Lack of reduction in racial disparities in cancer-specific mortality over a 20-year period.

BACKGROUND: To the authors' knowledge, it remains unknown whether race-based differences in cancer outcomes have changed with time. In the current study, the authors assessed whether racial disparities in cancer-specific mortality have improved over the last 20 years. METHODS: The Surveillance, Epidemiology, and End Results program was used to identify 2,713,474 patients diagnosed between 1988 and 2007 with either lung, breast, prostate, or colorectal cancer (the leading 3 causes of cancer-related mortality among each sex). After exclusions, 1,001,978 patients remained eligible for analysis. The impact of race on cancer-specific mortality was assessed using the regression model of Fine and Gray; an interaction model evaluated trends over time. RESULTS: African Americans presented with a more advanced stage of disease (P < .001) and underwent definitive therapy less often (P < .001) than whites. After adjustment for demographics and year of diagnosis, African Americans were found to have higher estimates of cancer-specific mortality than whites for all cancers combined (hazards ratio, 1.28; 95% confidence interval, 1.26-1.30 [P < .001]) and within each individual cancer (each P < .05). These differences did not change significantly between 1988 through 1997 and 1998 through 2007, except among patients with breast cancer, in whom survival disparities increased. These findings remained significant after adjustment for stage of disease at presentation and receipt of definitive therapy (hazards ratio for breast cancer mortality in African Americans vs whites: 1.37 from 1988-1997 and 1.53 from 1998-2007; P for interaction, < .001). CONCLUSIONS: The survival gap for African Americans has not closed over time. Race-based differences in outcome persist independent of stage of disease and treatment, suggesting that additional strategies beyond screening and improving access to care, such as further research into tumor biologies disproportionately affecting African Americans, are needed to improve survival for African American patients with cancer.

Inhibition of tyrosine kinase Fgr prevents radiation-induced pulmonary fibrosis (RIPF).

Cellular senescence is involved in the development of pulmonary fibrosis as well as in lung tissue repair and regeneration. Therefore, a strategy of removal of senescent cells by senolytic drugs may not produce the desired therapeutic result. Previously we reported that tyrosine kinase Fgr is upregulated in ionizing irradiation-induced senescent cells. Inhibition of Fgr reduces the production of profibrotic proteins by radiation-induced senescent cells in vitro; however, a mechanistic relationship between senescent cells and radiation-induced pulmonary fibrosis (RIPF) has not been established. We now report that senescent cells from the lungs of mice with RIPF, release profibrotic proteins for target cells and secrete chemotactic proteins for marrow cells. The Fgr inhibitor TL02-59, reduces this release of profibrotic chemokines from the lungs of RIPF mice, without reducing numbers of senescent cells. In vitro studies demonstrated that TL02-59 abrogates the upregulation of profibrotic genes in target cells in transwell cultures. Also, protein arrays using lung fibroblasts demonstrated that TL02-59 inhibits the production of chemokines involved in the migration of macrophages to the lung. In thoracic-irradiated mice, TL02-59 prevents RIPF, significantly reduces levels of expression of fibrotic gene products, and significantly reduces the recruitment of CD11b+ macrophages to the lungs. Bronchoalveolar lavage (BAL) cells from RIPF mice show increased Fgr and other senescent cell markers including p16. In human idiopathic pulmonary fibrosis (IPF) and in RIPF, Fgr, and other senescent cell biomarkers are increased. In both mouse and human RIPF, there is an accumulation of Fgr-positive proinflammatory CD11b+ macrophages in the lungs. Thus, elevated levels of Fgr in lung senescent cells upregulate profibrotic gene products, and chemokines that might be responsible for macrophage infiltration into lungs. The detection of Fgr in senescent cells that are obtained from BAL during the development of RIPF may help predict the onset and facilitate the delivery of medical countermeasures.

Development of a MicroRNA Signature Predictive of Recurrence and Survival in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Optimal patient selection for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) is unestablished. Molecular profiling may select patients at high risk for locoregional recurrence (LRR) who would benefit from radiation. METHODS: We included resectable pancreatic cancer (R-PDAC) patients, divided into training and validation cohorts, treated among three institutions with surgery and adjuvant chemotherapy, and borderline resectable or locally advanced pancreatic cancer (BR/LA-PDAC) patients treated with chemotherapy with or without radiation at the primary study institution. We isolated RNA from R-PDAC surgical specimens. Using NanoString, we identified miRNAs differentially expressed between normal and malignant pancreatic tissue. ElasticNet regression identified two miRNAs most predictive of LRR in the training cohort, miR-181b/d and miR-575, which were used to generate a risk score (RS). We evaluated the association of the median-dichotomized RS with recurrence and overall survival (OS). RESULTS: We identified 183 R-PDAC and 77 BR/LA-PDAC patients with median follow up of 37 months treated between 2001 and 2014. On multivariable analysis of the R-PDAC training cohort (n = 90), RS was associated with worse LRR (HR = 1.34; 95%CI 1.27-11.38; p = 0.017) and OS (HR = 2.89; 95%CI 1.10-4.76; p = 0.027). In the R-PDAC validation cohort, RS was associated with worse LRR (HR = 2.39; 95%CI 1.03-5.54; p = 0.042), but not OS (p = 0.087). For BR/LA-PDAC, RS was associated with worse LRR (HR = 2.71; 95%CI 1.14-6.48; p = 0.025), DR (HR = 1.93; 95%CI 1.10-3.38; p = 0.022), and OS (HR = 1.97; 95%CI 1.17-3.34; p = 0.011). Additionally, after stratifying by RS and receipt of radiation in BR/LA-PDAC patients, high RS patients who did not receive radiation had worse LRR (p = 0.018), DR (p = 0.006), and OS (p < 0.001) compared to patients with either low RS or patients who received radiation, irrespective of RS. CONCLUSIONS: RS predicted worse LRR and OS in R-PDAC and worse LRR, DR, and OS in BR/LA-PDAC. This may select patients who would benefit from radiation and should be validated prospectively.

11C-Choline PET Guided Salvage Radiation Therapy for Isolated Pelvic and Paraortic Nodal Recurrence of Prostate Cancer After Radical Prostatectomy: Rationale and Early Genitourinary or Gastrointestinal Toxicities.

PURPOSE: To assess gastrointestinal (GI) and genitourinary (GU) adverse events (AEs) of 11C-choline-positron emission tomography (CholPET) guided lymph node (LN) radiation therapy (RT) in patients who experience biochemical failure after radical prostatectomy. METHODS AND MATERIALS: From 2013 to 2016, 107 patients experienced biochemical failure of prostate cancer, had CholPET-detected pelvic and/or paraortic LN recurrence, and were referred for RT. Patients received androgen suppression and CholPET guided LN RT (median dose, 45 Gy) with a simultaneous integrated boost to CholPET-avid sites (median dose, 56.25 Gy), all in 25 fractions. RT-naïve patients had the prostatic fossa included in the initial treatment volumes followed by a sequential boost (median dose, 68 Gy). GI and GU AEs were reported per Common Terminology Criteria for Adverse Events (version 4.0) with data gathered retrospectively. Differences in maximum GI and GU AEs at baseline, immediately post-RT, and at early (median, 4 months) and late (median, 14 months) follow-up were assessed. RESULTS: Median follow-up was 16 months (interquartile range [IQR], 11-25). Median prostate-specific antigen at time of positive CholPET was 2.3 ng/mL (IQR, 1.3-4.8), with a median of 2 (IQR, 1-4) choline-avid LNs per patient. Most recurrences were within the pelvis (53%) or pelvis + paraortic (40%). Baseline rates of grade 1 to 2 GI AEs were 8.4% compared with 51.9% (4.7% grade 2) of patients post-RT (P < .01). These differences resolved by 4-month (12.2%, P = .65) and 14-month AE assessments (9.1%, P = .87). There was no significant change in grade 1 to 2 GU AEs post-RT (64.1%) relative to baseline (56.0%, P = .21), although differences did arise at 4-month (72.2%, P = .01) and 14-month (74.3%, P = .01) AE assessments. CONCLUSIONS: Salvage CholPET guided nodal RT has acceptably low rates of acute GI and GU AEs and no significant detriment in 14-month GI AEs. These data are of value in counseling patients and designing prospective trials evaluating the oncologic efficacy of this treatment strategy.

A Comparison of Patient-Reported Health-Related Quality of Life During Proton Versus Photon Chemoradiation Therapy for Esophageal Cancer.

PURPOSE: The purpose of this study was to compare Functional Assessment of Cancer Therapy-Esophagus (FACT-E) questionnaire changes during proton (PRT) or photon (XRT) chemoradiation therapy (CRT) for esophageal cancer (EC). METHODS AND MATERIALS: We reviewed patients enrolled in a prospective registry who received preoperative or definitive CRT for EC. Patients completed the FACT-E before CRT and during the last week of CRT. Analysis of variance testing was used to assess associations between patient and treatment characteristics and FACT-E score changes. RESULTS: One hundred twenty-five patients completed a baseline and posttreatment FACT-E; 63 received XRT and 62 received PRT. The mean age was 65 years; the PRT group was older (68 vs 64 years, P = .0063). The following characteristics were similar between cohorts: 83% male, 78% adenocarcinoma, and 89% stage II-III. The radiation therapy prescription dose was higher in the PRT group (≥50 Gy in 94% vs 67%, P < .0001), whereas the median clinical target volume was smaller in the PRT group (553 vs 668 cm3, P = .013). Most (96%) received concurrent weekly carboplatin-paclitaxel. The mean FACT-E score was 136.3 (standard deviation [SD] 21.0) at baseline and 119.6 (SD 24.8) post-CRT, with mean change of -16.7 (SD 19.8). Baseline scores were comparable between XRT and PRT groups (135.9 vs 136.7, P = .82). On univariate and multivariate analyses, less mean decline in FACT-E score was observed for PRT versus XRT (-12.7 vs -20.6, P = .026) and for trimodality versus definitive therapy (-13.0 vs -22.5, P = .008). CONCLUSIONS: For patients receiving CRT for EC, PRT was associated with less decline in FACT-E scores compared with XRT.

Increased utilization of external beam radiotherapy relative to cystectomy for localized, muscle-invasive bladder cancer: a SEER analysis.

OBJECTIVE: To assess recent utilization patterns of radiotherapy (RT) relative to cystectomy for muscle-invasive bladder cancer (MIBC) and evaluate survival trends over time in patients receiving RT. MATERIALS AND METHODS: The surveillance, epidemiology, and end results program (SEER) was used to identify patients diagnosed between 1992 and 2013 with localized MIBC. Patients with a prior history of non-bladder malignancy, who received no treatment, or did not have available treatment information, were excluded. Treatment utilization patterns were assessed using Cochran-Armitage tests for trend, and patient characteristics were compared using chi-square tests. Overall survival (OS) and cause-specific survival (CSS) were estimated using the Kaplan-Meier method. All-cause (ACM) and cause-specific mortality (CSM) were evaluated with multivariable Cox proportional hazards regression. RESULTS: Of 16175 patients analyzed, 11917 (74%) underwent cystectomy, and 4258 (26%) were treated with RT. Patients who received RT were older (median age 79 vs. 68, P < 0.01). Over time, the proportion of patients receiving RT relative to cystectomy increased (24% 1992-2002 vs. 28% 2003-2013, P < 0.01), despite median patient age throughout the study period remaining unchanged (71 for each 1992-2002 and 2003-2013, P = 0.41). For RT, compared with patients diagnosed earlier, those diagnosed from 2010-2013 showed improved OS (64% vs. 60% at 1 year, P < 0.01; 38% vs. 29% at 3 years, P < 0.01) and CSS (71% vs. 67% at 1 year, P = 0.01; 51% vs. 40% at 3 years, P < 0.01). On multivariable analysis, diagnosis from 2010-2013 was associated with a lower estimated risk of ACM (hazard ratio 0.77; 95% confidence interval 0.66-0.89, P < 0.001) and CSM (hazard ratio 0.81; 95% confidence interval 0.67-0.97, P = 0.02). CONCLUSION: Utilization of RT for localized MIBC increased relative to cystectomy from 1992 to 2013, despite the median age of treated patients remaining unchanged. More recent survival outcomes for patients receiving RT were improved, supporting continued use of bladder preservation strategies utilizing RT.

Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy.

PURPOSE: To analyze immune-related adverse events (ir-AEs) in patients treated with radiation and immune checkpoint blockade. METHODS AND MATERIALS: We retrospectively reviewed records from patients with metastatic non-small cell lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined using Common Terminology Criteria for Adverse Events version 4.0, were tabulated in relation to treatment variables, and associations with sequencing and timing were assessed. RESULTS: We identified 133 patients, of whom 28 received a CTLA-4 inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six patients received radiation within 14 days of an immune checkpoint inhibitor. Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs. CONCLUSIONS: Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated. Although conclusions are limited by the heterogeneity of patients and treatments, and future confirmatory studies are needed, this information can help guide clinical practice for patients receiving immune checkpoint therapy who require palliative radiation therapy.

A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab.

Case reports and preclinical data suggest radiotherapy and immunotherapy may synergize to generate "abscopal" responses outside the radiation field. This phenomenon remains relatively unexplored, prompting our systematic evaluation of metastatic melanoma patients treated with the CTLA-4 inhibitor ipilimumab and palliative radiation therapy. We evaluated 47 consecutive metastatic melanoma patients treated with ipilimumab and 65 courses of radiation. Responses of index lesions outside the radiation field were compared before and after radiotherapy, and parameters associated with favorable response were assessed. Median survival was 28 months, with an estimated 20% 5-y survival. Index lesions shrank in 7 instances prior to radiation therapy (11%), compared with 16 instances (25%) after radiation therapy; in 11 of the latter instances (69%), the index lesion had been increasing in size prior to radiotherapy (P = 0.03). In 68% of cases, radiotherapy was associated with an improved rate of index lesion response (P = 0.006). Radiation fraction size ≤ 3 Gy was the only parameter identified associated with favorable index lesion response (P = 0.014). Our systematic review of melanoma patients treated with radiotherapy and ipilimumab suggests that a subset of patients may have more favorable out-of-field responses following treatment with radiation. Interestingly, we found that multiple fraction radiation regimens were associated with a more favorable response. These results are encouraging regarding potential synergies between radiation and immunotherapy, but suggest that attention and even prospective testing of radiation parameters critical to producing abscopal effects in human patients would be of value.

Marital status and survival in patients with cancer.

PURPOSE: To examine the impact of marital status on stage at diagnosis, use of definitive therapy, and cancer-specific mortality among each of the 10 leading causes of cancer-related death in the United States. METHODS: We used the Surveillance, Epidemiology and End Results program to identify 1,260,898 patients diagnosed in 2004 through 2008 with lung, colorectal, breast, pancreatic, prostate, liver/intrahepatic bile duct, non-Hodgkin lymphoma, head/neck, ovarian, or esophageal cancer. We used multivariable logistic and Cox regression to analyze the 734,889 patients who had clinical and follow-up information available. RESULTS: Married patients were less likely to present with metastatic disease (adjusted odds ratio [OR], 0.83; 95% CI, 0.82 to 0.84; P < .001), more likely to receive definitive therapy (adjusted OR, 1.53; 95% CI, 1.51 to 1.56; P < .001), and less likely to die as a result of their cancer after adjusting for demographics, stage, and treatment (adjusted hazard ratio, 0.80; 95% CI, 0.79 to 0.81; P < .001) than unmarried patients. These associations remained significant when each individual cancer was analyzed (P < .05 for all end points for each malignancy). The benefit associated with marriage was greater in males than females for all outcome measures analyzed (P < .001 in all cases). For prostate, breast, colorectal, esophageal, and head/neck cancers, the survival benefit associated with marriage was larger than the published survival benefit of chemotherapy. CONCLUSION: Even after adjusting for known confounders, unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer. This study highlights the potentially significant impact that social support can have on cancer detection, treatment, and survival.