Nolan L. Gagne

A 17-year retrospective study of institutional results for eye plaque brachytherapy of uveal melanoma using 125I, 103Pd, and 131Cs and historical perspective

PURPOSE To compare overall survival, local and distant failure rates, ocular toxicity, and vision preservation in patients treated with eye plaque brachytherapy at Tufts Medical Center with those in the published literature. METHODS AND MATERIALS Records were reviewed for 53 patients with the diagnosis of uveal melanoma treated with plaque brachytherapy at Tufts Medical Center over the past 17 years. American Joint Committee on Cancer staging (T1, T2, or T3) were 4, 39, and 10 patients, respectively. All the patients were treated using (125)I (n=37), (103)Pd (n=5), or (131)Cs (n=11) to a dose of 85Gy (documented as 100Gy before 1996 for the same physical dose). RESULTS With a mean followup of 75 months, 38 of 53 patients were still alive. Five patients (all (125)I) developed liver metastases (9%) with no evidence of local failure. There were 10 definitive local failures and four additional transpupillary thermo-therapy procedures performed to ensure local control for lesions slow to respond. Twelve patients (23%) required enucleation. At most recent followup, 32 patients (71%) maintained 20/200 vision or better in the treated eye. In this first report of (131)Cs plaque therapy with a mean followup of 20 months, there were two transpupillary thermo-therapy procedures and one definitive failure requiring enucleation after 10 months. CONCLUSIONS Our disease control and ocular results were comparable to those in the literature given the extended followup. We are developing a multi-institutional, prospective clinical protocol for considering radionuclide selection and other prescriptive criteria.

Radiobiology for eye plaque brachytherapy and evaluation of implant duration and radionuclide choice using an objective function

PURPOSE Clinical optimization of Collaborative Ocular Melanoma Study (COMS) eye plaque brachytherapy is currently limited to tumor coverage, consensus prescription dosage, and dose calculations to ocular structures. The biologically effective dose (BED) of temporary brachytherapy treatments is a function of both chosen radionuclide R and implant duration T. This study endeavored to evaluate BED delivered to the tumor volume and surrounding ocular structures as a function of plaque position P, prescription dose, R, and T. METHODS Plaque-heterogeneity-corrected dose distributions were generated with MCNP5 for the range of currently available COMS plaques loaded with sources using three available low-energy radionuclides. These physical dose distributions were imported into the PINNACLE(3) treatment planning system using the TG-43 hybrid technique and used to generate dose volume histograms for a T = 7 day implant within a reference eye geometry including the ciliary body, cornea, eyelid, foveola, lacrimal gland, lens, optic disc, optic nerve, retina, and tumor at eight standard treatment positions. The equation of Dale and Jones was employed to create biologically effective dose volume histograms (BEDVHs), allowing for BED volumetric analysis of all ROIs. Isobiologically effective prescription doses were calculated for T = 5 days down to 0.01 days, with BEDVHs subsequently generated for all ROIs using correspondingly reduced prescription doses. Objective functions were created to evaluate the BEDVHs as a function of R and T. These objective functions are mathematically accessible and sufficiently general to be applied to temporary or permanent brachytherapy implants for a variety of disease sites. RESULTS Reducing T from 7 to 0.01 days for a 10 mm plaque produced an average BED benefit of 26%, 20%, and 17% for (103)Pd, (125)I, and (131)Cs, respectively, for all P; 16 and 22 mm plaque results were more position-dependent. (103)Pd produced a 16%-35% BED benefit over (125)I, whereas (131)Cs produced a 3%-7% BED detriment, independent of P, T, and plaque size. Additionally, corresponding organ at risk physical doses were lowest using (103)Pd in all circumstances. CONCLUSIONS The results suggest that shorter implant durations may correlate with more favorable outcomes compared to 7 day implants when treating small or medium intraocular lesions. The data also indicate that implant duration may be safely reduced if the prescription physical dose is likewise diminished and that (103)Pd offers a substantial radiobiological benefit over (125)I and (131)Cs irrespective of plaque position, implant duration, and tumor size.

BEDVH--A method for evaluating biologically effective dose volume histograms: Application to eye plaque brachytherapy implants

PURPOSE A method is introduced to examine the influence of implant duration T, radionuclide, and radiobiological parameters on the biologically effective dose (BED) throughout the entire volume of regions of interest for episcleral brachytherapy using available radionuclides. This method is employed to evaluate a particular eye plaque brachytherapy implant in a radiobiological context. METHODS A reference eye geometry and 16 mm COMS eye plaque loaded with (103)Pd, (125)I, or (131)Cs sources were examined with dose distributions accounting for plaque heterogeneities. For a standardized 7 day implant, doses to 90% of the tumor volume ( (TUMOR)D(90)) and 10% of the organ at risk volumes ( (OAR)D(10)) were calculated. The BED equation from Dale and Jones and published α/β and μ parameters were incorporated with dose volume histograms (DVHs) for various T values such as T = 7 days (i.e.,  (TUMOR) (7)BED(10) and  (OAR) (7)BED(10)). By calculating BED throughout the volumes, biologically effective dose volume histograms (BEDVHs) were developed for tumor and OARs. Influence of T, radionuclide choice, and radiobiological parameters on  (TUMOR)BEDVH and  (OAR)BEDVH were examined. The nominal dose was scaled for shorter implants to achieve biological equivalence. RESULTS  (TUMOR)D(90) values were 102, 112, and 110 Gy for (103)Pd, (125)I, and (131)Cs, respectively. Corresponding  (TUMOR) (7)BED(10) values were 124, 140, and 138 Gy, respectively. As T decreased from 7 to 0.01 days, the isobiologically effective prescription dose decreased by a factor of three. As expected,  (TUMOR) (7)BEDVH did not significantly change as a function of radionuclide half-life but varied by 10% due to radionuclide dose distribution. Variations in reported radiobiological parameters caused  (TUMOR) (7)BED(10) to deviate by up to 46%. Over the range of (OAR)α/β values,  (OAR) (7)BED(10) varied by up to 41%, 3.1%, and 1.4% for the lens, optic nerve, and lacrimal gland, respectively. CONCLUSIONS BEDVH permits evaluation of the relative biological effectiveness for brachytherapy implants. For eye plaques,  (TUMOR)BEDVH and  (OAR)BEDVH were sensitive to implant duration, which may be manipulated to affect outcomes.

Brachytherapy vs. external beam radiotherapy for choroidal melanoma: Survival and patterns-of-care analyses.

PURPOSE No modern randomized trials exist comparing external beam radiotherapy (EBRT) and plaque brachytherapy (BT) for choroidal melanoma, and the optimal treatment modality is currently unknown. This study compares the patterns of care and efficacy of EBRT vs. BT based on data in the Surveillance, Epidemiology, and End Results database. METHODS AND MATERIALS The Surveillance, Epidemiology, and End Results database was queried for patients aged 20-79 diagnosed with choroidal melanoma from 2004 to 2011, treated with EBRT or BT; included patients were clinically T1-T4, N0, and M0. Overall survival and cause-specific survival curves were calculated by the Kaplan-Meier method. Univariate and multivariate analyses were performed in the survival and patterns-of-care analyses. RESULTS A total of 1004 cases (380 EBRT and 624 BT) were included in the survival analysis. There was no difference in the 5-year overall survival (83.3% EBRT vs. 82.5% BT, p = 0.69) and 5-year cause-specific survival (88.3% EBRT vs. 88.3% BT, p = 0.92). In the survival analysis, older age and advanced tumor stage were predictors of increased risk of death. In the patterns-of-care analysis, later year of diagnosis and smaller tumor stage were predictors of BT use. CONCLUSIONS Advanced tumor stage and older age seem to be independent predictors for risk of death from choroidal melanoma. The use of BT favors smaller tumors and later year of diagnosis. There is no difference in survival between those treated with EBRT or BT, and the utilization of BT is increasing.

Quantifying the dosimetric influences of radiation coverage and brachytherapy implant placement uncertainty on eye plaque size selection

PURPOSE Quantify the dosimetric adequacy of the 2003 American Brachytherapy Society report tumor margin recommendations for Collaborative Ocular Melanoma Study (COMS) eye plaque size selection for radiation coverage and clinical plaque placement uncertainties. METHODS AND MATERIALS Plaque heterogeneity-corrected dose distributions were generated for the range of available COMS plaque diameters (φplaque) and radionuclides. These dose distributions were used to determine the radiation dose distribution diameter (φ℞) at the eye surface for each plaque as a function of central axis prescription depth (d℞) to assess adequacy of a 2-3-mm margin for various gross tumor volume (GTV) basal diameters (φGTV). Four sets of ellipsoidal tumors (φGTV=5, 8, 11, and 14mm) with a range of apical heights (dGTV=2-8mm) were contoured in a reference CT environment. Plaque placement uncertainties were quantified as circumferential displacements (Δ) at the outer scleral surface. Tumor dose-volume histograms were generated and compared for all Δ with D90 and D95 used to evaluate tumor margin adequacy. RESULTS For equivalent φplaque and prescription depths, φ℞ values were typically 0.4-0.8mm less for (103)Pd than for (125)I or (131)Cs. Δ≤3mm resulted in D90 and D95 values as low as 68% and 64% of the prescription dose, respectively. (103)Pd plaque dose distributions were more sensitive than (125)I or (131)Cs to placement uncertainties. CONCLUSIONS The American Brachytherapy Society-recommended tumor margin may be inadequate for prescription dose coverage given COMS plaque radiation characteristics and placement uncertainties. Better coverage is achieved assuming a GTV-to-planning target volume total basal expansion of 3mm or greater and/or prescribing beyond the tumor apex.

Keeping an eye on the ring: COMS plaque loading optimization for improved dose conformity and homogeneity

PURPOSE To improve tumor dose conformity and homogeneity for COMS plaque brachytherapy by investigating the dosimetric effects of varying component source ring radionuclides and source strengths. MATERIAL AND METHODS The MCNP5 Monte Carlo (MC) radiation transport code was used to simulate plaque heterogeneity-corrected dose distributions for individually-activated source rings of 14, 16 and 18 mm diameter COMS plaques, populated with (103)Pd, (125)I and (131)Cs sources. Ellipsoidal tumors were contoured for each plaque size and MATLAB programming was developed to generate tumor dose distributions for all possible ring weighting and radionuclide permutations for a given plaque size and source strength resolution, assuming a 75 Gy apical prescription dose. These dose distributions were analyzed for conformity and homogeneity and compared to reference dose distributions from uniformly-loaded (125)I plaques. The most conformal and homogeneous dose distributions were reproduced within a reference eye environment to assess organ-at-risk (OAR) doses in the Pinnacle(3) treatment planning system (TPS). The gamma-index analysis method was used to quantitatively compare MC and TPS-generated dose distributions. RESULTS Concentrating > 97% of the total source strength in a single or pair of central (103)Pd seeds produced the most conformal dose distributions, with tumor basal doses a factor of 2-3 higher and OAR doses a factor of 2-3 lower than those of corresponding uniformly-loaded (125)I plaques. Concentrating 82-86% of the total source strength in peripherally-loaded (131)Cs seeds produced the most homogeneous dose distributions, with tumor basal doses 17-25% lower and OAR doses typically 20% higher than those of corresponding uniformly-loaded (125)I plaques. Gamma-index analysis found > 99% agreement between MC and TPS dose distributions. CONCLUSIONS A method was developed to select intra-plaque ring radionuclide compositions and source strengths to deliver more conformal and homogeneous tumor dose distributions than uniformly-loaded (125)I plaques. This method may support coordinated investigations of an appropriate clinical target for eye plaque brachytherapy.

COMS eye plaque brachytherapy dosimetric sensitivity to source photon energy and seed design.

This study explores the influence of source photon energy on eye plaque brachytherapy dose distributions for a 16 mm COMS plaque filled with (103)Pd, (125)I, or (131)Cs sources or monoenergetic photon emissions ranging from 12 keV to 100 keV. Dose distributions were similarly created for all permutations of three common brachytherapy seed designs. Within this range, sources with average energy ≤22 keV may reduce dose to the opposite eye wall by more than a factor of 2 while maintaining tolerable proximal sclera doses when prescribing to depths of 9 mm or less. Current commercially-available brachytherapy sources can exhibit up to 15% relative dosimetric sensitivity to seed design at regions within the eye.

SU‐E‐T‐459: Radiobiological Evaluation of Implant Duration and Radionuclide Selection for COMS Eye Plaque Brachytherapy Using an Objective Function

PURPOSE The biologically effective dose (BED) of temporary brachytherapy treatments is a function of both chosen radionuclide (R) and implant duration (T). This study endeavored to evaluate BED delivered to the tumor volume and surrounding ocular structures as a function of plaque position (P), prescription dose, R, and T. METHODS Plaque-heterogeneity- corrected dose distributions were generated with MCNP5 for the range of currently-available COMS plaques using low-energy radionuclides. These physical dose distributions were imported into the Pinnacle3 TPS using the TG-43 hybrid technique and used to generate DVHs for a T=7d implant within a reference eye geometry at eight standard treatment positions. The Dale equation was employed to create biologically effective dose volume histograms (BEDVHs), allowing for BED volumetric analysis of all ROIs. Isobiologically-effective prescription doses were calculated for T=5-0.01d, with BEDVHs subsequently generated for all ROIs using correspondingly reduced prescription doses. Objective functions were created to evaluate the BEDVHs as a function of R and T. RESULTS Reducing T from 7 to 0.01d for a 10mm plaque produced an average BED benefit of 26%, 20%, and 17% for 103 Pd, 125 I, and 131 Cs, respectively, for all P; 16mm and 22mm plaque results were more position-dependent. 103 Pd produced a 16-35% BED benefit over 125 I, whereas 131 Cs produced a 3-7% BED detriment, independent of P, T, and plaque size. Additionally, corresponding OAR physical doses were lowest using 103 Pd in all circumstances. CONCLUSIONS Shorter implant durations may correlate with more favorable outcomes vs. 7d implants for small and medium lesions. T may be safely reduced if the prescription dose is appropriately diminished. 103 Pd offers a substantial 16- 35% radiobiological benefit over 125 I and 131 Cs irrespective of P, T, and tumor size. The objective functions used in this study can be applied to temporary or permanent brachytherapy implants for a variety of disease sites.