Contemporary prostate cancer treatment choices in multidisciplinary clinics referenced to national trends.

BACKGROUND: The purpose of this study was to assess treatment choices among men with prostate cancer who presented at The University of Texas MD Anderson Cancer Center multidisciplinary (MultiD) clinic compared with nationwide trends. METHODS: In total, 4451 men with prostate cancer who presented at the MultiD clinic from 2004 to 2016 were analyzed. To assess nationwide trends, the authors analyzed 392,710 men with prostate cancer who were diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. The primary endpoint was treatment choice as a function of pretreatment demographics. RESULTS: Univariate analyses revealed similar treatment trends in the MultiD and SEER cohorts. The use of procedural forms of definitive therapy decreased with age, including brachytherapy and prostatectomy (all P < .05). Later year of diagnosis/clinic visit was associated with decreased use of definitive treatments, whereas higher risk grouping was associated with increased use (all P < .001). Patients with low-risk disease treated at the MultiD clinic were more likely to receive nondefinitive therapy than patients in SEER, whereas the opposite trend was observed for patients with high-risk disease, with a substantial portion of high-risk patients in SEER not receiving definitive therapy. In the MultiD clinic, African American men with intermediate-risk and high-risk disease were more likely to receive definitive therapy than white men, but for SEER the opposite was true. CONCLUSIONS: Presentation at a MultiD clinic facilitates the appropriate disposition of patients with low-risk disease to nondefinitive strategies of patients with high-risk disease to definitive treatment, and it may obviate the influence of race.

Long-Term Prospective Outcomes of Intensity Modulated Radiotherapy for Locally Advanced Lung Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The optimal radiotherapy technique for unresectable locally advanced non-small cell lung cancer (NSCLC) is controversial, so evaluating long-term prospective outcomes of intensity-modulated radiotherapy (IMRT) is important. Objective: To compare long-term prospective outcomes of patients receiving IMRT and 3-dimensional conformal radiotherapy (3D-CRT) with concurrent carboplatin/paclitaxel for locally advanced NSCLC. Design, Setting, and Participants: A secondary analysis of a prospective phase 3 randomized clinical trial NRG Oncology-RTOG 0617 assessed 483 patients receiving chemoradiotherapy (3D-CRT vs IMRT) for locally advanced NSCLC based on stratification. Main Outcomes and Measures: Long-term outcomes were analyzed, including overall survival (OS), progression-free survival (PFS), time to local failure, development of second cancers, and severe grade 3 or higher adverse events (AEs) per Common Terminology Criteria for Adverse Events, version 3. The percentage of an organ volume (V) receiving a specified amount of radiation in units of Gy is reported as V(radiation dose). Results: Of 483 patients (median [IQR] age, 64 [57-70] years; 194 [40.2%] female), 228 (47.2%) received IMRT, and 255 (52.8%) received 3D-CRT (median [IQR] follow-up, 5.2 [4.8-6.0] years). IMRT was associated with a 2-fold reduction in grade 3 or higher pneumonitis AEs compared with 3D-CRT (8 [3.5%] vs 21 [8.2%]; P = .03). On univariate analysis, heart V20, V40, and V60 were associated with worse OS (hazard ratios, 1.06 [95% CI, 1.04-1.09]; 1.09 [95% CI, 1.05-1.13]; 1.16 [95% CI, 1.09-1.24], respectively; all P < .001). IMRT significantly reduced heart V40 compared to 3D-CRT (16.5% vs 20.5%; P < .001). Heart V40 (<20%) had better OS than V40 (≥20%) (median [IQR], 2.5 [2.1-3.1] years vs 1.7 [1.5-2.0] years; P < .001). On multivariable analysis, heart V40 (≥20%), was associated with worse OS (hazard ratio, 1.34 [95% CI, 1.06-1.70]; P = .01), whereas lung V5 and age had no association with OS. Patients receiving IMRT and 3D-CRT had similar rates of developing secondary cancers (15 [6.6%] vs 14 [5.5%]) with long-term follow-up. Conclusions and Relevance: These findings support the standard use of IMRT for locally advanced NSCLC. IMRT should aim to minimize lung V20 and heart V20 to V60, rather than constraining low-dose radiation bath. Lung V5 and age were not associated with survival and should not be considered a contraindication for chemoradiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT00533949.

Development and clinical implementation of a digital workflow utilizing 3D-printed oral stents for patients with head and neck cancer receiving radiotherapy.

OBJECTIVES: We describe the development of 3D-printed stents using our digital workflow and their effects on patients enrolled in the lead-in phase of a multi-center, randomized Phase-II trial. MATERIALS AND METHODS: Digital dental models were created for patients using intraoral scanning. Digital processes were implemented to develop the mouth-opening, tongue-depressing, and tongue-lateralizing stents using stereolithography. Time spent and material 3D-printing costs were measured. Physicians assessed mucositis using the Oral Mucositis Assessment Scale (OMAS) and collected MD Anderson Symptom Inventory (MDASI) reports and adverse events (AEs) from patients at various time points (TPs). OMAS and MDASI results were evaluated using paired t-test analysis. RESULTS: 18 patients enrolled into the lead-in phase across 6 independent clinical sites in the USA. 15 patients received stents (average design and fabrication time, 8 h; average material 3D-printing cost, 11 USD). 10 eligible patients with complete OMAS and MDASI reports across all TPs were assessed. OMAS increased significantly from baseline to week 3 of treatment (mean difference = 0.34; 95 % CI, 0.09-0.60; p = 0.01). MDASI increased significantly from baseline to week 3 of treatment (mean difference = 1.02; 95 % CI, 0.40-1.70; p = 0.005), and week 3 of treatment to end of treatment (mean difference = 1.90; 95 % CI, 0.90-2.92; p = 0.002). AEs (grades 1-3) were reported by patients across TPs. Mucositis and radiation dermatitis were primarily attributed to chemoradiation. CONCLUSIONS: 3D-printed stents were successfully fabricated and well tolerated by patients. As patients enroll in the randomized phase of this trial, data herein will establish a baseline for comparative analysis.

Long-Term Outcomes of NRG Oncology/RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Anal Canal Cancer.

PURPOSE: A multi-institutional phase 2 trial assessed long-term outcomes of dose-painted intensity modulated radiation therapy (IMRT) with 5-fluorouracil (5FU) and mitomycin-C (MMC) for anal canal cancer. METHODS AND MATERIALS: T2-4N0-3M0 anal cancers received 5FU (1000 mg/m2/d, 96-hour infusion) and MMC (10 mg/m2 bolus) on days 1 and 29 of dose-painted IMRT prescribed as follows: T2N0 = 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes, 28 fractions; T3-4N0-3 = 45Gy elective nodal, 50.4 Gy ≤3 cm and 54 Gy >3cm metastatic nodal and 54 Gy anal tumor planning target volumes, 30 fractions. Local-regional failures, distant metastases, and colostomy failures were assessed using the cumulative incidence method, and disease-free survival, overall survival, and colostomy-free survival were assessed using the Kaplan-Meier method. Late effects were scored using National Cancer Institute-Common Terminology Criteria for Adverse Events v3. RESULTS: Of 52 patients, 54% were stage II, 25% were stage IIIA, and 21% were stage IIIB. Median follow-up was 7.9 years (min-max, 0.02-9.2 years). Local-regional failure, colostomy failures, distant metastases, overall survival, disease-free survival, and colostomy-free survival at 5 years are 16% (95% confidence interval [CI], 7%-27%), 10% (95% CI, 4%-20%), 16% (95% CI, 7%-27%), 76% (95% CI, 61%-86%), 70% (95% CI, 56%-81%), and 74% (95% CI, 59%-84%); and at 8 years they are 16% (95% CI, 7%-27%), 12% (95% CI, 5%-23%), 22% (95% CI, 12%-34%), 68% (95% CI, 53%-79%), 62% (95% CI, 47%-74%) and 66% (95% CI, 51%-77%), respectively. Eight patients experienced local-regional failure, with 5 patients having persistent disease at 12 weeks. No isolated nodal failures occurred in the microscopic elective nodal volumes. Six patients required colostomy-5 for local-regional salvage and 1 for a temporary ostomy for anorectal dysfunction. Rates of late adverse events included: 28 patients (55%) with grade 2, 8 patients (16%) with grade 3, 0 patients with grade 4, and 2 patients (4%) with grade 5 events (sinus bradycardia and myelodysplasia, possibly owing to chemotherapy). Only 11 patients reported grade 1 to 3 sexual dysfunction. CONCLUSIONS: Dose-painted IMRT with 5FU/MMC for the treatment of anal canal cancer yields comparable long-term efficacy as conventional radiation cohorts. Enhanced normal tissue protection lowered rates of grade 3 and higher late effects without compromising pelvic tumor control.

Use of the Toxicity Index in Evaluating Adverse Events in Anal Cancer Trials: Analysis of RTOG 9811 and RTOG 0529.

Novel toxicity metrics that account for all adverse event (AE) grades and the frequency of may enhance toxicity reporting in clinical trials. The Toxicity Index (TI) accounts for all AE grades and frequencies for categories of interest. We evaluate the feasibility of using the TI methodology in 2 prospective anal cancer trials and to evaluate whether more conformal radiation (using Intensity Modulated Radiation Therapy) results in improved toxicity as measured by the TI. Patients enrolled on NRG/RTOG 0529 or nonconformal RT enrolled on the 5-Fluorouracil/Mitomycin arm of NRG/RTOG 9811 were compared using the TI. Patients treated on NRG/RTOG 0529 had lower median TI compared with patients treated with nonconformal RT on NRG/RTOG 9811 for combined GI/GU/Heme/Derm events (3.935 vs 3.996, P=0.014). The TI methodology is a feasible method to assess all AEs of interest and may be useful as a composite metric for future efforts aimed at treatment de-escalation or escalation.

Analysis of MRE11 and Mortality Among Adults With Muscle-Invasive Bladder Cancer Managed With Trimodality Therapy.

Importance: Bladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches. Objective: To evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis. Design, Setting, and Participants: This prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020. Exposures: Trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy. Main Outcomes and Measures: MRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio. Results: Of 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44). Conclusions and Relevance: Higher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.

Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial.

Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.

Phase I and II Study of Induction Chemotherapy With Methotrexate, Rituximab, and Temozolomide, Followed By Whole-Brain Radiotherapy and Postirradiation Temozolomide for Primary CNS Lymphoma: NRG Oncology RTOG 0227.

PURPOSE: This study investigated the treatment of primary CNS lymphoma with methotrexate, temozolomide (TMZ), and rituximab, followed by hyperfractionated whole-brain radiotherapy (hWBRT) and subsequent TMZ. The primary phase I end point was the maximum tolerated dose of TMZ. The primary phase II end point was the 2-year overall survival (OS) rate. Secondary end points were preirradiation response rates, progression-free survival (PFS), neurologic toxicities, and quality of life. PATIENTS AND METHODS: The phase I study increased TMZ doses from 100 to 150 to 200 mg/m(2). Patients were treated with rituximab 375 mg/m(2) 3 days before cycle 1; methotrexate 3.5 g/m(2) with leucovorin on weeks 1, 3, 5, 7, and 9; TMZ daily for 5 days on weeks 4 and 8; hWBRT 1.2 Gy twice-daily on weeks 11 to 13 (36 Gy); and TMZ 200 mg/m(2) daily for 5 days every 28 days on weeks 14 to 50. RESULTS: Thirteen patients (one ineligible) were enrolled in phase I of the study. The maximum tolerated dose of TMZ was 100 mg/m(2). Dose-limiting toxicities were hepatic and renal. In phase II, 53 patients were treated. Median follow-up for living eligible patients was 3.6 years, and 2-year OS and PFS were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG-9310, 2-year OS and PFS were significantly improved (P = .006 and .030, respectively). In phase II, the objective response rate was 85.7%. Among patients, 66% (35 of 53) had grade 3 and 4 toxicities before hWBRT, and 45% (24 of 53) of patients experienced grade 3 and 4 toxicities attributable to post-hWBRT chemotherapy. Cognitive function and quality of life improved or stabilized after hWBRT. CONCLUSION: This regimen is safe, with the best 2-year OS and PFS achieved in any Radiation Therapy Oncology Group primary CNS lymphoma trial. Randomized trials that incorporate this regimen are needed to determine its efficacy compared with other strategies.

Hypofractionated intensity-modulated radiotherapy for primary glioblastoma multiforme.

PURPOSE: A pilot study was designed to evaluate the safety and efficacy of a novel regimen of hypofractionated intensity-modulated radiotherapy (RT) in the adjuvant treatment of primary glioblastoma multiforme (GBM). The rationale of the study was to combine the potential radiobiologic advantage of hypofractionation to GBM with a highly conformal radiotherapeutic technique. The study was designed to measure the acute and chronic morbidity of patients treated with this regimen, response of GBM to the treatment, overall survival, and time to disease progression after therapy completion. METHODS AND MATERIALS: Twenty eligible patients were accrued between February 1999 and May 2000 for the study. All patients had Karnofsky performance scores of >/=70. All patients were treated with intensity-modulated RT using the NOMOS Peacock system. A dose of 50 Gy was delivered in 5-Gy daily fractions within 2 weeks to enhancing primary disease, residual tumor, or surgical cavity. Simultaneously, 30 Gy was prescribed in 3-Gy daily fractions to surrounding edema. The time to progression was measured with serial neurologic examinations and MRI or CT scans after RT completion. Acute and late toxicity was graded using Radiation Therapy Oncology Group neurotoxicity scores. RESULTS: Of the 20 patients, 18 were evaluated for outcome. The median time to disease progression was 6 months after RT completion. The median overall survival was 7 months after treatment completion. All recurrences were within 2 cm of the operative bed. Neurotoxicity during therapy was minimal, with all patients experiencing Grade 0 or 1 toxicity. Late toxicity included 10 patients with Grade 0, 2 patients with Grade 2, and 3 patients with Grade 4 toxicity, manifesting as brain necrosis requiring surgical reexcision. The survival of the 3 patients with brain necrosis was 23, 20, and 9 months. Mortality in all cases was the result of tumor recurrence, with no mortality resulting from brain necrosis. CONCLUSION: This regimen of hypofractionated intensity-modulated RT did not improve the time to disease progression or overall survival compared with historical experience using conventional fractionation. However, the treatment duration was reduced from 6 weeks to 2 weeks, which may be of palliative benefit in certain subsets of patients. This treatment regimen demonstrated a greater incidence of brain necrosis requiring surgical intervention; however, the 3 patients experiencing this toxicity had longer survival times. Future investigation may be useful to determine which fraction size may be optimal for GBM when highly conformal RT is used in the adjuvant setting.