Incidence of Strabismus Post-Plaque Brachytherapy in Patients With Uveal Melanoma.

PURPOSE: To determine the incidence and type of strabismus in patients with uveal melanoma treated with plaque brachytherapy. DESIGN: Multicenter, retrospective incidence estimation study. METHODS: A total of 438 eyes of 438 patients with uveal melanoma treated with plaque brachytherapy between October 2011 and May 2021. Intervention was Iodine 125, and Palladium 103 plaque brachytherapy. The variables reviewed included incidence of nonresolving strabismus post-plaque brachytherapy, type of strabismus developed, extraocular muscles operated, and modality of treatment received. RESULTS: A total of 438 patients underwent plaque brachytherapy treatment for uveal melanoma. Eleven patients developed strabismus post-plaque brachytherapy (2.5%, n = 11/438). Of these patients, 5 (1.1%, n = 5/438) developed strabismus immediately postoperation. Specifically, 2 patients (0.5%, n = 2/438) developed strabismus immediately postoperation due to slipped muscles, 2 patients (0.5%, n = 2/438) due to decompensated phorias, and 1 patient (0.5%, n = 1/438) due to a fibrotic muscle. Six patients (1.4%, n = 6/438) developed late-onset sensory strabismus. A total of 355 patients (81.1%, n = 355/438) had their extraocular muscles disinserted during surgery, with the lateral rectus being the most common, accounting for 45.4% (n = 161/355), followed by the superior rectus at 26.8% (n = 95/355). Strabismus surgery was the most common treatment modality, comprising 72.7% (n = 8/11) of patients. CONCLUSIONS: The incidence of strabismus after plaque brachytherapy treatment for uveal melanoma was low and primarily classified as late-onset sensory strabismus. Previous studies may underestimate the long-term incidence of strabismus after plaque brachytherapy by focusing primarily on strabismus present immediately postoperatively.

Management of Uveal Melanoma: Updated Cancer Care Alberta Clinical Practice Guideline.

OBJECTIVE: The purpose of this guideline update is to reassess and update recommendations in the prior guideline from 2016 on the appropriate management of patients with uveal melanoma. METHODS: In 2021, a multidisciplinary working group from the Provincial Cutaneous Tumour Team, Cancer Care Alberta, Alberta Health Services was convened to update the guideline. A comprehensive review of new research evidence in PubMed as well as new clinical practice guidelines from prominent oncology groups informed the update. An enhancement in methodology included adding levels of evidence and strength of recommendations. The updated guideline was circulated to all members of the Provincial Cutaneous Tumour Team for review and endorsement. RESULTS: New and modified recommendations address provider training requirements, diagnostic imaging for the detection of metastases, neo-adjuvant pre-enucleation radiotherapy, intravitreal anti-vascular endothelial growth factor agents for radiation retinopathy, genetic prognostic testing, surveillance following definitive local therapy, and systemic therapy for patients with metastatic uveal melanoma. DISCUSSION: The recommendations represent evidence-based standards of care agreed to by a large multidisciplinary group of healthcare professionals.

Optimising prediction of early metastasis-free survival in uveal melanoma using a four-category model incorporating gene expression profile and tumour size.

BACKGROUND: Largest basal diameter (LBD) appears to have independent prognostic value in uveal melanoma (UM). METHODS: All patients undergoing plaque brachytherapy or enucleation for UM involving the choroid and/or ciliary body between 2012 and 2019. RESULTS: A total of 348 patients with a mean age of 60±14 years were included and followed for a mean of 40±26 months (3.3±2.2 years). On multivariate analysis, LBD >12 mm remained a significant independent predictor of metastasis for both class 1 (HR 21.90; 95% CI 2.69 to 178.02; p=0.004) and class 2 (HR 2.45; 95% CI, 1.03 to 5.83; p=0.04) tumours. Four prognostic groups were created: group 1 (class 1, LBD <12 mm), group 2 (class 1, LBD ≥12 mm), group 3 (class 2, LBD <12 mm) and group 4 (class 2, LBD ≥12 mm). Life tables were used to calculate the 3-year and 5-year metastasis-free survival: group 1 (98 and 98%), group 2 (86 and 86%), group 3 (81 and 62%) and group 4 (54 and 47%). Compared with the reference category (group 1), the Cox proportional hazard model demonstrated a significant worsening of survival for each progressive category (group 2 (HR 21.59; p=0.004), group 3 (HR 47.12, p<0.001), and group 4 (HR 114.24; p<0.001)). In our dataset, the four-category Cox model performed poorer compared with the American Joint Committee on Cancer (AJCC) and gene expression profile (AJCC+GEP) in the Akaike's information criteria (AIC) (297 vs 291), fit better with the Bayesian information criteria (BIC) (309 vs 313) and performed similarly with the Harrel's C (0.86 (95% CI 0.80 to 0.91) vs 0.89 (0.84 to 0.94), respectively). CONCLUSIONS: Combination of GEP and LBD allows separation of patients into four easy-to-use prognostic groups and was similar to a model combining AJCC stage with GEP.

Automatic optimization of treatment dosimetry to improve visual outcomes in episcleral plaque brachytherapy.

PURPOSE: The aim of this study was to develop an automated dose optimization algorithm, powered by simulated annealing, for inverse planning of ocular plaque brachytherapy treatments, to improve tumor coverage and critical structure sparing for reduced treatment-related morbidity. METHODS AND MATERIALS: A simulated annealing based algorithm was built and evaluated by finding variable seed strengths that maximized dose uniformity across tumor base for model cases of various tumor heights and plaque sizes. This problem assessed its potential to find the minima in the energy function using differential loading. The algorithm was further developed to decrease doses to critical structures while maintaining desired tumor coverage. Doses to the optic disc and fovea were compared to those using uniform seed strengths for various model cases. Finally, 10 retrospective patient cases treated with uniform seed strengths were replanned with the developed algorithm to evaluate effectiveness for clinical application. RESULTS: The developed algorithm achieved dose reductions of up to 37.3% and 39.6% to the optic disc and fovea, respectively, compared to those using uniform seed strengths, depending on the tumor and plaque size used for the model cases. Applying the algorithm to 10 clinical scenarios resulted in dose reductions of 14% to the optic disc and fovea relative to clinical treatments performed with uniform seed strengths. CONCLUSIONS: The developed automatic dose optimization routine was able to achieve significant dose reductions to the critical structures relative to using uniformly loaded plaques both in the model and in the clinical cases.

Comparison of dose statistics for bladder wall and rectum wall vs whole organs for VMAT prostate treatment.

Dose-wall histograms (DWHs) have been used as alternatives to dose-volume histograms (DVHs) for hollow organs, with the rationale that the dose delivered to the interior of a hollow organ would be unrelated to the level of radiation damage. The purpose of this study is to conduct a statistical comparison of dose statistics for both walled and solid structure contours for both bladder and rectum in the treatment of intermediate risk prostate cancer with volumetric arc therapy (VMAT). Ten intermediate risk prostate cases were randomly selected. Rectum and bladder were first contoured as solid structures, and then the corresponding wall structures were generated using either a slice-by-slice cropping (2D method), or with a full 3D cropping tool (3D method). Each case was then inverse planned using a 2-arc VMAT technique. Two plans per case were created, 1 with a hypofractionated treatment and 1 with a standard fractionated treatment. DVHs were calculated for solid structure contours, and DWHs were calculated for the walled structure contours generated using 2D and 3D contouring tools. A nonparametric Spearman statistic correlation test was used to compare a large number of relevant dose histogram points, and to establish the relationship between dose statistics for walled and solid structures. Several notable relationships were observed. Maximum rectal dose was strongly correlated between the solid structure and both the 2D-generated (Spearman's correlation rs = 0.988, p < 0.01) and 3D-generated (rs = 0.952 p< 0.01) wall structures. This indicates that the rectal hot spot occurred in or near the wall for all cases, suggesting that both structure types give similar maximum dose information for rectum. Maximum bladder dose was not significantly correlated between solid structures and the 2D (rs = 0.596, p= 0.069) and 3D-generated (rs = 0.681, p= 0.03) counterparts. This suggests that the maximum dose is not consistently in or near the bladder wall. This favors the use of bladder wall contours when considering bladder toxicity, with the maximum dose to the wall potentially being more relevant radiobiologically. This analysis was extended to many other relevant points on the rectum and bladder histogram curves. Where correlations are strong, equations of best-fit are presented. This work establishes several statistically-significant relationships between bladder and rectum DVHs and DWHs for VMAT irradiation of intermediate-risk prostate cancer. This information may be used to inform contouring requirements for clinical trial design as well as for standard patient care.

Delivered dose changes in COMS plaque-based ocular brachytherapy arising from vitrectomy with silicone oil replacement.

PURPOSE: The purpose of the study was to determine dosimetric effects of performing concurrent I-125 Collaborative Ocular Melanoma Study plaque brachytherapy and vitrectomy with replacement using silicone oil, previously shown to be a means of shielding uninvolved parts of the eye. METHODS AND MATERIALS: Monte Carlo simulations using MCNP6 were performed to compare the dosimetry with all eye materials assigned as water, and for the vitreous (excluding the tumor), composed of polydimethylsiloxane oil for three generic, one large tumor, and two patient geometry scenarios. Dose was scored at the tumor apex, along the sclera, and within a 3D grid encompassing the eye. The assessed patient cases included vitrectomies to treat intraocular pathologies; not to enhance attenuation/shielding. RESULTS: The doses along the sclera and for the entire eye were decreased when the silicone oil replaced the vitreal fluid, with a maximum decrease at the opposite sclera of 63%. Yet, absolute changes in dose to critical structures were often small and likely not clinically significant. The dose at the tumor apex was decreased by 3.1-9.4%. Dose was also decreased at the edges of the tumor because of decreased backscatter at the tumor-oil interface. CONCLUSIONS: Concurrent silicone vitrectomy was found to reduce total radiation dose to the eye. Based on current radiation retinopathy predictive models, the evaluation of the absolute doses revealed only a subset of patients in which a clinically significant difference in outcomes is expected. Furthermore, the presence of the silicone oil decreased dose to the tumor edges, indicating that the tumor could be underdosed if the oil is unaccounted for.

Gene Expression Profiling as an Adjunctive Measure to Guide the Management of Indeterminate, High-Risk Choroidal Melanocytic Lesions: A Pilot Study.

PURPOSE: To describe our early experience with gene expression profiling (GEP) assessment for juxtafoveal, subfoveal, and peripapillary indeterminate high-risk melanocytic lesions to assist in making early treatment decisions in patients who did not feel comfortable with either close observation or definitive treatment. METHODS: A prospective cohort of patients with indeterminate lesions who underwent GEP were enrolled. Nonparametric statistical analysis was utilized given the small sample size. RESULTS: Fifteen patients were included in this series. Six (40%) were class 1A and 9 (60%) class 1B. Class 1A and 1B lesions had a median of three and four clinical risk factors, respectively (p = 0.27). There was no statistically significant difference for the largest basal diameter between the classes (p = 0.31); however, class 1B lesions were thicker than class 1A lesions (p = 0.03). None of the class 1A lesions showed definite growth or metastasis over a mean follow-up period of 17.1 ± 1.8 months from fine needle aspiration biopsy. All class 1B patients opted for plaque brachytherapy, and to date none of these patients have developed metastasis, with a mean follow-up of 18.7 ± 8.4 months. CONCLUSION: There may be a role for GEP assessment in high-risk, indeterminate, posteriorly located choroidal lesions to assist in treatment planning.

The Use of Intravitreal Anti-VEGF and Triamcinolone in the Treatment of Radiation Papillopathy.

BACKGROUND/AIMS: To evaluate a treatment regimen for radiation papillopathy. METHODS: This is a prospective noncomparative interventional case series of patients who developed radiation papillopathy after plaque brachytherapy for uveal melanoma. Treatment consisted of intravitreal bevacizumab (IVB) (1.25 mg in 0.05 mL) at the time of diagnosis, and 1 week later, intravitreal triamcinolone (IVK) (2.00 mg in 0.05 mL). One month later, patients again received both IVB and IVK. Patients were then switched to monotherapy with monthly IVB until the papillopathy resolved. RESULTS: Eleven patients developed radiation papillopathy, with 9 receiving treatment. On multivariate analysis, total radiation dose to the optic nerve was the only significant predictor of papillopathy (p = 0.005). Four of nine patients presented with a significant decline in visual acuity (VA) at the time of diagnosis of papillopathy. In all 4, significant improvement was documented following treatment. Five patients did not present with a decrease in VA, and in this group, 80% remained stable with treatment. CONCLUSIONS: In this series, patients who had a precipitous drop in VA at the time of diagnosis of radiation papillopathy returned to baseline VA following this treatment algorithm. This protocol was effective at maintaining stability of VA in 80% of those who developed papillopathy but did not present with an acute drop in VA.

Advanced Collapsed cone Engine dose calculations in tissue media for COMS eye plaques loaded with I-125 seeds.

PURPOSE: To investigate the dose calculation accuracy of the Advanced Collapsed cone Engine (ACE) algorithm for ocular brachytherapy using a COMS plaque loaded with I-125 seeds for two heterogeneous patient tissue scenarios. METHODS: The Oncura model 6711 I-125 seed and 16 mm COMS plaque were added to a research version (v4.6) of the Oncentra® Brachy (OcB) treatment planning system (TPS) for dose calculations using ACE. Treatment plans were created for two heterogeneous cases: (a) a voxelized eye phantom comprising realistic eye materials and densities and (b) a patient CT dataset with variable densities throughout the dataset. ACE dose calculations were performed using a high accuracy mode, high-resolution calculation grid matching the imported CT datasets (0.5 × 0.5 × 0.5 mm3 ), and a user-defined CT calibration curve. The accuracy of ACE was evaluated by replicating the plan geometries and comparing to Monte Carlo (MC) calculated doses obtained using MCNP6. The effects of the heterogeneous patient tissues on the dose distributions were also evaluated by performing the ACE and MCNP6 calculations for the same scenarios but setting all tissues and air to water. RESULTS: Average local percent dose differences between ACE and MC within contoured structures and at points of interest for both scenarios ranged from 1.2% to 20.9%, and along the plaque central axis (CAX) from 0.7% to 7.8%. The largest differences occurred in the plaque penumbra (up to 17%), and at contoured structure interfaces (up to 20%). Other regions in the eye agreed more closely, within the uncertainties of ACE dose calculations (~5%). Compared to that, dose differences between water-based and fully heterogeneous tissue simulations were up to 27%. CONCLUSIONS: Overall, ACE dosimetry agreed well with MC in the tumor volume and along the plaque CAX for the two heterogeneous tissue scenarios, indicating that ACE could potentially be used for clinical ocular brachytherapy dosimetry. In general, ACE data matched the fully heterogeneous MC data more closely than water-based data, even in regions where the ACE accuracy was relatively low. However, depending on the plaque position, doses to critical structures near the plaque penumbra or at tissue interfaces were less accurate, indicating that improvements may be necessary. More extensive knowledge of eye tissue compositions is still required.

Initial evaluation of Advanced Collapsed cone Engine dose calculations in water medium for I-125 seeds and COMS eye plaques.

PURPOSE: To investigate the dose calculation accuracy in water medium of the Advanced Collapsed cone Engine (ACE) for three sizes of COMS eye plaques loaded with low-energy I-125 seeds. METHODS: A model of the Oncura 6711 I-125 seed was created for use with ACE in Oncentra® Brachy (OcB) using primary-scatter separated (PSS) point dose kernel and Task Group (TG) 43 datasets. COMS eye plaque models of diameters 12, 16, and 20 mm were introduced into the OcB applicator library based on 3D CAD drawings of the plaques and Silastic inserts. To perform TG-186 level 1 commissioning, treatment plans were created in OcB for a single source in water and for each COMS plaque in water for two scenarios: with only one centrally loaded seed, or with all seed positions loaded. ACE dose calculations were performed in high accuracy mode with a 0.5 × 0.5 × 0.5 mm3 calculation grid. The resulting dose data were evaluated against Monte Carlo (MC) calculated doses obtained with MCNP6, using both local and global percent differences. RESULTS: ACE doses around the source for the single seed in water agreed with MC doses on average within < 5% inside a 6 × 6 × 6 cm3 region, and within < 1.5% inside a 2 × 2 × 2 cm3 region. The PSS data were generated at a higher resolution within 2 cm from the source, resulting in this improved agreement closer to the source due to fewer approximations in the ACE dose calculation. Average differences in both investigated plaque loading patterns in front of the plaques and on the plaque central axes were ≤ 2.5%, though larger differences (up to 12%) were found near the plaque lip. CONCLUSIONS: Overall, good agreement was found between ACE and MC dose calculations for a single I-125 seed and in front of the COMS plaques in water. More complex scenarios need to be investigated to determine how well ACE handles heterogeneous patient materials.

Delivered dose uncertainty analysis at the tumor apex for ocular brachytherapy.

PURPOSE: To estimate the total dosimetric uncertainty at the tumor apex for ocular brachytherapy treatments delivered using 16 mm Collaborative Ocular Melanoma Study (COMS) and Super9 plaques loaded with (125)I seeds in order to determine the size of the apex margin that would be required to ensure adequate dosimetric coverage of the tumor. METHODS: The total dosimetric uncertainty was assessed for three reference tumor heights: 3, 5, and 10 mm, using the Guide to the expression of Uncertainty in Measurement/National Institute of Standards and Technology approach. Uncertainties pertaining to seed construction, source strength, plaque assembly, treatment planning calculations, tumor height measurement, plaque placement, and plaque tilt for a simple dome-shaped tumor were investigated and quantified to estimate the total dosimetric uncertainty at the tumor apex. Uncertainties in seed construction were determined using EBT3 Gafchromic film measurements around single seeds, plaque assembly uncertainties were determined using high resolution microCT scanning of loaded plaques to measure seed positions in the plaques, and all other uncertainties were determined from the previously published studies and recommended values. All dose calculations were performed using plaque simulator v5.7.6 ophthalmic treatment planning system with the inclusion of plaque heterogeneity corrections. RESULTS: The total dosimetric uncertainties at 3, 5, and 10 mm tumor heights for the 16 mm COMS plaque were 17.3%, 16.1%, and 14.2%, respectively, and for the Super9 plaque were 18.2%, 14.4%, and 13.1%, respectively (all values with coverage factor k = 2). The apex margins at 3, 5, and 10 mm tumor heights required to adequately account for these uncertainties were 1.3, 1.3, and 1.4 mm, respectively, for the 16 mm COMS plaque, and 1.8, 1.4, and 1.2 mm, respectively, for the Super9 plaque. These uncertainties and associated margins are dependent on the dose gradient at the given prescription depth, thus resulting in the changing uncertainties and margins with depth. CONCLUSIONS: The margins determined in this work can be used as a guide for determining an appropriate apex margin for a given treatment, which can be chosen based on the tumor height. The required margin may need to be increased for more complex scenarios (mushroom shaped tumors, tumors close to the optic nerve, oblique muscle related tilt, etc.) than the simple dome-shaped tumor examined and should be chosen on a case-by-case basis. The sources of uncertainty contributing most significantly to the total dosimetric uncertainty are seed placement within the plaques, treatment planning calculations, tumor height measurement, and plaque tilt. This work presents an uncertainty-based, rational approach to estimating an appropriate apex margin.

ADC response to radiation therapy correlates with induced changes in radiosensitivity.

PURPOSE: Magnetic resonance imaging was used to compare the responses of human glioma tumor xenografts to a single fraction of radiation, where a change in radiosensitivity was induced by use of a suture-based ligature. METHODS: Ischemia was induced by use of a suture-based ligature. Six mice were treated with 800 cGy of 200 kVp x rays while the ligature was applied. An additional six mice had the ligature applied for the same length of time but were not irradiated. Quantitative maps of each tumor were produced of water apparent diffusion coefficient (ADC) and transverse relaxation time (T2). Mice were imaged before and at multiple points after treatment. Volumetric, ADC, and T2 responses of the ligated groups were compared to previously measured responses of the same tumor model to the same radiation treatment, as well as those from an untreated control group. RESULTS: Application of the ligature without irradiation did not affect tumor ADC values, but did produce a temporary decrease in tumor T2 values. Average tumor T2 was reduced by 6.2% 24 h after the ligature was applied. Average tumor ADC increased by 9.6% 7 days after irradiation with a ligature applied. This response was significantly less than that observed in the same tumor model when no ligature is present (21.8% at 7 days after irradiation). CONCLUSIONS: These observations indicate that the response of ADC to radiation therapy is not determined entirely by physical dose deposition, but at least in part by radiosensitivity and resultant biological response.

Monitoring T2 and ADC at 9.4 T following fractionated external beam radiation therapy in a mouse model.

The purpose of this study is to investigate the response of transverse relaxation time (T2) and apparent diffusion coefficient (ADC) in human glioma tumor xenografts during and after fractionated radiotherapy. Tumor-bearing mice were divided into four treatment groups (n=6 per group) that received a total dose of 800 cGy of 200 kVp x-rays, given over two or three fractions, with a fraction spacing of either 24 or 72 h. A fifth treatment group received 800 cGy in a single fraction, and a sixth group of mice served as an untreated control. All mice were scanned pretreatment, before each fraction and at multiple points after treatment using a 9.4 T magnetic resonance imaging (MRI) system. Quantitative T2 and ADC maps were produced. All treated groups showed an increase in mean tumor ADC, though the time for this response to reach a maximum and return toward baseline was delayed in the fractionated groups. The highest ADC was measured 7 days after the final fraction of treatment for all groups. There were no significant differences in the maximum measured change in ADC between any of the treated groups, with the average measured maximum value being 20.5% above baseline. After treatment, all groups showed an increase in mean tumor T2, with the average measured maximum T2 being 4.7% above baseline. This increase was followed by a transition to mean T2 values below baseline values, with the average measured tumor T2 being 92.4% of the pretreatment value. The transition between elevated and depressed T2 values was delayed in the cases of fractionated therapies and occurred between 3.6 and 7.3 days after the last fraction of treatment. These results further the understanding of the temporal evolution of T2 and ADC during fractionated radiotherapy and support their potential use as time-sensitive biomarkers for tumor response.

Temporal and dose dependence of T2 and ADC at 9.4 T in a mouse model following single fraction radiation therapy.

The purpose of this study is to use magnetic resonance imaging to monitor the response of human glioma tumor xenografts to single fraction radiation therapy. Mice were divided into four treatment groups (n = 6 per group) that received 50, 200, 400, or 800 cGy of 200 kVp x rays. A fifth group (n = 6) received no radiation dose and served as the control. Quantitative maps of the treated tumor tissue were produced of water apparent diffusion coefficient (ADC) and transverse relaxation time (T2). Mice were imaged before and at multiple time points after treatment. There was a statistically significant difference in tumor growth relative to that of the control for all treatment groups. Only the highest dose group showed T2 values that were significantly different at all measured time points after treatment. In this group, there was an 8.3% increase in T2 relative to controls 2 days after treatment, but when measured 14 days after treatment, mean tumor T2 had dropped to 10.1% below the initial value. ADC showed statistically significant differences from the control at all dose points. A radiation dose dependence was observed. In the highest dose group, the fractional increases in ADC were higher than those observed for T2. ADC was sensitive to radiation-induced changes in lower dose groups that did not have significant T2 change. At all doses, elevation of mean tumor ADC preceded deviations in tumor growth from the control. These observations support the potential application of ADC as a time and dose sensitive marker of tumor response to radiation therapy.