Development and Clinical Implementation of an Automated Virtual Integrative Planner for Radiation Therapy of Head and Neck Cancer.

Purpose: Head and neck (HN) radiation (RT) treatment planning is complex and resource intensive. Deviations and inconsistent plan quality significantly affect clinical outcomes. We sought to develop a novel automated virtual integrative (AVI) knowledge-based planning application to reduce planning time, increase consistency, and improve baseline quality. Methods and Materials: An in-house write-enabled script was developed from a library of 668 previously treated HN RT plans. Prospective hazard analysis was performed, and mitigation strategies were implemented before clinical release. The AVI-planner software was retrospectively validated in a cohort of 52 recent HN cases. A physician panel evaluated planning limitations during initial deployment, and feedback was enacted via software refinements. A final second set of plans was generated and evaluated. Kolmogorov-Smirnov test in addition to generalized evaluation metric and weighted experience score were used to compare normal tissue sparing between final AVI planner versus respective clinically treated and historically accepted plans. A t test was used to compare the interactive time, complexity, and monitor units for AVI planner versus manual optimization. Results: Initially, 86% of plans were acceptable to treat, with 10% minor and 4% major revisions or rejection recommended. Variability was noted in plan quality among HN subsites, with high initial quality for oropharynx and oral cavity plans. Plans needing revisions were comprised of sinonasal, nasopharynx, P-16 negative squamous cell carcinoma unknown primary, or cutaneous primary sites. Normal tissue sparing varied within subsites, but AVI planner significantly lowered mean larynx dose (median, 18.5 vs 19.7 Gy; P < .01) compared with clinical plans. AVI planner significantly reduced interactive optimization time (mean, 2 vs 85 minutes; P < .01). Conclusions: AVI planner reliably generated clinically acceptable RT plans for oral cavity, salivary, oropharynx, larynx, and hypopharynx cancers. Physician-driven iterative learning processes resulted in favorable evolution in HN RT plan quality with significant time savings and improved consistency using AVI planner.

Generation of Synthetic CT Images From MRI for Treatment Planning and Patient Positioning Using a 3-Channel U-Net Trained on Sagittal Images.

A novel deep learning architecture was explored to create synthetic CT (MRCT) images that preserve soft tissue contrast necessary for support of patient positioning in Radiation therapy. A U-Net architecture was applied to learn the correspondence between input T1-weighted MRI and spatially aligned corresponding CT images. The network was trained on sagittal images, taking advantage of the left-right symmetry of the brain to increase the amount of training data for similar anatomic positions. The output CT images were divided into three channels, representing Hounsfield Unit (HU) ranges of voxels containing air, soft tissue, and bone, respectively, and simultaneously trained using a combined Mean Absolute Error (MAE) and Mean Squared Error (MSE) loss function equally weighted for each channel. Training on 9192 image pairs yielded resulting synthetic CT images on 13 test patients with MAE of 17.6+/-3.4 HU (range 14-26.5 HU) in soft tissue. Varying the amount of training data demonstrated a general decrease in MAE values with more data, with the lack of a plateau indicating that additional training data could further improve correspondence between MRCT and CT tissue intensities. Treatment plans optimized on MRCT-derived density grids using this network for 7 radiosurgical targets had doses recalculated using the corresponding CT-derived density grids, yielding a systematic mean target dose difference of 2.3% due to the lack of the immobilization mask on the MRCT images, and a standard deviation of 0.1%, indicating the consistency of this correctable difference. Alignment of MRCT and cone beam CT (CBCT) images used for patient positioning demonstrated excellent preservation of dominant soft tissue features, and alignment comparisons of treatment planning CT scans to CBCT images vs. MRCT to CBCT alignment demonstrated differences of -0.1 (σ 0.2) mm, -0.1 (σ 0.3) mm, and -0.2 (σ 0.3) mm about the left-right, anterior-posterior and cranial-caudal axes, respectively.

Dosimetric impact of interfractional organs at risk variation during high-dose rate interstitial brachytherapy for gynecologic malignancies.

We sought to develop a framework for the identification and management of patients at risk for organs at risk (OARs) overdosing due to interfractional anatomic variation during high-dose rate interstitial brachytherapy for gynecologic malignancies. We analyzed 40 high-dose rate interstitial brachytherapy fractions from 10 patients. Planned OAR doses were compared to delivered doses, which were calculated from computed tomography scans obtained prior to each treatment fraction. Doses were converted to equivalent doses in 2 Gy fractions (EQD2) and doses to the most exposed 2 cm3 (D2cc) were reviewed. Patients were risk-stratified by identifying dose thresholds corresponding to a 10% or lower risk of receiving an OAR dose exceeding the corresponding planning constraint. For each OAR, 30% to 62.5% of patients received total doses greater than planned, although the magnitude of these differences was <4 Gy in over 75% of cases. Using EMBRACE II guidelines, one patient who had met the planning constraint for bladder and one for small bowel were found to have received doses exceeding the recommended limits. We next calculated thresholds for estimating the risk of OAR overdosing in individual patients and developed a framework based on these thresholds to direct time- and resource-intensive imaging and replanning efforts toward patients who are most likely to derive benefit. In summary, differential OAR dosing due to interfractional anatomic variation is common but likely rarely clinically meaningful. The proposed framework could decrease toxicity and maximize clinical efficiency.

Patient-reported voice and speech outcomes after whole-neck intensity modulated radiation therapy and chemotherapy for oropharyngeal cancer: prospective longitudinal study.

PURPOSE: To describe voice and speech quality changes and their predictors in patients with locally advanced oropharyngeal cancer treated on prospective clinical studies of organ-preserving chemotherapy-intensity modulated radiation therapy (chemo-IMRT). METHODS AND MATERIALS: Ninety-one patients with stage III/IV oropharyngeal cancer were treated on 2 consecutive prospective studies of definitive chemoradiation using whole-field IMRT from 2003 to 2011. Patient-reported voice and speech quality were longitudinally assessed from before treatment through 24 months using the Communication Domain of the Head and Neck Quality of Life (HNQOL-C) instrument and the Speech question of the University of Washington Quality of Life (UWQOL-S) instrument, respectively. Factors associated with patient-reported voice quality worsening from baseline and speech impairment were assessed. RESULTS: Voice quality decreased maximally at 1 month, with 68% and 41% of patients reporting worse HNQOL-C and UWQOL-S scores compared with before treatment, and improved thereafter, recovering to baseline by 12-18 months on average. In contrast, observer-rated larynx toxicity was rare (7% at 3 months; 5% at 6 months). Among patients with mean glottic larynx (GL) dose ≤20 Gy, >20-30 Gy, >30-40 Gy, >40-50 Gy, and >50 Gy, 10%, 32%, 25%, 30%, and 63%, respectively, reported worse voice quality at 12 months compared with before treatment (P=.011). Results for speech impairment were similar. Glottic larynx dose, N stage, neck dissection, oral cavity dose, and time since chemo-IMRT were univariately associated with either voice worsening or speech impairment. On multivariate analysis, mean GL dose remained independently predictive for both voice quality worsening (8.1%/Gy) and speech impairment (4.3%/Gy). CONCLUSIONS: Voice quality worsening and speech impairment after chemo-IMRT for locally advanced oropharyngeal cancer were frequently reported by patients, underrecognized by clinicians, and independently associated with GL dose. These findings support reducing mean GL dose to as low as reasonably achievable, aiming at ≤20 Gy when the larynx is not a target.

Parotid glands dose-effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.

PURPOSE: Doses actually delivered to the parotid glands during radiation therapy often exceed planned doses. We hypothesized that the delivered doses correlate better with parotid salivary output than the planned doses, used in all previous studies, and that determining these correlations will help make decisions regarding adaptive radiation therapy (ART) aimed at reducing the delivered doses. METHODS AND MATERIALS: In this prospective study, oropharyngeal cancer patients treated definitively with chemoirradiation underwent daily cone-beam computed tomography (CBCT) with clinical setup alignment based on the C2 posterior edge. Parotid glands in the CBCTs were aligned by deformable registration to calculate cumulative delivered doses. Stimulated salivary flow rates were measured separately from each parotid gland pretherapy and periodically posttherapy. RESULTS: Thirty-six parotid glands of 18 patients were analyzed. Average mean planned doses was 32 Gy, and differences from planned to delivered mean gland doses were -4.9 to +8.4 Gy, median difference +2.2 Gy in glands in which delivered doses increased relative to planned. Both planned and delivered mean doses were significantly correlated with posttreatment salivary outputs at almost all posttherapy time points, without statistically significant differences in the correlations. Large dispersions (on average, SD 3.6 Gy) characterized the dose-effect relationships for both. The differences between the cumulative delivered doses and planned doses were evident at first fraction (r=.92, P<.0001) because of complex setup deviations (eg, rotations and neck articulations), uncorrected by the translational clinical alignments. CONCLUSIONS: After daily translational setup corrections, differences between planned and delivered doses in most glands were small relative to the SDs of the dose-saliva data, suggesting that ART is not likely to gain measurable salivary output improvement in most cases. These differences were observed at first treatment, indicating potential benefit for more complex setup corrections or adaptive interventions in the minority of patients with large deviations detected early by CBCT.

Normal tissue anatomy for oropharyngeal cancer: contouring variability and its impact on optimization.

PURPOSE: To evaluate the variability of organ at risk (OAR) delineation and the resulting impact on intensity modulated radiation therapy (IMRT) treatment plan optimization in head-and-neck cancer. METHODS AND MATERIALS: An expert panel of 3 radiation oncologists jointly delineated OARs, including the parotid and submandibular glands (SM), pharyngeal constrictors (PC), larynx, and glottis (GL), in 10 patients with advanced oropharynx cancer in 3 contouring sessions, spaced at least 1 week apart. Contour variability and uncertainty, as well as their dosimetric impact on IMRT planning for each case, were assessed. RESULTS: The mean difference in total volume for each OAR was 1 cm(3) (σ 0.5 cm(3)). Mean fractional overlap was 0.7 (σ 0.1) and was highest (0.8) for the larynx and bilateral SMs and parotids and lowest (0.5) for PC. There were considerable spatial differences in contours, with the ipsilateral parotid and PC displaying the most variability (0.9 cm), which was most prominent in cases in which tumors obliterated fat planes. Both SMs and GL had the smallest differences (0.5 cm). The mean difference in OAR dose was 0.9 Gy (range 0.6-1.1 Gy, σ 0.1 Gy), with the smallest difference for GL and largest for both SMs and the larynx. CONCLUSIONS: Despite substantial difference in OAR contours, optimization was barely affected, with a 0.9-Gy mean difference between optimizations, suggesting relative insensitivity of dose distributions for IMRT of oropharynx cancer to the extent of OARs.

Dose--effect relationships for femoral fractures after multimodality limb-sparing therapy of soft-tissue sarcomas of the proximal lower extremity.

PURPOSE: We investigated the clinical and dosimetric predictors for radiation-associated femoral fractures in patients with proximal lower extremity soft tissue sarcomas (STS). METHODS AND MATERIALS: We examined 131 patients with proximal lower extremity STS who received limb-sparing surgery and external-beam radiation therapy between 1985 and 2006. Five (4%) patients sustained pathologic femoral fractures. Dosimetric analysis was limited to 4 fracture patients with full three-dimensional dose information, who were compared with 59 nonfracture patients. The mean doses and volumes of bone (V(d)) receiving specified doses (≥30 Gy, 45 Gy, 60 Gy) at the femoral body, femoral neck, intertrochanteric region, and subtrochanteric region were compared. Clinical predictive factors were also evaluated. RESULTS: Of 4 fracture patients in our dosimetric series, there were three femoral neck fractures with a mean dose of 57.6 ± 8.9 Gy, V30 of 14.5 ± 2.3 cc, V45 of 11.8 ± 1.1 cc, and V60 of 7.2 ± 2.2 cc at the femoral neck compared with 22.9 ± 20.8 Gy, 4.8 ± 5.6 cc, 2.5 ± 3.9 cc, and 0.8 ± 2.7 cc, respectively, for nonfracture patients (p < 0.03 for all). The femoral neck fracture rate was higher than at the subtrochanteric region despite lower mean doses at these subregions. All fracture sites received mean doses greater than 40 Gy. Also, with our policy of prophylactic femoral intramedullary nailing for high-risk patients, there was no significant difference in fracture rates between patients with and without periosteal excision. There were no significant differences in age, sex, tumor size, timing of radiation therapy, and use of chemotherapy between fracture and nonfracture patients. CONCLUSIONS: These dose-volume toxicity relationships provide RT optimization goals to guide future efforts for reducing pathologic fracture rates. Prophylactic femoral intramedullary nailing may also reduce fracture risk for susceptible patients.

Evaluating the relationships between rectal normal tissue complication probability and the portion of seminal vesicles included in the clinical target volume in intensity-modulated radiotherapy for prostate cancer.

PURPOSE: To compare dose-volume consequences of the inclusion of various portions of the seminal vesicles (SVs) in the clinical target volume (CTV) in intensity-modulated radiotherapy (IMRT) for patients with prostate cancer. METHODS AND MATERIALS: For 10 patients with prostate cancer, three matched IMRT plans were generated, including 1 cm, 2 cm, or the entire SVs (SV1, SV2, or SVtotal, respectively) in the CTV. Prescription dose (79.2 Gy) and IMRT planning were according to the high-dose arm of the Radiation Therapy Oncology Group (RTOG) 0126 protocol. We compared plans for percentage of rectal volume receiving minimum doses of 60-80 Gy and for rectal normal tissue complication probability (NTCP[R]). RESULTS: There was a detectable increase in rectal dose in SV2 and SVtotal compared with SV1. The magnitude of difference between plans was modest in the high-dose range. In 2 patients, there was underdosing of the planning target volume (PTV) because of constraints on rectal dose in the SVtotal plans. All other plans were compliant with RTOG 0126 protocol requirements. Mean NTCP increased from 14% to 17% and 18% for SV1, SV2, and SV total, respectively. The NTCP correlated with the size of PTV-rectum volume overlap (Pearson's r = 0.86; p < 0.0001), but not with SV volume. CONCLUSIONS: Doubling (1 to 2 cm) or comprehensively increasing (1 cm to full SVs) SV volume included in the CTV for patients with prostate IMRT is achievable in the majority of cases without exceeding RTOG dose-volume limits or underdosing the PTV and results in only a moderate increase in NTCP.

Dose-effect relationships for the submandibular salivary glands and implications for their sparing by intensity modulated radiotherapy.

PURPOSE: Submandibular salivary glands (SMGs) dysfunction contributes to xerostomia after radiotherapy (RT) of head-and-neck (HN) cancer. We assessed SMG dose-response relationships and their implications for sparing these glands by intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: A total of 148 HN cancer patients underwent unstimulated and stimulated SMG salivary flow rate measurements selectively from Wharton's duct orifices, before RT and periodically through 24 months after RT. Correlations of flow rates and mean SMG doses were modeled throughout all time points. IMRT replanning in 8 patients whose contralateral level I was not a target incorporated the results in a new cost function aiming to spare contralateral SMGs. RESULTS: Stimulated SMG flow rates decreased exponentially by (1.2%)(Gy) as mean doses increased up to 39 Gy threshold, and then plateaued near zero. At mean doses < or =39 Gy, but not higher, flow rates recovered over time at 2.2%/month. Similarly, the unstimulated salivary flow rates decreased exponentially by (3%)(Gy) as mean dose increased and recovered over time if mean dose was <39 Gy. IMRT replanning reduced mean contralateral SMG dose by average 12 Gy, achieving < or =39 Gy in 5 of 8 patients, without target underdosing, increasing the mean doses to the parotid glands and swallowing structures by average 2-3 Gy. CONCLUSIONS: SMG salivary flow rates depended on mean dose with recovery over time up to a threshold of 39 Gy. Substantial SMG dose reduction to below this threshold and without target underdosing is feasible in some patients, at the expense of modestly higher doses to some other organs.

Lack of osteoradionecrosis of the mandible after intensity-modulated radiotherapy for head and neck cancer: likely contributions of both dental care and improved dose distributions.

PURPOSE: To assess the prevalence and dosimetric and clinical predictors of mandibular osteoradionecrosis (ORN) in patients with head and neck cancer who underwent a pretherapy dental evaluation and prophylactic treatment according to a uniform policy and were treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between 1996 and 2005, all patients with head-and-neck cancer treated with parotid gland-sparing IMRT in prospective studies underwent a dental examination and prophylactic treatment according to a uniform policy that included extractions of high-risk, periodontally involved, and nonrestorable teeth in parts of the mandible expected to receive high radiation doses, fluoride supplements, and the placement of guards aiming to reduce electron backscatter off metal teeth restorations. The IMRT plans included dose constraints for the maximal mandibular doses and reduced mean parotid gland and noninvolved oral cavity doses. A retrospective analysis of Grade 2 or worse (clinical) ORN was performed. RESULTS: A total of 176 patients had a minimal follow-up of 6 months. Of these, 31 (17%) had undergone teeth extractions before RT and 13 (7%) after RT. Of the 176 patients, 75% and 50% had received >or=65 Gy and >or=70 Gy to >or=1% of the mandibular volume, respectively. Falloff across the mandible characterized the dose distributions: the average gradient (in the axial plane containing the maximal mandibular dose) was 11 Gy (range, 1-27 Gy; median, 8 Gy). At a median follow-up of 34 months, no cases of ORN had developed (95% confidence interval, 0-2%). CONCLUSION: The use of a strict prophylactic dental care policy and IMRT resulted in no case of clinical ORN. In addition to the dosimetric advantages offered by IMRT, meticulous dental prophylactic care is likely an essential factor in reducing ORN risk.