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.

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.

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.

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.

Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer.

BACKGROUND: A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy. METHODS: We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival. RESULTS: With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group. CONCLUSIONS: Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].).

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.

Are increased tumor aneuploidy and heightened cell proliferation along with heterogeneity associated with patient outcome for carcinomas of the uterine cervix? A combined analysis of subjects treated in RTOG 9001 and a single-institution trial.

PURPOSE: To look for possible associations between measurements of DNA index (DI), S-phase fraction (SPF), and tumor heterogeneity (TH) using flow cytometry and overall survival for patients with invasive cervical carcinoma treated with definitive irradiation. METHODS AND MATERIALS: A total of 57 patients with International Federation of Obstetrics and Gynecology Stages IB(2) through IVB cervical carcinomas treated with definitive radiotherapy with or without concurrent chemotherapy were enrolled into this registry study that involved flow cytometric analysis of fresh tissue from each cervical cancer obtained by pretreatment biopsy. These specimens were evaluated for DNA aneuploidy (DI 1.5), SPF (15%), and TH (uniploid vs. multiploid). RESULTS: In these analyses 27 of the patients were treated in Radiation Therapy Oncology Group protocol 9001, and an additional 30 were offered chemoradiation at a single institution. Forty-one patients had DI 1.5. Twenty-nine patients had SPF 15%, and 2 had no determinable SPF. Forty-three patients had uniploid and 14 multiploid tumors. The 4-year estimated overall survival rate for the entire study cohort was 62% (95% confidence interval 48%-74%). With a median follow-up of 3.7 years, there were no observable associations by univariate analysis for DI, SPF, or TH concerning patient survival. CONCLUSIONS: There were no statistically significant associations among DI, SPF, or TH and patient outcome. Additional studies are indicated to identify tumor biomarkers that could predict patients at risk for disseminated disease.

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.

Outcomes of iodine 125 plaque radiotherapy after initial observation of suspected small choroidal melanomas: a pilot study.

PURPOSE: To determine the visual and survival outcomes for patients undergoing plaque radiotherapy of suspected small choroidal melanomas after observation for growth in a pilot study. DESIGN: Noncomparative interventional case series. PARTICIPANTS: Forty-five patients with suspected small choroidal melanomas who were seen at the Bascom Palmer Eye Institute between 1974 and 2001 and had iodine 125 (I125) plaque radiotherapy between 1991 and 2002. METHODS: Patients with suspected small choroidal melanomas were monitored by clinical examination, photography, and echography. When the melanoma grew or developed orange pigment, patients were treated with I125 plaque radiotherapy. Outcomes included visual acuity, ocular complications, tumor dimensions, metastasis, and death. MAIN OUTCOME MEASURE: Melanoma-specific mortality. RESULTS: In our pilot study, 1 patient died from metastatic melanoma. One patient developed metastatic disease and is still alive. One patient developed marginal tumor recurrence after treatment and after enucleation was performed. Globe conservation was achieved in 97.8% of patients. In patients with tumor margins >2 mm from the optic nerve, vision was preserved with less than a doubling of the visual angle (within approximately 2 Snellen lines of preoperative acuity) in 90.6% (29/32) of patients at 1 year postoperatively, 65.6% (21/32) at 2 years, and 52.2% (12/23) in the long term (4-11 years). CONCLUSIONS: Five-year melanoma-specific mortality after I125 plaque radiotherapy of suspected small choroidal melanomas was 3.9% (95% confidence interval, 0%-11.2%). This information can be used to counsel patients with small suspected choroidal melanomas and to compare with other treatment modalities.