bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative assessment of cardiorespiratory fitness, skeletal muscle function, and body composition in adults with primary malignant glioma
Authors: Jones L. , Friedman A. , West M. , Mabe S. , Fraser J. , Kraus W. , Friedman H. , Major N. , Reardon D.
Published: August 2020

e13002

Background: The neuropsychological impact of malignant glioma is well documented; the physiological and functional effects are not known. We conducted a pilot study to quantitatively assess cardiorespiratiory fitness, skeletal muscle function, and body composition of patients with primary malignant glioma. Methods: Using a cross-sectional design, patients with clinically stable postsurgical (10 ± 7 days post surgery) high-grade glioma (HGG; n=25) and low-grade glioma (LGG) were studied. Participants performed a cardiopulmonary exercise test (CPET) with expired gas analysis to assess peak exercise capacity (VO2peak) and other parameters of cardiovascular function. Other physiological outcomes included skeletal muscle cross-sectional area (CSA; magnetic resonance imaging), isokinetic muscle strength (isokinetic dynamometer), and body composition (air displacement plethysmography). QOL was assessed by the Functional Assessment of Cancer Therapy-Brain scale (FACT-BR). Results: CPET was a feasible and safe procedure for malignant glioma patients with no serious adverse events. Peak VO2 indexed to total body weight and lean body mass for both groups was 13.0 mL.min-1 and 19 mL.min-1; the equivalent to 59% and 38% below age and sex-predicted normative values, respectively. Skeletal muscle isokinetic strength was significantly lower in HGG relative to LGG patients (83 vs. 125 Nm, p=.025) and predicted peak VO2 (r = 0.44, p<0.05). In patients with HGG, only self-reported exercise behavior was correlated with QOL (r = 0.42; p=.046) while sex (male) (r = 0.44; p=.037), lean mass (r = -0.41; p=.049), and VO2peak (r = -0.40; p=.052) were associated with fatigue. Conclusions: CPET is a safe and feasible tool to evaluate physical functioning in select patients with malignant glioma. Postsurgical glioma patients have markedly reduced exercise capacity, isokinetic strength and CSA. Muscle strength is an important contributor to poor VO2peak in this population. Prospective studies are now required to determine whether such abnormalities influence prognosis as well as test the effect of appropriately selected interventions to prevent and/or mitigate dysfunction.

No significant financial relationships to disclose.
Assessment of diabetes mellitus (DM) as a risk factor for development of cisplatin-induced nephrotoxicity (CIN)
Authors: Weese J. , Sandhu P. D. , Mody A. , Ozer H. , Jafari M. , Tfayli A. H. , Kojouri K.
Published: August 2020

e13537

Background: DM is the most common cause of kidney disease in the US, and it may increase the risk of CIN. In vivo studies however suggest that DM not only is not a risk factor for CIN, it may even be protective. This may be explained by dysfunction of organic cation transporter-2, the critical transporter for cisplatin uptake in proximal tubules, in diabetic kidneys. We conducted a case-control study to assess the relationship between DM and CIN. Methods: Records of all patients (pts) who received cisplatin between 1/1/00 and 12/31/06 at Oklahoma City VA Hospital were reviewed. DM was diagnosed if pt had (1) been taking anti-diabetic treatment, or (2) Hgb A1C ≥6.5%, or (3) ≥2 fasting outpatient serum glucose levels 126–199 mg/dl, or (4) ≥1 serum glucose level ≥200 mg/dl at any time, prior to receiving cisplatin. CIN was defined as increase in serum creatinine (SCr) by ≥50% above baseline and higher than upper limit of normal, after exclusion of other causes of elevated SCr, during or within 8 weeks of completion of treatment. Continuous variables are reported by means and ranges, and compared using 2-tailed student's t test. Odds ratio (OR) was calculated to compare risk of CIN between diabetics and non-diabetics. Results: Two hundred pts (2 females, 198 males) received cisplatin in the study period, 50 (25%) were diabetic. Distribution of age (years, diabetics: 62 [46–77]; non-diabetics: 60 [26–79], p = 0.18) and baseline SCr (mg/dl, diabetics: 1.0 [0.4–1.5]; non-diabetics: 1.0 [0.5–1.6], p = 0.86) were similar between the two groups. Overall 15% of pts (30 of 200) developed CIN. Risk of CIN was not different between diabetics (8 of 50 pts, 16%) and non-diabetics (22 of 150 pts, 14.7%); OR = 1.11 (95% CI = 0.46 to 2.67) (Table). Conclusions: DM was not shown to be a risk factor for development of CIN. This finding is consistent with in vivo data obtained through animal diabetic models.

[Table: see text]

No significant financial relationships to disclose.
An open-label, dose-escalating study of Maxy-G34, a novel potent, long-acting Pegylated G-CSF, compared with pegfilgrastim (PF) for the treatment of chemotherapy induced neutropenia (CIN)
Authors: Schwartzberg L. S. , Sankar S. L. , Apt D. , Goldstein E. , Vetticaden S. J. , Chitour K. , Gilfoyle D. , Kim S. , Keilholz U. , Possinger K.
Published: August 2020

e14500

Background: rhG-CSF reduces the incidence and duration of CIN in patients (pts) receiving myelosuppressive chemotherapy. Maxy-G34 is a recombinant, modified human G-CSF, containing three 5 kD PEG groups. These modifications alter both renal and receptor mediated clearance, leading to a longer half-life and the potential for enhanced activity. Phase I studies demonstrated safety of Maxy-G34 in normal volunteers with a dose dependent rapidly reversible increase in the absolute neutrophil count (ANC). The effect of Maxy-G34 on CIN was evaluated in an open-label, active-comparator controlled, dose-ranging study. Methods: The primary efficacy endpoint was duration of severe, Grade 4 neutropenia (G4N) in treatment cycle 1. Adults with high-risk Stage I-IIIa breast cancer eligible for TAC chemotherapy received Maxy-G34 at 10, 30, 45, 60 or 100 μg/kg or the active control PF 6 mg, given sub- cutaneously 24-hours after each dose of TAC for 6 cycles. Blood samples were collected daily and analyzed at a central laboratory throughout each of the 21-day chemotherapy cycles to determine ANC and evaluate PK profile of Maxy-G34. Results: All dose groups of Maxy-G34 enrolled 6 pts each, except the 100 μg/kg group (3 pts), and the PF group (8 pts). The mean durations of G4N in cycle 1 were 2.2 days for 10 μg/kg, 1.8 days for 30 μg/kg, 0.8 days for 45 μg/kg, 2.2 days for 60 μg/kg, and 1.7 days for 100 μg/kg Maxy-G34 groups vs. 2.0 days for PF. The rate of FN was 2.6% across all Maxy-G34 doses vs. 4.2% for PF. CD34+ cell counts increased across Maxy-G34 groups following recovery from nadir with maximum concentration in treatment cycle 1 ranging from 25.8 to 133.3 cells/mL versus 49.6 cells/mL for PF. The average half-life and Cmax obtained after Maxy-G34 were approximately 2-fold higher than PF. Adverse events were consistent with those reported for G-CSF and TAC with no serious unexpected adverse events. Grade 3/4 AEs for Maxy-G34 was 9.5% vs. 8.5% for PF. No neutralizing antibodies related to Maxy-G34 were observed. Conclusion: Once-per-cycle Maxy-G34 appears to be effective in reducing CIN with no new safety signals. Further Phase II studies are planned.

[Table: see text]
Pharmacogenetics of peripheral neuropathy in elderly patients (>65 years) with advanced gastric cancer receiving oxaliplatin-based chemotherapy within a randomized phase II study
Authors: Goekkurt E. , Al-Batran S. , Obermann L. , Pauligk C. , Homann N. , Hartmann J. T. , Moehler M. , Hofheinz R. D. , Gerhard E. , Stoehlmacher J.
Published: August 2020

e14515

Background: Peripheral neuropathy (PNP) is a dose-limiting side effect of oxaliplatin based chemotherapy. High grade PNP may compromise quality of life especially in elderly patients (pts). A randomized multicenter phase II study was conducted to compare fluorouracil, leucovorin, oxaliplatin with or without docetaxel (FLO vs. FLOT, respectively) in elderly pts with advanced gastric cancer (AGC). Our purpose was to identify pharmacogenetic markers as predictors of high grade PNP within this study. Methods: 143 pts were enrolled in this study. Pts. were numerically >65 years or numerically >59 years but classified biologically >65 years as defined by an Instrumental Activities of Daily Living score of <8. PNP was classified according to an oxaliplatin specific scale. Genotyping was performed using PCR-based RFLP or TaqMan®-based allelic discrimination. 20 polymorphisms in 13 genes being part of the metabolism of the applied drugs or DNA repair were analyzed. Statistical analyses were based on stepwise multivariate cox regression models and included genotypes and clinical parameters. Results: Median age was 71 years (range 60–83). Pts received in median 6 cycles of treatment (range 1–12). 130 pts were evaluable for PN at time of analyses. Of these, 68 received FLO and 62 received FLOT. Cumulative grade 3 PNP occurred in 49% of pts without a significant difference between FLO and FLOT receiving pts (44% and 53%, respectively, p=0.4). Genotypes of TS and MTHFR could be identified as independent risk factors for grade 3 PNP by multivariate analyses. Pts carrying a TS promoter genotype known to be associated with low TS expression (2R/2R, 2R/3RC, 3RC/3RC) were at higher risk for developing grade 3 PNP compared to pts without one of these genotypes (OR 3.0 [95%CI 1.27; 7.06], p=0.01). Pts carrying MTHFR1298AC or CC genotypes were also at higher risk for experiencing grade 3 PNP compared to pts with the wildtype MTHFR-1298AA genotype (OR 3.1 [95%CI 1.26; 7.60], p=0.01). In fact, 89% of pts that experienced grade 3 PNP were carriers of at least one of these risk genotypes. Conclusions: Polymorphisms of TS and MTHFR might be associated with grade 3 PNP in AGC pts receiving oxaliplatin based chemotherapy.

No significant financial relationships to disclose.
Phase I study combining an IGFR inhibitor (IMC-A12) and an mTOR inhibitor (temsirolimus) in patients with solid tumors or lymphoma
Authors: Naing A. , LoRusso P. , Mills G. , Berry D. , Doyle L. , Rohren E. , Burger A. , Chen H. , Busaidy N. L. , Kurzrock R.
Published: August 2020

e14535

Background: IMC-A12 is a fully humanized IgG1/ lambda monoclonal antibody directed at the type I Insulin-Like Growth Factor Receptor (IGF-IR). Temsirolimus, an ester of the macrocyclic immunosuppressive agent sirolimus, is a cytostatic cell cycle inhibitor, which specifically inhibits the mammalian target of rapamycin (mTOR). A paradoxical increase in AKT activation by an mTOR inhibitor through an IGF-1R-dependent mechanism may compromise the therapeutic effect of mTOR inhibitors. Hence we evaluated the combination of temsirolimus and IMC-A12. Methods: This standard “3+3” design used a fixed dose of 25 mg IV weekly of temsirolimus with an escalating weekly dose of IV IMC-A12 at 3 mg/kg, 4 mg/kg and 6 mg/kg with no intrapatient dose escalation. The goal of this study is to define the MTD and to evaluate the biologic effects and metabolic activity of IMC-A12 and temsirolimus, individually and in combination. Patients with advanced solid tumors and lymphoma are eligible. No history of diabetes is allowed in dose escalation cohorts. Results: To date, 11 patients (4 males and 7 females, median age 47) with various solid tumor histologies have been enrolled across 3 dose cohorts with the current dose cohort at 6 mg/kg weekly IV of IMC-A12 and 25 mg weekly IV of temsirolimus. The MTD has not been determined. The most common grade 1 and grade 2 toxicities have been dysgeusia (n=5), fatigue (n=5), hyperglycemia (n=6), hypertriglyceridemia (n=6), leucopenia (n=4), mucositis (n=4), and ocular flashes of light (n=3). No grade 3 or 4 toxicity lasted more than 7 days (nausea n=1; vomiting n=1; thrombocytopenia n=1). Two patients (metastatic prostate cancer and metastatic breast cancer) demonstrated prolonged stable disease for 4 and 6 months, respectively. Conclusions: Preliminary data suggest that the combination is well tolerated and that it warrants further investigation. The expansion phase of this study will evaluate the biologic effects and metabolic activity of IMC-A12 and temsirolimus, individually and in combination, through the use of RPPA (Reverse Phase Protein Assays) and PET scans.

[Table: see text]
Bioluminescence evaluation of efficacy of oncolytic treatment with Newcastle disease virus (NDV) in malignant pleural mesothelioma
Authors: Silberhumer G. , Brader P. , Wong J. , Zamarin D. , Serganova I. , Blasberg R. , Palese P. , Fong Y.
Published: August 2020

e14536

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that arises from multipotent cells of the pleura. Chemotherapy and radiation have very limited therapeutic effects, and average survival time after diagnosis varies between 10 and 16 months. Immunotherapy, gene therapy (oncolytic viral therapy), and photodynamic therapy offer alternative treatment options, with promising results in animal studies. In the following study, the oncolytic efficacy of Newcastle disease virus (NDV(F3aa)-GFP) on MPM is tested and investigated by bioluminescence imaging. Methods: NDV(F3aa)-GFP was tested for viral cytotoxicity at different multiplicities of infection (MOI) against several mesothelioma cell lines in vitro by analyzing release of intracellular lactate dehydrogenase. For in vivo studies, MSTO 211H cells were transduced with firefly (Photinus pyralis) luciferase (FLuc)- encoding cDNAs (MSTO td 211H). Tumor-bearing animals (1e7 cells injected intrapleurally) were treated with either single or multiple doses of NDV(F3aa)-GFP (1e7 plaque-forming units) at different time points (days 1, 3, and 10) and followed by bioluminescence imaging. Results: Mesothelioma cell lines exhibited susceptibility to NDV lysis in the following order of sensitivity: MSTO 211H>MSTO td 211H>H-2452>VAMT>JMN. The cell lines H-2052, H-2373, and HMESO were not sensitive to viral treatment. In vivo studies with MSTO td 211H cells showed complete response to viral therapy in >75% of the animals, resulting in eradication of tumor detected by bioluminescence imaging at day 10 after treatment. Control animals were sacrificed after 23 days due to tumor burden, while >72% of the virally treated animals survived >50 days after tumor injection. No signs of toxicity were observed in the treatment group. In addition, multiple treatment showed a significantly better response compared with single treatment (p=0.005). Conclusions: NDV appears to be an efficient viral oncolytic agent in therapy of malignant pleural mesothelioma in a murine model, and warrants further investigation as a potential therapeutic agent.

No significant financial relationships to disclose.
Extended phase I trial of the oral pan-Bcl-2 inhibitor AT-101 by multiple dosing schedules in patients with advanced cancers
Authors: Saleh M. N. , Pitot H. , Maleski J. , Leopold L. , Forero A.
Published: August 2020

e14537

Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral, pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d) and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI/EORTC, 2005; James, ASCO, 2006 and Saleh, ASCO, 2007). MTD in the QD schedule has been previously reported. In this study different dosing schedules of AT-101 were tested in adults with advanced cancers and final results for the pulse dosing schedule of twice a day for three days every other week (b.i.d. x 3d EOW) are being reported. Methods: Serial patient (pt) cohorts received AT-101 at escalating doses of 30–80 mg b.i.d. x 3d EOW. Adverse events (AEs) were graded by the NCI CTCAE v3.0. Efficacy was determined by RECIST. Results: 37 pts have been enrolled. Safety data is available on 34/37 pts. In this b.i.d. x 3d EOW dosing schedule, ileus/small bowel obstruction (SBO) occurred in 3 pts (one at each dose level of 30, 40 and 50 mg) and was the dose limiting toxicity for this schedule. Of note, the SBO that occurred at 30 mg was felt to be unrelated to study agent therefore, 30 mg b.i.d. x 3d EOW was the MTD determined for this schedule. The most common (>50%) grade 1–2 AEs included: nausea, vomiting, diarrhea, fatigue and anorexia. Grade 3–4 AEs occurring in > 2 pts include: nausea, abdominal pain, elevated AST (3 pts each), vomiting, fatigue, dehydration (4 pts each), hypokalemia (5 pts). Stable disease was reported in 13/37 (35%) pts. One pt with NSCLC continues on study with stable disease for 33 cycles and 2 additional pts were on study with stable disease for 18 and 9 cycles. The mean Plasma Cmax was 301 ng/ml (+ 477 ng/ml SD) and mean AUC for 30 mg b.i.d.x3d EOW was 1080 ng*hr/ml (+ 1990 ng/ml SD) with a median peak concentration at 4 hours post dose. Conclusions: Pulse dosing of AT-101 achieved an MTD of 30mg b.i.d. x 3d EOW and is associated with reduced toxicity than continuous daily dosing, and may be preferable in combination regimens.

[Table: see text]
In vitro-acquired resistance gene expression profile and in vivo response to oxaliplatin-based treatment
Authors: Martinez Cardús A. , Martinez-Balibrea E. , Musulén E. , Ginés A. , Manzano J. L. , Layos L. , Quiroga V. , Aranda E. , Abad A.
Published: August 2020

e15041

Background: Resistance to oxaliplatin is one of the main problems of colorectal cancer (CRC) treatment success. It is not clear if intrinsic and acquired resistance processes are developed by related mechanisms. In a previous work (Martinez-Cardús et al. Mol Cancer Ther, January 2009), we determined a profile of oxaliplatin-acquired resistance related genes by using an in vitro model. In the present work, we analyzed this genetic profile in paraffin-embedded primary adenocarcinomas from CRC patients treated with oxaliplatin-fluoropyrimidine. mRNA expression data was correlated with response rate and time to progression (TTP) in order to determine the role of these genes as markers of resistance to oxaliplatin-based treatment. Material and Method: mRNA levels were analyzed by using Real Time PCR. β-actin and 18s were used as housekeeping genes and, as a reference sample, we used commercial pool of mRNA from different human tumours. Chi- square and Fisher test were used in order to value differences in response rate to treatment. TTP was studied by using Kaplan Meyer curves and Log rank test. Median and percentile 33 and 66 were used as threshold values to determine both high and low expression level groups for each gene analyzed. We considered statistically significant a two-sided p-value lower than 0.05. Results: Forty-four advanced CRC patients treated with fluoropyrimidine plus oxaliplatin were analyzed. 54.5% of them were males; primary tumour was localized in colon in a 65.9% of cases. According to qRT-PCR analysis, the in vitro oxaliplatin acquired resistance related genes could be detected in the tumours but the expression of any of them correlated significantly with in vivo resistance to oxaliplatin-based treatment by using the three different threshold values to define groups. Conclusions: According to our results, these genes could not be used as markers of resistance to oxaliplatin-based treatment in non-treated tumours. Thereby, oxaliplatin resistance acquisition genes seems not to be involved in intrinsic drug resistance probably due to the fact that acquired and intrinsic oxaliplatin resistance are not related mechanisms. Further studies to typify oxaliplatin intrinsic resistance potential markers are guaranteed.

No significant financial relationships to disclose.
Does severity of underlying chronic liver disease (CLD) affect treatment outcome of hepatocellular carcinoma (HCC) patients undergoing systemic chemotherapy (CT)?
Authors: Yeo W. , Mo F. K. , Hui E. P. , Lam K. C. , Ho W. M. , Koh J. , Ma B. , Mok T. , Chan A. , Chan S. L.
Published: August 2020

e15513

Background: HCC is a common cause of morbidity and mortality. CT has been one of the treatments offered to patients (pts) who are not candidate of curative surgery. Treatment of HCC could be complicated by underlying CLD. In this study, we aimed to assess pre-CT severity of CLD on treatment outcome of HCC pts who were entered into our previously reported phase III prospective randomized CT study (J Natl Cancer Inst 2005). Methods: The severity of CLD for each pt was arbitrary assessed by adopting the Child-Pugh's classification. Patients’ characteristics were compared. Treatment outcomes in terms of responses, survival and treatment-related toxicities (NCI CTC) were compared. Results: 160 were Child's A; 28 were Child's B. Proportion of pts with cirrhosis (45% vs 71%, P=0.01) and pre-CT bilirubin level (11 vs. 15 umol/l, p=0.02) were significantly higher, while age (52 vs 45 yrs, p=0.05) and albumin level (35 vs 30 g/l, p<0.0001) were significantly lower among Child's B pts. For Child's A and B pts: the median no. of CT cycles received were 4.0 vs 2.5 (p=0.01), the response rates were 17% vs 8.3% (p=0.28), the median survival were 21 vs 10.7 months (p= 0.002). When toxicity during CT were compared, Child's B pts had significantly higher rate of grade 3/4 neutropenia (0.6% vs. 7.1%, p=0.05), hyperbilirubinaemia (11.9% vs. 28.6%, p=0.02), hyponatremia (3.1% vs. 3.6%, p=0.001) and gastrointestinal bleeding (3.1% vs. 17.9%, p=0.001). Conclusions: Child's B HCC pts experienced increased treatment-related toxicities during CT. This has probably led to a shorter duration of CT and a lower response rate to CT. Their shorter survival could also be attributed to the severity of underlying CLD. Future trials on systemic therapy in HCC patients may need to consider stratifying patients according to severity of CLD.

No significant financial relationships to disclose.
Phase II capecitabine and gemcitabine fixed dose rate (FDR) in patients with advanced pancreatic cancer
Authors: Tonini G. , Vincenzi B. , Vasile E. , Catalano V. , Virzì V. , Fontana A. , Intagliata S. , Catalano G. , Falcone A. , Santini D.
Published: August 2020

e15530

Background: The aims of this phase II trial are to determine the activity and the safety of the new combination modality with Gemcitabine fixed dose rate (FDR) infusion and Capecitabine in patients with advanced pancreatic cancer. Methods: Patients with unresectable pancreatic cancer who had pathologically confirmed adenocarcinoma, no prior chemotherapy, ECOG PS < 2 and measurable disease were enrolled. Gemcitabine (800 mg/mq IV infused in 80 minutes on days 1 and 8) and Capecitabine (650 mg/mq orally twice daily for 14 days) were administered and repeated every 21 days. Results: 47 patients were enrolled between January 2004 and October 2008. Median age was 66 (range: 37–79), 18 female and 29 male. A total of 299 cycles were administered, median cycles for patient were 6 (range: 1–17). CR was observed in one patient (2.1 %) and 10 patients achieved PR (21.3 %) giving an overall response rate of 23.4 % in intention-to-treat population. 22 pts (46.8 %) had stable disease obtaining an overall tumour control of 70.2 %. The median time to progression was 5.2 months (95 % CI, 2.4–7.6); the median overall survival was 8.4 months (95 % CI, 5.5–20). Grade 3–4 neutropenia was observed in 29.8 % of subjects, thrombocytopenia in 6.4 %. Grade 1–2 non-hematological toxicities were asthenia (61.7 %), diarrhea (29.8%), stomatitis (29.8 %) and hand foot syndrome (2.1 %). There were no treatment-related deaths. Gemcitabine was skipped at least once/reduced in 51/10.6 % of the patients, respectively. Capecitabine was skipped at least once/reduced in 16/8 % of the patients, respectively. Conclusions: The combination of FDR Gemcitabine and Capecitabine with this modality of infusion is feaseble, safe and seems to be active.

No significant financial relationships to disclose.
Capecitabine (C), oxaliplatin (OXP), and radiation (RT) in resectable esophagus cancer (EC): A phase II trial with gene expression profiling (GEP)
Authors: Khushalani N. I. , Miecznikowski J. , Wang D. , Nowak N. , Nava H. , Nava M. E. , Tan W. , Iyer R. , Yang G. , Pendyala L.
Published: August 2020

e15543

Background: Novel chemotherapy regimens in combination with RT aim to improve the pathologic complete response (pCR) in EC. Following our dose-finding phase I study, the present phase II neo-adjuvant (NA) EC trial was designed to examine the pCR rate using C, OXP and RT, with secondary end-points of evaluating toxicity, quality of life, and GEP of tumor tissue for correlation to therapeutic response. Methods: EC patients (PTS) with stages II-IVa, adequate organ function and performance status (ECOG 0–1) were eligible. Treatment consisted of OXP, 85mg/m2 iv on days 1, 15 and 29, C (oral or enteral tube) 625 mg/m2 bid on days of RT, and 50.4 Gy RT (3-D conformal) in 28 fractions, followed by an esophagectomy (E) 4–6 weeks later. 2 cycles of OXP + C were administered post-operatively. GEP using Agilent microarrays was conducted on primary tumor tissue pre-treatment (Rx), day (D) 17 and at E; > 50% viable tumor cells were required. Results: 20 PTS have been enrolled (17 male, 3 female); median age 59.5 yrs; 17 adenocarcinomas & 3 squamous-cell cancers. Clinical stage: II (3), III (13) and IVa (4). 18 PTS have completed NA therapy; Grade 4 toxicity includes anemia (1), lymphopenia (2); grade 3 toxicity includes esophagitis (1), pneumonia (1), wound infection (1), anastomotic leak (2), esophageal fistula (1), bowel obstruction (1), fatigue (1), hyperbilirubinemia (1), elevated ALT, AST (1 & 2, respectively), hypoalbuminemia (3), OXP hypersensitivity (2) & leucopenia (1). One PT died > 60d post- operatively secondary to infection. 15 PTS have undergone an E with 3 pCR (20%). Analysis on pre-Rx GEP on 17 PTS revealed a distinct pattern for pCR PTS with 325 over-expressed and 79 under-expressed genes. Ongoing functional analysis will characterize GEP changes in 1) pCR PTS pre-Rx & at D17, 2) pCR & non-pCR PTS pre-Rx, and 3) by histology. Validation will be performed via RT-PCR. Accrual to the trial continues. Conclusions: C, OXP & RT appears to be a tolerable and efficacious NA regimen for EC. The exploratory GEP analysis may provide insight on predicting response to NA therapy. Acknowledgement: The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Roche Laboratories, Inc.

[Table: see text]
Assessment of prognostic factors in pancreatic ductal adenocarcinoma: Focus on the retroperitoneal margin
Authors: Bellizzi A. M. , Bloomston M. , Bellizzi S. M. , Marsh W. L. , Frankel W. L.
Published: August 2020

e15670

Background: Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer death in the West, with a nearly superimposable incidence and mortality. Resection is the only chance for cure, and various features in resection specimens correlate with outcome. While most consider the uncinate margin (UM) to be the true retroperitoneal margin, it has been suggested that the posterior pancreatic surface (PPS) may also be important. At another site with a retroperitoneal margin (i.e. rectum), 1 mm margins are significant. We thus evaluated margin status in various ways, focusing on the retroperitoneal region and emphasizing outcome. Methods: We identified all pancreaticoduodenectomies for PDA over a 6 year period in which the PPS was histologically evaluable. Tumors were assessed for the following: size, stage, grade, lymph node (LN) status, vascular and perineural invasion, and margin status. Margin status was evaluated in 3 ways: traditional margins (tumor at pancreatic neck, bile duct, and/or uncinate margins), 1 mm margins (traditional + tumor within 1 mm of UM), and PPS margins (traditional + tumor within 1 mm of PPS or UM). Kaplan-Meier survival curves were constructed with univariate factors compared by log rank analysis; multivariate analysis was done using the Cox proportional hazard model. Results: Fifty-one tumors exhibited the following features: size (mean 3.3 cm), stage (48 T3), grade (27 low, 24 high), LN status (11 neg, 40 pos), positive margins (13 traditional, 23 1 mm, and 32 PPS). Nearly all tumors exhibited at least focal vascular and perineural invasion. Grade influenced survival (p=0.0001), while size (p=0.417) and traditional and PPS margins did not (p=0.5 and 0.95). LN status and 1 mm margins trended toward significance (p=0.17 and 0.2). Conclusions: Use of a two-tiered grading system is highly correlated with survival. Neither tumor size, LN status, nor traditional or PPS margins are significant, while 1 mm margins trend toward significance. Although lack of significance of some features (i.e. size, LN status, and traditional margin status) may be attributable to modest sample size, lack of significance of the PPS may reflect its anatomic nature (i.e. not a true surgical margin). Additional study of 1 mm margins in a larger tumor set is warranted.

No significant financial relationships to disclose.
Uncommon sites for metastasis of neuroendocrine tumor in adults
Authors: Srirajaskanthan R. , Desai K. , Jayaratnam A. , Carras E. , Toumpanakis C. , Meyer T. , Caplin M.
Published: August 2020

e15683

Background: Neuroendocrine tumours are relatively slow growing tumours. They often present with significant metastatic disease affecting liver, lymph nodes, lungs and bone. However tumour masses may be found at unusual/uncommon sites e.g. breast, orbital soft tissue and the heart raising the possibility of this being metastatic focus or presence of another primary tumour. Detection of these sites could have a significant impact on the available treatment options. Aim: to determine the most appropriate imaging modality and type of tumour metastases. Methods: We reviewed 300 consecutive clinic patients. We identified 18 patients with metastasis at uncommon sites i.e. breast, orbital and cardiac. We retrospectively evaluated clinical notes and recent radiological investigations of these patients. To characterise these lesions additional investigations included cross sectional imaging, PET imaging (68Gallium DOTA Octreotate PET and 18F- FDG PET) and histological evaluation of the metastasis where appropriate. Patients with breast metastasis underwent bilateral mammogram, patients with peri-ocular involvement underwent MRI of the brain and the orbit. Results: 18 patients had tumour masses at uncommon sites. Of these 15 masses were in the breast; 4 were in the orbital muscles and 2 patients had pericardial metastasis. Of the 15 patients with breast lesions 12 had confirmed neuroendocrine tumour metastases and 3 had breast cancer. It should be noted that breast cancer lesions were positive on the 68Gallium Octreotate PET imaging. One patient who had a defined metastasis in the pericardium showed avid uptake on the 68Gallium DOTA Octreotate PET and scan and cardiac MRI, the other patient had pericardial metastases confirmed at post mortem. Conclusions: Clear knowledge of these uncommon sites of metastasis is useful in terms of arranging further investigations and excluding other cancers. It is also important to realise that although somatostatin receptor scintigraphy especially 68Gallium DOTA Octreotate PET is very useful in detecting NET metastasis, it may also show avid uptake in patients with breast cancer and hence histological evaluation of these lesions are important. Undoubtedly within our cohort of patients and generally there is an under-diagnosis of lesions in uncommon sites.

No significant financial relationships to disclose.
Patient characteristics associated with dose-limiting sunitinib adverse events
Authors: Atkinson B. , Hart J. , Lin E. , Tannir N. , Jonasch E.
Published: August 2020

e16110

Background: Sunitinib, an inhibitor of multiple tyrosine kinases, is FDA approved for metastatic renal cell cancer (mRCC). Though better tolerated than historical therapies, sunitinib is associated with adverse events (AEs) that may require dose modifications (DM). We sought to identify 1) baseline patient (pt) characteristics that predispose for DM, 2) the most common AEs requiring DM in a non-protocol setting, and 3) the impact of dose limiting AEs on treatment continuation. Methods: Single-center, retrospective chart review. Pts ≥ 18 years of age with mRCC of clear-cell histology on sunitinib therapy with active follow-up at MDACC were eligible. Univariate and multivariate logistic regression analysis of 66 pt variables (demographics, laboratory analysis, past medical and treatment history, etc) and dose-limiting AEs was completed, with a 6 month endpoint of sunitinib continuation, alternative therapy, or death. Results: From January 1, 2006 through September 30, 2007, 146 pts were identified meeting eligibility criteria. By univariate analysis, increased age (p=0.04; OR 1.04, 1.002–1.081 CI) and elevated BUN (p=0.03; OR 1.06, 1.006 –1.108 CI) were directly associated with increased incidence of dose-limiting AEs. ECOG PS of 2 (p=0.04; OR 0.3, 0.114–0.951 CI) was associated with a decreased incidence of dose limiting AEs. In a multivariate analysis, only BUN remained significant. 57% of patients (n= 83) had dose-limiting AEs. DM were often attributed to multiple AEs (55%), with fatigue, mucositis, hand-foot syndrome and nausea being the most common. At 6 months follow-up, 63% of pts with dose-limiting AEs remained on sunitinib vs. 37% (p=0.18). There was no difference in death rate at 6 months between the two groups. Conclusions: Elevated baseline BUN is associated with an increased rate of DM in patients with RCC receiving sunitinib. Despite the high-incidence of AEs, pts can be maintained on sunitinib with DM and without an adverse impact on outcome. Whether specific AEs are biologic indicators of activity should be evaluated in a larger clinical trial.

[Table: see text]
Curative intended radiation therapy for young patients with invasive uterine cervical carcinoma: Clinical outcomes in 105 patients in a Japanese multi-institutional study
Authors: Niibe Y. , Ariga T. , Kazumoto T. , Kodaira T. , Etou H. , Suzuki O. , Kinoshita R. , Tsujino K. , Takemoto M. , Hayakawa K.
Published: August 2020

e16558

Background: Recently, the number of young patients with invasive uterine cervical carcinoma is increasing in Japan because of earlier sexual activity and low rate of receiving screening test of uterine cervical carcinoma in Japan. However, no large studies have been performed so far to evaluate the clinical outcomes of curative intended radiation therapy for young patients with invasive uterine cervical carcinoma in Japan. Then, the current study was designed. Methods: One hundred and five patients under 40 years old were registered in the mulitiinstitutional study. The median age was 34.5 years old (range: 24–39 years old). According to FIGO, clinical stage was as follows. Stage Ib/IIa/IIb/IIIa/IIIb/IVa were 10/4/38/2/47/3, respectively. The median maximal tumor diameter was 5.5 cm (range: 2–9.2 cm). Curative intended radiation therapy was the combination of high-dose rate intracavitary brachytherapy (HDR-ICBT) combined with external beam radiation therapy (ERT). The total dose of ERT ranged from 44 Gy to 68 Gy. The total dose of HDR-ICBT to point A ranged from 12 Gy to 48 Gy. Eighty five patients received chemotherapy. Results: The 5-year overall survival rate and local control rate of all patients was 58.4 % and 59.3 %, respectively. The 5-year overall survival rates of stage Ib/IIa/IIb/IIIa/IIIb/IVa were 90.0 %/not available (NA)/73.8%/100%/37.4%/0%, respectively. The 5-year local control rates of Stage Ib/IIa/IIb/IIIa/IIIb/IVa were 80.0 %/50.0 %/73.8 %/100 %/54.6 %/NA, respectively. Sixteen patients experienced grade 3 or greater late radiation morbidity. Conclusions: Clinical outcomes of stage I-II in the young were equivalent to the Japanese standard treatment results of all ages. However, clinical outcomes of stage IIIb and IVa in the young were worse than those of all ages (5-year OS of all ages in Japan: IIIb: 50 %, IVa: 25 %).

No significant financial relationships to disclose.
Evaluation of PET imaging in treatment decision making for early stage head and neck squamous cell cancer
Authors: Dulala R. , Campian J. L. , Dubner S. , Frank D. , Gabalski E. , Thomas A. , Akerman M. , Mehrotra B.
Published: August 2020

e17017

Background: Positron emission tomography (PET) scanning is widely used in staging of patients (pts.) with head and neck squamous cell cancers (HNSCC). However, the role of PET scan in pts. with early stage disease and clinically negative nodes remains controversial. The purpose of our study was to correlate preoperative PET scan findings in early stage disease with operative pathological findings of neck dissection. Methods: A retrospective review of medical records of all pts. treated at Long Island Jewish Medical Center with T1N0 HNSCC from 2002 to 2008 was undertaken. Institutional Review Board approval was obtained for this study. Eligibility criteria included: clinically staged T1N0, documented pre-operative PET scans and primary surgical management including a neck lymph node dissection as part of initial treatment. Data collected included age, gender, physical examination findings, PET scan results, operative pathology and modalities of treatment. Results: Sixty six pts with early stage T1N0 HNSCC were identified. Twelve of sixty six pts met eligibility criteria for this study. Median age was 61 years (range: 27 to 84 yrs), M:F ratio was 1:1. Primary sites of tumor were: tongue (n = 8) 67%; oral cavity (n = 3) 25%; larynx (n = 1) 8%. Preoperative PET scan was positive at primary sites in all pts (n = 12). Additionally, PET positivity was noted in regional lymph node sites in six of twelve pts. Operative pathology confirmed tumor presence in all primary sites. However, nodal involvement was not found in any pt. Median numbers of lymph nodes dissected were 25 (range:13–34). Based on these clinical data, the calculated statistical parameters for preoperative PET scan in detecting occult neck lymph node metastases were: negative predictive value: 100%; positive predictive value: 50%: specificity: 50%; sensitivity: 0%. Conclusions: The clinical application of PET scans in early stage (T1N0) HNSCC may be limited by its high false positive rate. A high negative predictive value suggests that a negative result can exclude metastatic lymph nodes involvement in this group of pts. with early stage disease. Correlation with SUV values of the PET scans and comparisons between the relative PET avidity of the primary tumors and the nodal uptake are ongoing.

No significant financial relationships to disclose.
Neoadjuvant docetaxel, cisplatin, and 5-fluorouracil before concurrent chemoradiotherapy or concurrent cetuximab-radiotherapy in locally advanced squamous cell carcinoma of the head and neck
Authors: Billan S. , Abdah-Bortnyak R. , Mezid F. , Bernstein Z. , Gez E. , Nasrallah H. , Kuten A.
Published: August 2020

e17045

Background: Encouraging results have recently been reported in patients with locally advanced squamous cell carcinoma of the head and neck. The present study assessed the feasibility of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CHT-RT) or concurrent cetuximab-radiotherapy. Methods: Induction chemotherapy consisted of TPF (docetaxel 75 mg/m(2), cisplatin 75 mg/m(2), 5-fluorouracil 750 mg/m(2)/d continuous infusion for 96 h) every three weeks, followed by CHT-RT regimen (radiotherapy 70 Gy total dose fractionated at 2Gy per day, 5 days a week concurrently with weekly cisplatin 40 mg/m(2) or cetuximab with loading dose of 400 one week before starting radiotherapy and 250 weekly during the radiotherapy) 4–7 weeks later. Percutaneus endoscopic gastrectomy inserted before the combined treatment. The National Cancer Institute Common Toxicity Criteria (version 2) were used for classification of adverse events. Results: Between march 2007 and november 2008, 29 previously untreated patients (19 male and 4 female) with stage III-IV squamous cell carcinoma of the oral cavity, larynx, oropharynx, or hypopharynx were included to the study. The median age was 60 years (range, 56–75 years). The stage distribution was as follows: stage II, 1 patient; stage III, 14 patients; and stage IV, 14 patients. 16 patients had a performance status of 0 and 11 had a performance status of 1. The response rate (RR) after IC was: complete response (CR) for 10 pts (34%), partial response (PR) for 13 pts (57%) and no response (NR) for 3 pts (13%). Toxicity from IC included neutropenia Gr III,IV 25%,neutropenic fever 9%, mucositis and diarrhrea Gr III, IV 22% . 60% of patients completed 3 cycles, 20% received 2 cycles and 20% received only one cycle of TPF. The toxicity from the concurrent phase included mucositis Gr III-IV in 70% of patients,dermatitis Gr III-IV in 43% and no case of neutropenia Gr III-IV. The combined treatment was interrupted only in 4 patients for one week. Conclusions: TPF was well tolerated with high response rate and low rate of acute toxicity. Three cycles of TPF followed by combined treatment are feasible.

No significant financial relationships to disclose.
The value of personalized treatment (Rx) planning (PTP): Cost savings (sav) by the Microculture Kinetic (MiCK) chemosensitivity (CS) assay, evidence from a large American self-insured company (ASIC)
Authors: Latimer R. G. , Presant C. A. , Hallquist A. E. , Perree M. , Agapitos D.
Published: August 2020

e17541

Background: Costs of cancer (CA) patient (PT) Rx are high. A novel CS assay MiCK was predictive of chemotherapy (CT) activity and survival in leukemia PTs (Blood. 2001;98:241b) and is in solid tumor testing. We performed a cost sav analysis for CS assay in a large ASIC population. Methods: An ASIC of 48,927 employees submitted 3.5 years claims data on all PTs with diagnoses of CA lung, breast, colon or ovary. Analysis of average Rx costs was made based upon total CT usage, Rx of selected PTs including therapeutic drug administration (admin), CT admin, supportive care (SC) drugs, CT drugs, biotherapy (BT) drugs, growth factors, home infusion costs, and cost of the MiCK assay. Average CT and BT drug costs were determined. We assumed high MiCK predictability for CT activity from solid tumor pilot studies and leukemia results. 4 models were evaluated: CT with a single active drug from MiCK for the duration actually given (ASC); CT with active drugs for the entire time (AC100); CT for 50% of the time period (AC 50) assuming a CT “holiday” for the other 50% of time; and CT with active drugs plus BT for 50% of the time (ACB 50). The costs in these 4 models were compared to actual claims payments. Results: 196 PTs had CA during the 3.5 year period. 55 had CT. Total costs for CT were $5,647,165. Costs for IV CT drugs, SC drugs and drug admin were $1,149,404. Assuming the use only of active CT selected by MiCK assay, under model ASC average sav/PT was 85.3% of CT, SC and admin costs. Under model AC100, the average sav/PT were 26.0%. Under model ACB 50, the sav were 48.6%. In model AC 50, the sav were 62.7%. When the overall costs were evaluated, model ASC sav were 17.4%, model AC 100 5.3%, model ACB 50 9.9% and model AC 50 12.8%. Conclusions: PTP using the MiCK CS assay could save a high percentage of CT costs, and a substantial percentage of overall costs of CA care in an ASIC. Sav varied from 9.9% to 62.7% depending on effectiveness and duration of Rx, and necessity for continuing BT not testable by MiCK. The true value of PTP with MiCK could be higher, since use of active CT would increase quality of life and employment, and reduce disability and side effects.

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Academic cancer researchers’ perspective on a federally mandated centralized comprehensive database of all cancer clinical trials results
Authors: Novik Y. , Escalon L. , Rolnitzky L.
Published: August 2020

e17576

Background: Campbell et al. (2002) examined the data sharing habits of geneticists and other life scientists from universities that receive funding from the NIH and found that genetics researchers are refusing to share results with colleagues, hindering the ability to replicate published results. This has not been explored in cancer research. Data sharing, data transparency, and collaboration adds value to research by reducing redundancy (time, resources, exposing trial participants to unnecessary risk). In cancer research there are existing results databases from the NCI to caBIG. The purpose of this study is to ascertain from the perspective of academic cancer researchers whether there is a need for a federally mandated comprehensive database of all cancer clinical trial results. Methods: The 11 question online questionnaire addressed data sharing. Responses are presented as percents of respondents who agree with each statement accompanied by 95% confidence intervals (CI). The 24 respondents included physicians, research nurses, regulatory staff, data management, and administration who work in cancer research in an academic setting. Results: Overall, 92% (95% CI, 74–98%) agree that a centralized comprehensive database will reduce redundancy, 100% (95% CI, 86–100%) agree that disclosing results to fellow researchers will help researchers to design better cancer clinical trials, and 96% (95% CI, 80–99%) agree that there is a need for a federally mandated comprehensive database of all clinical trial results. On database access 100% (95% CI, 86–100%) agree for academic researchers, 58% (95% CI, 39–76%) agree for the pharmaceutical industry, 50% (95% CI, 31–69%) agree for trial participants, 29% (95% CI, 15–49%) agree for the public, and 21% (95% CI, 9–40%) agree for media. Conclusions: This study is a step in exploring how the academic cancer research community feels about data sharing. The study population is small and limited to a single institution. To support generalizability of the findings, it is necessary to enlarge the population by increasing the number of participants from the chosen institution and/or to include other academic institutions in future studies.

No significant financial relationships to disclose.
Phase II trial of erlotinib maintenance therapy after platinun-based chemotherapy in advanced non-small cell lung cancer (NSCLC)
Authors: Cobo M. , Martinez J. , Montesa A. , Gil-Calle S. , Villar-Chamorro E. , Ales I. , Gutierrez V. , Durán G. , Carabantes- Ocón F. , Benavides M.
Published: August 2020

e19013

Background: phase II trial-efficacy & toxicity of sequential erlotinib in advanced NSCLC after platinum-based CT Methods: Pts with adv NSCLC, PS 0/1, adequate renal, hepatic and bone marrow function, no PD after CT. Treatment: erlotinib 150 mg/day starting 3–4 weeks after CT until progression. Safety was evaluated monthly and tumor evaluation bimonthly. Results: 47 pts enrrolled:42(89%)stageIV & 5(11%)wet IIIB, all valid for response & toxicity. Median age 62 y(r:39 -77): 39(83%) males and 8(17%) females. Histology: adenocarcinoma 8(61.7%), bronquioloalveolar 3(6.4%), large cell 3(6.4%), squamous12(25.5%). PS 0: 23(49%), PS 1:24(51%). 38(81.9%) completed 6 cycles of CT. Response: CR: 1(2.1%), PR: 2(51.1%), EE: 22 (46%). Sequential erlotinib improved RR in 6 (12.8%), 23 (48.9) prolonged stabilization, 18 (38.3%) had progression. Median TTP and OS were 9.4 m (95% CI, 4.96–13–84), and 19.23 m (95% CI, 8.82–29.64). No significant differences in TTP according to age, sex, PS, histology or previous response to CT, but yes depending on RR to erlotinib: PR: 31.5 m (95% CI 15.37–47.63), EE: 12.8 m (95% CI, 10.58–15.03), PD: 6.3 m (95% CI, 5.36–7.3), p < 0.001; and moreover depending on smoking status: Never: 21.67 m(95% CI, 5.39–37.94), previous smoker > 5 years: 14.03 m(95% CI, 10.77–17.30), previous smoker 1 year: 7.77 m(95% CI, 7.62–7.91), current smoker: 5.9 m(95% CI, 5.12–6.34), p <0.001. In Cox-regression model, smoking status ( p< 0.001), and response to erlotinib (p=0.002) were associated with a significant difference in TTP. Similar results in OS, although in Cox-regression model only never smoker or > 5 years previous smoker pts had a significant better survival. Toxicity: The most frequent was skin rash, grade (g) 1 in 11(23.4%), g 2: 16(34%) and g 3: 3(6.4%). Only 1 p had diarrea g 3, and no other side effects were observed. We found a significant benefit in p with g 2–3 skin toxicity respect g 0–1, in both TTP( p= 0.0003) and OS (p= 0.0014). Conclusions: Erlotinib-maintenance therapy after platinum-based CT had promising results. Pts with the best benefit were those with response to erlotinib, in never or past (> 5 years) smokers and with g 2–3 skin toxicity.

No significant financial relationships to disclose.