Faculty Bibliography

Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States, with poor response to current standard of care, short progression-free and overall survival. Immunotherapies that target cytotoxic T lymphocyte antigen-4, programmed cell death protein-1, and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma, renal cell carcinoma, and non-small cell lung cancer due to high numbers of somatic mutations, combined with cytotoxic T-cell responses. However, single checkpoint blockade was ineffective in pancreatic cancer, highlighting the challenges including the poor antigenicity, a dense desmoplastic stroma, and a largely immunosuppressive microenvironment. In this review, we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy, radiotherapy, and targeted therapy. These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.

Background: E2205 was a single-arm, phase II trial that added an epidermal growth factor receptor (EGF-R) inhibitor, cetuximab (C), to CRT. The trial was closed early due to pulmonary toxicity. We investigated the potential role of cetuximab and type of radiation (IMRT vs conventional). Methods: Patients were treated with CRT: Oxaliplatin (OX) 85mg/m²days 1,15,29; infusional 5-fluorouracil (5-FU) 180mg/m²/24hours x 35 days; C 400mg/m²day 1 then 250mg/m²days 8,15,22,29 and radiation (IMRT allowed) 180cGy/day x 25 fractions (Monday-Friday), followed by esophagectomy. Results: Of 21 eligible patients enrolled, 17 had surgery (died pulmonary embolism 4 days after CRT, died G3 diarrhea/PD during CRT, died sepsis/hypoxia during CRT). pCR = 7/17. Four post-op deaths from acute respiratory distress syndrome (ARDS) resulted in 7 total study-related deaths. None of the patients who received IMRT died (0/3). 1/6 had ARDS if more than 4 fields with conventional or 3D planning was used. 3 of 15 treated with RT that met the criteria of E1201 guidelines (no more than 3-4 RT fields, normal lung more than 2 cm outside the target volume < 40 Gy, no IMRT). Overall, there was no demonstrable association of ARDS to radiation technique: 4/22 overall, 0/3 if IMRT was used. Conclusions: This regimen is not recommended. There is no clear association between use of IMRT and ARDS. The cause of ARDS remains undetermined. Cetuximab may have played a role

BACKGROUND: Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality. METHODS: This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group. CONCLUSION: Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study. IMPLICATIONS FOR PRACTICE: Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.

Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. A Phase I trial of CD40 immunotherapy in combination with gemcitabine demonstrated the combination was safe and achieves tumor responses in patients with pancreatic ductal adenocarcinoma. We investigated the effectiveness of gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy in an orthotopic pancreatic mouse model. Methods: Pancreatic cells obtained from a Kras^G12D;Trp53^R172H (KPC) genetically engineered mouse were cultivated in cell culture and surgically implanted into the pancreata of immunocompetent syngeneic C57/Bl6 mice allowing for tumor formation in situ. Two weeks after KPC cell implantation, mice were treated with 120 mg/kg gemcitabine and 120 mg/kg nab-paclitaxel by intraperitoneal injection. Forty eight hours after chemotherapy administration, mice were treated with 100 ug of FGK45 CD40 immunotherapy. Mouse tumors and spleens were harvested from euthanized mice ten days after drug treatment. Tumor and spleens were analyzed histologically and by flow cytometry. Results: Mice treated with combination chemotherapy and immunotherapy had a significant reduction in tumor volume in comparison to vehicle treated mice. Combination chemotherapy did not cause a significant decrease in tumor volume. No changes were seen in stromal remodeling using trichrome histological staining. Mice treated with CD40 immunotherapy had an increase in spleen size indicating an immune response. Histological and flow cytometry analysis revealed an increase in CD45+ cells in the tumors of the CD40 immunotherapy treated samples in comparison to chemotherapy alone. Conclusions: CD40 immunotherapy in combination with gemcitabine and albumin-bound paclitaxel has significant antitumor activity in an orthotopic pancreatic cancer mouse model provoking an immune response in the tumors. Future experiments will focus on identifying immune mediators critical for drug efficacy

BACKGROUND: HIV status may affect outcomes after definitive chemoradiotherapy for anal cancer. OBJECTIVE: Here, we report a large series in the highly active antiretroviral therapy era comparing outcomes between HIV-positive and HIV-negative patients with anal cancer. DESIGN: This was a retrospective chart review. SETTINGS: The study was conducted at an outpatient oncology clinic at large academic center. PATIENTS: A total of 107 patients were reviewed, 39 HIV positive and 68 HIV negative. All of the patients underwent definitive chemoradiation for anal cancer. MAIN OUTCOME MEASURES: Data on patient characteristics, treatment, toxicity, and outcomes were collected. Overall survival, colostomy-free survival, local recurrence-free survival, and distant metastasis-free survival were analyzed. RESULTS: Median follow-up was 15 months. HIV-positive patients were younger (median, 52 vs 64 years; p < 0.001) and predominantly men (82% men vs 49% men; p = 0.001). There were no significant differences in T, N, or stage groups. HIV-positive patients had a significantly longer duration from biopsy to start of chemoradiation (mean number of days, 82 vs 54; p = 0.042). There were no differences in rates of acute toxicities including diarrhea, fatigue, or dermatitis. HIV-positive patients had significantly higher rates of hospitalization (33% vs 15%; p = 0.024). The 3-year overall survival rate was 42% in HIV-positive and 76% in HIV-negative patients (p = 0.037; HR, 2.335 (95% CI, 1.032-5.283)). Three-year colostomy-free survival was 67% in HIV-positive and 88% in HIV-negative patients (p = 0.036; HR, 3.231 (95% CI, 1.014-10.299)). Differences in overall survival rates were not significant on multivariate analysis. LIMITATIONS: This study was limited by its retrospective design and small patient numbers. CONCLUSIONS: In this cohort, HIV-positive patients had significantly worse overall and colostomy-free survival rates than HIV-negative patients. However, differences in survival were not significant on multivariate analysis. Additional studies are necessary to establish the etiology of this difference.

OBJECTIVE: To compare clinical and treatment characteristics and outcomes in locally advanced anal cancer, a potentially curable disease, in patients referred from a public or private hospital. METHODS: We retrospectively reviewed 112 anal cancer patients from a public and a private hospital who received definitive chemoradiotherapy at the same cancer center between 2004 and 2013. Tumor stage, radiotherapy delay, radiotherapy duration, and unplanned treatment breaks >/=10 days were compared using t-test and chi(2) test. Overall survival (OS), disease free survival (DFS), and colostomy free survival (CFS) were examined using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard models for OS and DFS were developed. RESULTS: The follow-up was 14.9 months (range, 0.7-94.8 months). Public hospital patients presented with significantly higher clinical T stage (P<0.05) and clinical stage group (P<0.05), had significantly longer radiotherapy delays (P<0.05) and radiotherapy duration (P<0.05), and had more frequent radiation therapy (RT) breaks >/=10 days (P<0.05). Three-year OS showed a marked trend in favor of private hospital patients for 3-year OS (72.8% vs. 48.9%; P=0.171), 3-year DFS (66.3% vs. 42.7%, P=0.352), and 3-year CFS (86.4% vs. 68.9%, P=0.299). Referral hospital was not predictive of OS or DFS on multivariate analysis. CONCLUSIONS: Public hospital patients presented at later stage and experienced more delays in initiating and completing radiotherapy, which may contribute to the trend in poorer DFS and OS. These findings emphasize the need for identifying clinical and treatment factors that contribute to decreased survival in low socioeconomic status (SES) populations.

Despite overall progress in the therapy of local and locally advanced esophageal, gastroesophageal junction, and gastric adenocarcinomas, death as a result of these tumors remains a common outcome. Most randomized phase III trials on which level-one evidence has been built have included the heterogeneous histologies and locations associated with these tumors. However, the different etiologies, molecular biology, and recurrence patterns associated with gastroesophageal malignancies suggest the need to split rather than lump. Biologic and response differences exist between squamous and adenocarcinomas, as well as diffuse and intestinal histologies. This may be a cause behind conflicting outcomes in similar trials. The accepted standard of chemoradiotherapy for locally advanced esophageal and gastroesophageal junction cancers is based on a few positive trials, with the best chemotherapy and total dose of radiation remaining controversial. In the West, the staging evaluations of locally advanced gastric cancer are not uniform. Yet, these evaluations will inform the results of preoperative and perioperative treatments. Although postoperative chemoradiotherapy for gastric cancer has been an accepted treatment option for the last decade, more recent studies have called into question the need for radiotherapy. In perioperative strategies, it has yet to be determined whether histologic or molecular changes in the operative specimen should inform postoperative treatment. An appropriate place for targeted therapy needs to be found in preoperative and postoperative treatment regimens. Finally, because so much is lost when trials are forced to close for lack of accrual, it is imperative to build multidisciplinary consensus before they are launched.