Sean M. Vance

Selective radiosensitization of p53 mutant pancreatic cancer cells by combined inhibition of Chk1 and PARP1

We have recently shown that inhibition of HRR (homologous recombination repair) by Chk1 (checkpoint kinase 1) inhibition radiosensitizes pancreatic cancer cells and others have demonstrated that Chk1 inhibition selectively sensitizes p53 mutant tumor cells. Furthermore, PARP1 [poly (ADP-ribose) polymerase-1] inhibitors dramatically radiosensitize cells with DNA double strand break repair defects. Thus, we hypothesized that inhibition of HRR (mediated by Chk1 via AZD7762) and PARP1 [via olaparib (AZD2281)] would selectively sensitize p53 mutant pancreatic cancer cells to radiation. We also used 2 isogenic p53 cell models to assess the role of p53 status in cancer cells and intestinal epithelial cells to assess overall cancer specificity. DNA damage response and repair were assessed by flow cytometry, γH2AX, and an HRR reporter assay. We found that the combination of AZD7762 and olaparib produced significant radiosensitization in p53 mutant pancreatic cancer cells and in all of the isogenic cancer cell lines. The magnitude of radiosensitization by AZD7762 and olaparib was greater in p53 mutant cells compared with p53 wild type cells. Importantly, normal intestinal epithelial cells were not radiosensitized. The combination of AZD7762 and olaparib caused G2 checkpoint abrogation, inhibition of HRR, and persistent DNA damage responses. These findings demonstrate that the combination of Chk1 and PARP1 inhibition selectively radiosensitizes p53 mutant pancreatic cancer cells. Furthermore, these studies suggest that inhibition of HRR by Chk1 inhibitors may be a useful strategy for selectively inducing a BRCA1/2 ‘deficient-like’ phenotype in p53 mutant tumor cells, while sparing normal tissue.

Perineural Invasion Predicts Increased Recurrence, Metastasis, and Death From Prostate Cancer Following Treatment With Dose-Escalated Radiation Therapy

PURPOSE To assess the prognostic value of perineural invasion (PNI) for patients treated with dose-escalated external-beam radiation therapy for prostate cancer. METHODS AND MATERIALS Outcomes were analyzed for 651 men treated for prostate cancer with EBRT to a minimum dose ≥75 Gy. We assessed the impact of PNI as well as pretreatment and treatment-related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival. RESULTS PNI was present in 34% of specimens at biopsy and was significantly associated with higher Gleason score (GS), T stage, and prostate-specific antigen level. On univariate and multivariate analysis, the presence of PNI was associated with worse FFBF (hazard ratio = 1.7, p <0.006), FFM (hazard ratio = 1.8, p <0.03), and CSS (HR = 1.4, p <0.05) compared with absence of PNI; there was no difference in overall survival. Seven-year rates of FFBF, FFM, and CCS were 64% vs. 80%, 84% vs. 92%, and 91% vs. 95% for those patients with and without PNI, respectively. On recursive partitioning analysis, PNI predicted for worse FFM and CSS in patients with GS 8-10, with FFM of 67% vs. 89% (p <0.02), and CSS of 69% vs. 91%, (p <0.04) at 7 years for those with and without PNI, respectively. CONCLUSIONS The presence of PNI in the prostate biopsy predicts worse clinical outcome for patients treated with dose-escalated external-beam radiation therapy. Particularly in patients with GS 8-10 disease, the presence of PNI suggests an increased risk of metastasis and prostate cancer death.

The addition of low-dose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with dose-escalated external-beam radiation therapy for high-risk prostate cancer.

The objective of this study was to determine whether the addition of low‐dose‐rate brachytherapy or androgen‐deprivation therapy (ADT) improves clinical outcome in patients with high‐risk prostate cancer (HiRPCa) who received dose‐escalated radiotherapy (RT).

Dose to the inferior rectum is strongly associated with patient reported bowel quality of life after radiation therapy for prostate cancer.

PURPOSE To evaluate rectal dose and post-treatment patient-reported bowel quality of life (QOL) following radiation therapy for prostate cancer. METHODS Patient-reported QOL was measured at baseline and 2-years via the expanded prostate cancer index composite (EPIC) for 90 patients. Linear regression modeling was performed using the baseline score for the QUANTEC normal tissue complication probability model and dose volume histogram (DVH) parameters for the whole and segmented rectum (superior, middle, and inferior). RESULTS At 2-years the mean summary score declined from a baseline of 96.0-91.8. The median volume of rectum treated to ≥70 Gy (V70) was 11.7% for the whole rectum and 7.0%, 24.4%, and 1.3% for the inferior, middle, and superior rectum, respectively. Mean dose to the whole and inferior rectum correlated with declines in bowel QOL while dose to the mid and superior rectum did not. Low (V25-V40), intermediate (V50-V60) and high (V70-V80) doses to the inferior rectum influenced bleeding, incontinence, urgency, and overall bowel problems. Only the highest dose (V80) to the mid-rectum correlated with rectal bleeding and overall bowel problems. CONCLUSIONS Segmental DVH analysis of the rectum reveals associations between bowel QOL and inferior rectal dose that could significantly influence radiation planning and prognostic models.

Influence of Comorbidity on the Risk of Death: A Single Institution Study of 1132 Women With Early-stage Uterine Cancer

Purpose/Objective(s): The impact of competing medical comorbidity on survival endpoints in women with early stage endometrial carcinoma (EC) is not well studied. The study goal was to utilize a validated comorbidity scoring system to determine its impact on all-cause mortality as well as on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with early-stage EC. Materials and Methods: For this IRB-approved study, we reviewed our prospectively maintained uterine cancer database of 1720 patients. We identified 1132 patients with EC FIGO stages I-II who underwent hysterectomy from 1984 to 2011. Age-adjusted Charlson Comorbidity Index (AACCI) at time of hysterectomy was retrospectively calculated by physician chart review. The cause of death (uterine cancer-related and unrelated) was correlated with AACCI. Univariate and multivariate modeling with Cox regression analysis was used to determine significant predictors of OS, DSS, and RFS. The Kaplan-Meier and the log-rank test methods were used to evaluate survival outcomes. Results: After a median follow-up of 51 months, 262 deaths were recorded (42 from EC [16%], and 220 [84%] from other causes). Median AACCI score for the study cohort was 3 (range, 0 to 15). On the basis of AACCI, patients were grouped as follows: 0 to 2 (group 1, n=379), 3 to 4 (group 2, n=532), and ≥5 (group 3, n=221). By AACCI grouping, the 5-year RFS, DSS, and OS were 95%, 98%, and 97% for group 1, 89%, 95%, and 87% for group 2, and 86%, 95% and 72% for group 3 (P<0.0001). The cause of death in the first 10 years after hysterectomy in our study was mainly non-uterine cancer-related (78% vs. 22% for uterine cancer-related) causes. On multivariate analyses, higher AACCI, lymphovascular space invasion (LVSI), higher tumor grade, age, and involvement of the lower uterine segment were significant predictors of shorter OS. On multivariate analysis for DSS and RFS, only high tumor grade and LVSI were significant predictors. Conclusions: The cause of death for women with early stage EC is mainly nonuterine cancer-related. Comorbidity score is a significant predictor of OS in our study cohort. Comorbidity scores may be useful as a stratification factor in any prospective clinical trial for women with early-stage EC.

Percentage of Cancer Volume in Biopsy Cores Is Prognostic for Prostate Cancer Death and Overall Survival in Patients Treated With Dose-Escalated External Beam Radiotherapy

PURPOSE To investigate the prognostic utility of the percentage of cancer volume (PCV) in needle biopsy specimens for prostate cancer patients treated with dose-escalated external beam radiotherapy. METHODS AND MATERIALS The outcomes were analyzed for 599 men treated for localized prostate cancer with external beam radiotherapy to a minimal planning target volume dose of 75 Gy (range, 75-79.2). We assessed the effect of PCV and the pretreatment and treatment-related factors on the freedom from biochemical failure, freedom from metastasis, cause-specific survival, and overall survival. RESULTS The median number of biopsy cores was 7 (interquartile range, 6-12), median PCV was 10% (interquartile range, 2.5-25%), and median follow-up was 62 months. The PCV correlated with the National Comprehensive Cancer Network risk group and individual risk features, including T stage, prostate-specific antigen level, Gleason score, and percentage of positive biopsy cores. On log-rank analysis, the PCV stratified by quartile was prognostic for all endpoints, including overall survival. In addition, the PCV was a stronger prognostic factor than the percentage of positive biopsy cores when the two metrics were analyzed together. On multivariate analysis, the PCV predicted a worse outcome for all endpoints, including freedom from biochemical failure, (hazard ratio, 1.9; p = .0035), freedom from metastasis (hazard ratio, 1.7, p = .09), cause-specific survival (hazard ratio, 3.9, p = .014), and overall survival (hazard ratio, 1.8, p = .02). CONCLUSIONS For patients treated with dose-escalated external beam radiotherapy, the volume of cancer in the biopsy specimen adds prognostic value for clinically relevant endpoints, particularly in intermediate- and high-risk patients. Although the PCV determination is more arduous than the percentage of positive biopsy cores, it provides superior risk stratification.

Combination therapy improves prostate cancer survival for patients with potentially lethal prostate cancer: The impact of Gleason pattern 5

PURPOSE To investigate the impact of Gleason pattern 5 (GP5) prostate cancer after either external beam radiotherapy (EBRT) or the combination of EBRT with low-dose rate brachytherapy boost (combo). METHODS AND MATERIALS Between 1998 and 2008, 467 patients with National Comprehensive Cancer Network high-risk prostate cancer were treated with EBRT (n = 326) or combo (low-dose rate to 90-108 Gy using I-125 followed by EBRT) (n = 141). Freedom from biochemical failure, freedom from metastasis (FFM), cancer-specific survival (CSS), and overall survival were evaluated. RESULTS Combo patients were younger (66 vs. 72 years, p < 0.001) and had fewer comorbidities (Charlson comorbidity index 3.7 vs. 4.4, p < 0.001). EBRT patients had higher tumor stages (T3-4: 30% vs. 21%, p = 0.03) and lower Gleason scores (8-10: 61% vs. 75%, p = 0.01). Androgen deprivation therapy use was similar between cohorts (85% vs. 87%, p = 0.5), but EBRT patients had longer androgen deprivation therapy use (median 14 vs. 12 months, p = 0.05). GP5 predicted worse FFM (p < 0.001, hazard ratio [HR] 3.3, 95% confidence interval [CI]1.8-6.2]) and CSS (p < 0.001, HR 5.9, 95% CI 2.7-12.9) for the EBRT group, but not for the combo group (p = 0.86, HR 0.48, 95% CI 0.1-2.4 for metastasis and p = 0.5, HR 1.6, 95% CI 0.33-8.0 for CSS). In those with GP5 (n = 143), combo was associated with improved outcomes in all endpoints. On univariate analysis, 5-year outcomes for combo vs. EBRT were as follows: freedom from biochemical failure 89% vs. 65%, FFM 89% vs. 67%, CSS 93% vs. 78%, and overall survival 88% vs. 67% (p < 0.05 for all). CONCLUSION Combo was associated with improved outcomes for men with GP5 prostate cancer. This highlights the importance of local therapy, especially in patients with the highest pathologic grade disease.

Characterization of a commercial hybrid iterative and model-based reconstruction algorithm in radiation oncology.

PURPOSE Iterative reconstruction (IR) reduces noise, thereby allowing dose reduction in computed tomography (CT) while maintaining comparable image quality to filtered back-projection (FBP). This study sought to characterize image quality metrics, delineation, dosimetric assessment, and other aspects necessary to integrate IR into treatment planning. METHODS CT images (Brilliance Big Bore v3.6, Philips Healthcare) were acquired of several phantoms using 120 kVp and 25-800 mAs. IR was applied at levels corresponding to noise reduction of 0.89-0.55 with respect to FBP. Noise power spectrum (NPS) analysis was used to characterize noise magnitude and texture. CT to electron density (CT-ED) curves were generated over all IR levels. Uniformity as well as spatial and low contrast resolution were quantified using a CATPHAN phantom. Task specific modulation transfer functions (MTF task) were developed to characterize spatial frequency across objects of varied contrast. A prospective dose reduction study was conducted for 14 patients undergoing interfraction CT scans for high-dose rate brachytherapy. Three physicians performed image quality assessment using a six-point grading scale between the normal-dose FBP (reference), low-dose FBP, and low-dose IR scans for the following metrics: image noise, detectability of the vaginal cuff/bladder interface, spatial resolution, texture, segmentation confidence, and overall image quality. Contouring differences between FBP and IR were quantified for the bladder and rectum via overlap indices (OI) and Dice similarity coefficients (DSC). Line profile and region of interest analyses quantified noise and boundary changes. For two subjects, the impact of IR on external beam dose calculation was assessed via gamma analysis and changes in digitally reconstructed radiographs (DRRs) were quantified. RESULTS NPS showed large reduction in noise magnitude (50%), and a slight spatial frequency shift (∼ 0.1 mm(-1)) with application of IR at L6. No appreciable changes were observed for CT-ED curves between FBP and IR levels [maximum difference ∼ 13 HU for bone (∼ 1% difference)]. For uniformity, differences were ∼ 1 HU between FBP and IR. Spatial resolution was well conserved; the largest MTFtask decrease between FBP and IR levels was 0.08 A.U. No notable changes in low-contrast detectability were observed and CNR increased substantially with IR. For the patient study, qualitative image grading showed low-dose IR was equivalent to or slightly worse than normal dose FBP, and is superior to low-dose FBP (p < 0.001 for noise), although these did not translate to differences in CT number, contouring ability, or dose calculation. The largest CT number discrepancy from FBP occurred at a bone/tissue interface using the most aggressive IR level [-1.2 ± 4.9 HU (range: -17.6-12.5 HU)]. No clinically significant contour differences were found between IR and FBP, with OIs and DSCs ranging from 0.85 to 0.95. Negligible changes in dose calculation were observed. DRRs preserved anatomical detail with <2% difference in intensity from FBP combined with aggressive IRL6. CONCLUSIONS These results support integrating IR into treatment planning. While slight degradation in edges and shift in texture were observed in phantom, patient results show qualitative image grading, contouring ability, and dosimetric parameters were not adversely affected.

Limitations of the cancer of the prostate risk assessment (CAPRA) prognostic tool for prediction of metastases and prostate cancer-specific mortality in patients treated with external beam radiation therapy

Objectives:To assess the performance of the Cancer of the Prostate Risk Assessment (CAPRA) prognostic tool for freedom-from-metastases (FFM) and cause-specific survival (CSS) in patients with localized prostate cancer treated with definitive external beam radiotherapy (EBRT), and to determine whether the performance of CAPRA is influenced by androgen deprivation therapy (ADT) use or the presence of Gleason pattern 5 (GP-5). Materials and Methods:A total of 612 patients from a prospective database of 718 patients treated with dose-escalated EBRT from 1998 to 2008 who met CAPRA scoring criteria were included in the study. Performance of CAPRA and association of CAPRA score, GP-5 and short-term or long-term ADT use (STAD or LTAD, respectively) with FFM and CSS were evaluated using Cox models. The impact of ADT use on accuracy of the CAPRA-based CaPSURE model for CSS was assessed. The discriminatory ability of the CAPRA model and modified models incorporating GP-5 and ADT use were compared using the C-index. Results:Increasing CAPRA score correlated with worse FFM and CSS, and was prognostic for FFM and CSS for the overall cohort. CAPRA showed poorer discrimination for FFM and CSS in patients treated with EBRT+LTAD than those who received EBRT alone or EBRT+STAD. The addition of GP-5 and ADT use to CAPRA score increased the predictive accuracy of the CAPRA model for both FFM (C-index 0.809 vs. 0.779, P<0.001) and CSS (C-index 0.864 vs. 0.796, P=0.003). Conclusions:The CAPRA score should be modified to incorporate GP-5 and ADT use for risk adjustment and risk prediction in prostate cancer patients who receive EBRT.

SU-F-18C-06: Prospective Patient Evaluation of Iterative Reconstruction in Radiation Oncology

PURPOSE This work incorporates iterative reconstruction (IR) into a dose reduction study to characterize image quality metrics, delineation, and dosimetric assessment, with the goal of reducing imaging dose in Radiation Oncology. METHODS Three-dimensional noise power spectrum (NPS) analysis characterized noise magnitude/texture (120 kVp, 50-200 mAs, IR levels 1-6 yielding noise reduction of 0.89-0.55 compared to filtered backprojection (FBP)). Task-specific Modulation Transfer Functions (MTFtask) were characterized across varied subject contrasts. A prospective dose reduction study (500 to 150 mAs) was conducted for 12 patients (43 inter-fraction CTs) for high-dose rate brachytherapy. Three physicians performed qualitative image assessment between full-dose FBP (FD-FBP, 500 mAs), low-dose FBP (LD-FBP, 150-250 mAs), and low-dose IRL5-6 (LD-IR) scans for image noise, cuff/bladder interface detectability, spatial resolution, texture, and segmentation confidence. Comparisons between LD-FBP and LD-IR were conducted for the following metrics: delineation (bladder and rectum evaluated via overlap indices (OI) and Dice similarity coefficients (DSC)), noise, boundary changes, dose calculation, and digitally reconstructed radiographs (DRRs). RESULTS NPS showed ∼50% reduction in noise magnitude and ∼0.1 1/mm spatial frequency shift with IRL6. The largest MTFtask decrease between FBP and IR was 0.08 A.U. Qualitative patient image evaluation revealed LD-IR was equivalent or slightly worse than FD-FBP, and superior to LD-FBP for all metrics except low contrast interface and texture. The largest CT number discrepancy from FBP occurred at a bone/tissue interface using IRL6 (-1.2 ± 4.9 HU (range: -17.6 - 12.5 HU)). No significant contour differences (OIs and DSCs = 0.85 - 0.95) and dose calculation discrepancy (<0.02%) were observed. DRRs preserved anatomical detail and demonstrated <2% difference in intensity between LD-FBP and LD-IRL6. CONCLUSION While phantom analysis showed slight noise texture differences with IR, patient results revealed that image quality, contouring ability, and dosimetric parameters were not adversely affected, thus support integrating IR into treatment planning. Research supported in part by a grant from Philips HealthCare.