Long-term outcomes of patients with conjunctival extranodal marginal zone lymphoma.

Comprehensive information on clinical features and long-term outcomes of primary conjunctival extranodal marginal zone lymphoma (PCEMZL) is scarce. We present a large single-institution retrospective study of 72 patients. The median age was 64 years, and 63.9% were female. Stage I was present in 87.5%. Radiation therapy (RT) alone was the most common treatment (70.8%). Complete response (CR) was 87.5%, and 100% in RT-treated patients. With a median follow-up of 6.7 years, relapse/progression and death occurred in 19.4% each, with one relapse within the RT field. The 10-year progression-free survival (PFS) and overall survival (OS) were 68.4% (95% CI 52.8%-79.8%) and 89.4% (95% CI 77.4%-95.2%), respectively. The 10-year rate for time to progression from diagnosis was 22.5% (95% CI 11.6%-35.7%). The 10-year PFS and OS of MALT-IPI 0 versus 1-2 were 83.3% versus 51.3%, (p = .022) and 97.6% versus 76.6%, (p = .0052), respectively. The following characteristics were associated with shorter survival: age > 60 years (PFS: HR = 2.93, 95% CI 1.08-7.95; p = .035, OS: HR = 9.07, 95% CI 1.17-70.26; p = .035) and MALT-IPI 1-2 (PFS: HR = 2.67, 95% CI 1.12-6.31; p = .027, OS: HR = 6.64, 95% CI 1.45-30.37; p = .015). CR following frontline therapy was associated with longer PFS (HR = 0.13, 95% CI 0.04-0.45; p = .001), but not OS. Using the Fine and Gray regression model with death without relapse/progression as a competing risk, RT and CR after frontline therapy were associated with lower risk of relapse (SHR = 0.34, 95% CI 0.12-0.96 p = .041 and SHR = 0.11, 95% CI 0.03-0.36; p < .001, respectively). Patients with PCEMZL treated with frontline RT exhibit excellent long-term survival, and the MALT-IPI score appropriately identifies patients at risk for treatment failure.

Predictors of Local Recurrence and Progression-Free Survival in Iodine-125 Brachytherapy-Treated Uveal Melanomas: A Modern Institutional Study.

Introduction: Iodine-125 brachytherapy is an effective eye-sparing treatment for uveal melanoma. Previous work has shown that uveal melanomas cluster into distinct molecular classes based on gene expression profiles - discriminating low-grade from high-grade tumors. Our objective was to identify clinical and molecular predictors of local recurrence (LR) and progression-free survival (PFS). Methods: We constructed a retrospective database of uveal melanoma patients from the University of Miami's electronic medical records that were treated between January 8, 2012, and January 5, 2019, with either COMS-style or Eye Physics plaque. Data on tumor characteristics, pretreatment retinal complications, post-plaque treatments, LR, and PFS were collected. Univariate and multivariate Cox models for cumulative incidence of LR and PFS were conducted using SAS version 9.4. Results: We identified 262 patients, with a median follow-up time of 33.5 months. Nineteen patients (7.3%) had LR, and 56 patients (21.4%) were classified as PFS. We found that ocular melanocytosis (hazard ratio = 5.55, p < 0.001) had the greatest impact on PFS. Genetic expression profile did not predict LR outcomes (hazard ratio = 0.51, p = 0.297). Conclusion: These findings help physicians identify predictors for short-term brachytherapy outcomes, allowing better shared decision making with patients preoperatively when deciding between brachytherapy versus enucleation. Patients stratified to higher risk groups based on preoperative characteristics such as ocular melanocytosis should be monitored more closely. Future studies must validate these findings using a prospective cohort study.

Dosimetric comparison of circular Eye Physics and Collaborative Ocular Melanoma Study plaques to treat uveal melanoma.

PURPOSE: We sought to formally compare Collaborative Ocular Melanoma Study (COMS) and similar-shaped (circular) eye physics (EP) plaques dosimetrically by examining both tumor coverage and critical structure doses. METHODS AND MATERIALS: The plans of patients with uveal melanoma treated consecutively with eye plaque brachytherapy at a single institution from January 2016 to December 2017 were reviewed. Both a COMS plan and an EP plan using plaques of the same shape were generated for each patient using the Isoaid Plaque Simulator software such that >90% of the tumor + 2 mm margin received 85 Gy over 72 hours from iodine-125 sources. Dose statistics were recorded and analyzed using standard statistical methods. RESULTS: Plans from a total of 62 patients were analyzed. The mean tumor volume was 0.46 cm3 (range: 0.02-2.02), and tumors were located on average 5.89 mm (range: 0-15.0) from the macula and 6.25 mm (range: 0-16.0) from the optic disc. All plans met the treatment planning criteria for tumor coverage and were optimized to reduce dose to the adjacent organs at risk. There were no significant differences in the mean doses to the fovea (mean difference [MD] = -0.87 Gy; 95% confidence interval [CI]: -4.90 to 3.16; p = 0.80), macula (MD = -1.02 Gy; 95% CI: -4.15 to 2.11; p = 0.65), or optic disc (MD = 1.07 Gy; 95% CI: -0.77 to 2.91; p = 0.34) between the COMS and circular EP plaques. CONCLUSIONS: Overall, neither the COMS plaques nor the circular EP plaques provided consistently superior dosimetry for the treatment of uveal melanoma. The choice of plaque may be based on other considerations such as cost and surgeon preference.

NRG oncology RTOG 9006: a phase III randomized trial of hyperfractionated radiotherapy (RT) and BCNU versus standard RT and BCNU for malignant glioma patients.

From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m2 of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1-3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p = 0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p = 0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p = 0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p = 0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p = 0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p = 0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.

Association of Radiomics and Metabolic Tumor Volumes in Radiation Treatment of Glioblastoma Multiforme.

PURPOSE: To build a framework for investigation of the associations between imaging, clinical target volumes (CTVs), and metabolic tumor volumes (MTVs) features for better understanding of the underlying information in the CTVs and dependencies between these volumes. High-throughput extraction of imaging and metabolomic quantitative features from magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging of glioblastoma multiforme (GBM) results in tens of variables per patient. In radiation therapy of GBM the relevant metabolic tumor volumes (MTVs) are related to aberrant levels of N-acetyl aspartate (NAA) and choline (Cho). The corresponding clinical target volumes (CTVs) for radiation therapy are based on contrast-enhanced T1-weighted (CE-T1w) and T2-weighted (T2w)/fluid-attenuated inversion recovery MRI. METHODS AND MATERIALS: Necrotic portions, enhancing lesion, and edema were manually contoured on CE-T1w/T2w images for 17 GBM patients. Clinical target volumes and MTVs for NAA (MTVNAA) and Cho (MTVCho) were constructed. Imaging and metabolic features related to size, shape, and signal intensities of the volumes were extracted. Tumors were also scored categorically for 10 semantic imaging traits by a neuroradiologist. All features were investigated for redundancy. Two-way correlations between imaging and CTVs/MTVs features were visualized as heatmaps. Associations between MTVNAA and MTVCho and imaging features were studied using Spearman correlation. RESULTS: Forty-eight imaging features were extracted per patient. Half of the imaging traits were replaced with automatically extracted continuous variables. Twenty features were extracted from CTVs and MTVs. A series of semantic imaging traits were replaced with automatically extracted continuous variables. There were multiple (22) significant correlations of imaging measures with CTVs/MTVNAA, whereas there were only 6 with CTVs/MTVCho. CONCLUSIONS: A framework for investigation of codependencies between MRI and magnetic resonance spectroscopic imaging radiomic features and CTVs/MTVs has been established. The MTV for NAA was found to be closely associated with MRI volumes, whereas very few imaging features were related to MTVCho, indicating that Cho provides additional information to imaging.

Spectral-domain optical coherence tomography evaluation of choroidal melanoma and nevus fine-needle aspiration biopsy incision sites.

The authors present three cases in which spectral-domain optical coherence tomography was used to identify fine-needle aspiration biopsy incision sites. These biopsies were performed to obtain tissue for gene expression profiling of choroidal tumors. A transvitreal route into the apex of the tumors was utilized for the biopsies while the patients underwent pars plana vitrectomy, membrane peel, laser ablation, phacoemulsification with posterior chamber intraocular lens implantation, and intravitreal triamcinolone acetonide. To the best of the authors' knowledge, this is the first report documenting fine-needle aspiration biopsy incision wound architecture of the posterior segment with optical coherence tomography.

Uveal melanoma gene expression status post radiotherapy.

PURPOSE: Gene expression profiling has been shown to yield two distinct molecular genetic signatures for uveal melanoma. These class designations tend to predict tumor aggressiveness and the likelihood of metastasis. Tumors with a class 1 genetic signature are generally much less aggressive than tumors with a class 2 genetic signature. Gene expression analysis for previously treated uveal melanoma has not yet been reported. The authors report three cases where genetic analysis was successfully obtained from uveal melanoma that was previously treated years earlier with radiotherapy. CASE REPORT: The patients in all three cases received globe-conserving radiotherapy for treatment of choroidal melanoma before gene expression profiling was readily available. The patients in cases 1 and 2 received 125I plaque brachytherapy while the patient in case 3 received proton irradiation therapy. When secondary surgery was necessary to stabilize these eyes from the effects of radiation retinopathy, fine-needle aspiration biopsy was also performed for gene expression profiling. Genomic analysis revealed a class 1 molecular signature for the patient in case 1 and a class 2 molecular signature for the patients in cases 2 and 3. CONCLUSIONS: Gene expression profiling for uveal melanoma may be obtained from patients who were previously treated with radiotherapy; however, the implication of these results will benefit from ongoing clinical evaluation.

Novel Use of Endoscopic Clips as Fiducials for Radiotherapy in Small Bowel Lymphoma.

A 31-year-old woman was diagnosed with duodenal grade 1 follicular lymphoma. The patient underwent radiotherapy and on surveillance enteroscopy, the lymphoma was persistently identified in the duodenum and jejunum. Endoscopic clips were used as fiducials to better localize the tumor during radiotherapy. Endoscopic clips are increasingly used as tumor localization tools because of their favorable risk-benefit ratio. In our case, endoscopic clipping was necessary to properly localize the tumor after prior treatment failure, and the patient now has no evidence of disease. Larger studies are needed to demonstrate the efficacy of clips in tumor localization and improved disease-related morbidity.

Microincisional vitrectomy for retinal detachment in I-125 brachytherapy-treated patients with posterior uveal malignant melanoma.

PURPOSE: To analyze functional and anatomical outcomes following 23/25(+) gauge microincisional pars plana vitrectomy surgery (MIVS) in patients with radiation-related retinal detachment after successful 125-iodine (I-125) brachytherapy treatment for malignant uveal melanoma. PATIENTS AND METHODS: Retrospective case series of 102 consecutive eyes of 102 patients with history of uveal melanoma treated with I-125 brachytherapy that underwent MIVS at the Bascom Palmer Eye Institute. All cases were evaluated for surgical complications and local tumor control. Extended follow-up included Snellen's best-corrected visual acuity, intraocular pressure evaluation, quantitative echography, indirect ophthalmoscopy, and fundus imaging with optical coherence tomography/wide-field photography. RESULTS: All patients had radiation-related complications, including retinal detachment (102 eyes), vasculopathy (91 eyes), optic neuropathy (32 eyes), and/or vitreous hemorrhage (8 eyes). Sixty-seven patients had vitreoretinal traction. Average follow-up after MIVS was 19.5 months, and from plaque removal was 57.7 months. Interval from plaque to MIVS was 38.1 months. Initial visual acuity was 20/258, which improved to 20/101 at 1 month, 20/110 at 3 months, 20/116 at 6 months, and 20/113 at 12 months (P < 0.05). No eyes required enucleation. Melanoma-related mortality was 0.9% (1/102). There was no intra- or extraocular tumor dissemination, and no tumor recurrence. CONCLUSION: MIVS was effective in improving visual function and anatomy in patients with radiation-related retinal detachment. Tumors decreased in size and there was no evidence of recurrence or tumor dissemination. This combined procedure addresses the modifiable causes of visual loss in patients with previously treated malignant uveal melanoma and has the potential to enhance their visual function.

Long-term followup comparing two treatment dosing strategies of (125) I plaque radiotherapy in the management of small/medium posterior uveal melanoma.

Objective. To investigate the efficacy of two different dosing strategies of radioactive iodine-125 ((125)I) in the management of small- and medium-sized posterior uveal melanoma. Patients and Methods. The medical records of consecutive patients with choroidal melanomas between 1.5 and 5.0 mm in apical height treated initially with (125)I plaque radiotherapy were reviewed. Patients were treated with one of the following two treatment dosing strategies: (1) 85 Gy to the apical height of the tumor (group 1) or (2) 85 Gy to a prescription point of 5.0 mm (group 2). Results. Of 95 patients, 55 patients were treated to the apical height of the tumor, and 40 were treated to a prescription point of 5.0 mm. Comparative analysis of the incidence rates of specific complications between the two groups demonstrates that group 2 had a significantly higher incidence of radiation retinopathy, radiation optic neuropathy, and/or visually significant cataract formation than group 1 (P = 0.028). Conclusion. Treatment of choroidal melanomas less than 5 mm in apical height with (125)I brachytherapy to the true apical height is equally effective when compared to treatment with 85 Gy to 5.0 mm. Treatment to the apical height of the tumor may result in lower incidence of radiation-related complications.

Intravitreal bevacizumab combined with plaque brachytherapy reduces melanoma tumor volume and enhances resolution of exudative detachment.

BACKGROUND: The purpose of this study was to evaluate intravitreal bevacizumab as an adjuvant treatment to plaque brachytherapy in the treatment of choroidal melanoma. METHODS: This was a retrospective, consecutive study of 124 patients treated from 2007 to 2009 for choroidal melanoma with plaque brachytherapy. Patients were treated with I-125 plaque brachytherapy with 2 mm margins and 85 Gy to the tumor apex. Consecutive patients were injected intravitreally with 2.5 mg/0.1 mL bevacizumab at a site away from the primary tumor and immediately following plaque removal. Choroidal melanomas were observed using indirect ophthalmoscopy, wide-angle photography, and ultrasound. The main outcome measures were tumor volume, resolution of exudative retinal detachment, and visual acuity. RESULTS: One hundred and twenty-four patients met our inclusion criteria and were included in the analysis. The mean patient age was 65.7 years, and the mean apical tumor height was 4.0 ± 2.7 mm and basal diameter was 12.7 ± 3.0 mm. Mean follow-up was 24 months. Prior to treatment, 100% of tumors had exudative retinal detachment, and pretreatment visual acuity was 20/55 (median 20/40). Tumor control was 100%, metastasis was 0% at last follow-up, and 89.8% had complete resolution of exudative retinal detachment, with a mean time to resolution of 3.36 months. At one month, 43% had complete resolution of exudative retinal detachment, which increased to 73% at 4 months. Visual acuity was 20/62 (median 20/40) at 4 months, with stabilization to 20/57 (median 20/40) at 8 months, 20/56 (median 20/30) at 12 months, and 20/68 (median 20/50) at 24 months. Tumor volume following combined therapy was shown to be reduced by 22.2% at 3 months, 28.9% at 6 months, 39.3% at 12 months, and 52.2% at 24 months (all P < 0.001). All patients tolerated the procedure well without systemic side effects. CONCLUSION: Intravitreal bevacizumab may be used as an adjuvant agent following plaque brachytherapy. Treated choroidal melanomas show reduction in tumor volume as well as resolution of exudative retinal detachments.

Early SD-OCT diagnosis followed by prompt treatment of radiation maculopathy using intravitreal bevacizumab maintains functional visual acuity.

PURPOSE: To evaluate the benefits of intravitreal bevacizumab in patients with visually compromising radiation maculopathy following iodine-125 plaque brachytherapy for uveal melanoma. METHODS: In this Institutional Review Board-approved, consecutive, retrospective study from 2006-2009 of patients maintaining 20/50 or better vision following treatment for visually compromising radiation maculopathy, patients were evaluated with spectral domain optical coherence tomography at 2-4 month intervals following plaque removal. Treatment with intra-vitreal bevacizumab commenced at the first signs of radiation vasculopathy on spectral domain optical coherence tomography with associated decreased best corrected visual acuity, followed by repeat injections for recurrent or persistent vasculopathic changes. RESULTS: At 3 years following plaque brachytherapy, 81 of 159 (50.9%) patients treated for radiation maculopathy demonstrated 20/50 or better vision at median follow up of 36 months, which demonstrates significant improvement in vision as compared to the Collaborative Ocular Melanoma Study (P < 0.0001). These 81 patients were given a mean of five injections (range 1-17) over a mean of 17.6 months (range 1-54 months), starting at 15.8 months (range 3-50 months) after plaque brachytherapy. For those eyes that maintained 20/50 or better vision at the final follow-up, pretreatment mean best corrected visual acuity of 20/43 improved to 20/31. CONCLUSION: This study demonstrates that spectral domain optical coherence tomography can detect early vasculopathic changes secondary to radiation maculopathy and that prompt treatment with intravitreal bevacizumab may delay vision loss and maintain or possibly improve visual acuity in half of eyes diagnosed with radiation maculopathy. Radiation maculopathy remains a therapeutically manageable morbidity associated with radiation therapy for posterior uveal melanoma.

Mucosal melanomas of the head and neck: the role of postoperative radiation therapy.

Objectives. Mucosal melanomas are rarer than their cutaneous counterparts and are associated with a poorer prognosis. We report the clinical outcomes of patients with mucosal melanomas of the head and neck region generally treated with definitive surgery followed by postoperative radiation therapy (RT). Methods. We reviewed the records of 17 patients treated at the University of Miami in 1990-2007. Patients generally received conventionally fractionated RT regimens to the postoperative bed. Elective nodal RT was not routinely delivered. Eight patients received adjuvant chemotherapy or immunotherapy. Results. Median followup was 35.2 months (range 5-225). As the first site of failure: 3 patients recurred locally, 2 regionally and 2 distantly. All 3 patients who recurred locally had not received RT. Of the 5 locoregional recurrences, 4 were salvaged successfully with multimodality therapy with no evidence of disease at last followup. Overall survival was 64.7% at 2 years and 51.5% at 5 years. Conclusions. Patients with mucosal melanoma of the head and neck are best treated with surgery to achieve negative margins, followed by postoperative RT to optimize local control. Elective nodal irradiation may not be indicated in all cases, as regional failures were not predominant. Distant metastases were fewer when compared to historical data, potentially due to advancements in adjuvant therapies as well as aggressive multi-modality salvage at time of failure.

Evaluation of the surgical learning curve for I-125 episcleral plaque placement for the treatment of posterior uveal melanoma: a two decade review.

PURPOSE: To evaluate the surgical learning curve in episceral plaque brachytherapy placement in the management of posterior uveal melanoma. METHODS: A retrospective chart review of two cohorts of 250 consecutive patients undergoing plaque placement for posterior uveal melanoma from 2002 to 2004 and from 2008 to 2009 was conducted. The plaque-tumor apposition rates verified by intraoperative echography were evaluated and correlated with surgical volume over a 19-year period. RESULTS: In an initial study of 29 consecutive patients undergoing plaque placement from January 1992 to January 1995, a suboptimal plaque placement rate of 21% (n = 29) was identified. This percentage declined to 12% (n = 100) from January 2002 to January 2004, and further declined to 4% (n = 150) from June 2008 to August 2009. The tumor-plaque apposition rates for these three groups were 79% (1992-1995), 88% (2002-2004), and 96% (2008-2009). An estimated surgical volume of 1275 cases was performed to achieve a >90% precision rate for first application of primary plaque centration. CONCLUSION: There are challenges to mastering the precise placement of radioactive plaques for posterior uveal melanoma. We have demonstrated a significant learning curve for plaque placement techniques, and have emphasized the importance of intraoperative ultrasound in the verification of plaque placement, thus allowing for intraoperative repositioning.

Ophthalmic vasculature alterations following systemic chemotherapy and periocular Carboplatin treatment of advanced retinoblastoma.

The purpose of this study was to report significant alterations in orbital vasculature following combined systemic chemoreduction/laser ablation and periocular carboplatin treatment and to discuss treatment implications in two cases of advanced retinoblastoma. Assessment of orbital and ophthalmic vasculature was done following nine cycles of systemic chemotherapy. Intra-arterial chemotherapy was provided 6 months following completion of systemic chemoreduction, when the tumor was clearly active and progressive. Orbital angiography of both eyes, performed prior to the intra-arterial melphalan injection, documented sclerosis of the ophthalmic artery vasculature with delayed transit time, decreased choroidal blush, and anomalous vessels in the eye receiving periocular carboplatin injections. The orbital vasculature in the contralateral eye was not affected. Orbital and ophthalmic vascular alterations may occur with the use of combined systemic chemotherapy and periocular carboplatin. Systemic chemotherapy and focal transpupillary laser tumor ablation, alone, did not appear to impact the orbital and ophthalmic vascular supply. Impaired vascular supply may have significant influence on the impact of the efficacy of standard and future experimental therapeutic options.

Long-term toxicity following 3D conformal radiation therapy for prostate cancer from the RTOG 9406 phase I/II dose escalation study.

PURPOSE: To update the incidence of late toxicity of RTOG 9406, a three-dimensional conformal radiation therapy (3DCRT) dose escalation trial for prostate cancer. METHODS AND MATERIALS: A total of 1,084 men were registered to this Phase I/II trial of 3DCRT (eligible patients, 1,055). The dose for level I was 68.4 Gy; 73.8 Gy for level II; 79.2 Gy for level III; 74 Gy for level IV; and 78 Gy for level V. Patients in levels I to III received 1.8 Gy/fraction, and those in levels IV to V received 2.0 Gy/fraction. Disease group I patients were treated at the prostate only, group 2 patients were treated at the prostate and at the seminal vesicles with a prostate boost, and group 3 patients were treated at the prostate and seminal vesicles. The median follow-up period for surviving patients was 6.1 y (level V) to 12.1 y (level I). RESULTS: The incidence rates of RTOG grade 3 or less gastrointestinal or genitourinary toxicity were 3%, 4%, 6%, 7%, and 9% in group 1 and 6%, 2%, 6%, 9%, and 12% in group 2 at dose levels of I, II, III, IV, and V, respectively. In group 1, level V patients had a higher probability of grade 2 late or greater gastrointestinal or genitourinary toxicity than those in levels I, II, and III (hazard ratio [HR] = 1.93, p = 0.0101; HR = 2.29, p = 0.0007; HR = 2.52, p = 0.0002, respectively). In group 2, dose level V patients had a higher probability of grade 2 or greater late gastrointestinal or genitourinary toxicity than those in dose levels II, III, and IV (HR = 2.61, p = 0.0002; HR = 2.22, p = 0.0051; HR = 1.60, p = 0.0276, respectively). CONCLUSIONS: Tolerance to high-dose 3DCRT remains excellent. There is significantly more grade 2 or greater toxicity with a dose of 78 Gy at 2 Gy/fraction than with 68.4 Gy to 79.2 Gy at 1.8 Gy/fraction and with 74 Gy at 2 Gy/fraction.