O.Y. Mian

Management Options in Locally Advanced Pancreatic Cancer

Pancreatic ductal adenocarcinoma is a highly lethal cancer that is rarely curable at the time of presentation. Unfortunately, most patients are diagnosed with either metastatic or locally advanced disease, which is not amenable to surgery owing to the high likelihood of incomplete resection. Given the generally poor prognosis with propensity for metastatic failure greater than that for local failure, treatment options are variable, and include chemotherapy, radiotherapy, targeted therapies, and combinations thereof. This review summarizes the current evidence for definitive management of locally advanced pancreatic adenocarcinoma, as well as the role of palliative therapies. Future directions, including the development of predictive biomarkers and novel systemic agents, are also discussed.

GSTP1 Loss Results in Accumulation of Oxidative DNA Base Damage and Promotes Prostate Cancer Cell Survival Following Exposure to Protracted Oxidative Stress

Epigenetic silencing of glutathione S‐transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR).

Androgen deprivation followed by acute androgen stimulation selectively sensitizes AR-positive prostate cancer cells to ionizing radiation

Purpose: The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen-deprived prostate cancer cells leads to formation of double-strand breaks (DSB). Here, we exploit this finding and investigate the extent and timing of androgen-induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR). Experimental Design: Androgen-induced DNA damage was assessed by comet assays and γH2A.X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models. Results: We document that androgen treatment of androgen-deprived prostate cancer cell lines resulted in a dose- and time-dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor and topoisomerase II beta but not on cell-cycle progression. In vitro models demonstrated a synergistic interaction between IR and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice. Conclusions: These results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy. Clin Cancer Res; 22(13); 3310–9. ©2016 AACR. See related commentary by Chua and Bristow, p. 3124

The human sodium-dependent ascorbic acid transporters SLC23A1 and SLC23A2 do not mediate ascorbic acid release in the proximal renal epithelial cell

Sodium‐dependent ascorbic acid membrane transporters SLC23A1 and SLC23A2 mediate ascorbic acid (vitamin C) transport into cells. However, it is unknown how ascorbic acid undergoes cellular release, or efflux. We hypothesized that SLC23A1 and SLC23A2 could serve a dual role, mediating ascorbic acid cellular efflux as well as uptake. Renal reabsorption is required for maintaining systemic vitamin C concentrations. Because efflux from nephron cells is necessary for reabsorption, we studied whether SLC23A1 and SLC23A2 mediate efflux of ascorbic acid in the human renal nephron. We found high gene expression of SLC23A1 but no expression of SLC23A2 in the proximal convoluted and straight tubules of humans. These data rule out SLC23A2 as the ascorbic acid release protein in the renal proximal tubular epithelia cell. We utilized a novel dual transporter‐based Xenopus laevis oocyte system to investigate the function of the SLC23A1 protein, and found that no ascorbate release was mediated by SLC23A1. These findings were confirmed in mammalian cells overexpressing SLC23A1. Taken together, the data for SLC23A1 show that it too does not have a role in cellular release of ascorbic acid across the basolateral membrane of the proximal tubular epithelial cell, and that SLC23A1 alone is responsible for ascorbic acid uptake across the apical membrane. These findings reiterate the physiological importance of proper functioning of SLC23A1 in maintaining vitamin C levels for health and disease prevention. The ascorbate efflux mechanism in the proximal tubule of the kidney remains to be characterized.

Intraoperative Registered Ultrasound and Fluoroscopy (iRUF) for dose calculation during prostate brachytherapy: Improved accuracy compared to standard ultrasound-based dosimetry

BACKGROUND AND PURPOSE Intraoperative transrectal ultrasound dosimetry during low-dose-rate prostate brachytherapy is imprecise due to sonographic distortion caused by seed echoes and needle tracks that obscure seed positions or create false signals as well as traumatic edema. Here we report the results of a pilot study comparing a combined ultrasound and fluoroscopy-based seed localization method (iRUF) to standard ultrasound-based dosimetry (USD). MATERIAL AND METHODS Eighty patients undergoing permanent Pd-103 seed implantation for prostate cancer were prospectively enrolled. Seed implantation was performed using standard USD for intraoperative dose tracking. Upon implant completion, six X-ray images were intraoperatively acquired using a mobile C-arm and transverse ultrasound images of the implanted prostate were also acquired. Three-dimensional seed locations were reconstructed from X-ray images and registered to the ultrasound for iRUF dosimetry. Day 1 CT/MRI scans were performed for post-implant dosimetry. Prostate and urethral dosimetric parameters were separately calculated for analysis on iRUF, USD, and CT/MRI data sets. Differences and similarities between dosimetric values measured by iRUF, USD, and CT/MRI were assessed based on root mean squared differences, intraclass correlation coefficients (ICC), and Wilcoxon signed rank test. RESULTS Data from 66 eligible patients were analyzed. Compared to CT/MRI, iRUF dosimetry showed higher correlation with overall ICC of 0.42 (0.01 for USD) and significantly smaller root mean squared differences (overall 16.5 vs 21.5 for iRUF and USD) than USD for all prostate and urethral dosimetric parameters examined. USD demonstrated a tendency to overestimate dose to the prostate when compared to iRUF. CONCLUSIONS iRUF approximated post-implant CT/MRI prostate and urethral dosimetry to a greater degree than USD. A phase II trial utilizing iRUF for intraoperative dynamic plan modification is underway, with the goal to confirm capability to minimize and correct for prostate underdosage not otherwise detected.

Development of an evidence-based strategy to assess and manage substance use in oncology patients

Background This project will empower cancer patients to address their substance use by establishing an evidence-based strategy for identifying and managing substance use during cancer treatment. The question is: Does the proactive identification and management of substance use in oncology patients improve specific patient outcomes such as quality of life, treatment adherence, and reduction in treatment complications? A multidisciplinary team identified substance use as a contributing factor in several adverse patient outcomes. Further research revealed that there are currently no evidence-based standards to guide the care of patients with alcohol and illicit substance use (AISU) who are diagnosed with cancer. AISU during cancer treatment significantly worsens quality of life outcomes, including problems with pain, sleep, dyspnea, total distress, anxiety, coping, shortness of breath, diarrhea, poor emotional functioning, fatigue and poor appetite[1-4]. AISU in cancer patients may also cause significant safety risks in the short and long term[5-9] and increased mortality [10]. After completing a literature review and an exhaustive needs assessment, the team developed a program to implement Screening, Brief Intervention, and Referral to Therapy (SBIRT) in the outpatient radiation oncology department. The implementation plan includes motivational interviewing training, clinical pathways, and risk-based intervention toolkits that will incorporate oncology-specific resources. Conclusions AISU in cancer patients is a threat to safety and quality of life, and patients who use substances during cancer treatment represent an opportunity to improve wellness in a vulnerable population. A program that incorporates the use of SBIRT as part of routine patient care should improve both cancer-specific and all-cause patient outcomes and is critical to patient safety.

Dosimetric predictors of sexual function decline following LDR brachytherapy for prostate cancer (PCa).

113 Background: Conventional dosimetric standards for implant quality do not adequately predict patient reported QoL measures following prostate brachytherapy. We used a dynamic learning knowledgebase (Oncospace) to explore relationships between dose and patient-reported outcomes. Methods: Patient reported quality of life outcomes were prospectively collected for 366 patients with stage cT1-T2 PCa over a 10 year interval. Patients received Pd-103 seed implantation under real-time ultrasound guidance, and completed a QoL instrument (IIEF-5) prior to treatment and at follow-up. Multivariate risk models were used to evaluate dose/toxicity relationships and the Oncospace learning environment generated prediction models using granular dose volume relationships. Results: Median follow-up was 36 months (SD 28.5). In the cohort, 23.7% (n = 87) received combined brachytherapy and EBRT; 14.7% (n = 54) had received prior androgen suppression therapy. Sexual QoL data at minimum of 2 years was available in 141 men. Th...

SU-F-R-47: Quantitative Shape Relationship Analysis of PTV Modification for Critical Anatomy Sparing and Its Impact On Pathologic Response for Neoadjuvant Stereotactic Radiotherapy for Pancreatic Cancer

PURPOSE Stereotactic body radiation therapy (SBRT) may be used to increase surgery candidacy in borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer. However, the planning target volume (PTV) may need to be limited to avoid toxicity when the gross tumor volume (GTV) is anatomically involved with surrounding critical structures. Our study aims to characterize the coverage of GTV and investigate the association between modified PTV and pathologic (pCR) or near pathologic (npCR) complete response rates determined from the surgical specimen. METHODS Patients treated with neoadjuvant pancreas SBRT followed by surgery from 2010-2015 were selected from Oncospace. Overlap volume histogram (OVH) analysis was performed to determine the extent of compromise of the PTV from both the GTV and a standard target (GTV+3mm). Subsequently, normalized overlap volume (%) was calculated for: (1) GTV-PTV, and (2) GTV+3mm expansion-PTV. A logistic regression model was used to identify the association between the overlap ratios and ≥ npCR(pCR/npCR) stratified by active breathing control (ABC) versus free-breathing status. RESULTS Eighty-one (BRPC: n=42, LAPC: n=39) patients were available for analysis. Nearly 40% (31/81) had ≥npCR and 75% (61/81) were able to complete ABC. Mean coverage of the GTV-PTV was 92.6% (range, 59.9%-100%, SD = 8.68) and coverage of the GTV+3mm expansion-PTV was 85. 2% (range, 59.9% -100.0%, SD= 8.67). Among the patients with ABC, every 10% increase in GTV coverage doubled the odds to have ≥npCR (OR = 1.82, p=0.06). Coverage of GTV+3mm expansion was not associated with ≥npCR regardless of ABC status. CONCLUSION Preferential sparing of critical anatomy over GTV-PTV coverage with ABC management suggests worse ≥npCR rates for neoadjuvant SBRT in BRPC and LAPC. Limiting the GTV and GTV+3mm expansion in free-breathing patients was not associated with pathologic response perhaps due to larger GTV definitions as a result of motion artifacts in free-breathing CT scans. Collaboration with Toshiba, Elekta, and Phillips.

Prevalence of Substance Use in Patients With Cancer Receiving Radiation Therapy

BACKGROUND Individuals with cancer and risky alcohol and illicit substance use (AISU) are more likely to suffer diminished quality of life and subpar treatment outcomes. The prevalence of AISU in patients with cancer is poorly understood. OBJECTIVES This article reports on the results of a needs assessment to quantify AISU in individuals with cancer seeking care in the radiation oncology department of a large, academic medical center. METHODS Medical records were reviewed for all patients seen in the radiation oncology department in a one-week (five-day) period in the fall of 2014 (N = 397). Demographic and prevalence data were analyzed. FINDINGS The prevalence rates of AISU in this sample were slightly lower than estimates for the general population and inconsistency was noted in the documentation of relevant information. Despite the limitations, data analyses suggested that a significant percentage of patients receiving radiation therapy for cancer diagnoses exhibited substance use patterns that placed them at increased risk for negative short- and long-term outcomes. The findings support the need for systematic substance use screening, assessment, and risk-based interventions as an essential component of comprehensive cancer care.

SU-E-T-170: Characterization of the Location, Extent, and Proximity to Critical Structures of Target Volumes Provides Detail for Improved Outcome Predictions Among Pancreatic Cancer Patients

Purpose: In radiotherapy, size, location and proximity of the target to critical structures influence treatment decisions. It has been shown that proximity of the target predicts dosimetric sparing of critical structures. In addition to dosimetry, precise location of disease has further implications such as tumor invasion, or proximity to major arteries that inhibit surgery. Knowledge of which patients can be converted to surgical candidates by radiation may have high impact on future treat/no-treat decisions. We propose a method to improve our characterization of the location of pancreatic cancer and treatment volume extent with respect to nearby arteries with the goal of developing features to improve clinical predictions and decisions. Methods: Oncospace is a local learning health system that systematically captures clinical outcomes and all aspects of radiotherapy treatment plans, including overlap volume histograms (OVH) – a measure of spatial relationships between two structures. Minimum and maximum distances of PTV and OARs based on OVH, PTV volume, anatomic location by ICD-9 code, and surgical outcome were queried. Normalized distance to center from the left and right kidney was calculated to indicate tumor location and laterality. Distance to critical arteries (celiac, superior mesenteric, common hepatic) is validated by surgical status (borderline resectable, locally advanced converted to resectable). Results: There were 205 pancreas stereotactic body radiotherapy patients treated from 2009–2015 queried. Location/laterality of tumor based on kidney OVH show strong trends between location by OVH and by ICD-9. Compared to the locally advanced group, the borderline resectable group showed larger geometrical distance from critical arteries (p=0.03). Conclusion: Our platform enabled analysis of shape/size-location relationships. These data suggest that PTV volume and attention to distance between PTVs and surrounding OARs and major arteries may be promising for improving characterization of treatment anatomy that can refine our ability for outcome predictions and decision making. Elekta, Toshiba