Zonal Intratumoral Delivery of Nanoparticles Guided by Surface Functionalization.

Delivery of small molecules and anticancer agents to malignant cells or specific regions within a tumor is limited by penetration depth and poor spatial drug distribution, hindering anticancer efficacy. Herein, we demonstrate control over gold nanoparticle (GNP) penetration and spatial distribution across solid tumors by administering GNPs with different surface chemistries at a constant injection rate via syringe pump. A key finding in this study is the discovery of different zone-specific accumulation patterns of intratumorally injected nanoparticles dependent on surface functionalization. Computed tomography (CT) imaging performed in vivo of C57BL/6 mice harboring Lewis lung carcinoma (LLC) tumors on their flank and gross visualization of excised tumors consistently revealed that intratumorally administered citrate-GNPs accumulate in particle clusters in central areas of the tumor, while GNPs functionalized with thiolated phosphothioethanol (PTE-GNPs) and thiolated polyethylene glycol (PEG-GNPs) regularly accumulate in the tumor periphery. Further, PEG functionalization resulted in larger tumoral surface coverage than PTE, reaching beyond the outer zone of the tumor mass and into the surrounding stroma. To understand the dissimilarities in spatiotemporal evolution across the different GNP surface chemistries, we modeled their intratumoral transport with reaction-diffusion equations. Our results suggest that GNP surface passivation affects nanoparticle reactivity with the tumor microenvironment, leading to differential transport behavior across tumor zones. The present study provides a mechanistic understanding of the factors affecting spatiotemporal distribution of nanoparticles in the tumor. Our proof of concept of zonal delivery within the tumor may prove useful for directing anticancer therapies to regions of biomarker overexpression.

Prognostic and predictive impact of MGMT promoter methylation status in high risk grade II glioma.

BACKGROUND: MGMT promoter methylation has been associated with favorable prognosis and survival outcomes in patients with glioblastoma and WHO grade III glioma. However, the effects of promoter methylation of MGMT in patients with WHO grade II gliomas have not been established. The purpose of the current study is to evaluate the prognostic impact and predictive values of MGMT methylation in patients with grade II glioma. METHODS: The National Cancer Database (NCDB) was queried (2004-2016) for patients with newly diagnosed grade II glioma. Demographics and clinical characteristics of these patients were examined. Statistics included Kaplan-Meier overall survival (OS) analysis alongside Cox proportional hazards modeling. RESULTS: A total of 11,223 patients met the selection criteria; 1252 patients (11%) had MGMT testing. Of the patients who had MGMT testing, 58.5% were MGMT methylated (mMGMT), and 43.5% were MGMT unmethylated (uMGMT). mMGMT patients had greater median overall survival (77.3 months) than both uMGMT patients (42.6 months) and patients with no MGMT status reported (61.9 months (p < 0.001 for both). mMGMT was also associated with improved OS, when compared to patients with uMGMT, for patients receiving adjuvant chemoradiation or adjuvant radiation therapy. CONCLUSIONS: This is the largest study to date demonstrating both the prognostic and predictive impact of MGMT methylation on patients with grade II glioma. The current results show that mMGMT is a prognostic factor and possibly a predictive biomarker for grade II glioma patients. MGMT methylation status can be used to determine and stratify patients by risk levels, and thus select patients for treatment intensification. IMPORTANCE OF STUDY: The present study is the largest to date examining the prognostic and predictive significance of MGMT methylation (mMGMT) in patients with WHO grade II glioma. The results suggest that mMGMT is prognostic with increasing overall survival rates for patients with mMGMT compared to uMGMT patients. The results also suggest that mMGMT is predictive as shown by improved overall survival in patients receiving gross total resection, adjuvant chemoradiation or adjuvant radiation therapy, but no difference was observed in patients receiving adjuvant chemotherapy or no adjuvant treatment.

Quantifying the rate and predictors of occult lymph node involvement in patients with clinically node-negative non-small cell lung cancer.

PURPOSE: It is essential to evaluate the risk of occult lymph node (LN) disease in early-stage non-small cell lung cancer (NSCLC), especially because delivering stereotactic ablative radiotherapy (SABR) assumes no occult spread. This study was designed to assist clinicians in roughly quantifying this risk for cN0 NSCLC. METHODS: The National Cancer Data Base was queried for cN0 cM0 lung squamous cell or adenocarcinoma who underwent surgery and LN dissection without neoadjuvant therapy. Statistics included multivariable logistic regression to evaluate factors associated with pN + disease. RESULTS: 109,964 patients were included. For tumors with size ≤1.0, 1.1-2.0, 2.1-3.0, 3.1-4.0, 4.1-5.0, 5.1-6.0, 6.1-7.0, and >7.0 cm, the pN + rate was 4.4, 7.7, 12.9, 18.0, 20.2, 22.5, 24.4, and 26.4%, respectively. When examining patients with more complete LN dissections (defined as removal of at least 10 LNs), the respective values were 6.6, 11.5, 17.6, 25.3, 26.8, 29.7, 30.7, and 31.6%. Moderately-poorly differentiated disease and adenocarcinomas were associated with a higher rate of pN + disease (p < .001 for both). For every cm increase in tumor size, the relative occult nodal risk increased by 10-14% (p < .001). For every elapsed day from initial diagnosis, the relative risk increased by ∼1% (p < .001). Graphs with best-fit lines were created based on tumor size, histology, and differentiation to aid physicians in estimating the pN + risk. CONCLUSIONS: This nationwide study can allow clinicians to roughly estimate the rate of occult LN disease in cN0 NSCLC. These data can also assist in guiding enrollment on randomized trials of SABR ± immunotherapy, individualizing follow-up imaging surveillance, and patient counseling to avoid post-diagnosis delays.

Outcomes following stereotactic radiosurgery or whole brain radiation therapy by molecular subtype of metastatic breast cancer.

BACKGROUND: This study quantified clinical outcomes by molecular subtype of metastatic breast cancer (BC) following whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS). Doing so is important for patient counseling and to assess the potential benefit of combining targeted therapy and brain radiotherapy for certain molecular subtypes in ongoing trials. MATERIALS AND METHODS: The National Cancer Database was queried for BC (invasive ductal carcinoma) cases receiving brain radiotherapy (divided into WBRT and SRS ). Statistics included multivariable logistic regression to determine factors associated with SRS delivery, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling. RESULTS: Of 1,112 patients, 186 (16.7%) received SRS and 926 (83.3%) underwent WBRT. Altogether, 410 (36.9%), 195 (17.5%), 162 (14.6%), and 345 (31.0%) were ER+/HER2-, ER+/HER2+, ER-/HER2+, and ER-/HER2-, respectively. In the respective molecular subtypes, the proportion of subjects who underwent SRS was 13.4%, 19.4%, 24.1%, and 15.7%. Respective OS for WBRT patients were 12.9, 22.8, 10.6, and 5.8 months; corresponding figures for the SRS cohort were 28.3, 40.7, 15.0, and 12.9 months (p < 0.05 for both). When comparing OS between treatment different histologic subtypes, patients with ER-/HER2+ and ER-/HER2- disease had worse OS than patients with ER+/HER2- disease, for both patients treated with SRS and for patients treated with WBRT. CONCLUSIONS: Molecular subtype may be a useful prognostic marker to quantify survival following SRS/WBRT for metastatic BC. Patients with HER 2-enriched and triple-negative disease had the poorest survival following brain irradiation, lending credence to ongoing studies testing the addition of targeted therapies for these subtypes.

The impact of HER2-directed targeted therapy on HER2-positive DCIS of the breast.

BACKGROUND: In invasive breast cancer, HER2 is a well-established negative prognostic factor. However, its significance on the prognosis of ductal carcinoma in situ (DCIS) of the breast is unclear. As a result, the impact of HER2-directed therapy on HER2-positive DCIS is unknown and is currently the subject of ongoing clinical trials. In this study, we aim to determine the possible impact of HER 2-directed targeted therapy on survival outcomes for HER2-positive DCIS patients. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven DCIS diagnosed from 2004-2015. Patients were divided into two groups based on the adjuvant therapy they received: systemic HER2-directed targeted therapy or no systemic therapy. Statistics included multivariable logistic regression to determine factors predictive of receiving systemic therapy, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS. RESULTS: Altogether, 1927 patients met inclusion criteria; 430 (22.3%) received HER2-directed targeted therapy; 1497 (77.7%) did not. Patients who received HER2-directed targeted therapy had a higher 5-year OS compared to patients that did not (97.7% vs. 95.8%, p = 0.043). This survival benefit remained on multivariable analysis. Factors associated with worse OS on multivariable analysis included Charlson-Deyo Comorbidity Score ≥ 2 and no receipt of hormonal therapy. CONCLUSION: In this large study evaluating HER2-positive DCIS patients, the receipt of HER2-directed targeted therapy was associated with an improvement in OS. The results of currently ongoing clinical trials are needed to confirm this finding.

Survival Outcomes and Patterns of Management for Anal Adenocarcinoma.

BACKGROUND: Anal adenocarcinoma (AA) is a rare histologic subtype of anal cancer believed to have worse outcomes than anal squamous cell carcinoma (AS). This study aimed to examine practice patterns and treatment outcomes for this rare subtype using the National Cancer Data Base (NCDB). METHODS: Patients who had new diagnoses of anal cancer treated with chemoradiation were selected from the NCDB from 2004 to 2015. The patients were divided into two histologic groups (AA or AS). Statistics included the Chi square test to analyze categorical proportions in demographic information, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS. RESULTS: The study analyzed 24,461 patients. Compared with AS patients, AA patients were more likely to be male, to present with a higher cancer stage, to be older (> 65 years), and to undergo surgery with an abdominoperineal resection (APR). The median OS was 72.5 months for the AA patients and 143.8 months for the AS patients (P < 0.001). Survival was longer for the AA patients undergoing APR within 6 months after chemoradiation (CRT) than for the AA patients who had an APR 6 months after CRT (88.3 vs. 58.1 months; P < 0.001). In the multivariable analysis, the factors associated with worse survival included adenocarcinoma subtype, age of 55 years or older, male gender, T stage of 3 or higher, comorbidity score of 1 or higher, lower income, and treatment at a nonacademic institution. CONCLUSIONS: In this largest study of anal adenocarcinoma to date, trimodality therapy was associated with better survival than chemoradiation alone.

Socioeconomic Factors Associated with Lack of Treatment in Early Stage Non-Small Cell Lung Cancer.

With modern radiotherapy, stage I non-small cell lung cancer (S1NSCLC) cure is extended to nonsurgical candidates. Despite this, some S1NSCLC remains untreated. We aim to identify factors associated with no treatment. 62,213 S1NSCLC cases were identified (SEER: 2004-2012). Demographics were compared using Chi-squared. Multivariate analysis was performed using COX proportional HR. 11.9% of the 7373 patients lacked treatment. No insurance, Medicaid-dependence, unmarried status, advancing age, lower income, African American and Asian/Pacific Islander race, and male sex are associated with no treatment (p < .0001). No treatment portends a worse cancer-specific survival (21% vs 66% at 5Y, p < .0001) and OS (10% vs 50% at 5Y, p < .0001).

Neoadjuvant stereotactic body radiation therapy for nonmetastatic pancreatic adenocarcinoma.

Background: Neoadjuvant therapy is a strategy for resectable and borderline resectable pancreatic cancer, but a consensus approach regarding optimal management is undetermined. Neoadjuvant options include chemotherapy with/without radiotherapy. Stereotactic body radiation therapy (SBRT) is a novel radiation technique that may provide benefit over conventionally fractionated radiation therapy (CFRT) in the neoadjuvant setting. The purpose of the present study is to determine neoadjuvant treatment with SBRT to other neoadjuvant treatment options for patients with resectable pancreatic cancer. Material and methods: The National Cancer Database was queried (2004-2015) for patients with nonmetastatic pancreatic adenocarcinoma receiving neoadjuvant therapy followed by pancreatectomy. Patients were categorized based on the type of neoadjuvant treatment administered. Statistics included temporal trend assessment by annual percent change (APC), predictors for SBRT by multivariable logistic regression, Kaplan-Meier overall survival (OS) analysis without and with propensity matching, and Cox proportional hazards modeling for univariable OS analysis. Results: Of 5828 patients, 332 (5.7%), 3234 (55.5%) and 2262 (38.8%) received neoadjuvant chemo-SBRT, chemotherapy, and chemo-CFRT, respectively. SBRT utilization increased from 0% in 2004 to 9.5% in 2015, with a greater APC after 2010 (p < .001). SBRT was more likely to be utilized in patients with T3-4 and node-positive disease (p < .05 for all). The chemo-SBRT cohort was associated with a higher OS rate before and after propensity matching (p < .05 for both). The rate of R0 resection was higher in radiotherapy groups than the chemotherapy cohort (p < .001). Conclusions: Utilization of neoadjuvant SBRT for pancreatic cancer is increasing. In the neoadjuvant setting, chemo-SBRT may improve R0 resection and OS over chemotherapy and chemo-CFRT, although confirmatory prospective studies are needed for confirmation.

The impact of molecular status on survival outcomes for invasive micropapillary carcinoma of the breast.

Invasive micropapillary carcinoma (IMPC) is an uncommon variant of breast cancer. Previous studies demonstrated this subtype is often hormone receptor (HR)-positive, resulting in survival outcomes similar to invasive ductal carcinoma. However, many of these studies were conducted prior to HER2 testing availability. We aim to determine the impact of molecular marker status (including HER2 status) on IMPC survival outcomes. The National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven IMPC from 2007 to 2012. Only patients with known HR and HER2 status were included. Cox multivariate regression was used to determine prognostic factors. In total, 865 patients were included; median follow-up was 2.5 years. Overall, 651 patients (75.3%) had HR + HER2- disease, 128 (14.8%) had HR + HER2+ disease, 41 (4.7%) had HR-HER2 + disease, and 45 (5.2%) had triple negative disease. Patients with triple negative disease were more likely to have poorly differentiated histology (66.7%), lymphovascular invasion (73.3%), stage 3 disease (37.8%), undergone mastectomy (68.9%), and positive surgical margins (15.6%). On Cox multivariate regression, those with triple negative disease had worse overall survival (hazard ratio [HR] 7.28, P < 0.001). Other adverse prognostic factors included African-American descent (HR 2.24, P = 0.018), comorbidity score of 1 (HR 2.50, P = 0.011), comorbidity score ≥2 (HR 3.27, P = 0.06), and ≥3 positive lymph nodes (HR 3.23, P = 0.007). Similar to invasive ductal carcinoma, triple negative disease in IMPC results in worse survival outcomes. This is the largest and first study to characterize molecular status (including HER2 status) in patients with IMPC and its impact on survival outcomes.

Metaplastic Breast Cancer: Practice Patterns, Outcomes, and the Role of Radiotherapy.

PURPOSE: Metaplastic breast cancer (MBC) is a rare, aggressive form of breast cancer with limited data to guide management. This study of a large, contemporary US database described national practice patterns and addressed the impact of radiotherapy (RT) on survival. METHODS: The National Cancer Data Base was queried (2004-2013) for women with non-metastatic MBC. Multivariable logistic regression ascertained factors associated with RT administration. Kaplan-Meier analysis evaluated overall survival (OS) between patients treated with either lumpectomy or mastectomy with or without RT, while substratifying patients into pT1-2N0 and pT3-4/N+ subcohorts. Cox proportional hazards modeling determined variables associated with OS. RESULTS: Of 5211 total patients, 447 (9%) had lumpectomy alone, 1831 (35%) had post-lumpectomy RT, 2020 (39%) had mastectomy alone, and 913 (18%) had post-mastectomy RT (PMRT). Most patients underwent chemotherapy (79%), and mastectomy was the most common surgical approach (56%). RT delivery was impacted by many factors, including higher nodal disease (p < 0.001), but not T classification or estrogen receptor status (p > 0.05 for both). Post-lumpectomy RT was associated with higher OS in both the pT1-2N0 and pT3-4/N+ subsets (p < 0.001 for both), while PMRT was associated with OS benefits in pT3-4/N+ cases (p < 0.001), but not in pT1-2N0 cases (p = 0.259). CONCLUSIONS: In the largest study to date evaluating MBC, practice patterns of surgery, systemic therapy, and RT are described. The addition of RT in the post-lumpectomy setting was associated with higher OS, in addition to pT3-4/N+ in the post-mastectomy setting. Although not implying causation, further work is required to corroborate the conclusions herein.

Addition of chemotherapy to hypofractionated radiotherapy for glioblastoma: practice patterns, outcomes, and predictors of survival.

This study evaluated practice patterns, outcomes, and predictors of survival with respect to the addition of chemotherapy to definitive hypofractionated radiation therapy (HFRT) for glioblastoma in a general patient population. The National Cancer Data Base was queried for patients diagnosed with glioblastoma between 2005 and 2012 that received definitive HFRT with or without chemotherapy. Patient, tumor, and treatment parameters were extracted. Statistics included Kaplan-Meier analysis to evaluate overall survival (OS) as well as Cox proportional hazards modeling to determine variables associated with receipt of chemotherapy and OS. Propensity score matching was performed in order to assess groups in a balanced manner while reducing indication biases. 693 patients met the inclusion criteria, of which 297 (42.9%) received HFRT alone, while 396 (57.1%) received chemotherapy and radiation therapy. Median follow-up was 5.2 months. Factors independently associated with chemotherapy delivery included age ≤ 65, methylated MGMT, and Asian race. Chemotherapy use was associated with improved median OS (6.8 vs. 4.3 months, p < 0.001). This persisted in both age groups of age ≤ 65 (8 vs. 4.4 months, p < 0.001) and > 65 years (6.1 vs. 4.3 months, p = 0.002) as well as on propensity-matched analysis (6.0 vs. 4.3 months, p < 0.001). In this patient population, novel independent predictors of OS were identified, which included the addition of chemotherapy (p < 0.001), receipt of surgery other than biopsy (both p < 0.05), and treatment at an academic institution (p = 0.002). Addition of chemotherapy to definitive HFRT was associated with improved OS in patients ≤ 65 and > 65 years of age. Chemotherapy was an independent predictor of OS, along with receipt of surgery and treatment at an academic institution.

Management of pathologic node-positive disease following initial surgery for clinical T1-2 N0 esophageal cancer: patterns of care and outcomes from the national cancer data base.

PURPOSE: Although clinical T1-2N0 esophageal cancer (EC) is often initially surgically resected (without neoadjuvant therapy), several studies have illustrated substantial rates of discovering pathologically node-positive disease. This study evaluated national practice patterns of adjuvant therapy for this population. METHODS: The National Cancer Database (NCDB) was queried (2004-2013) for patients with cT1-2N0M0 EC that received up-front surgery (esophagectomy/local techniques) with subsequent discovery of nodal metastasis. Patients receiving any neoadjuvant therapy were excluded. Multivariable logistic regression determined factors predictive of receiving adjuvant therapy. Kaplan-Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. Propensity score matching assessed groups in a balanced manner while reducing indication biases. RESULTS: Altogether, 715 patients met inclusion criteria; 114 (16%) underwent adjuvant chemotherapy, 183 (26%) chemoradiation, 16 (2%) radiotherapy alone, and 402 (56%) observation. Observation was more likely performed with advanced age (p = .002) and at nonacademic centers (p = .001). Median OS in the respective cohorts were 42.6, 35.1, 22.2, and 27.0 months. Both chemotherapy and chemoradiation were statistically similar (p = .462) but superior to observation (p < .05 for both). There was a survival benefit to any adjuvant treatment (median OS 38.5 vs. 27.0 months, p < .001), which persisted after propensity matching (median OS 35.1 vs. 24.3 months, p < .001). On multivariable analysis, any adjuvant treatment was independently associated with improved OS, along with treatment at an academic center (p < .05 for all). CONCLUSIONS: In the largest study to date evaluating patterns of care for pN + disease following resection of cT1-2N0 EC, a strikingly high proportion of patients were observed. Adjuvant treatment, ideally chemotherapy or chemoradiation, independently correlated with higher survival, and should be considered in able patients. Treatment at academic facilities also associated with higher survival, which has implications for patient counseling.

The role of adjuvant chemotherapy in locally advanced bladder cancer.

PURPOSE: The standard of care for locally advanced bladder cancer (LABC) is neoadjuvant chemotherapy followed by cystectomy. However, the role of adjuvant therapy is unclear. The purpose of this study was to evaluate the outcomes of adjuvant chemotherapy for patients with LABC following neoadjuvant chemotherapy and cystectomy, and to determine whether select patients may benefit from adjuvant chemotherapy. METHODS: The National Cancer Data Base (NCDB) was queried (2004-2013) for patients with newly diagnosed pT3-4N0-3M0 bladder cancer that received neoadjuvant chemotherapy and cystectomy. Patients were divided into two groups based on the adjuvant therapy they received: chemotherapy alone or observation. Statistics included multivariable logistic regression to determine factors predictive of receiving adjuvant chemotherapy, Kaplan-Meier analysis to evaluate overall survival (OS) and Cox proportional hazards modeling to determine variables associated with OS. RESULTS: Altogether, 2592 patients met inclusion criteria; 901 (34.8%) patients received adjuvant chemotherapy, while 1691 (65.2%) were observed. Patients treated with adjuvant chemotherapy were more likely to have positive margins were younger and more likely to receive treatment at a nonacademic facility. There was no difference in median OS between patients treated with or without adjuvant chemotherapy (22.6 vs. 21.1 months; p = .267). However, a longer median OS was observed with the use of adjuvant chemotherapy was observed among patients with N2-3 disease (17.5 vs. 14.4 months; p = .005) and positive surgical margins (16.7 vs. 12.2 months; p = .025). On multivariate analysis, advancing age, pT4 stage, positive N stage, positive margins and lower socioeconomic status were associated with worse OS. CONCLUSIONS: In the largest study to date evaluating efficacy of adjuvant chemotherapy, while no difference in OS was observed for adjuvant chemotherapy in all patients, a longer OS was observed among patients with N2-3 disease or with positive surgical margins. Prospective studies are recommended to further evaluate these findings.

Trends in cardiac mortality in women with ductal carcinoma in situ.

PURPOSE: In certain ductal carcinoma in situ (DCIS) subpopulations, there is no consensus regarding whether to postoperatively irradiate; decisions are often made based on potential risk of cardiac toxicities. Given the utility of Surveillance, Epidemiology, and End Results (SEER) data for studying cardiac mortality in invasive disease, this is the first such study specific for DCIS patients, evaluating trends in cardiac mortality after left-sided radiotherapy (RT). METHODS: The SEER database was queried for patients with DCIS that received RT and had known unilaterality. The central design of this study was to compare cardiac-specific mortality (CSM) between left- and right-sided DCIS patients as stratifying for "older" RT (1973-1982) versus more "modern" RT (1983-1992 or 1993-2002). Survival analysis was performed using Kaplan-Meier methodology and multivariate Cox regression modeling for factors associated with overall survival (OS) and CSS. RESULTS: Left- and right-sided patients were demographically balanced. CSM was worse for left-sided patients with DCIS diagnosed in 1973-1982 [hazard ratio (HR) 1.295; 95% confidence interval (CI) 1.182-1.420], but not in 1983-1992 (HR 1.022; 95% CI 0.949-1.100) or in 1993-2002 (HR 0.989; 95% CI 0.935-1.046)]. On multivariate analysis, laterality was not associated with OS in either decade. However, left-sided laterality was independently associated with CSM during the 1973-1982 time period, but not the more recent time periods. Examining temporal patterns in the 1973-1982 cohort, cardiac mortality was significantly increased during 10-19 and ≥20 years after diagnosis, but there was no significant increase in cardiac mortality for patients diagnosed up to 10 years after diagnosis. CONCLUSIONS: In the largest such DCIS series to date, left-sided RT was an independent risk factor for increased cardiac mortality from 1973 to 1982, but not after 1983. Using modern RT techniques and maintaining low heart doses, RT may not induce excess CSM in the DCIS population.

Addition of chemotherapy to definitive radiotherapy for IB1 and IIA1 cervical cancer: Analysis of the National Cancer Data Base.

PURPOSE: The standard treatment for stage IB1 and IIA1 cervical carcinoma is surgery. For non-operative cases, the National Comprehensive Cancer Network recommends definitive radiotherapy (RT) with or without chemotherapy. This study sought to determine whether the addition of chemotherapy to RT improved overall survival (OS) for patients with stage IB1 and IIA1 cervical cancer. METHODS: We used the National Cancer Data Base to identify patients with stage IB1 or stage IIA1 cervical cancer diagnosed in 2004 to 2012 who received definitive RT with or without chemotherapy. Patient, tumor, and treatment facility characteristics were assessed. Kaplan-Meier analysis was performed to compare overall survival (OS) between groups. Cox regression analysis was performed to identify factors associated with survival. Propensity-score matching was used to compare survival outcomes while accounting for indication bias. RESULTS: 825 patients met the specified criteria. 275 (33.3%) of patients received treatment with RT alone, whereas 550 (66.7%) were treated with CRT. The median OS in patients treated with RT alone was 121.1months, while the median OS for patients treated with CRT was not reached (hazard ratio [HR]=0.719; 95% confidence interval [CI] 0.549-0.945). Propensity-score matched analysis confirmed that CRT was superior to RT alone (HR=0.701; 95% CI 0.509 to 0.963). CONCLUSIONS: Our study suggests the addition of chemotherapy to definitive RT in patients with stage IB1 or stage IIA1 cervical cancer is associated with an improvement in OS. Prospective studies are recommended to validate these results and to further investigate the quality of life differences associated with chemotherapy use.

Definitive chemoradiation at high volume facilities is associated with improved survival in glioblastoma.

The standard of care for glioblastoma (GBM) is maximal safe resection followed by concurrent chemoradiation (CRT). For several neoplasms, receipt of radiation treatment at high-volume facilities has been associated with improved overall survival (OS). The purpose of the present investigation was to determine if there was an association between receipt of CRT for GBM at facilities with a higher case volume and improved OS. The National Cancer Data Base was queried for patients with GBM diagnosed between 2006 and 2012 that received full-course CRT. Statistics included Kaplan-Meier analysis to compare OS between patients treated facilities with the highest quartile volume (HVF) to those treated at lower case volume facilities, multivariate logistic regression to determine factors associated with treatment at a HVF, and Cox proportional hazards modeling to determine variables associated with OS. A total of 4892 patients met the specified criteria. Fourteen facilities (9.9%) treated the highest quartile volume of patients, while 69 (48.6%) treated the lowest quartile volume (LVF) of patients. Treatment at the HVF was associated with improved median OS (16.5 vs. 14.1 months, p < 0.001). Treatment at a LVF also independently predicted for worse OS on multivariate analysis, along with age >70 years, and a resection limited to a biopsy. This is the first study to demonstrate that treatment of GBM with CRT at a HVF is associated with improved survival. Major goals of future oncologic care should be to achieve greater standardization of quality of treatment across facilities with different case volumes.

Patterns of care and outcomes of multi-agent versus single-agent chemotherapy as part of multimodal management of low grade glioma.

For high-risk low-grade gliomas (LGGs), adjuvant radiotherapy (RT) with procarbazine/lomustine/vincristine (PCV) chemotherapy increases overall survival (OS) over RT alone. However, in practice, temozolomide (TMZ) is often used instead of PCV. Using the National Cancer Data Base (NCDB), we provide the first investigation of practice patterns and outcomes of chemoradiotherapy with single-agent chemotherapy (SAC, analogous to TMZ) or multi-agent chemotherapy (MAC, analogous to PCV) for LGG. Patients with high-risk Grade II LGGs were queried in the NCDB. Inclusion was limited to patients treated with definitive RT and chemotherapy. Patients were divided into cohorts receiving SAC or MAC. Kaplan-Meier analysis compared overall survival (OS), and Cox proportional hazards models determined variables independently associated with OS. Of 1029 patients, 989 (96.1%) received SAC, while 40 (3.9%) received MAC. Patients treated more recently (2010-2012) were less likely to receive MAC (p = 0.029). No differences in median OS were observed between patients treated with MAC and SAC (45.3 vs. 59.2 months, p = 0.861). Independent predictors of worse OS included age >40, high Charlson-Deyo index, other governmental/unrecorded insurance status, biopsy only, astrocytoma histology, Western geographical region, and higher income. Substuting MAC with SAC had no impact on OS (p = 0.804). There is a significantly greater utilization of SAC compared to MAC in the US. There were no differences in OS between patients receiving SAC and MAC, nor did this factor impact OS on multivariate analysis, suggesting that the practice of substituting MAC with SAC for management of LGG may not adversely affect outcome.

Personalized radiation therapy for glioblastoma.

Glioblastoma is the most common primary brain tumor with an estimated 14,000 Americans diagnosed with this disease annually. This disease is treated with maximal surgical resection followed by adjuvant radiation therapy. Radiation therapy was initially delivered to the whole brain and with no concurrent or adjuvant systemic therapy. Advances in imaging and treatment delivery have allowed for partial brain irradiation to minimize radiation dose to normal structures, as well as sparing structures important for memory such as the hippocampus, decreasing morbidity and toxicity. While there is no consensus on the optimal radiation volume needed to successfully treat glioblastoma, there is consensus that the tumor bed with margin is preferable to treatment of the whole brain. Additionally, advances in knowledge regarding tumor biology have demonstrated the benefit of concurrent and adjuvant chemotherapy, as well as demonstrated that methylation of genes in the tumor can predispose greater responsiveness to chemotherapy. The following review describes the advancements in specific radiation techniques that have been used to improve the therapeutic ratio for management of glioblastoma and methods used to personalize radiation treatment for patients based on genomic markers as well as clinical factors. The review also describes future investigations that are currently taking place in order to enable a further improvement of clinical outcomes for patients with glioblastoma.

Salvage intensity modulated radiotherapy using endorectal balloon after radical prostatectomy: clinical outcomes.

OBJECTIVES: To evaluate biochemical non-evidence of disease and adverse events of salvage intensity-modulated radiotherapy using an endorectal balloon for prostate cancer patients after radical prostatectomy. METHODS: Data of 107 patients (median age 65 years) with persistent (>0.1 ng/mL) or rising prostate-specific antigen after radical prostatectomy were retrospectively analyzed. The mean dose to clinical target volume was 70 Gy in 32 fractions (the equivalent dose in 2 Gy fraction is 73.2 Gy based on α:ß = 2). Biochemical non-evidence of disease and predictive factors were assessed. Genitourinary toxicity and gastrointestinal toxicity were also evaluated using the Radiation Therapy Oncology Group toxicity criteria. RESULTS: The median follow up was 37 months (range 6-126 months). A total of 48 patients developed biochemical recurrence. The 3- and 5-year biochemical non-evidence of disease rates of all patients were 52.6% and 48.8%, respectively. The Gleason score (≥4 + 3, ≤3 + 4) and pre-intensity-modulated radiotherapy prostate-specific antigen level (≥0.5 ng/mL, <0.5 ng/mL) were significant predictive factors for biochemical non-evidence of disease in univariate analysis. In multivariate analysis, only the Gleason score was detected as a significant variable. The highest late genitourinary toxicities were grade 2 in 13% and grade 3 in 6% of patients. The highest late gastrointestinal toxicities were grade 2 in 6% and grade 3 in 3% of patients. CONCLUSION: Despite a relatively high radiation dose, intensity-modulated radiotherapy with an endorectal balloon can be delivered with acceptable toxicity and efficacy for patients developing biochemical recurrence after radical prostatectomy.

Radiation Pneumonitis, Really? A Case of Pulmonary Toxicity from CDK4/6 Inhibitor.

BACKGROUND/AIM: Radiation pneumonitis is a known complication of radiotherapy. It is also a rare complication of CDK4/6 inhibitors, and it can be difficult to differentiate the two. This is a report of a case of pulmonary toxicity from a CDK4/6 inhibitor, which was initially ascribed to radiation pneumonitis. CASE REPORT: A 77-year-old female was diagnosed with pneumonitis after receiving radiation to the thoracic spine. She had also been treated with abemaciclib. Upon review, the patient's lung mean dose was 11.54 Gy with a V20 of 17.02%, and the area of pneumonitis was largely outside of the treatment field. Abemaciclib was ceased. The patient was started on supportive oxygen as well as steroids. She no longer required oxygen and she was discharged from the hospital. Radiation pneumonitis is largely correlated with the volume of lung radiated and dose of radiation to the lung. CDK4/6 inhibitor pulmonary toxicity, while rare, is possible and will likely become more frequent with increasing use of these agents. CONCLUSION: Patients receiving CDK4/6 inhibitors are at an increased risk for pneumonitis. It can be confused with radiation pneumonitis and must be included in the differential diagnosis.