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Supplementary Table 1. Description of radiation treatment volumes (GTV, CTV, and PTV) Supplementary Table 2. Description of dose to organs at risk and treatment interruptions Supplemental Table 3. Subject count for key steps within the RT-phase of the clinical trial Supplemental Table 4. Subject count for key steps within the ADJ-phase of the clinical trial

Radiation induced intestinal damage histology and collagen deposition information.

Supplementary Legend

The effect of ascorbate and catalase on clonogenic cell survival in PDAC.

Supplemental Figure 1: P-AscH- treatment in combination with RT and TMZ decreases the systemic the systemic oxidaitive stress marker 4-hydroxy-2-nonenal modified proteins. S1A-SAB.

Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH−, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH− decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH− radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH−, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH− in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH− during the radiotherapy “beam on.” Specifically, treatment with P-AscH− increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH−–treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH− in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH− efficacy is warranted in a phase II clinical trial.Significance:These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.

Purpose:Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH−) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH− to standard RT/TMZ therapy.Patients and Methods:This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH−) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH− phase). Eight P-AscH− dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH− doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH− was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03).Results:Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n = 8), median PFS was 10 months and median OS was 23 months.Conclusions:P-AscH−/RT/TMZ is safe with promising clinical outcomes warranting further investigation.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic neuroendocrine tumors. Delivering a sufficient tumor radiation dose remains challenging because of critical-organ dose limitations. Adding 131I-metaiodobenzylguanidine (131I-MIBG) to PRRT may be advantageous in this regard. Methods: A phase 1 clinical trial was initiated for patients with nonoperable progressive neuroendocrine tumors using a combination of 90Y-DOTATOC plus 131I-MIBG. Treatment cohorts were defined by radiation dose limits to the kidneys and the bone marrow. Subject-specific dosimetry was used to determine the administered activity levels. Results: The first cohort treated subjects to a dose limit of 1,900 cGy to the kidneys and 150 cGy to the marrow. No dose-limiting toxicities were observed. Tumor dosimetry estimates demonstrated an expected dose increase of 34%–83% using combination therapy as opposed to 90Y-DOTATOC PRRT alone. Conclusion: These findings demonstrate the feasibility of using organ dose for a phase 1 escalation design and suggest the safety of using 90Y-DOTATOC and 131I-MIBG.

Purpose The number of studies that evaluate treatment margins for high grade gliomas (HGG) are limited. We hypothesize that patients with HGG who are treated with a gross tumor volume (GTV) to planning tumor volume (PTV) expansion of ≤1 cm will have progression-free survival (PFS) and overall survival (OS) rates similar to those treated in accordance with standard protocols by the Radiation Therapy Oncology Group or European Organisation for Research and Treatment of Cancer. Furthermore, the PFS and OS of subgroups within the study population will have equivalent survival outcomes with GTV1-to-PTV1 margins of 1.0 cm and 0.4 cm. Methods and materials Treatment plans and outcomes for patients with pathologically confirmed HGG were analyzed (n = 267). Survival (PFS and OS) was calculated from the time of the first radiation treatment and a χ2 test or Fisher exact test was used to calculate the associations between margin size and patient characteristics. Survival was estimated using Kaplan-Meier and compared using the log-rank test. All analyses were performed on the univariate level. Results The median PFS and OS times were 10.6 and 19.1 months, respectively. By disease, the median PFS and OS times were 8.6 and 16.1 months for glioblastoma and 26.7 and 52.5 months for anaplastic glioma. The median follow-up time was 18.3 months. The treatment margin had no effect on outcome and the 1.0 cm GTV1-PTV1 margin subgroup (n = 212) showed median PFS and OS times of 10.7 and 19.1 months, respectively, and the 0.4 cm margin subgroup (n = 55) 10.2 and 19.3 months, respectively. In comparison with the standard treatment with 2 cm to 3 cm margins, there was not a significant difference in outcomes. Conclusions There is no apparent difference in survival when utilizing smaller versus larger margins as defined by the guidelines of the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer. Although there remains no class I evidence that outcomes after treatment with smaller margins are identical to those after treatment with larger margins, this large series with long-term follow up suggests that a reduction of the margins is safe and further investigation is warranted.

Ketogenic diets (KD) are high in fat and low in carbohydrates, forcing cells to utilize mitochondrial fatty acid oxidation for energy production. Since cancer cells demonstrate increased mitochondrial oxidative stress relative to normal cells, we hypothesized that a KD may selectively enhance metabolic oxidative stress in head and neck cancer cells, sensitizing them to radiation and platinum-based chemotherapy without causing increased toxicity in surrounding normal tissues. This hypothesis was tested in preclinical murine xenografts and in a phase 1 clinical trial (NCT01975766). In this study, mice bearing human head and neck cancer xenografts (FaDu) were fed either standard mouse chow or KetoCal® KD (90% fat, 8% carbohydrate, 2% protein) and exposed to ionizing radiation. Tumors were harvested from mice to test for glutathione, a biomarker of oxidative stress. In parallel, patients with locally advanced head and neck cancer were enrolled in a phase 1 clinical trial where they consumed KD and received radiation with concurrent platinum-based chemotherapy. Subjects consumed KetoCal KD via percutaneous endoscopic gastrostomy (PEG) tube and were also allowed to orally consume water, sugar-free drinks, and foods approved by a dietitian. Oxidative stress markers including protein carbonyls and total glutathione were assessed in patient blood samples both pre-KD and while consuming the KD. Mice bearing FaDu xenografts that received radiation and KD demonstrated a slight improvement in tumor growth rate and survival compared to mice that received radiation alone; however a variation in responses was seen dependent on the fatty acid composition of the diet. In the phase 1 clinical trial, a total of twelve patients were enrolled in the study. Four patients completed five weeks of the KD as per protocol (with variance in compliance). Eight patients did not tolerate the diet with concurrent radiation and platinum-chemotherapy (5 were patient decision and 3 were removed from study due to toxicity). The median number of days consuming a KD in patients who did not complete the study was 5.5 (range: 2-8 days). Reasons for discontinuation included "stress of diet compliance" (1 patient), grade 2 nausea (3 patients), and grade 3 fatigue (1 patient). Three patients were removed from the trial due to dose-limiting toxicities including: grade 4 hyperuricemia (2 patients) and grade 3 acute pancreatitis (1 patient). Median weight loss was 2.95% for the KD-tolerant group and 7.92% for patients who did not tolerate the diet. In conclusion, the ketogenic diet shows promise as a treatment combined with radiation in preclinical mouse head and neck cancer xenografts. A phase 1 clinical trial evaluating the safety and tolerability of KD demonstrated difficulty with diet compliance when combined with standard-of-care radiation therapy and cisplatin chemotherapy.

Pharmacological ascorbate (P-AscH-) combined with standard of care (SOC) radiation and temozolomide is being evaluated in a phase 2 clinical trial (NCT02344355) in the treatment of glioblastoma (GBM). Previously published data demonstrated that paramagnetic iron (Fe3+) catalyzes ascorbate's oxidation to form diamagnetic iron (Fe2+). Because paramagnetic Fe3+ may influence relaxation times observed in MR imaging, quantitative MR imaging of P-AscH--induced changes in redox-active Fe was assessed as a biomarker for therapy response. Gel phantoms containing either Fe3+ or Fe2+ were imaged with T2* and quantitative susceptibility mapping (QSM). Fifteen subjects receiving P-AscH- plus SOC underwent T2* and QSM imaging four weeks into treatment. Subjects were scanned: pre-P-AscH- infusion, post-P-AscH- infusion, and post-radiation (3–4 h between scans). Changes in T2* and QSM relaxation times in tumor and normal tissue were calculated and compared to changes in Fe3+ and Fe2+ gel phantoms. A GBM mouse model was used to study the relationship between the imaging findings and the labile iron pool. Phantoms containing Fe3+ demonstrated detectable changes in T2* and QSM relaxation times relative to Fe2+ phantoms. Compared to pre-P-AscH-, GBM T2* and QSM imaging were significantly changed post-P-AscH- infusion consistent with conversion of Fe3+ to Fe2+. No significant changes in T2* or QSM were observed in normal brain tissue. There was moderate concordance between T2* and QSM changes in both progression free survival and overall survival. The GBM mouse model showed similar results with P-AscH- inducing greater changes in tumor labile iron pools compared to the normal tissue. Conclusions T2* and QSM MR-imaging responses are consistent with P-AscH- reducing Fe3+ to Fe2+, selectively in GBM tumor volumes and represent a potential biomarker of response. This study is the first application using MR imaging in humans to measure P-AscH--induced changes in redox-active iron., Highlights • Quantitative imaging can detect tissue differences in Fe3+ and Fe2+ concentrations. • Pharmacological ascorbate treatment increases T2* relaxation times in GBM tumors. • T2* is a potential biomarker of response in GBM subjects to treatment with pharmacological ascorbate.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic neuroendocrine tumors. Delivering a sufficient tumor radiation dose remains challenging because of critical-organ dose limitations. Adding

Peptide receptor radionuclide therapy (PRRT) is an effective form of treatment of patients with metastatic neuroendocrine tumors, delivering modest objective tumor response rates but notable survival and symptomatic benefits. The first PRRT approved by the US Food and Drug Administration was lutetium 177-DOTATATE and is for use in adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. The treatment paradigm typically leads to significant improvement in symptomology coupled with an extended period of progression-free survival. Side effects are limited, with a small fraction of individuals experiencing clinically significant long-term renal or hematologic toxicity.

PURPOSE: First line treatment with platinum-based chemotherapy with or without immunotherapy improves survival in metastatic non-small cell lung cancer (NSCLC). Preclinical studies suggest that pharmacological ascorbate (P-AscH-) enhances tumor response to platinum therapy. Hence, we conducted a single-arm phase II study to evaluate the efficacy of P-AscH- in combination with platinum-doublet chemotherapy in patients with advanced stage NSCLC (NCT02420314). METHODS: Chemotherapy naïve advanced stage NSCLC patients with an ECOG PS of 0-2 were enrolled to receive 4-cycles of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks (wks). Ascorbate (75 g) infusions were given twice a wk for 12-wks. The primary endpoint was to assess tumor objective response per RECIST v1.1. The trial was conducted as an optimal Simon two-stage design. After initial therapy, patients could receive maintenance or consolidation treatment. Secondary endpoints were to evaluate tolerability, progression-free survival (PFS) and overall survival (OS). Serum cytokines and chemokines were measured at baseline, C2d1, and C4d21± 7d. RESULTS: Forty subjects were enrolled. The study met its primary endpoint with 38 efficacy evaluable subjects. The objective response rate was 34.2%. All were confirmed partial responses (cPR). Disease control rate was 84.2% (stable disease + cPR). Median duration of follow up was 11.7 months (mo), mPFS was 5.7 mo (95% CI:4.2-6.7), and mOS was 12.5 mo (95% CI:7.5-21.4). Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 (cytopenia) events. These events were not attributed to P-AscH-. Common (≥5%) grade 3 TRAE included transient hypertension (27.5%), lymphopenia (22.5%), fatigue (7.5%), anemia (7.5%) and hypokalemia (5%). Cytokine and chemokines data suggest that protocol regimen elicited an immune response with multiple distinct cytokine signatures. Immunophenotyping of peripheral blood mononuclear cells (n=7) demonstrated a mean fold increase in effector CD8 T cells of 4.9 in patients with PFS ≥ 6 mo compare to 1.6 in patients with PFS < 6 mo. Assessments of serum iron profile and somatic alterations in KRAS, KEAP1, NFE2L2 and STK11 genes are underway. CONCLUSIONS: This phase II trial met the primary objective of improving the tumor response rate in advanced stage NSCLC by adding P-AscH- to platinum-based chemotherapy. P-AscH- appears to alter the host immune response. These promising findings warrant further investigation. Citation Format: Muhammad Furqan, Taher Abu-Hejleh, Kellie L. Bodeker, Laura M. Pietrok, Stacey M. Hartwig, Mikaela M. Tremblay, Micaela G. Fosdick, Jon Houtman, Steven Varga, Casey F. Pulliam, Michael Petronek, Melissa A. Fath, Sarah L. Mott, Aaron D. Bossler, Andrew M. Bellizzi, Jun Zhang, Hariharasudan Mani, Varun Monga, Brian J. Smith, Joseph Cullen, Brett A. Wagner, Garry R. Buettner, John M. Buatti, Douglas R. Spitz, Bryan G. Allen. Pharmacological ascorbate enhances platinum-based chemotherapy responses in metastatic non-small cell lung cancer (NSCLC): A phase II clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT164.

Pharmacological ascorbate (P-AscH-; high dose intravenous infusions of vitamin C generating milli-molar plasma concentrations) has re-emerged as an anti-cancer therapy. Phase 1 clinical trials combining P-AscH- with chemotherapy and ionizing radiation demonstrate safety and promising clinical outcomes in a variety of malignancies. In a first-in-human trial, subjects with newly diagnosed glioblastoma (GBM) and undetectable MGMT promoter methylation were treated with P-AscH-, ionizing radiation, and temozolomide. Results demonstrate median progression-free survival (PFS) of 10 months and median overall survival (OS) of 23 months, comparing favorably to historical GBM patients expressing MGMT. P-AscH-‘s anti-cancer mechanism is dependent upon the presence of redox active labile iron. In the presence of redox active iron, the formation of hydrogen peroxide, which causes oxidative stress and eventual cell death, selectively forms in cancer cells. Treatment with P-AscH- increased cancer cells’ labile iron pool, further enhancing sensitivity to P-AscH-. We investigated the capability of MR imaging (T2* relaxation time) to measure the redox active iron and predict response to P-AscH-. T2* relaxation time is influenced by in-field inhomogeneities, such as redox active paramagnetic iron. The active phase 2 trial evaluating P-AscH-, radiation, and temozolomide for GBM, obtains T2* imaging prior to (baseline) and immediately after ascorbate infusion (NCT02344355). A preliminary analysis of the baseline scan for the first 15 subjects suggests those with faster GBM T2* relaxation times (≤ 58 ms) have more redox active labile iron pools as well as an improved median PFS (11.4 months) compared to those with slower T2* relaxation times (> 58 ms; median PFS of 8.5 months). Pre-clinical studies evaluating the effectiveness of iron nano-particle supplementation in GBM animal models are on-going. (Supported by P01 CA217797, R01 CA169046, U01 CA140206, T32 CA078586, P30 CA086862, as well as the Gateway for Cancer Research grant G-17–1500.)

Objectives: Celecoxib is a cyclooxygenase-2-specific inhibitor indicated to treat acute pain and pain secondary to osteoarthritis and rheumatoid arthritis. Surgical models of acute pain have demonstrated superior pain relief to placebo. The objective of this study was to test the safety and efficacy of celecoxib for pain relief after tonsillectomy compared to placebo. Methods: Adult subjects were randomized to 200 mg celecoxib versus placebo with a loading dose the night before surgery then twice daily for 10 days. Subjects were instructed to supplement the study drug with hydrocodone/acetaminophen liquid or acetaminophen for pain as needed. Subjects completed a daily diary regarding their pain, nausea, vomiting, diet, and activity. Results: Seventeen subjects enrolled. Intraoperative blood loss was similar between groups, and no subject had postoperative bleeding. Three patients returned to the emergency department for treatment, and 2 patients could not complete the diaries, all in the placebo group. Subjects in the placebo group required statistically significant ( P < .05) higher doses of narcotic and acetaminophen to control pain. Pain and diet rating scores were slightly better in the celecoxib group compared to placebo. Conclusions: In this small cohort, celecoxib reduced postoperative narcotic and acetaminophen requirements compared to placebo without complications.

TPS791 Background: FOLFIRINOX or gemcitabine/nab-paclitaxel are both frontline chemotherapy options for patients with metastatic pancreas cancer. For most who cannot tolerate the triplet, the latter doublet is the preferred option. Through previous work by our group, pharmacologic ascorbate is known to synergize with gemcitabine; preliminary in vitro data from our group suggests a similar synergistic response with paclitaxel. Though ascorbate has been utilized in cancer therapy, few robust trials have investigated intravenous delivery of ascorbate to deliver plasma concentrations that are cytotoxic to tumor cells. Our prior studies have demonstrated ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We hypothesize that production of hydrogen peroxide mediates the increased susceptibility of pancreatic cancer cells to ascorbate-induced metabolic oxidative stress, resulting in improved treatment outcomes, which has led to the development of the clinical trial (NCT02905578). Methods: All participants receive gemcitabine (1000 mg/m2 weekly) and nab-paclitaxel (125 mg/m2) on cycle days 1, 8, and 15 of a 28-day cycle. Participants are randomized to ± pharmacologic ascorbate (75-gram infusion 3x weekly) in addition to chemotherapy. Study therapy continues until tumor progression. The primary objective is to determine overall survival in patients when treated with combination gemcitabine, nab-Paclitaxel and high-dose ascorbic acid compared to gemcitabine and nab-paclitaxel in patients with non-resectable pancreatic cancer. Secondary objectives include determining objective response rate as well as progression free survival using RECIST 1.1 criteria employing a blinded reviewer for RECIST measurements. The study opened to accrual in 2018 with a goal of enrolling 65 participants. Oversight.Study is conducted under IND 105715 (J. Cullen, sponsor). The University of Iowa Biomedical IRB (IRB-01) serves as the IRB of record. Clinical trial information: NCT02905578.

Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH−, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH− decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH− radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH−, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH− in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH− during the radiotherapy “beam on.” Specifically, treatment with P-AscH− increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH−–treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH− in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH− efficacy is warranted in a phase II clinical trial. Significance: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.

Ketogenic diets are low in carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Relative to normal cells, cancer cells are believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a ketogenic diet concurrent with radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a ketogenic diet or standard rodent chow, treated with conventionally fractionated radiation (2 Gy/fraction), and tumor growth rates were assessed daily. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modfied proteins as a marker of oxidative stress. Based on this and another previously published preclinical study, phase 1 clinical trials in locally advanced NSCLC and pancreatic cancer were initiated, combining standard radiation and chemotherapy with a ketogenic diet for six weeks (NSCLC) or five weeks (pancreatic cancer). The xenograft experiments demonstrated prolonged survival and increased 4HNE-modfied proteins in animals consuming a ketogenic diet combined with radiation compared to radiation alone. In the phase 1 clinical trial, over a period of three years, seven NSCLC patients enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study and one was withdrawn due to a dose-limiting toxicity. Over the same time period, two pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose-limiting toxicity. The preclinical experiments demonstrate that a ketogenic diet increases radiation sensitivity in a pancreatic cancer xenograft model. However, patients with locally advanced NSCLC and pancreatic cancer receiving concurrent radiotherapy and chemotherapy had suboptimal compliance to the oral ketogenic diet and thus, poor tolerance.

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H(2)O(2); however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O(2)(.−) and H(2)O(2) are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H(2)O(2). In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

Objective: To investigate outcomes and prognostic factors in patients treated with once daily high-dose (≥ 60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LSSCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy. Methods: We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (≥ 60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months and use of prophylactic cranial irradiation (PCI). Results: 42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5 year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p

To investigate outcomes and prognostic factors in patients treated with once daily high-dose (≥60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LS-SCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy.We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (≥60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months, and use of prophylactic cranial irradiation (PCI).42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5-year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p0.01) but not OS.In this single institution series, daily HDRT demonstrated a 2-year OS of 47% in LS-SCLC. This compares well to the historical survival of daily fractionation (47%) from INT 0096 reported by Turrisi

Patient accrual is essential for the success of oncology clinical trials. Recruitment for trials involving the development of quantitative imaging biomarkers may face different challenges than treatment trials. This study surveyed investigators and study personnel for evaluating accrual performance and perceived barriers to accrual and for soliciting solutions to these accrual challenges that are specific to quantitative imaging-based trials. Responses for 25 prospective studies were received from 12 sites. The median percent annual accrual attained was 94.5% (range, 3%–350%). The most commonly selected barrier to recruitment (n = 11/25, 44%) was that “patients decline participation,” followed by “too few eligible patients” (n = 10/25, 40%). In a forced choice for the single greatest recruitment challenge, “too few eligible patients” was the most common response (n = 8/25, 32%). Quantitative analysis and qualitative responses suggested that interactions among institutional, physician, and patient factors contributed to accrual success and challenges. Multidisciplinary collaboration in trial design and execution is essential to accrual success, with attention paid to ensuring and communicating potential trial benefits to enrolled and future patients.

Purpose: A ketogenic diet (KD) is a high fat, low carbohydrate diet that forces cells to utilize mitochondrial fatty acid oxidation for energy production. It has been previously shown that cancer cells have defects in mitochondrial oxidative metabolism resulting in increased oxidative stress relative to non-malignant cells. Because radiation and platinum based chemotherapy also induce oxidative damage, we hypothesized that a KD may enhance radiation and platinum chemotherapy efficacy in head and neck cancer. The KD's ability to enhance radiation and chemotherapy efficacy were assessed in murine head and neck cancer xenograft models. The safety and tolerability of a KD in combination with standard of care radiation and platinum-based chemotherapy in head and neck cancer patients was assessed in a phase I clinical trial. Methods: Mice bearing FaDu human head and neck cancer xenografts were fed either standard mouse chow or commercially prepared KD and treated with varying combination of cetuximab (CTX), cisplatin, and/or radiation (IR) and tumor growth was measured via calipers. Tumor homogenates and mice serum were harvested to test for markers including glutathione, 4HNE, PCNA, and IL6. Based on this study and other previously published pre-clinical studies, a phase I clinical trial in locally advanced head and neck cancer combining standard radiation and chemotherapy while consuming a KD was initiated. Subjects consumed a KD by PEG or nasogastric-tube and were also allowed to orally consume water, sugar-free drinks approved by the dietician, and approved snacks and meals approved by the dietician. Oxidative stress markers including protein carbonyl and glutathione were assessed. Results: Mice bearing xenografts treated with KD + IR + CTX had significantly increased survival relative to mice treated with IR + CTX. Collected tumor homogenates in KD + IR + CTX treated mice demonstrated increased 4HNE modified proteins relative to tumor homogenates from IR +CTX mice. In the phase I clinical trial, a total of twelve subjects were enrolled in the study. Four subjects completed five weeks of the KD as per protocol. Median follow-up from completion of RT was 13.1 months (range 8.0-26.7 months). Of the eight subjects that did not tolerate the diet, median number of days subjects stayed on diet was 5.5 (range: 2-8 days). Reasons for discontinuation included “stress of diet compliance” (1), grade 2 nausea (3), and grade 3 fatigue (1). Three subjects were removed for dose limiting toxicities: grade 4 hyperuricemia (2) and grade 3 acute pancreatitis (1). Median weight loss was 2.95% for the KD group and 7.92% for subjects that did not tolerate the diet. Subject serums demonstrated increased oxidative stress as they continued the diet. Conclusions: KD shows promise as adjuvant treatment in mouse xenograft model of head and neck cancer but in our small study there was difficulty with compliance and tolerability when combined with standard of care radiation and chemotherapy. Citation Format: Daniel MA, Carryn Anderson, Samuel N. Rodmann, Kayla Follmer, Visarut Buranasudja, Kellie Bodeker, Jessica R. Parkhurst, Michael McCormack, Andrew Davis, Douglas R. Spitz, John Buatti, Bryan G. Allen, Melissa A. Fath. Ketogenic diet with concurrent chemoradiation in head and neck squamous cell carcinoma: Pre-clinical and phase I trial results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-252.

P-AscH– radiosensitizes pancreatic cancer (PDAC) in vitro and in vivo. The purpose of this Phase I trial is to determine the safety and tolerability of P-AscH- when combined with gemcitabine and radiation. Patients with locally advanced PDAC who were to undergo gemcitabine and radiotherapy were enrolled (Clinical Trials.gov NCT0152890). Patients were given P-AscH– (50-100 g/daily), 5 days/week and Gemcitabine as prescribed per standard of care guidelines. Intensity modulated radiation therapy was also administered at either 50.4 Gy in 28 fractions or 50 Gy in 25 fractions. The primary endpoints were safety and tolerability of P-AscH– other co-primary endpoints were dose-limiting toxicity and maximum tolerated dose. Since June, 2014, 14 patients have enrolled and 11 have completed therapy. Both 75 gram and 100 gram infusions achieved plasma ascorbate levels of 20 mM. The adverse event most commonly attributable to P-AscH– was dry mouth during infusion. No other adverse events were observed to be greater in intensity or frequency than with gemcitabine and radiation alone. Grade 3 or greater adverse events were hematologic in nature which occurred in all patients to varying severity. One P-AscH–-related toxicity was reported with non-cardiac chest pain which did not alter ongoing treatment. Common grade 1 and 2 adverse events included chills, abdominal pain, dry mouth, fatigue, nausea, vomiting, and thrombocytopenia, all in similar frequency and intensity to chemoradiotherapy alone. Progression Free and overall survival is 10.8 months and 13.1 months, respectively, compared to 6.0 months and 11.1 months, for historical controls. Our preliminary results demonstrate that P-AscH– in combination with gemcitabine/radiation is safe and tolerable.

Response evaluation criteria in solid tumors (RECIST) is the accepted method for determining tumor progression. However, RECIST may not estimate disease burden accurately because the axial plane often does not produce the actual longest diameter. Volumetric measurements may be an alternative to better determine tumor size. Our aim was to compare volumetric measurements with RECIST in pancreatic ductal adenocarcinomas (PDA) and hepatocellular carcinomas (HCC).RECIST and volumetric measurements were determined in 9 patients with metastatic PDA and 17 patients with HCC who subsequently underwent liver transplantation. Gross pathologic measurements after hepatectomy also were analyzed for volumes.Three-dimensional diameter in volumetric analysis was 38% and 36% higher than RECIST diameter in PDA and HCC, respectively (P.01). However, RECIST yielded 78% and 23% larger estimated tumor volumes than volumetric analysis in PDA and HCC, respectively (P.01). Gross pathologic volume in HCC showed a linear correlation with both volumetric analysis (r = .95; P.01) and RECIST (r = .96; P.01) but RECIST significantly overestimated gross pathologic volume by an average of 28% (P.01) whereas volumetric analysis was similar to gross pathologic volume (P = .56). In categorizing treatment response in PDA, RECIST and volumetric analysis were in moderate agreement (κ = .49).RECIST significantly may overestimate tumor burden compared with volumetric measurements in both PDA and HCC. Volumetric analysis may be the preferred method to detect tumor progression.

Purpose To conduct a randomized clinical trial to determine whether the combination of pentoxifylline (PTX) and vitamin E given for 6 months after breast/chest wall irradiation effectively prevents radiation-induced fibrosis (RIF). Methods and Materials Fifty-three breast cancer patients with localized disease were enrolled and randomized to treatment with oral PTX 400 mg 3 times daily and oral vitamin E 400 IU daily for 6 months after radiation (n=26), or standard follow up (n=27). Tissue compliance meter (TCM) measurements were obtained at 18 months to compare tissue compliance in the irradiated and untreated breast/chest wall in treated subjects and controls. Measurements were obtained at 2 mirror image sites on each breast/chest wall, and the average difference in tissue compliance was scored. Differences in TCM measurements were compared using a t test. Subjects were followed a minimum of 2 years for local recurrence, disease-free survival, and overall survival. Results The mean difference in TCM measurements in the 2 groups was 0.88 mm, median of 1.00 mm (treated) and 2.10 mm, median of 2.4 mm (untreated). The difference between the 2 groups was significant ( P =.0478). Overall survival (100% treated, 90.6% controls at 5 years) and disease-free survival (96.2% treated, 86.8% controls at 5 years) were not significantly different in the 2 groups. Conclusions This study of postirradiation breast cancer patients treated with PTX/vitamin E or standard follow-up indicated a significant difference in radiation-induced fibrosis as measured by TCM. There was no observed impact on local control or survival within the first 2 years of follow-up. The treatment was safe and well tolerated. Pentoxifylline/vitamin E may be clinically useful in preventing fibrosis after radiation in high-risk patients.

Upon receipt of the National Institutes of Health Clinical and Translational Science Award, the University of Iowa’s Institute for Clinical and Translational Science committed to develop an infrastructure for research professionals. Three goals were established: (1) identification of research professionals within the University of Iowa, (2) development of an educational series, including orientation and continuing education, and (3) development of a mentoring system. The purpose of this paper is to describe the process of development, initiation, and outcomes of a successful networking, educational, and mentoring system crafted for research professionals at the University of Iowa. Clin Trans Sci 2011; Volume 4: 42–47