Comparison of Outcomes in Patients With Muscle-invasive Bladder Cancer Treated With Radical Cystectomy Versus Bladder Preservation.

PURPOSE: Radical cystectomy currently remains the standard of care for muscle-invasive bladder cancer. However, surgery can be associated with considerable morbidity and mortality, including the removal of the bladder. An alternative strategy is to preserve the bladder through concurrent chemoradiation following a maximal transurethral resection of the tumor. National protocols using a bladder-preservation approach have demonstrated disease-specific outcomes comparable to radical cystectomy in selected patients, but these results have not been replicated in previously reported population-based series. Here, we describe an outcomes analysis of patients with muscle-invasive bladder cancer treated with either radical surgery or bladder-preserving chemoradiation (BPCRT) for those patients meeting BPCRT criterion using the National Cancer Database (NCDB). MATERIALS AND METHODS: Using the NCDB, patients with American Joint Commission on Cancer clinical T2-3, N0, M0 urothelial carcinoma diagnosed between 2004 and 2013 were included for analysis. Only patients treated with definitive intent with either radical cystectomy or concurrent chemotherapy and radiation after a maximal transurethral tumor resection were included. Propensity-score matching was used. RESULTS: Among 8454 eligible patients, 7276 (86%) underwent radical cystectomy, and 1178 (14%) underwent BPCRT. Patients undergoing BPCRT were significantly older (median age, 77 vs. 68 y; P<0.001) and had higher Charlson-Deyo comorbidity scores (P=0.002). Using propensity-matched analysis, 1002 patients remained in each cohort, and there was no significant difference in survival found between the 2 cohorts (median overall survival, 2.7 vs. 3.0 y [P=0.20]; 4-year overall survival, 39.1% and 42.6% [P=0.15], for BPCRT and surgery, respectively). In addition, the hazard ratio (HR) of surgery versus BPCRT decreased over time, with an initial HR of 1.27 favoring BPCRT which decreased by a factor of 0.85 per year. CONCLUSIONS: From 2004 to 2013, ∼14% of patients from the NCDB who potentially met bladder-preservation criteria underwent the procedure. Our propensity-matched analysis is the only report of its kind to demonstrate similar survival outcomes with bladder preservation when patients are properly selected. This study is also the first to demonstrate a dynamic HR between radical surgery and BPCRT over time.

The Impact of Graduates' Job Preferences on the Current Radiation Oncology Job Market.

PURPOSE: To examine the role of radiation oncology (RO) graduates' application patterns and personal preferences in current labor concerns. METHODS AND MATERIALS: An anonymous, voluntary survey was distributed to 665 domestic RO graduates from 2013 to 2017. Questions assessed graduates' regional (Northeast [NE]; Midwest [MW]; South [SO]; West [WT]) job type and population size preferences. Top regional choice was compared across other categorical and numerical variables using the χ2 test and analysis of variance, respectively. RESULTS: Complete responses were obtained from 299 (45.0% response rate) participants: 82 (27.4%), 74 (24.7%), 85 (28.4%), and 58 (19.4%) graduated from NE, MW, SO, and WT programs. The most to least commonly applied regions were SO (69.2%), MW (55.9%), and then NE/WT (55.2% each). The first and last regional choices were the WT (29.4%) and MW (15.7%), respectively. The most and least common application and top choice preferences were consistent in terms of city size: >500,000 (86.0% and 64.5%, respectively) and <100,001 (26.1% and 7.0%, respectively). The majority of applicants applied to both academic and nonacademic positions (60.9%), with top job type choice being equally split. The majority of respondents independently received a job offer in their preferred region (75.3%), city population size (72.6%) or job type (81.9%). Additionally, 52.5% received a job offer that included all three preferences. Those who underwent residency training (44.3% vs 62.0%-83.6%, P < .001) or medical schooling (50.7% vs 56.3%-75.6%, P < .001) or grew up in the MW (60.8% vs 70.0%-74.7%, P < .001) were least likely to choose this region as their top regional choice compared with other regions. CONCLUSIONS: The MW and jobs in smaller cities are less appealing to RO graduates, even if they receive training in the MW, which may contribute to current job market concerns. Nonetheless, the majority of respondents received a job offer in the region, population size, and job type of their top choice. Assessing prospective candidates' city size and geographic preferences and prioritizing applicants who are compatible with positions may help address potential job market discrepancies.

Adenosquamous Carcinoma of the Esophagus: An NCDB-Based Investigation on Comparative Features and Overall Survival in a Rare Tumor.

OBJECTIVES: Esophageal adenosquamous carcinoma (ASC) is a rare tumor with characteristics of adenocarcinoma (AC) and squamous cell carcinoma (SCC), the two most common esophageal cancers. Its behavior is aggressive but poorly understood. Using the National Cancer Database (NCDB), the clinical features and overall survival of ASC were compared with AC and SCC. METHODS: The NCDB was queried for patients with esophageal ASC, AC, and SCC. Univariate association of histology with patient characteristics and overall survival were analyzed and socioeconomic characteristics were balanced. RESULTS: Clinical M stage was 0 in a significantly lower proportion of ASC (69.0%) than in AC (70.9%) or SCC (75.6%) (p < 0.001). Median survival was lower in patients with ASC (9.6 months) than with AC (13.5) or SCC (9.7) and 2-year OS was lower in patients with ASC (23.8%) than with AC (34.6%) or SCC (26.5%) (p < 0.001). The OS hazard ratio for ASC was 1.14 when compared to AC (95% CI = 1.016-1.267, p = 0.025) and 1.10 when compared to SCC, but the latter was not significant (95% CI = 0.980-1.222, p = 0.111). CONCLUSION: ASC is a rare tumor among esophageal carcinomas with a greater burden of metastatic disease than AC or SCC and worse OS than AC.

Correlation of Acute and Late Brainstem Toxicities With Dose-Volume Data for Pediatric Patients With Posterior Fossa Malignancies.

PURPOSE: Radiation-induced brainstem toxicity after treatment of pediatric posterior fossa malignancies is incompletely understood, especially in the era of intensity modulated radiation therapy (IMRT). The rates of, and predictive factors for, brainstem toxicity after photon RT for posterior fossa tumors were examined. METHODS AND MATERIALS: After institutional review board approval, 60 pediatric patients treated at our institution for nonmetastatic infratentorial ependymoma and medulloblastoma with IMRT were included in the present analysis. Dosimetric variables, including the mean and maximum dose to the brainstem, the dose to 10% to 90% of the brainstem (in 10% increments), and the volume of the brainstem receiving 40, 45, 50, and 55 Gy were recorded for each patient. Acute (onset within 3 months) and late (>3 months of RT completion) RT-induced brainstem toxicities with clinical and radiographic correlates were scored using Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Patients aged 1.4 to 21.8 years underwent IMRT or volumetric arc therapy postoperatively to the posterior fossa or tumor bed. At a median clinical follow-up period of 2.8 years, 14 patients had developed symptomatic brainstem toxicity (crude incidence 23.3%). No correlation was found between the dosimetric variables examined and brainstem toxicity. Vascular injury or ischemia showed a strong trend toward predicting brainstem toxicity (P=.054). Patients with grade 3 to 5 brainstem toxicity had undergone treatment to significant volumes of the posterior fossa. CONCLUSION: The results of the present series demonstrate a low, but not negligible, risk of brainstem radiation necrosis for pediatric patients with posterior fossa malignancies treated with IMRT. No specific dose-volume correlations were identified; however, modern treatment volumes might help limit the incidence of severe toxicity. Additional work investigating inherent biologic sensitivity might also provide further insight into this clinical problem.

The role of postmastectomy radiotherapy in women with pathologic T3N0M0 breast cancer.

BACKGROUND: The authors determined the impact of postmastectomy radiotherapy (PMRT) on overall survival (OS) among patients with pT3N0M0 breast cancer in the National Cancer Data Base. METHODS: A total of 3437 patients with pT3N0M0 breast cancer who initially were treated with mastectomy between 2003 and 2011 were identified. Of these women, 1644 (47.8%) received PMRT (67% treated with chest wall RT alone and 33% treated with chest wall and regional lymph node irradiation). Univariable and multivariable analyses were conducted to identify characteristics associated with PMRT and OS. In addition, propensity score matching and interaction effect testing also were performed. RESULTS: PMRT was associated with age <40 years, private insurance coverage, treatment facility location within 10 miles of the patient's home zip code, Charlson-Deyo comorbidity score of 0, tumor size ≥7 cm, and treatment with chemotherapy or hormone therapy (all P<.05). PMRT was associated with improved 5-year OS (86.3% for patients treated with PMRT vs 66.4% for patients not treated with PMRT; P<.01). In addition to PMRT (hazard ratio, 0.72; 95% confidence interval, 0.59-0.87 [P<.01]), age ≤50 years, treatment at an academic/research program, Charlson-Deyo comorbidity score of 0, tumor size <7 cm, chemotherapy receipt, and hormone therapy receipt were associated with improved OS on multivariable analyses (all P<.05). Interaction testing found that PMRT improved OS independent of age, facility type, Charlson-Deyo comorbidity score, tumor grade and size, surgical margin status, and receipt of chemotherapy or hormone therapy (all P>.1). Finally, propensity score matching analysis confirmed the impact of PMRT on OS (P = .02). It is interesting to note that regional lymph node irradiation did not improve OS versus chest wall RT alone (P = .09). CONCLUSIONS: Among patients with pT3N0M0 breast cancer in the National Cancer Data Base, PMRT was found to be associated with improved OS regardless of surgical margin status, tumor size, and receipt of systemic therapy. Cancer 2017;123:2829-39. © 2017 American Cancer Society.

Association of Lymphovascular Space Invasion With Locoregional Failure and Survival in Patients With Node-Negative Oral Tongue Cancers.

Importance: The indications for adjuvant therapy in resected oral tongue cancers are based on both clinical and pathological factors, with clear evidence for adjuvant radiation in patients with pathologically positive neck lymph nodes, positive margins, and extracapsular extension, but the data for patients with no nodal disease are sparse. Objective: To investigate determinants of failure and survival in patients with node-negative oral tongue cancer. Design, Setting, and Participants: Medical records for patients with oral tongue cancer treated with definitive surgery from 2003 to 2013 were reviewed. All patients were cN0 negative and classified as pathologically node-negative (pN0) if a neck dissection was performed. Patients received adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) based on standard clinical and pathological determinants. Main Outcomes and Measures: Kaplan-Meier and multivariable (MVA) logistic regression and Cox proportional hazard regression analyses were performed to identify patient, tumor, and treatment characteristics predictive of locoregional control (LRC) and overall survival (OS). Results: A total of 180 patients met entry criteria, with a median follow-up time of 4.9 years (range, 0.9-12.5 years); 102 patients (56.7%) were female and 42 patients (23.3%) were younger than 45 years at diagnosis. One hundred fifty-three patients (85%) had T1/T2 tumors, and 112 patients (62%) had elective neck dissections with confirmed pN0. Lymphovascular space invasion (LVSI) was present in 36 patients (20%). On MVA, LVSI (OR, 0.06; 95% CI, 0.02-0.19; P < .01) was associated with worse LRC. Elective neck dissection (odds ratio [OR], 2.99; 95% CI, 1.16-7.73; P = .02) and receipt of RT (OR, 7.74; 95% CI, 2.27-26.42; P < .01) were associated with improved LRC. Three-year LRC rates were significantly lower for patients with LVSI (38.8%; 95% CI, 22.8%, 54.6%) than those without LVSI (81.9%; 95% CI, 74.4%, 87.4%). On MVA, only LVSI (hazard ratio, 2.20; 95% CI, 1.19-4.06; P = .01) and age greater than 44 years (hazard ratio, 4.38; 95% CI, 1.34-14.27; P = .01) were associated with worse OS. Three-year OS rates were significantly lower in patients with LVSI (71.3%; 95% CI, 53.2%-83.4%) than those without LVSI (90.3%; 95% CI, 83.8%-94.3%). Conclusions and Relevance: Lymphovascular space invasion in patients with node-negative oral tongue cancer treated with upfront definitive surgery is associated with worse LRC and OS. Node-negative oral cavity cancers with LVSI warrant consideration of further adjuvant therapy, which should be further evaluated in a prospective setting.

The role of adjuvant radiotherapy in pathologically lymph node-positive prostate cancer.

BACKGROUND: Postoperative management of prostate cancer with lymph node involvement (LNI) is controversial. Retrospective evidence supports the selective use of radiotherapy (RT) after extended pelvic lymph node dissection. It is unclear whether this is generalizable to practice in the United States, where extended dissection is uncommon. The authors identified patients with LNI who potentially could derive a survival benefit with adjuvant RT plus androgen-deprivation therapy (ADT). METHODS: Patients with N1M0 prostate adenocarcinoma who underwent radical prostatectomy (RP) and subsequently received ADT from 2003 through 2011 were identified from the National Cancer Database. Kaplan-Meier analyses, log-rank tests, and multivariable Cox proportional hazards regression were performed using overall survival (OS) as the primary outcome. RESULTS: In total, 906 of 2569 eligible patients (35.3%) received RT, and RT was more frequently received by patients who were diagnosed in later years, had fewer positive lymph nodes, had involved surgical margins, and were aged <65 years (all P < .05). The 5-year OS rate was 87% versus 82% in those who received RT versus those who did not (P = .007). After propensity score matching, 826 patients remained in each cohort. RT retained an association with OS (5-year OS: 88% vs 81%; P = .009; hazard ratio, 1.43; 95% confidence interval, 1.10-1.86; P = .008). No interaction was identified between the effect of RT on OS across tested strata of total lymph nodes examined, lymph node ratio, total number of positive lymph nodes, margin status, Gleason score, and prostate-specific antigen. CONCLUSIONS: RT plus ADT was associated with improved OS after RP in patients with LNI. These results may help guide therapy in the absence of randomized evidence. Cancer 2017;123:512-520. © 2016 American Cancer Society.

Evaluating Intensity-Modulated Radiation Therapy in Locally Advanced Non-Small-Cell Lung Cancer: Results From the National Cancer Data Base.

INTRODUCTION: Reports have suggested improvements in dosimetry, toxicity, and quality of life with intensity-modulated radiation therapy (IMRT) in locally advanced non-small-cell lung cancer (NSCLC). The selection criteria for those patients who may benefit is unclear. This study sought to identify subgroups of patients who may derive survival benefit from intensity modulated radiation therapy (IMRT) compared with 3D conformal radiation therapy (3DCRT). METHODS AND MATERIALS: The National Cancer Data Base was queried for stage III NSCLC treated with radiation and chemotherapy alone with curative intent. All received ≥ 58 Gy. Kaplan-Meier and log-rank test were performed to compare overall survival (OS) by treatment modality. A multivariable Cox proportional hazards model was used to assess association with OS. Propensity score matching was also implemented. RESULTS: A total of 2543 patients treated between 2003 and 2006 were eligible; 422 (16.6%) received IMRT, 2121 (83.4%) received 3DCRT. In patients with T3 and T4 disease, IMRT was associated with an improvement in median OS and 5-year survival rate (17.2 vs. 14.6 months; 19.9% vs. 13.4%, P = .021.) In multivariable analysis, there was an interaction between treatment type and T stage that was found to be significant (P = .03). In the propensity matched cohort of T3 and T4 patients, the use of IMRT remained associated with improved OS (hazard ratio, 0.80; 95% confidence interval, 0.64-1.00; P = .048). CONCLUSIONS: Use of IMRT in patients with T3 and T4 tumors was associated with improved overall survival in this large population-based analysis. This is a novel finding that is in concordance with the well-described dosimetric benefits of IMRT in NSCLC.

Outcomes and prognostic factors in modern era management of major salivary gland cancer.

OBJECTIVES: There is a dearth of prospective evidence regarding cancer of the major salivary glands. Outcomes and management of major salivary gland are based largely on retrospective series spanning many decades and changes in surgical, radiation, imaging and systemic therapy strategies and technique. We sought to report contemporary patterns of relapse and prognostic factors for major salivary gland cancer. MATERIALS AND METHODS: 112 patients with major salivary gland cancers underwent resection with or without adjuvant therapy between January 1997 and September 2010. Outcomes were documented with follow-up until December 2014. Survival was calculated by the Kaplan-Meier method. Log-rank test and Cox proportional hazards regression were performed with locoregional control (LRC), distant control (DC) and overall survival (OS) as the primary outcome variables. RESULTS: Median follow-up was 55.1 months. Rates of LRC for stage I/II and III/IV at five years were 95.7% and 61.9% respectively. Rates of DC at five years for stage I/II and III/IV were 93% and 56.9% respectively. Multivariate analysis identified larger tumor size, clinical nerve involvement and in parotid cancers, advanced T stage, no adjuvant radiation, and older age at diagnosis to be associated with increased risk of locoregional recurrence (all p<0.05). Distant metastasis was associated with sublingual site, degree of clinical nerve involvement, high grade, tumor size and in parotid tumors additionally deep lobe involvement on multivariate analysis (all p<0.05). CONCLUSION: Several prognostic factors were identified that may help guide decisions regarding adjuvant therapy. DM remains a significant concern in the management of this disease.

Predictors of local recurrence after rituximab-based chemotherapy alone in stage III and IV diffuse large B-cell lymphoma: guiding decisions for consolidative radiation.

PURPOSE: The role of consolidative radiation therapy (RT) for stage III and IV diffuse large B-cell lymphoma (DLBCL) in the era of rituximab is not well defined. There is evidence that some patients with bulky disease may benefit, but patient selection criteria are not well established. We sought to identify a subset of patients who experienced a high local failure rate after receiving rituximab-based chemotherapy alone and hence may benefit from the addition of consolidative RT. METHODS AND MATERIALS: Two hundred eleven patients with stage III and IV DLBCL treated between August 1999 and January 2012 were reviewed. Of these, 89 had a complete response to systemic therapy including rituximab and received no initial RT. Kaplan-Meier analysis and Cox proportional hazards regression were performed, with local recurrence (LR) as the primary outcome. RESULTS: The median follow-up time was 43.9 months. Fifty percent of patients experienced LR at 5 years. In multivariate analysis, tumor ≥ 5 cm and stage III disease were associated with increased risk of LR. The 5-year LR-free survival was 47.4% for patients with ≥ 5-cm lesions versus 74.7% for patients with <5-cm lesions (P=.01). In patients with <5-cm tumors, the maximum standardized uptake value (SUVmax) was ≥ 15 in all patients with LR. The 5-year LR-free survival was 100% in SUV<15 versus 68.8% in SUV ≥ 15 (P=.10). CONCLUSIONS: Advanced-stage DLBCL patients with stage III disease or with disease ≥ 5 cm appear to be at an increased risk for LR. Patients with <5-cm disease and SUVmax ≥ 15 may be at higher risk for LR. These patients may benefit from consolidative RT after chemoimmunotherapy.

The 21-gene recurrence score and locoregional recurrence in breast cancer patients.

PURPOSE: Although the 21-gene recurrence score (RS) assay has been validated to assess the risk of distant recurrence in hormone receptor-positive breast cancer patients, the relationship between RS and the risk of locoregional recurrence (LRR) remains unclear. The purpose of this study was to determine if RS is associated with LRR in breast cancer patients and whether this relationship varies based on the type of local treatment [mastectomy or breast-conserving therapy (BCT)]. METHODS: 163 consecutive estrogen receptor-positive breast cancer patients at our institution had an RS generated from the primary breast tumor between August 2006 and October 2009. Patients were treated with lumpectomy and radiation (BCT) (n = 110) or mastectomy alone (n = 53). Patients were stratified using a pre-determined RS of 25 and then grouped according to local therapy type. RESULTS: Median follow-up was 68.2 months. Patients who developed an LRR had stage I or IIA disease, >2 mm surgical margins, and received chemotherapy as directed by RS. While an RS > 25 did not predict for a higher rate of LRR, an RS > 24 was associated with LRR in our subjects. Among mastectomy patients, the 5-year LRR rate was 27.3 % in patients with an RS > 24 versus 10.7 % (p = 0.04) in those whose RS was ≤ 24. RS was not associated with LRR in patients who received BCT. CONCLUSIONS: Breast cancer patients treated with mastectomy for tumors that have an RS > 24 are at high risk of LRR and may benefit from post-mastectomy radiation.

Reassessing dose constraints of organs at risk in children with abdominal neuroblastoma treated with definitive radiation therapy: a correlation with late toxicity.

BACKGROUND: In children treated with definitive radiation therapy (RT) for abdominal neuroblastoma, normal tissue constraints for organs at risk (OARs) are not well-standardized or evidence-based. In this study, we analyze dosimetric data of principal abdominal OARs, reassess existing RT planning constraints, and examine corresponding acute and late toxicity to OARs. PROCEDURE: The treatment plans of 30 consecutive children who underwent definitive RT for high-risk abdominal neuroblastoma were reviewed. Dose-volume histogram (DVH) statistics were recorded for the ipsilateral kidney (if unresected), contralateral kidney, and liver. DVH data were analyzed to determine if OAR constraints from recent protocols were met and correlated with the development of toxicity. RESULTS: The median follow-up period was 53.0 months. Ten, thirteen, and ten percent of patients' RT plans did not meet OAR DVH constraints for the liver, ipsilateral kidney, and contralateral kidney, respectively. Of the three patients whose plans did not achieve ipsilateral kidney DVH constraint(s), two developed evidence of late ipsilateral kidney hypoplasia, but maintained normal laboratory kidney function. No patient experienced late toxicity of the contralateral kidney nor developed RT-related late hepatic complications. CONCLUSIONS: In children treated for abdominal neuroblastoma, the risk of developing clinically significant RT-related late toxicity of the kidney and liver is not appreciable, even when current DVH parameters for OARs are not achieved in planning. Toxicity outcomes did not necessarily correlate with present-day OAR dose constraints. Currently utilized DVH constraints are highly variable, and must be further studied and supported by toxicity outcomes to more accurately characterize risk of complications.

Deletion of the G6pc2 gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein does not affect the progression or incidence of type 1 diabetes in NOD/ShiLtJ mice.

OBJECTIVE: Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), now known as G6PC2, is a major target of autoreactive T cells implicated in the pathogenesis of type 1 diabetes in both mice and humans. This study aimed to determine whether suppression of G6p2 gene expression might therefore prevent or delay disease progression. RESEARCH DESIGN AND METHODS: G6pc2(-/-) mice were generated on the NOD/ShiLtJ genetic background, and glycemia was monitored weekly up to 35 weeks of age to determine the onset and incidence of diabetes. The antigen specificity of CD8(+) T cells infiltrating islets from NOD/ShiLtJ G6pc2(+/+) and G6pc2(-/-) mice at 12 weeks was determined in parallel. RESULTS: The absence of G6pc2 did not affect the time of onset, incidence, or sex bias of type 1 diabetes in NOD/ShiLtJ mice. Insulitis was prominent in both groups, but whereas NOD/ShiLtJ G6pc2(+/+) islets contained CD8(+) T cells reactive to the G6pc2 NRP peptide, G6pc2 NRP-reactive T cells were absent in NOD/ShiLtJ G6pc2(-/-) islets. CONCLUSIONS: These results demonstrate that G6pc2 is an important driver for the selection and expansion of islet-reactive CD8(+) T cells infiltrating NOD/ShiLtJ islets. However, autoreactivity to G6pc2 is not essential for the emergence of autoimmune diabetes. The results remain consistent with previous studies indicating that insulin may be the primary autoimmune target, at least in NOD/ShiLtJ mice.