MRI to delineate the gross tumor volume of nasopharyngeal cancers: which sequences and planes should be used?

BACKGROUND: Magnetic resonance imaging (MRI) has been found to be better than computed tomography for defining the extent of primary gross tumor volume (GTV) in advanced nasopharyngeal cancer. It is routinely applied for target delineation in planning radiotherapy. However, the specific MRI sequences/planes that should be used are unknown. METHODS: Twelve patients with nasopharyngeal cancer underwent primary GTV evaluation with gadolinium-enhanced axial T1 weighted image (T1) and T2 weighted image (T2), coronal T1, and sagittal T1 sequences. Each sequence was registered with the planning computed tomography scans. Planning target volumes (PTVs) were derived by uniform expansions of the GTVs. The volumes encompassed by the various sequences/planes, and the volumes common to all sequences/planes, were compared quantitatively and anatomically to the volume delineated by the commonly used axial T1-based dataset. RESULTS: Addition of the axial T2 sequence increased the axial T1-based GTV by 12% on average (p = 0.004), and composite evaluations that included the coronal T1 and sagittal T1 planes increased the axial T1-based GTVs by 30% on average (p = 0.003). The axial T1-based PTVs were increased by 20% by the additional sequences (p = 0.04). Each sequence/plane added unique volume extensions. The GTVs common to all the T1 planes accounted for 38% of the total volumes of all the T1 planes. Anatomically, addition of the coronal and sagittal-based GTVs extended the axial T1-based GTV caudally and cranially, notably to the base of the skull. CONCLUSIONS: Adding MRI planes and sequences to the traditional axial T1 sequence yields significant quantitative and anatomically important extensions of the GTVs and PTVs. For accurate target delineation in nasopharyngeal cancer, we recommend that GTVs be outlined in all MRI sequences/planes and registered with the planning computed tomography scans.

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.

The Special Medical Physics Consult Process for Reirradiation Patients.

PURPOSE: To present a systematic approach to the reirradiation special medical physics consult (ReRT-SMPC) process. MATERIALS AND METHODS: An in-house reirradiation committee of physicians and physicists was formed to develop a streamlined and well-documented approach to ReRT-SMPCs. Dosimetric goals and considerations for tissue repair were generated by the committee with input from the literature, clinical trial guidelines, and physician experience. Procedural workflow was also defined. RESULTS: The total number of ReRT-SMPCs performed in our department in 2018 was 401, corresponding to 369 unique patients and 16% of the total number of patients receiving external beam radiation in our department that year. This constituted a large increase over the 183 ReRT-SMPCs performed in 2017. We have found that a standardized ReRT-SMPC workflow helps to safeguard patients, documents the clinical decision-making process for medical and legal purposes, and facilitates the peer-review process. The data being collected from each consult along with toxicity and outcomes data can be used to help inform future re-treatment guidelines. CONCLUSIONS: As the number of patients returning for additional courses of radiation continues to increase, a uniform method for the ReRT-SMPC workflow and analysis is a powerful tool for ensuring patient safety, understanding and predicting treatment toxicity, and refining reirradiation dosimetric limits.

The impact of breathing motion versus heterogeneity effects in lung cancer treatment planning.

The purpose of this study is to investigate the effects of tissue heterogeneity and breathing-induced motion/deformation on conformal treatment planning for pulmonary tumors and to compare the magnitude and the clinical importance of changes induced by these effects. Treatment planning scans were acquired at normal exhale/inhale breathing states for fifteen patients. The internal target volume (ITV) was defined as the union of exhale and inhale gross tumor volumes uniformly expanded by 5 mm. Anterior/posterior opposed beams (AP/PA) and three-dimensional (3D)-conformal plans were designed using the unit-density exhale ("static") dataset. These plans were further used to calculate (a) density-corrected ("heterogeneous") static dose and (b) heterogeneous cumulative dose, including breathing deformations. The DPM Monte Carlo code was used for dose computations. For larger than coin-sized tumors, relative to unit-density plans, tumor and lung doses increased in the heterogeneity-corrected plans. In comparing cumulative and static plans, larger normal tissue complication probability changes were observed for tumors with larger motion amplitudes and uncompensated breathing-induced hot/cold spots in lung. Accounting for tissue heterogeneity resulted in average increases of 9% and 7% in mean lung dose (MLD) for the 6 MV and 15 MV photon beams, respectively. Breathing-induced effects resulted in approximately 1% and 2% average decreases in MLD from the static value, for the 6 and 15 MV photon beams, respectively. The magnitude of these effects was not found to correlate with the treatment plan technique, i.e., AP/PA versus 3D-CRT. Given a properly designed ITV, tissue heterogeneity effects are likely to have a larger clinical significance on tumor and normal lung treatment evaluation metrics than four-dimensional respiratory-induced changes.

Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies.

PURPOSE: A phase II trial was conducted to determine if high-dose radiation with concurrent hepatic arterial floxuridine would improve survival in patients with unresectable intrahepatic malignancies. PATIENTS AND METHODS: Three-dimensional conformal high-dose radiation therapy was delivered concurrently with hepatic arterial floxuridine in 128 patients. The radiation dose was based on a normal-tissue complication probability model and subjected the patient to an estimated maximum risk of radiation-induced liver disease of 10% to 15%. The study design provided more than 80% power to detect a two-fold increase in median survival compared with historical controls at a 5% significance level. RESULTS: The median radiation dose delivered was 60.75 Gy (1.5-Gy fractions bid). At a median follow-up time of 16 months (26 months in patients who were alive) the median survival was 15.8 months (95% CI, 12.6 to 18.3 months), significantly longer than in the historical control. The actuarial 3-year survival was 17%. The total dose was the only significant predictor of survival. Primary hepatobiliary tumors had a significantly greater tendency to remain confined to the liver than did colorectal cancer metastases. Overall toxicity was acceptable, with 27 patients (21%) and 11 patients (9%) developing grade 3 and 4 toxicity, respectively, and one treatment-related death. CONCLUSION: The results suggest that, compared with historical controls, high-dose focal liver irradiation with hepatic artery floxuridine prolongs survival in patients with unresectable chemotherapy-refractory metastatic colorectal cancer and primary hepatobiliary tumors. This provides a rationale for intensification of local therapy for unresectable hepatobiliary cancers and integration of this regimen with newer systemic therapy for patients with colorectal cancer.

Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy.

PURPOSE: For chemotherapy to act synergistically and safely with radiation against high-grade gliomas, drugs must pass the endothelial junctions of the blood-tumor barrier (BTB) to reach all tumor cells, and should not pass the blood-brain barrier (BBB) to cause toxicity to normal brain. The objective of this study was to assess BBB/BTB status using magnetic resonance imaging (MRI) during a course of radiotherapy of high-grade gliomas. PATIENTS AND METHODS: Sixteen patients with grade 3 or 4 supratentorial malignant glioma receiving conformal radiotherapy (RT) underwent contrast-enhanced MRI before, during, and after completion of RT. A gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) uptake index was analyzed with respect to the tumor and RT dose received. RESULTS: In the nonenhanced tumor region, contrast uptake increased significantly after the receipt of approximately 10 Gy (P < .01), and reached a maximum after the receipt of approximately 30 Gy. In the initially contrast-enhanced tumor region, contrast uptake decreased over the course of RT and became significant after completion of RT in patients without progressive disease. The healthy brain showed only nonsignificant changes during and after irradiation. CONCLUSION: Contrast MRI reveals increases in Gd-DTPA uptake in the initially nonenhanced tumor region but not in the remaining brain during the course of RT, suggesting opening of the BTB. This finding suggests that the effect of conformal radiation is more selective on the BTB than the BBB, and there may be a window extending from 1 week after the initiation of radiotherapy to 1 month after the completion of treatment during which a pharmaceutical agent has maximum access to high-grade gliomas.

Long-term results of high-dose conformal radiotherapy for patients with medically inoperable T1-3N0 non-small-cell lung cancer: is low incidence of regional failure due to incidental nodal irradiation?

PURPOSE: To report the results of high-dose conformal irradiation and examine incidental nodal irradiation and nodal failure in patients with inoperable early-stage non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: This analysis included patients with inoperable CT-staged T1-3N0M0 NSCLC treated on our prospective dose-escalation trial. Patients were treated with radiation alone (total dose, 63-102.9 Gy in 2.1-Gy daily fractions) with a three-dimensional conformal technique without intentional nodal irradiation. Bilateral highest mediastinal and upper/lower paratracheal, prevascular and retrotracheal, sub- and para-aortic, subcarinal, paraesophageal, and ipsilateral hilar regions were delineated individually. Nodal failure and doses of incidental irradiation were studied. RESULTS: The potential median follow-up was 104 months. For patients who completed protocol treatment, median survival was 31 months. The actuarial overall survival rate was 86%, 61%, 43%, and 21% and the cause-specific survival rate was 89%, 70%, 53%, and 35% at 1, 2, 3, and 5 years, respectively. Weight loss (p = 0.008) and radiation dose in Gy (p = 0.013) were significantly associated with overall survival. In only 22% and 13% of patients examined did ipsilateral hilar and paratracheal (and subaortic for left-sided tumor) nodal regions receive a dose of > or = 40 Gy, respectively. Less than 10% of all other nodal regions received a dose of > or = 40 Gy. No patients failed initially at nodal sites. CONCLUSIONS: Radiation dose is positively associated with overall survival in patients with medically inoperable T1-3N0 NSCLC, though long-term results remain poor. The nodal failure rate is low and does not seem to be due to high-dose incidental irradiation.

Evaluating the influence of setup uncertainties on treatment planning for focal liver tumors.

PURPOSE: A mechanism has been developed to evaluate the influence of random setup variations on dose during treatment planning. The information available for studying these factors shifts from population-based models toward patient-specific data as treatment progresses and setup measurements for an individual patient become available. This study evaluates the influence of population as well as patient-specific setup distributions on treatment plans for focal liver tumors. METHODS AND MATERIALS: Eight patients with focal liver tumors were treated on a protocol that involved online setup measurement and adjustment, as well as ventilatory immobilization. Summary statistics from these three-dimensional conformal treatments yielded individual and population distributions of position at initial setup for each fraction. A convolution model for evaluation of the influence of random setup variation on calculated dose distributions has been previously described and investigated for application to focal liver radiotherapy by our department. Individual patient doses based on initial setup positions were calculated by convolving the calculated dose distribution with an anisotropic probability distribution function representing the individual patient's random variations. A separate convolution using population-averaged random variations was performed. Individual beam apertures were then adjusted to provide plans that ensured proper dose to the clinical target volume following convolution with population distributions, as well as individual patient position uncertainty models. RESULTS: Individual patient setup distributions for the course of treatment had random setup variations (sigma) that ranged from 2.5 to 5.7 mm (left-right), 2.1 to 8.3 mm (anterior-posterior), and 4.1 to 10.8 mm (cranial-caudal). The population random components were 4.2 mm (left-right), 4.1 mm (anterior-posterior), and 7.0 mm (cranial-caudal) at initial setup. The initial static planned dose distribution overestimated the volume of liver irradiated to high doses, because inclusion of setup uncertainties generally blurred the resulting doses, shifting the higher-dose region of normal liver dose-volume histograms to lower doses. Furthermore, the population-based dose convolution tended to predict a higher risk of radiation damage to the liver (based on an in-house parameterization of the Lyman normal tissue complication probability model) than the individual patient calculations. For an individual plan, application of different individual random variations yielded change in effective volume differences with a 3% range. Plan adjustment to account for random setup variations generally resulted in a lower change in effective volume than initial planning using a planning target volume followed by calculation of delivered dose based on random offsets. CONCLUSION: This study hints at the factors that most strongly influence planning of liver treatments taking into account geometric variations. Given a setup verification methodology that rapidly reduces systematic offsets, the importance of realistic incorporation of geometric variations as an initial step in treatment planning, as well as possible plan refinement, is demonstrated.

Evaluating changes in tumor volume using magnetic resonance imaging during the course of radiotherapy treatment of high-grade gliomas: Implications for conformal dose-escalation studies.

OBJECTIVE: To determine whether changes in tumor volume occur during the course of conformal 3D radiotherapy of high-grade gliomas by use of magnetic resonance imaging (MRI) during treatment and whether these changes had an impact on tumor coverage. METHODS AND MATERIALS: Between December 2000 and January 2004, 21 patients with WHO Grades 3 to 4 supratentorial malignant gliomas treated with 3D conformal radiotherapy (median dose, 70 Gy) were enrolled in a prospective clinical study. All patients underwent T1-weighted contrast-enhancing and T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging at approximately 1 to 2 weeks before radiotherapy, during radiotherapy (Weeks 1 and 3), and at routine intervals thereafter. All MRI scans were coregistered to the treatment-planning CT. Gross tumor volume (GTV Pre-Rx) was defined from a postoperative T1-weighted contrast-enhancing MRI performed 1 to 2 weeks before start of radiotherapy. A second GTV (GTV Week 3) was defined by use of an MRI performed during Week 3 of radiotherapy. A uniform 0.5 cm expansion of the respective GTV, PTV (Pre-Rx), and PTV (Week 3) was applied to the final boost plan. Dose-volume histograms (DVH) were used to analyze any potential adverse changes in tumor coverage based on Week 3 MRI. RESULTS: All MRI scans were reviewed independently by a neuroradiologist (DGH). Two patients were noted to have multifocal disease at presentation and were excluded from analysis. In 19 cases, changes in the GTV based on MRI at Week 3 during radiotherapy were as follows: 2 cases had an objective decrease in GTV (> or =50%); 12 cases revealed a slight decrease in the rim enhancement or changes in cystic appearance of the GTV; 2 cases showed no change in GTV; and 3 cases demonstrated an increase in tumor volume. Both cases with objective decreases in GTV during treatment were Grade 3 tumors. No cases of tumor progression were noted in Grade 3 tumors during treatment. In comparison, three of 12 Grade 4 tumors had tumor progression, based on MRI obtained during Week 3 of radiotherapy. Median increase in GTV (Week 3) was 11.7 cc (range, 9.8-21.3). Retrospective DVH analysis of PTV (Pre-Rx) and PTV (Week 3) demonstrated a decrease in V(95%)(PTV volume receiving 95% of the prescribed dose) in those 3 cases. CONCLUSIONS: Routine MR imaging during radiotherapy may be essential in ensuring tumor coverage if highly conformal radiotherapy techniques such as stereotactic boost and intensity-modulated radiotherapy are used in dose-escalation trials that utilize smaller treatment margins.

Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity.

PURPOSE: Poor pulmonary function (PF) is often considered a contraindication to definitive radiation therapy for lung cancer. This study investigated whether baseline PF was associated with radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC) receiving conformal radiation therapy (CRT). METHODS AND MATERIALS: NSCLC patients treated with CRT and tested for PF at baseline were eligible. Baseline predicted values of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and diffusion capacity of lung for carbon monoxide (DLCO) were analyzed. Additional factors included age, gender, smoking status, Karnofsky performance status, coexisting chronic obstructive pulmonary disease (COPD), tumor location, histology, concurrent chemotherapy, radiation dose, and mean lung dose (MLD) were evaluated for RILT. The primary endpoint was symptomatic RILT (SRILT), including grade ≥2 radiation pneumonitis and fibrosis. RESULTS: There was a total of 260 patients, and SRILT occurred in 58 (22.3%) of them. Mean FEV1 values for SRILT and non-SRILT patients were 71.7% and 65.9% (P=.077). Under univariate analysis, risk of SRILT increased with MLD (P=.008), the absence of COPD (P=.047), and FEV1 (P=.077). Age (65 split) and MLD were significantly associated with SRILT in multivariate analysis. The addition of FEV1 and age with the MLD-based model slightly improved the predictability of SRILT (area under curve from 0.63-0.70, P=.088). CONCLUSIONS: Poor baseline PF does not increase the risk of SRILT, and combining FEV1, age, and MLD may improve the predictive ability.

Pattern of failure after high-dose thoracic radiation for non-small cell lung cancer: the University of Michigan experience.

PURPOSE: Our main purpose is to study the pattern of local failure for patients with non-small cell lung cancer treated with conformal therapy. METHODS: This study included patients who failed locally and a matched group without failures after 3D conformal radiation per a radiation dose-escalation trial. Radiation doses ranged from 65.1 to 102.9 Gy in 2.1 Gy fractions, originally computed using an equivalent path length algorithm. The recurrent gross target volumes (RGTV) were contoured. The original and recurrent planning target volume (PTV and RPTV) were generated by 1 cm uniform expansion from GTV. DVHs and generalized equivalent uniform doses (EUD={Σ i (di ) a }1/a ) were computed. Marginal failures were defined for RGTVs covered by the original 10 to 90 % isodose surfaces. RESULTS: There were no significant differences between the failed and control groups with regard to average original GTV volumes, GTV and PTV doses, and minimum PTV doses. Of the 18 RGTVs, four had marginal failure, 12 failed mostly within, and two failed outside of the original PTV. The mean EUDs were 57.1 Gy (95 % confidence interval (CI) 43.9-70.6) and 47.5 Gy (95 % CI 33.7-61.2), for the RGTVs and RPTVs, respectively, significantly below the prescribed doses (p=0.03). EUDs were less than 60 Gy for 39 % of the RGTVs and 56 % of the RPTVs. CONCLUSIONS: Recurrent tumors had significantly lower doses than the prescribed dose suggesting that some of these failures could have been avoided with modern technology such as 4D CT simulation and image-guided radiation therapy.

Influence of rotations on dose distributions in spinal stereotactic body radiotherapy (SBRT).

PURPOSE: To evaluate the impact of rotational setup errors on dose distribution in spinal stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Thirty-nine cone beam computed tomography (CBCT) scans from 16 SBRT treatment courses were analyzed. Alignment (including rotation) to the treatment planning computed tomography was performed, followed by translational alignment that reproduced the actual positioning. The planned fluence was then applied to determine the delivered dose to the targets and organs at risk. RESULTS: The mean planning target volume (PTV) was 71.01 mL (SD +/- 60.05; range, 22.62-250.65 mL). Prescribed dose (to the 62-82% isodose) was 14-30 Gy in one to six fractions. The average rotational displacements were 0.38 +/- 1.21, 1.12 +/- 1.82, and -0.51 +/- 2.0 degrees with maximal rotations of -4.29, 5.76, and -6.64 degrees along the x (pitch), y (yaw), and z (roll) axes, respectively. PTV coverage changed by an average of -0.07 Gy (SD +/- 0.20 Gy) between the rotated and the original plan, representing 0.92% of prescription dose (SD +/- 2.65%). For the spinal cord, planned with 2-mm expansion to create a planning organ at risk volume (PRV), the difference in minimum dose to the upper 10% of the PRV volume was 0.03 +/- 0.3 Gy (maximum, 0.9 Gy). Other organs at risk saw insignificant changes in dose. CONCLUSIONS: PRV expansion generally assures safe treatment delivery in the face of typically encountered rotations. Given the variability of delivered dose within this expansion for certain cases, caution should be taken to properly interpret doses to the cord when considering clinical dose limits.

Intra and interfraction mediastinal nodal region motion: implications for internal target volume expansions.

The purpose of this study was to determine the intra and interfraction motion of mediastinal lymph node regions. Ten patients with nonsmall-cell lung cancer underwent controlled inhale and exhale computed tomography (CT) scans during two sessions (40 total datasets) and mediastinal nodal stations 1-8 were outlined. Corresponding CT scans from different sessions were registered to remove setup error and, in this reference frame, the centroid of each nodal station was compared for right-left (RL), anterior-posterior (AP), and superior-inferior (SI) displacement. In addition, an anisotropic volume expansion encompassing the change of the nodal region margins in all directions was used. Intrafraction displacement was determined by comparing same session inhale-exhale scans. Interfraction reproducibility of nodal regions was determined by comparing the same respiratory phase scans between two sessions. Intrafraction displacement of centroid varied between nodal stations. All nodal regions moved posteriorly and superiorly with exhalation, and inferior nodal stations showed the most motion. Based on anisotropic expansion, nodal regions expanded mostly in the RL direction from inhale to exhale. The interpatient variations in intrafraction displacement were large compared with the displacements themselves. Moreover, there was substantial interfractional displacement ( approximately 5 mm). Mediastinal lymph node regions clearly move during breathing. In addition, deformation of nodal regions between inhale and exhale occurs. The degree of motion and deformation varies by station and by individual. This study indicates the potential advantage of characterizing individualized nodal region motion to safely maximize conformality of mediastinal nodal targets.

Designing targets for elective nodal irradiation in lung cancer radiotherapy: a planning study.

PURPOSE: To assess doses received by mediastinal and hilar lymph node stations (LNS) delineated according to published recommendations when "standard" two-dimensional (2D) elective fields are applied and to assess doses to critical structures when fields are designed using 2D and three-dimensional (3D) treatment planning for elective irradiation. METHODS AND MATERIALS: LNS were delineated on axial CT scans according to existing recommendations. For each case and tumor location, 2D anteroposterior-posteroanterior (AP-PA) elective fields were applied using the AP-PA CT topograms. From the 2D portal fields, 3D dose distributions were then calculated to particular LNS. Next, 3D plans were prepared for elective nodal irradiation for tumors of different lobes. Doses for critical structures were compared for 2D and 3D plans. RESULTS: LNS 1/2R, 1/2L, 3A, 3P, 5, 6, and 8 were not adequately covered in a substantial part of plans by standard 2D portals when guidelines for delineation were strictly followed. The magnitude of the lack of coverage increased with margin application. There was a trend for a higher yet probably still safe dose delivered to lung for 3D plans compared with 2D plans with a prescription dose of 45 Gy. CONCLUSIONS: 2D fields did not entirely cover LNS delineated according to the recommendations for 3D techniques. A strict adherence to these guidelines may lead to larger portals than traditionally constructed using 2D methods. Some modifications for clinical implementation are discussed.