year, 500,000 patients are treated with radiotherapy for head and neck cancer, resulting in relatively high survival rates. However, in 40% of patients, quality of life is severely compromised because of radiation-induced impairment of salivary gland function and consequent xerostomia (dry mouth). New radiation treatment technologies enable sparing of parts of the salivary glands. We have determined the parts of the major salivary gland, the parotid gland, that need to be spared to ensure that the gland continues to produce saliva after irradiation treatment. In mice, rats, and humans, we showed that stem and progenitor cells reside in the region of the parotid gland containing the major ducts. We demonstrated in rats that inclusion of the ducts in the radiation field led to loss of regenerative capacity, resulting in long-term gland dysfunction with reduced saliva production. Then we showed in a cohort of patients with head and neck cancer that the radiation dose to the region of the salivary gland containing the stem/progenitor cells predicted the function of the salivary glands one year after radiotherapy. Finally, we showed that this region of the salivary gland could be spared during radiotherapy, thus reducing the risk of post-radiotherapy xerostomia.

Normal Tissue Complication Probability (NTCP) modeling of late rectal bleeding following external beam radiotherapy for prostate cancer: A Test of the QUANTEC-recommended NTCP model

Abstract Purpose/background. Validating a predictive model for late rectal bleeding following external beam treatment for prostate cancer would enable safer treatments or dose escalation. We tested the normal tissue complication probability (NTCP) model recommended in the recent QUANTEC review (quantitative analysis of normal tissue effects in the clinic). Material and methods. One hundred and sixty one prostate cancer patients were treated with 3D conformal radiotherapy for prostate cancer at the British Columbia Cancer Agency in a prospective protocol. The total prescription dose for all patients was 74 Gy, delivered in 2 Gy/fraction. 159 3D treatment planning datasets were available for analysis. Rectal dose volume histograms were extracted and fitted to a Lyman-Kutcher-Burman NTCP model. Results. Late rectal bleeding (>grade 2) was observed in 12/159 patients (7.5%). Multivariate logistic regression with dose-volume parameters (V50, V60, V70, etc.) was non-significant. Among clinical variables, only age was significant on a Kaplan-Meier log-rank test (p=0.007, with an optimal cut point of 77 years). Best-fit Lyman-Kutcher-Burman model parameters (with 95% confidence intervals) were: n = 0.068 (0.01, +infinity); m =0.14 (0.0, 0.86); and TD50 = 81 (27, 136) Gy. The peak values fall within the 95% QUANTEC confidence intervals. On this dataset, both models had only modest ability to predict complications: the best-fit model had a Spearmans rank correlation coefficient of rs = 0.099 (p = 0.11) and area under the receiver operating characteristic curve (AUC) of 0.62; the QUANTEC model had rs=0.096 (p= 0.11) and a corresponding AUC of 0.61. Although the QUANTEC model consistently predicted higher NTCP values, it could not be rejected according to the χ2 test (p = 0.44). Conclusions. Observed complications, and best-fit parameter estimates, were consistent with the QUANTEC-preferred NTCP model. However, predictive power was low, at least partly because the rectal dose distribution characteristics do not vary greatly within this patient cohort.

Treatment planning constraints to avoid xerostomia in head-and-neck radiotherapy: an independent test of QUANTEC criteria using a prospectively collected dataset.

PURPOSE The severe reduction of salivary function (xerostomia) is a common complication after radiation therapy for head-and-neck cancer. Consequently, guidelines to ensure adequate function based on parotid gland tolerance dose-volume parameters have been suggested by the QUANTEC group and by Ortholan et al. We perform a validation test of these guidelines against a prospectively collected dataset and compared with a previously published dataset. METHODS AND MATERIALS Whole-mouth stimulated salivary flow data from 66 head-and-neck cancer patients treated with radiotherapy at the British Columbia Cancer Agency (BCCA) were measured, and treatment planning data were abstracted. Flow measurements were collected from 50 patients at 3 months, and 60 patients at 12-month follow-up. Previously published data from a second institution, Washington University in St. Louis (WUSTL), were used for comparison. A logistic model was used to describe the incidence of Grade 4 xerostomia as a function of the mean dose of the spared parotid gland. The rate of correctly predicting the lack of xerostomia (negative predictive value [NPV]) was computed for both the QUANTEC constraints and Ortholan et al. recommendation to constrain the total volume of both glands receiving more than 40 Gy to less than 33%. RESULTS Both datasets showed a rate of xerostomia of less than 20% when the mean dose to the least-irradiated parotid gland is kept to less than 20 Gy. Logistic model parameters for the incidence of xerostomia at 12 months after therapy, based on the least-irradiated gland, were D(50) = 32.4 Gy and and γ = 0.97. NPVs for QUANTEC guideline were 94% (BCCA data), and 90% (WUSTL data). For Ortholan et al. guideline NPVs were 85% (BCCA) and 86% (WUSTL). CONCLUSION These data confirm that the QUANTEC guideline effectively avoids xerostomia, and this is somewhat more effective than constraints on the volume receiving more than 40 Gy.

Dose-Dependent Cortical Thinning After Partial Brain Irradiation in High-Grade Glioma.

PURPOSE Radiation-induced cognitive deficits may be mediated by tissue damage to cortical regions. Volumetric changes in cortex can be reliably measured using high-resolution magnetic resonance imaging (MRI). We used these methods to study the association between radiation therapy (RT) dose and change in cortical thickness in high-grade glioma (HGG) patients. METHODS AND MATERIALS We performed a voxel-wise analysis of MRI from 15 HGG patients who underwent fractionated partial brain RT. Three-dimensional MRI was acquired pre- and 1 year post RT. Cortex was parceled with well-validated segmentation software. Surgical cavities were censored. Each cortical voxel was assigned a change in cortical thickness between time points, RT dose value, and neuroanatomic label by lobe. Effects of dose, neuroanatomic location, age, and chemotherapy on cortical thickness were tested using linear mixed effects (LME) modeling. RESULTS Cortical atrophy was seen after 1 year post RT with greater effects at higher doses. Estimates from LME modeling showed that cortical thickness decreased by -0.0033 mm (P<.001) for every 1-Gy increase in RT dose. Temporal and limbic cortex exhibited the largest changes in cortical thickness per Gy compared to that in other regions (P<.001). Age and chemotherapy were not significantly associated with change in cortical thickness. CONCLUSIONS We found dose-dependent thinning of the cerebral cortex, with varying neuroanatomical regional sensitivity, 1 year after fractionated partial brain RT. The magnitude of thinning parallels 1-year atrophy rates seen in neurodegenerative diseases and may contribute to cognitive decline following high-dose RT.

Effect of bladder filling on doses to prostate and organs at risk: a treatment planning study

In the present study, we aimed to evaluate effects of bladder filling on dose–volume distributions for bladder, rectum, planning target volume (PTV), and prostate in radiation therapy of prostate cancer. Patients (n=21) were scanned with a full bladder, and after 1 hour, having been allowed to void, with an empty bladder. Radiotherapy plans were generated using a four‐field box technique and dose of 70 Gy in 35 fractions. First, plans obtained for full‐ and empty‐bladder scans were compared. Second, situations in which a patient was planned on full bladder but was treated on empty bladder, and vice versa, were simulated, assuming that patients were aligned to external tattoos. Doses to the prostate [equivalent uniform dose (EUD)], bladder and rectum [effective dose (Deff)], and normal tissue complication probability (NTCP) were compared. Dose to the small bowel was examined. Mean bladder volume was 354.3 cm3 when full and 118.2 cm3 when empty. Median prostate EUD was 70 Gy for plans based on full‐ and empty‐bladder scans alike. The median rectal Deff was 55.6 Gy for full‐bladder anatomy and 56.8 Gy for empty‐bladder anatomy, and the corresponding bladder Deff was 29.0 Gy and 49.3 Gy respectively. In 1 patient, part of the small bowel (7.5 cm3) received more than 50 Gy with full‐bladder anatomy, and in 6 patients, part (2.5 cm3−30 cm3) received more than 50 Gy with empty‐bladder anatomy. Bladder filling had no significant impact on prostate EUD or rectal Deff. A minimal volume of the small bowel received more than 50 Gy in both groups, which is below dose tolerance. The bladder Deff was higher with empty‐bladder anatomy; however, the predicted complication rates were clinically insignificant. When the multileaf collimator pattern was applied in reverse, substantial underdosing of the planning target volume (PTV) was observed, particularly for patients with prostate shifts in excess of 0.5 cm in any one direction. However, the prostate shifts showed no correlation with bladder filling, and therefore the PTV underdosing also cannot be related to bladder filling. For some patients, bladder dose–volume constraints were not fulfilled in the worst‐case scenario—that is, when a patient planned with full bladder consistently arrived for treatment with an empty bladder. PACS numbers: 87.53.‐j, 87.53.Kn, 87.53.Tf

Internal fiducial markers can assist dose escalation in treatment of prostate cancer: result of organ motion simulations

Use of internal fiducial markers and electronic portal imaging (EPI) to realign patients has been shown to significantly reduce positioning uncertainties in prostate radiation treatment. This creates the possibility of improving the treatment by decreasing the planning target volume (PTV) margin added to the clinical target volume (CTV), which in turn may allow dose escalation. Conformal treatment plans for three prostate cancer patients were evaluated by using different PTV margins with dose prescription of 70 Gy/35 fr initially. Two beam arrangements, 4-field-box (4FB) and 4-field-oblique (4FO), were used. Then, two dose escalation schemes, 74 Gy and 78 Gy, with tighter PTV margins, were chosen from the first simulation and were tested. A Monte Carlo model was developed to simulate the daily geometric uncertainty and calculate the dose to each organ. After the whole treatment, dose-volume histograms were produced and tumour control probability, prostate equivalent uniform dose and the effective dose to critical organs were calculated. By comparing these radiobiological metrics, optimized dose escalation schemes were found. The results show that using internal fiducial markers and EPI, the prescription dose can be escalated to 78 Gy/39 fr with a 4 mm PTV margin. Based on the available dose-response data for intermediate risk prostate patients, this is estimated to result in a 20% increase of local control and significantly reduced rectal complications.