K.L. Du

Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

BACKGROUND & AIMS The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. METHODS We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. RESULTS Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. CONCLUSIONS Radiation treatment causes macrophages murine PDA to acquire an immune-suppressive phenotype and disabled T-cell-mediated anti-tumor responses. MCSF blockade negates this effect, allowing radiation to have increased efficacy in slowing tumor growth.

Predictors of Complete Response and Disease Recurrence Following Chemoradiation for Rectal Cancer

Objective Approximately 10–40% of rectal patients have a complete response (CR) to neoadjuvant chemoradiation (CRT), and these patients have improved survival. Thus, non-operative management (“watch-and-wait” approach) may be an option for select patients. We aimed to identify clinical predictors of CR following CRT. Methods Patients treated with definitive CRT for T3–T4, locally unresectable T1–T2, low-lying T2, and/or node-positive rectal cancer from August 2004 to February 2015 were retrospectively reviewed. Most patients were treated with 50.4 Gy radiation and concurrent 5-fluoruracil or capecitabine. Patients were considered to have a CR if surgical pathology revealed ypT0N0M0 (operative management), or if they had no evidence of residual disease on clinical and radiographic assessment (non-operative management). Statistical analysis was carried out to determine predictors of CR and long-term outcomes. Results Complete records were available on 138 patients. The median follow-up was 24.5 months. Thirty-six patients (26.3%) achieved a CR; 30/123 operatively managed patients (24.5%) and 6/15 (40%) non-operatively managed patients. None of the 10 patients with mucinous adenocarcinoma achieved a CR. Carcinoembryonic antigen (CEA) ≥5 μg/L at diagnosis (OR 0.190, 95% CI 0.037–0.971, p = 0.046), tumor size ≥3 cm (OR 0.123, 95% CI 0.020–0.745, p = 0.023), distance of tumor from the anal verge ≥3 cm (OR 0.091, 95% CI 0.013–0.613, p = 0.014), clinically node-positive disease at diagnosis (OR 0.201, 95% CI 0.045–0.895, p = 0.035), and interval from CRT to surgery ≥8 weeks (OR 5.267, 95% CI 1.068–25.961, p = 0.041) were independent predictors of CR. The CR group had longer 3-year distant metastasis-free survival (DMFS) (93.7 vs. 63.7%, p = 0.016) and 3-year disease-free survival (DFS) (91.1 vs. 67.8%, p = 0.038). Three-year locoregional control (LRC) (96.6 vs. 81.3%, p = 0.103) and overall survival (97.2 vs. 87.5%, p = 0.125) were higher in the CR group but this did not achieve statistical significance. CR was not an independent predictor of LRC, DMFS, or DFS. Conclusion CEA at diagnosis, tumor size, tumor distance from the anal verge, node positivity at diagnosis, and interval from CRT to surgery were predictors of CR. These clinical variables may offer insight into patient selection and timing of treatment response evaluation in the watch-and-wait approach.

HIV Infection Is Associated With Poor Outcomes for Patients With Anal Cancer in the Highly Active Antiretroviral Therapy Era.

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.

Inhibition of Hsp27 Radiosensitizes Head-and-Neck Cancer by Modulating Deoxyribonucleic Acid Repair

PURPOSE To present a novel method of tumor radiosensitization through Hsp27 knockdown using locked nucleic acid (LNA) and to investigate the role of Hsp27 in DNA double strand break (DSB) repair. METHODS AND MATERIALS Clonogenic survival assays, immunoblotting, the proximity ligation assay, and γH2AX foci analysis were conducted in SQ20B and FaDu human head-and-neck cancer cell lines treated with Hsp27 LNA and Hsp27 short hairpin RNA (shRNA). Additionally, nude mice with FaDu flank tumors were treated with fractionated radiation therapy after pretreatment with Hsp27 LNA and monitored for tumor growth. RESULTS Hsp27 LNA and Hsp27 shRNA radiosensitized head-and-neck cancer cell lines in an Hsp27-dependent manner. Ataxia-Telangectasia Mutated-mediated DNA repair signaling was impaired in irradiated cells with Hsp27 knockdown. ATM kinase inhibition abrogated the radiosensitizing effect of Hsp27. Furthermore, Hsp27 LNA and shRNA both attenuated DNA repair kinetics after radiation, and Hsp27 was found to colocalize with ATM in both untreated and irradiated cells. Last, combined radiation and Hsp27 LNA treatment in tumor xenografts in nude mice suppressed tumor growth compared with either treatment alone. CONCLUSIONS These results support a radiosensitizing property of Hsp27 LNA in vitro and in vivo, implicate Hsp27 in double strand break repair, and suggest that Hsp27 LNA might eventually serve as an effective clinical agent in the radiotherapy of head-and-neck cancer.

Radiation therapy improves survival in rectal small cell cancer - Analysis of Surveillance Epidemiology and End Results (SEER) data

BackgroundSmall cell carcinoma of the rectum is a rare neoplasm with scant literature to guide treatment. We used the Surveillance Epidemiology and End Results (SEER) database to investigate the role of radiation therapy in the treatment of this cancer.MethodsThe SEER database (National Cancer Institute) was queried for locoregional cases of small cell rectal cancer. Years of diagnosis were limited to 1988–2010 (most recent available) to reduce variability in staging criteria or longitudinal changes in surgery and radiation techniques. Two month conditional survival was applied to minimize bias by excluding patients who did not survive long enough to receive cancer-directed therapy. Patient demographics between the RT and No_RT groups were compared using Pearson Chi-Square tests. Overall survival was compared between patients who received radiotherapy (RT, n = 43) and those who did not (No_RT, n = 28) using the Kaplan-Meier method. Multivariate Cox proportional hazards model was used to evaluate important covariates.ResultsMedian survival was significantly longer for patients who received radiation compared to those who were not treated with radiation; 26 mo vs. 8 mo, respectively (log-rank P = 0.009). We also noted a higher 1-year overall survival rate for those who received radiation (71.1% vs. 37.8%). Unadjusted hazard ratio for death (HR) was 0.495 with the use of radiation (95% CI 0.286-0.858). Among surgery, radiotherapy, sex and age at diagnosis, radiation therapy was the only significant factor for overall survival with a multivariate HR for death of 0.393 (95% CI 0.206-0.750, P = 0.005).ConclusionsUsing SEER data, we have identified a significant survival advantage with the use of radiation therapy in the setting of rectal small cell carcinoma. Limitations of the SEER data apply to this study, particularly the lack of information on chemotherapy usage. Our findings strongly support the use of radiation therapy for patients with locoregional small cell rectal cancer.

Comparison of anal cancer outcomes in public and private hospital patients treated at a single radiation oncology center

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 χ(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.

Outcomes of rectal cancer with liver oligometastases.

PURPOSE In patients with oligometastatic colorectal cancer to the liver, long term survival is possible and a multi-modality treatment approach may be considered. This is a report of a single institution experience of oligometastatic rectal cancer patients after treatment of the primary tumor and pelvic lymph nodes with extended course chemoradiation therapy. METHODS Between 2004 and 2013, 26 oligometastatic rectal cancer patients with liver metastases were treated with extended course chemoradiation at our institution followed by total mesorectal excision (TME). Amongst these there were 17 men and 9 women. The mean age at the time of diagnosis was 59.8 years, with a range from 36 to 87 years of age. Eleven patients had metastases in other sites in addition to liver, and one patient in our cohort had lung metastasis with no liver metastasis. Kaplan-Meier method was used to generate overall survival (OS), progression free survival (PFS), distant metastases (DM) and local control (LC). RESULTS OS rates were 95%, and 70% at 12 and 24 months respectively, with a mean survival time of 40.5 months. PFS rates were 91% and 36% at 12 and 24 months respectively, with a mean PFS time of 23.1 months. LC rates were 91% and 66% at 12 and 24 months respectively. DM rates were 0% and 61% at 12 and 24 months respectively. Finally, when censoring deaths, progression of liver metastases and distant progression, Kaplan-Meier analysis demonstrated five events of local failure. CONCLUSIONS This series demonstrated an OS of 70% at 24 months, with a mean survival of 40.5 months. Significantly, LC was only 66% despite the use of extended course chemoradiation and TME. This data suggests that many patients with oligometastatic rectal cancer will survive past 2 years, and that a substantial number will fail locally as well as distantly. Therefore, a multimodality approach is reasonable. Recent data suggests that a hypofractionated radiation regiment of 25 Gy in 5 Gy fractions allows an equivalent LC compared to extended course chemoradiation with 50.4 Gy in 1.8 Gy fractions. A short course of radiation may be more consistent with the goals of care of the oligometastatic rectal cancer patient who is at high risk of recurrence.

Biomarkers that Predict Response to Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer

Neoadjuvant chemoradiation has been a standard of care for locally advanced rectal cancers. Recent reports suggest that a pathologic complete response to neoadjuvant treatment correlates to improved overall survival. In addition, some series suggest that patients who have a complete response to neoadjuvant therapy may safely defer surgery in favor of a “watch and wait” approach, therefore avoiding the potential complications and adverse bowel function associated with surgery. It is therefore important to understand the clinical and biologic factors which affect the response of rectal cancers to chemoradiation. This review highlights the current literature examining the biomarkers of tumor response to chemoradiation.

Food as medicine: A randomized controlled trial (RCT) of home delivered, medically tailored meals (HDMTM) on quality of life (QoL) in metastatic lung and non-colorectal GI cancer patients.

155 Background: Malnutrition incidence in cancer approaches 85%, disproportionately burdening those with lung, GI, and advanced stage cancers. Malnourished patients have impaired chemotherapy response, shorter survival, longer hospital stays, and decreased QoL. Home delivered meals are nutritional interventions that improve patient well-being, nutrition, and lower healthcare costs in the elderly but have not been studied as an intervention in cancer patients. HDMTM are nutritionist prescribed home delivered meals tailored to patients symptoms, co-morbidities, and health needs. Preliminary data in 211 cancer patients showed with HDMTM 87% ate more than half of meals, 91% lived more independently, 89% ate more nutritiously, and 70% had less fatigue. HDMTM may be a strategy to reduce financial toxicity and healthcare utilization and improve QoL in cancer patients, but no primary data exists evaluating its efficacy. METHODS We sought to develop the first RCT evaluating patient-centered QoL improvement from nutritional intervention with HDMTM in those with metastatic lung and non-colorectal GI cancer. We established a partnership with Gods Love We Deliver, a 501c3 non-profit specializing in HDMTM. RESULTS We developed a protocol for a single-institution RCT of standard of care (SoC) versus SoC and HDMTM in metastatic lung and non-colorectal GI cancer patients with primary aim comparing QoL between arms at 12 weeks using the FACT-G questionnaire. Sample size is 180. Secondary aims assess HDMTMs impact on nutritional status, weight, mood, survival, food security, financial toxicity, healthcare utilization, and cost effectiveness. Eligible patients tolerate oral alimentation, have PS 0-3, and newly diagnosed (< 6 weeks) metastatic cancer. All patients have pre-randomization nutritional evaluation by an oncologic dietician. CONCLUSIONS We present the first PRMC reviewed and IRB approved RCT evaluating the efficacy of HDMTM in metastatic cancer patients with primary endpoint of patient reported QoL. Investigating HDMTM expands our knowledge of nutrition as an effective arm of palliative oncology.

Abstract A145: Radiation therapy induces tumor-promoting immune suppression in the microenvironment of pancreatic carcinoma

Radiation therapy (RT) has shown marginal efficacy in patients with pancreatic ductal adenocarcinoma (PDA). Two of the past three randomized controlled trials investigating the efficacy of RT for patients with locally advanced unresectable PDA have shown a statistically significant worse survival by 40% or more for patients receiving RT. We postulated that RT reprograms inflammatory cells within the tumor microenvironment to an immune suppressive phenotype limiting the efficacy of RT in invasive PDA and accelerating disease progression in surrounding pre-invasive foci. We found that RT markedly accelerates the progression of pre-invasive PDA in a dose-dependent manner and reduces animal survival by more than 6 months. In both invasive and pre-invasive PDA, RT reprograms immunogenic macrophages towards an immune-suppressive M2 phenotype resulting in CD8 T cell scarcity and Th2 and Treg differentiation of CD4 T cells. Moreover, adoptive transfer of T cells harvested from RT-treated tumors accelerates tumor growth in recipient hosts. We show that M-CSF blockade concurrent with RT prevents immune-suppressive macrophage and T cell reprogramming and markedly enhances the efficacy of RT in PDA. These data suggest that targeting macrophage reprogramming can unleash the utility of RT for PDA. Citation Format: Lena Tomkotter, Gregor Werba, Susanna Nguy, Sara Alothman, Dalia Alqunaibit, Shaun Tiwari, Nancy Ngoc Giao Ly, Donnele Daley, Atsuo Ochi, Rocky Barilla, Alejandro Torres-Hernandez, Ilenia Pellicciotta, Kevin Du, George Miller. Radiation therapy induces tumor-promoting immune suppression in the microenvironment of pancreatic carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A145.