Arsen Osipov

Review of systemic therapies for locally advanced and metastatic rectal cancer

Rectal cancer, along with colon cancer, is the second leading cause of cancer-related deaths in the U.S. Up to a quarter of patients have metastatic disease at diagnosis and 40% will develop metastatic disease. The past 10 years have been extremely exciting in the treatment of both locally advanced and metastatic rectal cancer (mRC). With the advent of neoadjuvant chemoradiation, increased numbers of patients with locally advanced rectal cancer (LARC) are surviving longer and some are seeing their tumors shrink to sizes that allow for resection. The advent of biologics and monoclonal antibodies has propelled the treatment of mRC further than many could have hoped. Combined with regimens such as FOLFOX or FOLFIRI, median survival rates have been increased to an average of 23 months. However, the combinations of chemotherapy regimens seem endless for rectal cancer. We will review the major chemotherapies available for locally advanced and mRC as well as regimens currently under investigation such as FOLFOXIRI. We will also review vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors as single agents and in combination with traditional chemotherapy regimens.

Identifying prognostic intratumor heterogeneity using pre- and post-radiotherapy 18F-FDG PET images for pancreatic cancer patients

BACKGROUND To stratify risks of pancreatic adenocarcinoma (PA) patients using pre- and post-radiotherapy (RT) PET/CT images, and to assess the prognostic value of texture variations in predicting therapy response of patients. METHODS Twenty-six PA patients treated with RT from 2011-2013 with pre- and post-treatment 18F-FDG-PET/CT scans were identified. Tumor locoregional texture was calculated using 3D kernel-based approach, and texture variations were identified by fitting discrepancies of texture maps of pre- and post-treatment images. A total of 48 texture and clinical variables were identified and evaluated for association with overall survival (OS). The prognostic heterogeneity features were selected using lasso/elastic net regression, and further were evaluated by multivariate Cox analysis. RESULTS Median age was 69 y (range, 46-86 y). The texture map and temporal variations between pre- and post-treatment were well characterized by histograms and statistical fitting. The lasso analysis identified seven predictors (age, node stage, post-RT SUVmax, variations of homogeneity, variance, sum mean, and cluster tendency). The multivariate Cox analysis identified five significant variables: age, node stage, variations of homogeneity, variance, and cluster tendency (with P=0.020, 0.040, 0.065, 0.078, and 0.081, respectively). The patients were stratified into two groups based on the risk score of multivariate analysis with log-rank P=0.001: a low risk group (n=11) with a longer mean OS (29.3 months) and higher texture variation (>30%), and a high risk group (n=15) with a shorter mean OS (17.7 months) and lower texture variation (<15%). CONCLUSIONS Locoregional metabolic texture response provides a feasible approach for evaluating and predicting clinical outcomes following treatment of PA with RT. The proposed method can be used to stratify patient risk and help select appropriate treatment strategies for individual patients toward implementing response-driven adaptive RT.

Influence of Body Mass Index and Albumin on Perioperative Morbidity and Clinical Outcomes in Resected Pancreatic Adenocarcinoma.

Obesity is a known risk factor for PDA and recent reports suggest obesity has a negative impact on clinical outcomes in patients with PDA. Pretreatment body mass index (BMI) and serum albumin (SA) have been shown to be associated with worse overall survival in patients with advanced and metastatic PDA. However, minimal data exists on the impact of BMI and SA on perioperative and long-term clinical outcomes in patients with early-stage resected PDA. Herein, we report on the impact of these variables on perioperative clinical outcomes, overall survival (OS) and disease free survival (DFS) in patients with resected PDA. With IRB approval, we evaluated 1,545 patients with PDA treated at a single institution from 2007–2013 and identified 106 patients who underwent upfront resection with curative intent. BMI and SA were calculated preoperatively and at the time of last clinical evaluation. Influence of preoperative BMI, SA, change in either variable, and influence of other clinical and pathologic variables on perioperative morbidity and mortality was assessed. The impact of these variables on DFS and OS was assessed with cox regression modeling and ANOVA. Actuarial estimates for DFS and OS were calculated using Kaplan-Meier methods. Median follow up time was 16 months (3–89). Mean age was 68 years. Median survival was 14 months (3–65) and median time to recurrence was 11 months (1–79). Length of hospital stay was associated with BMI (p = .023), change in BMI (p = .003) and SA (p = .004). Post-operative transfusion rate was associated with SA (p = .021). There was a strong correlation between BMI change and positive margin (p = .04) and lymph node status (p = .01). On multivariate analysis, change in SA (p = .03) and node positivity (p = .008) were associated with decreased DFS. Additionally, preoperative SA (p = .023), node positivity (p = .026) and poor differentiation (p = .045) were associated with worse OS on multivariate analysis. Low preoperative SA was associated with worse DFS and OS in patients with resected PDA. Lower BMI and SA were associated with longer post-operative hospital stay. Our study is one of the first to describe how pre-operative BMI and SA and post-operative changes in these variables impact clinical and perioperative outcomes. This data supports nutritional status and weight loss as predictors of outcome in resected pancreatic cancer patients and warrants further prospective investigation.

Impact of margin status and lymphadenectomy on clinical outcomes in resected pancreatic adenocarcinoma: implications for adjuvant radiotherapy

BACKGROUND Adjuvant chemoradiotherapy (CRT) in the treatment of pancreatic ductal adenocarcinoma (PDA) is controversial. Minimal data exists regarding the clinical significance of margin clearance distance and lymph node (LN) parameters, such as extent of dissection and LN ratio. We assessed the impact of these variables on clinical outcomes to more clearly define the subset of patients who may benefit from adjuvant radiotherapy (RT). METHODS We identified 106 patients with resected stage 1-3 PDA from 2007-2013. Resection margins were categorized as positive (tumor at ink), ≤1, or >1 mm. LN evaluation included total number examined (NE), number of positive nodes (NP), ratio of NP to NE (NR), extent of dissection, and positive periportal LNs. The impact of these variables was assessed on disease-free survival (DFS) and overall survival (OS) using multivariate cox proportional hazards modeling. RESULTS In patients receiving adjuvant chemotherapy (CT) alone, greater margin clearance led to improved DFS (P=0.0412, HR =0.51). Range of NE was 4-37, with a mean of 19. NE was not associated with DFS or OS, yet absolute NP of 5 or more was associated with a significantly worse DFS (P=0.005). Whereas periportal lymphadenectomy did not result in improved DFS or OS, patients with positive periportal LN had worse clinical outcomes (DFS, P=0.0052; OS, P=0.023). The use of adjuvant CRT was associated with improved OS (P=0.049; HR=0.29). CONCLUSIONS In patients receiving adjuvant CT alone, there was a clinically significant benefit to clearing the surgical margin beyond tumor at ink. Having ≥5 NP and positive periportal LN led to significantly worse clinical outcomes. The addition of adjuvant RT to CT in resected PDA improved OS. A comprehensive evaluation of resection margin distance and LN parameters may identify more patients at risk for locoregional failure who may benefit from adjuvant CRT.

Neoadjuvant PET and MRI-based intensity modulated radiotherapy leads to less toxicity and improved pathologic response rates in locally advanced rectal cancer

Background Neoadjuvant chemoradiation (NeoCRT) is standard of care for the treatment of locally advanced rectal cancer (LARC). Contemporary radiation techniques and pre-treatment imaging may impact toxicities and pathologic response (PR). Herein we compare intensity modulated radiotherapy (IMRT) and advanced pre-treatment imaging in the neoadjuvant treatment of LARC and resulting impact on toxicities and pathologic outcomes relative to 3 dimensional conformal radiotherapy (3DCRT). Methods LARC patients treated at 4 large academic centers in the US from 2007-2016 were reviewed. Patients received 5-FU-based NeoCRT concurrently with IMRT or 3DCRT. PR was recorded as none, partial, or complete. Common terminology for adverse events version 4 was used to grade toxicities. Toxicity rates were compared using Chi-square analysis. Multivariable models were fit adjusting for age, gender, pre-tx CT to identify independent predictors of PR and toxicity. Results A total of 128 patients were analyzed: 60.1% male and 39.8% female, median age 57.7 years (range, 31-85 years). Clinical characteristics were similar across RT groups. The outcome of partial and complete PR was similar for IMRT and 3DCRT (48.1%, 23.1% vs. 31.7%, 23.3%), respectively. After adjusting for gender, age, and pre-RT chemotherapy type, IMRT and pretreatment PET and/or MRI imaging was significantly associated with increased odds for complete and partial response (OR =2.95, 95% CI: 1.21-7.25, P=0.018; OR =14.70, 95% CI: 3.69-58.78, P<0.0001). Additionally, IMRT was associated with reduced rates of dehydration, dermatitis, rectal pain, rectal bleeding, and diverting ostomy (P<0.05). Overall rates of grade 2 and higher toxicities were significantly reduced in IMRT vs. 3DCRT after adjusting for confounders (OR =0.27, 95% CI: 0.08-0.87). Conclusions NeoCRT IMRT with pretreatment PET and/or MRI for LARC leads to reduced acute toxicities and improved PR compared to 3DCRT. Given the challenges associated with prospective validation of these data, IMRT with pretreatment PET and/or MRI should be considered standard treatment for LARC.

DNA sequencing to identify potentially novel targets for therapy in pancreatic cancer.

275 Background: Molecular differences in solid tumors have been shown to correlate with heterogeneity of response. Unfortunately, minimal data exists in pancreatic ductal adenocarcinoma (PDA). Next generation sequencing (NGS) may provide genetic signatures that allow prognostic stratification and predict response to targeted therapy. Methods: DNA was extracted from biopsy specimens of 64 patients (pts) with PDA at Cedars-Sinai Medical Center. DNA sequencing was performed for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (Foundation Medicine, Cambridge, MA). We report all genetic alterations including those classified as variants of unknown significance (VUS) as these may potentially be important for further study. Results: 94% of our patients had KRAS mutations, SMAD(39%) P53 (69%), and CDKN2A (48%). 17% of the pts had all 4 mutations. 4.6% had none. MLL and ARID genes, both involved in chromatin remodeling, were a...

Impact of margin status and lymphadenectomy on clinical outcomes in resected pancreatic cancer: Implications for adjuvant radiotherapy.

429 Background: Adjuvant chemoradiotherapy (CRT) in the treatment of pancreatic ductal adenocarcinoma (PDA) is controversial. Minimal data exists regarding the clinical significance of margin clearance distance and lymph node (LN) parameters, such as extent of dissection and LN ratio. We assess the impact of these variables on clinical outcomes to identify the subset of patients who may benefit from adjuvant CRT. Methods: We identified 106 patients with resected stage 1-3 PDA from 2007-13. Resection margins were categorized as positive (tumor at ink), ≤ 1 mm, or > 1 mm. LN evaluation included total number examined (NE), number of positive nodes (NP), ratio of NP to NE (NR), and presence of periportal adenopathy. The impact of these variables was assessed on disease-free survival (DFS) and overall survival (OS) using multivariate cox proportional hazards modeling. Actuarial estimates for DFS and OS were calculated using Kaplan-Meier methods. Results: Margin status was highly correlated with NP (p=0.012). M...