Dosimetric impact of the positioning variation of tumor treating field electrodes in the PriCoTTF-phase I/II trial.

PURPOSE: The aim of the present study based on the PriCoTTF-phase I/II trial is the quantification of skin-normal tissue complication probabilities of patients with newly diagnosed glioblastoma multiforme treated with Tumor Treating Field (TTField) electrodes, concurrent radiotherapy, and temozolomide. Furthermore, the skin-sparing effect by the clinically applied strategy of repetitive transducer array fixation around their center position shall be examined. MATERIAL AND METHODS: Low-dose cone-beam computed tomography (CBCT) scans of all fractions of the first seven patients of the PriCoTTF-phase I/II trial, used for image guidance, were applied for the dosimetric analysis, for precise TTField transducer array positioning and contour delineation. Within this trial, array positioning was varied from fixation-to-fixation period with a standard deviation of 1.1 cm in the direction of the largest variation of positioning and 0.7 cm in the perpendicular direction. Physical TTField electrode composition was examined and a respective Hounsfield Unit attributed to the TTField electrodes. Dose distributions in the planning CT with TTField electrodes in place, as derived from prefraction CBCTs, were calculated and accumulated with the algorithm Acuros XB. Dose-volume histograms were obtained for the first and second 2 mm scalp layer with and without migrating electrodes and compared with those with fixed electrodes in an average position. Skin toxicity was quantified according to Lyman's model. Minimum doses in hot-spots of 0.05 cm2 and 25 cm2 ( Δ D0.05cm 2 , Δ D25cm 2 ) size in the superficial skin layers were analyzed. RESULTS: Normal tissue complication probabilities (NTCPs) for skin necrosis ranged from 0.005% to 1.474% (median 0.111%) for the different patients without electrodes. NTCP logarithms were significantly dependent on patient (P < 0.0001) and scenario (P < 0.0001) as classification variables. Fixed positioning of TTField arrays increased skin-NTCP by a factor of 5.50 (95%, CI: 3.66-8.27). The variation of array positioning increased skin-NTCP by a factor of only 3.54 (95%, CI: 2.36-5.32) (P < 0.0001, comparison to irradiation without electrodes; P = 0.036, comparison to irradiation with fixed electrodes). NTCP showed a significant rank correlation with D25cm2 over all patients and scenarios (rs  = 0.76; P < 0.0001). CONCLUSION: Skin-NTCP calculation uncovers significant interpatient heterogeneity and may be used to stratify patients into high- and low-risk groups of skin toxicity. Array position variation may mitigate about one-third of the increase in surface dose and skin-NTCP by the TTField electrodes.

Adaptation Time as a Determinant of the Dosimetric Effectiveness of Online Adaptive Radiotherapy for Bladder Cancer.

Interfraction anatomic deformations decrease the precision of radiotherapy, which can be improved by online adaptive radiation therapy (oART). However, oART takes time, allowing intrafractional deformations. In this study on focal radiotherapy for bladder cancer, we analyzed the time effect of oART on the equivalent uniform dose in the CTV (EUDCTV) per fraction and for the accumulated dose distribution over a treatment series as measure of effectiveness. A time-dependent digital CTV model was built from deformable image registration (DIR) between pre- and post-adaptation imaging. The model was highly dose fraction-specific. Planning target volume (PTV) margins were varied by shrinking the clinical PTV to obtain the margin-specific CTV. The EUDCTV per fraction decreased by-4.4 ± 0.9% of prescribed dose per min in treatment series with a steeper than average time dependency of EUDCTV. The EUDCTV for DIR-based accumulated dose distributions over a treatment series was significantly dependent on adaptation time and PTV margin (p < 0.0001, Chi2 test for each variable). Increasing adaptation times larger than 10 min by five minutes requires a 1.9 ± 0.24 mm additional margin to maintain EUDCTV for a treatment series. Adaptation time is an important determinant of the precision of oART for one half of the bladder cancer patients, and it should be aimed at to be minimized.

Comparison of Online-Onboard Adaptive Intensity-Modulated Radiation Therapy or Volumetric-Modulated Arc Radiotherapy With Image-Guided Radiotherapy for Patients With Gynecologic Tumors in Dependence on Fractionation and the Planning Target Volume Margin.

Importance: Patients with newly diagnosed locally advanced cervical carcinomas or recurrences after surgery undergoing radiochemotherapy whose tumor is unsuited for a brachytherapy boost need high-dose percutaneous radiotherapy with small margins to compensate for clinical target volume deformations and set-up errors. Cone-beam computed tomography-based online adaptive radiotherapy (ART) has the potential to reduce planning target volume (PTV) margins below 5 mm for these tumors. Objective: To compare online ART technologies with image-guided radiotherapy (IGRT) for gynecologic tumors. Design, Setting, and Participants: This comparative effectiveness study comprised all 7 consecutive patients with gynecologic tumors who were treated with ART with artificial intelligence segmentation from January to May 2022 at the West German Cancer Center. All adapted treatment plans were reviewed for the new scenario of organs at risk and target volume. Dose distributions of adapted and scheduled plans optimized on the initial planning computed tomography scan were compared. Exposure: Online ART for gynecologic tumors. Main Outcomes and Measures: Target dose coverage with ART compared with IGRT for PTV margins of 5 mm or less in terms of the generalized equivalent uniform dose (gEUD) without increasing the gEUD for the organs at risk (bladder and rectum). Results: The first 10 treatment series among 7 patients (mean [SD] age, 65.7 [16.5] years) with gynecologic tumors from a prospective observational trial performed with ART were compared with IGRT. For a clinical PTV margin of 5 mm, IGRT was associated with a median gEUD decrease in the interfractional clinical target volume of -1.5% (90% CI, -31.8% to 2.9%) for all fractions in comparison with the planned dose distribution. Online ART was associated with a decrease of -0.02% (90% CI, -3.2% to 1.5%), which was less than the decrease with IGRT (P < .001). This was not associated with an increase in the gEUD for the bladder or rectum. For a PTV margin of 0 mm, the median gEUD deviation with IGRT was -13.1% (90% CI, -47.9% to 1.6%) compared with 0.1% (90% CI, -2.3% to 6.6%) with ART (P < .001). The benefit associated with ART was larger for a PTV margin of 0 mm than of 5 mm (P = .004) due to spreading of the cold spot at the clinical target volume margin from fraction to fraction with a median SD of 2.4 cm (90% CI, 1.9-3.4 cm) for all patients. Conclusions and Relevance: This study suggests that ART is associated with an improvement in the percentage deviation of gEUD for the interfractional clinical target volume compared with IGRT. As the gain of ART depends on fractionation and PTV margin, a strategy is proposed here to switch from IGRT to ART, if the delivered gEUD distribution becomes unfavorable in comparison with the expected distribution during the course of treatment.

Long-Term Follow-Up of Patients with Conjunctival Lymphoma after Individualized Lens-Sparing Electron Radiotherapy: Results from a Longitudinal Study.

Irradiation with electrons is the primary treatment regime for localized conjunctival low-grade lymphomas. However, radiation-induced cataracts are a major cause of treatment-related morbidity. This study investigates whether lens-sparing electron irradiation produces sufficient disease control rates while preventing cataract formation. All consecutive patients with strictly conjunctival, low-grade Ann Arbor stage IE lymphoma treated with superficial electron irradiation between 1999 and 2021 at our department were reviewed. A total of 56 patients with 65 treated eyes were enrolled with a median follow-up of 65 months. The median dose was 30.96 Gy. A lens-spearing technique featuring a hanging rod blocking the central beam axis was used in 89.2% of all cases. Cumulative incidences of 5- and 10-year infield recurrences were 4.3% and 14.6%, incidences of 5- and 10-year outfield progression were 10.4% and 13.4%. We used patients with involvement of retroorbital structures treated with whole-orbit photon irradiation without lens protection-of which we reported in a previous study-as a control group. The cumulative cataract incidence for patients treated with electrons and lens protection was significantly lower (p = 0.005) when compared to patients irradiated without lens protection. Thus, electrons are an effective treatment option for conjunctival low-grade lymphomas. The presented lens-sparing technique effectively prevents cataract formation.

Machine-learning-based prediction of the effectiveness of the delivered dose by exhale-gated radiotherapy for locally advanced lung cancer: The additional value of geometric over dosimetric parameters alone.

Purpose: This study aimed to assess interfraction stability of the delivered dose distribution by exhale-gated volumetric modulated arc therapy (VMAT) or intensity-modulated arc therapy (IMAT) for lung cancer and to determine dominant prognostic dosimetric and geometric factors. Methods: Clinical target volume (CTVPlan) from the planning CT was deformed to the exhale-gated daily CBCT scans to determine CTVi, treated by the respective dose fraction. The equivalent uniform dose of the CTVi was determined by the power law (gEUDi) and cell survival model (EUDiSF) as effectiveness measure for the delivered dose distribution. The following prognostic factors were analyzed: (I) minimum dose within the CTVi (Dmin_i), (II) Hausdorff distance (HDDi) between CTVi and CTVPlan, (III) doses and deformations at the point in CTVPlan at which the global minimum dose over all fractions per patient occurs (PDmin_global_i), and (IV) deformations at the point over all CTVi margins per patient with the largest Hausdorff distance (HDPworst). Prognostic value and generalizability of the prognostic factors were examined using cross-validated random forest or multilayer perceptron neural network (MLP) classifiers. Dose accumulation was performed using back deformation of the dose distribution from CTVi to CTVPlan. Results: Altogether, 218 dose fractions (10 patients) were evaluated. There was a significant interpatient heterogeneity between the distributions of the normalized gEUDi values (p<0.0001, Kruskal-Wallis tests). Accumulated gEUD over all fractions per patient was 1.004-1.023 times of the prescribed dose. Accumulation led to tolerance of ~20% of fractions with gEUDi <93% of the prescribed dose. Normalized Dmin >60% was associated with predicted gEUD values above 95%. Dmin had the highest importance for predicting the gEUD over all analyzed prognostic parameters by out-of-bag loss reduction using the random forest procedure. Cross-validated random forest classifier based on Dmin as the sole input had the largest Pearson correlation coefficient (R=0.897) in comparison to classifiers using additional input variables. The neural network performed better than the random forest classifier, and the gEUD values predicted by the MLP classifier with Dmin as the sole input were correlated with the gEUD values characterized by R=0.933 (95% CI, 0.913-0.948). The performance of the full MLP model with all geometric input parameters was slightly better (R=0.952) than that based on Dmin (p=0.0034, Z-test). Conclusion: Accumulated dose distributions over the treatment series were robust against interfraction CTV deformations using exhale gating and online image guidance. Dmin was the most important parameter for gEUD prediction for a single fraction. All other parameters did not lead to a markedly improved generalizable prediction. Dosimetric information, especially location and value of Dmin within the CTV i , are vital information for image-guided radiation treatment.

Feasibility, Method and Early Outcome of Image-Guided Volumetric Modulated Arc Radiosurgery Followed by Resection for AJCC Stage IIA-IIIB High-Risk Large Intraocular Melanoma.

The main objective of this prospective observational study was the characterization of the feasibility and early outcome of image-guided (IG) volumetric modulated arc (VMAT) radiosurgery (SRS) followed by resection for patients with large intraocular melanoma. Our study included consecutive patients with unfavorable-risk melanoma, enrolled in an ophthalmic oncology center. IG-VMAT-SRS was applied by high-resolution 4D image guidance and monitoring. Current stereotactic technique parameters were evaluated for comparison. Side effects and eye function, based on a 5-point CTC assessment score, were quantified. In patients with tumors located more than 0.7-1 mm apart from the optic nerve, partial to complete volume-sparing of the optic nerve head could be achieved. In 95.5% of this subgroup, the vitality of the optic nerve and vision could be preserved by the multimodality-treatment approach (mean follow-up: 18 months (7.5-36 months)). The advanced technology of stereotactic radiotherapy demonstrated the achievability of steep dose gradients around the high-dose volume, with 4D-IG-VMAT dose application. These results enforce IG-VMAT-SRS followed by resection as one of the major therapeutic options for patients with large intraocular melanoma. The combination of 4D-IG high-precision SRS and resection provides an effective treatment for large intraocular melanoma, with few side effects, and enables an eye bulb and even vision preserving modus operandi.

Accelerated radiotherapy and concurrent chemotherapy for patients with contralateral central or mediastinal lung cancer relapse after pneumonectomy.

BACKGROUND: Treatment options are very limited for patients with lung cancer who experience contralateral central or mediastinal relapse following pneumonectomy. We present results of an accelerated salvage chemoradiotherapy regimen. METHODS: Patients with localized contralateral central intrapulmonary or mediastinal relapse after pneumonectomy were offered combined chemoradiotherapy including concurrent weekly cisplatin (25 mg/m(2)) and accelerated radiotherapy [accelerated fractionated (AF), 60 Gy, 8×2 Gy per week] to reduce time for repopulation. Based on 4D-CT-planning, patients were irradiated using multifield intensity-modulated radiotherapy (IMRT) or helical tomotherapy. RESULTS: Between 10/2011 and 12/2012, seven patients were treated. Initial stages were IIB/IIIA/IIIB: 3/1/3; histopathological subtypes scc/adeno/large cell: 4/1/2. Tumour relapses were located in mediastinal nodal stations in five patients with endobronchial tumour in three patients. The remaining patients had contralateral central tumour relapses. All patients received 60 Gy (AF), six patients received concurrent chemotherapy. Median dose to the remaining contralateral lung, esophagus, and spinal cord was 6.8 (3.3-11.4), 8.0 (5.1-15.5), and 7.6 (2.8-31.2) Gy, respectively. With a median follow-up of 29 [17-32] months, no esophageal or pulmonary toxicity exceeding grade 2 [Common terminology criteria for adverse events (CTC-AE) v. 3] was observed. Median survival was 17.2 months, local in-field control at 12 months 80%. Only two local recurrences were observed, both in combination with out-field metastases. CONCLUSIONS: This intensified accelerated chemoradiotherapy schedule was safely applicable and offers a curative chance in these pretreated frail lung cancer patients.

Helical tomotherapy for whole-brain irradiation with integrated boost to multiple brain metastases: evaluation of dose distribution characteristics and comparison with alternative techniques.

PURPOSE: To quantitatively evaluate dose distribution characteristics achieved with helical tomotherapy (HT) for whole-brain irradiation (WBRT) with integrated boost (IB) to multiple brain metastases in comparison with alternative techniques. METHODS AND MATERIALS: Dose distributions for 23 patients with 81 metastases treated with WBRT (30 Gy/10 fractions) and IB (50 Gy) were analyzed. The median number of metastases per patient (N(mets)) was 3 (range, 2-8). Mean values of the composite planning target volume of all metastases per patient (PTV(mets)) and of the individual metastasis planning target volume (PTV(ind met)) were 8.7 ± 8.9 cm(3) (range, 1.3-35.5 cm(3)) and 2.5 ± 4.5 cm(3) (range, 0.19-24.7 cm(3)), respectively. Dose distributions in PTV(mets) and PTV(ind met) were evaluated with respect to dose conformity (conformation number [CN], RTOG conformity index [PITV]), target coverage (TC), and homogeneity (homogeneity index [HI], ratio of maximum dose to prescription dose [MDPD]). The dependence of dose conformity on target size and N(mets) was investigated. The dose distribution characteristics were benchmarked against alternative irradiation techniques identified in a systematic literature review. RESULTS: Mean ± standard deviation of dose distribution characteristics derived for PTV(mets) amounted to CN = 0.790 ± 0.101, PITV = 1.161 ± 0.154, TC = 0.95 ± 0.01, HI = 0.142 ± 0.022, and MDPD = 1.147 ± 0.029, respectively, demonstrating high dose conformity with acceptable homogeneity. Corresponding numbers for PTV(ind met) were CN = 0.708 ± 0.128, PITV = 1.174 ± 0.237, TC = 0.90 ± 0.10, HI = 0.140 ± 0.027, and MDPD = 1.129 ± 0.030, respectively. The target size had a statistically significant influence on dose conformity to PTV(mets) (CN = 0.737 for PTV(mets) ≤4.32 cm(3) vs CN = 0.848 for PTV(mets) >4.32 cm(3), P=.006), in contrast to N(mets). The achieved dose conformity to PTV(mets), assessed by both CN and PITV, was in all investigated volume strata well within the best quartile of the values reported for alternative irradiation techniques. CONCLUSIONS: HT is a well-suited technique to deliver WBRT with IB to multiple brain metastases, yielding high-quality dose distributions. A multi-institutional prospective randomized phase 2 clinical trial to exploit efficacy and safety of the treatment concept is currently under way.

Potentials of robust intensity modulated scanning proton plans for locally advanced lung cancer in comparison to intensity modulated photon plans.

BACKGROUND AND PURPOSE: The potentials of lung sparing, dose escalation, and the robustness of intensity modulated proton plans (IMPT(robust)), obtained by minimax optimization on multiple scenarios, were studied. MATERIALS AND METHODS: IMPT(robust) optimization as described by Fredriksson et al. [23] was evaluated by means of comparative treatment planning using breath hold CT data from 6 non-small cell lung cancer (NSCLC) patients. IMPT(robust) and single field uniform dose (SFUD) proton plans were compared to Tomotherapy and 7-field intensity modulated photon therapy (IMXT). Plan robustness against set-up errors, range uncertainties, and between field motions were analyzed as well as lung exposure quantified by the mean lung dose (MLD) and the partial lung volumes receiving at least 20, 10, and 5 Gy(RBE) (V20, V10, V5). Robustness was analyzed with regard to stability of the effective uniform dose (EUD) and the dose level reached or exceeded in 95% of the CTV (D95). RESULTS: MLD by IMPT(robust) was less than by SFUD, and Tomotherapy in each patient, on average by 14.8% and 28.5% (p<0.05, Friedman test). V20-V5 were higher with Tomotherapy compared to both proton therapy techniques, on average by a factor of >1.8. Robustness of IMPT(robust) was high. EUD and D95 values were maintained above 96% and 94% of the reference plan values for all tested scenarios. With dose escalation to 86 Gy(RBE) lung tissue tolerances were maintained. CONCLUSIONS: IMPT(robust) proved advantageous in terms of lung exposure and possible dose escalation while being also markedly robust. However, motion during delivery of a field remains a major problem of IMPT(robust) to be mitigated by high scanning speed and variable spot size.