bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination of bortezomib with a FLT3 inhibitor potentiates inhibition of proliferation and apoptosis of AML in vitro
Authors: Cheng P. C. , Crane J. , Hunter T.
Published: August 2020

e14551

Background: FLT3 receptor tyrosine kinase activating mutations contribute to leukemogenesis and poor prognosis in approximately 30% of acute myeloid leukemia (AML). An internal tandem duplication (ITD) mutation in the juxtamembrane domain of FLT3 results in loss of autoinhibition that leads to constitutive, ligand-independent activation of the receptor, with subsequent activation of multiple downstream signaling pathways, including RAS/MAPK and STAT5. Early phase clinical trials of FLT3 inhibitors show a lack of durability of responses, suggesting combination therapy may work better. Methods: In the course of conducting a synthetic lethality screen with a FLT3 inhibitor on the Ba/F3 murine cell line stably expressing human FLT3 or FLT3-ITD, we identified bortezomib, a proteasome inhibitor, as having potent activity against FLT3-ITD cells. The effects of drugs on proliferation, apoptosis, and phosphosignaling were quantified in Ba/F3 cells and in the HL60 (WT FLT3) and MV4–11 (FLT3-ITD) human cell lines, using an MTS- based colorimetric assay, caspase 3 and 7 activity assays, and immunoblotting, respectively. Results: A highly potent and specific FLT3 inhibitor was shown to have an IC50 of 1.9 nM, inhibiting proliferation, inducing apoptosis, and abrogating downstream STAT5 and ERK phosphorylation in FLT3-ITD cells. The IC50 of bortezomib for FLT3-ITD cells was 10 nM as compared to an IC50 of 40 nM for WT FLT3 cells. Surprisingly, bortezomib abrogated tyrosine phosphorylation of FLT3, STAT5, and ERK within 60 min of adding drug. When the FLT3 inhibitor and bortezomib were used at IC25 concentrations, a more pronounced inhibition of cell proliferation was observed when they were used in combination than with either alone. Conclusions: Bortezomib preferentially kills FLT3- ITD cells, showing a four-fold more potent inhibition of cell proliferation, induces apoptosis, and abrogates activation of FLT3 and its downstream effector pathways. The combination of proteasome inhibition with FLT3 inhibition results in enhanced cytotoxicity. The mechanism by which bortezomib affects the FLT3-ITD signaling axis and the possible synergy with FLT3 inhibitors remains to be elucidated.

No significant financial relationships to disclose.
Effect of a mouth rinse formulation with human trefoil factor 1-secreting Lactococcus lactis in experimental oral mucositis in hamsters
Authors: Rottiers P. , Caluwaerts S. , Steidler L. , Vandenbroucke K. , Watkins B. , Sonis S. , Coulie B.
Published: August 2020

e14570

Background: Oral mucositis (OM) is a painful and dose-limiting toxicity of cancer chemotherapy and irradiation, characterized by breakdown of the oral mucosa. Trefoil factors (TFFs) are involved in protecting and healing mucosal tissue, and might thus represent a pharmacological tool for treatment of OM. Local delivery of recombinant TFFs at the oral mucosa by living, genetically modified Lactococcus (L.) lactis bacteria (ActoBiotics) seems a promising, safe and cost-effective clinical approach for the prevention and attenuation of oral mucositis. Methods: An environmentally contained Lactococcus lactis strain (AG013), engineered to express human (h)TFF1, was formulated for topical administration in the form of a mouth rinse. Efficacy of AG013 was assessed in a clinically relevant hamster model of acute, radiation-induced OM. The dosing regimen was 1.3 x 109 CFU/dose, once (qd) or three rinses (tid) daily, from day 0 (=day of radiation) to day 18. OM was scored from day 6 to day 28 using the WHO grading scale, and compared to the score of placebo-treated hamsters. The viability and survival of live L. lactis and the pharmacokinetics of the hTFF1 secreted were studied in healthy and OM hamsters. Results: Topical application of AG013 to the oral mucosa significantly reduced the severity and course of radiation-induced OM. In the AG013-treated groups, the number of animals days with ulcerative mucositis (grade 3 or higher) was significantly reduced to 27.5% and 30.8% (qd and tid respectively; P < 0.001), compared to 45.8 % in the placebo-treated group. Based on the observed survival and weight changes, AG013 appeared to be well-tolerated. Pharmacokinetic studies demonstrated that both living L. lactis and the hTFF1 secreted could be recovered from the administration site, for maximum 24 hours post-dosing, without systemic exposure. Conclusions: Oral administration of AG013 is safe and effective in reducing the severity and the course of OM in the hamster model, and therefore supports proof-of-concept for a mouth rinse formulation of AG013 to treat OM patients.

[Table: see text]
Phase I dose-escalation study of thoracic radiotherapy in combination with gefitinib in patients with IIIB/IV non-small cell lung cancer (NCT00497250)
Authors: Fan M. , Xie L. , Xu X. , Zhang G. , Chen J. , Fu X. , Zhou X. , Li W. , Jiang G.
Published: August 2020

e14581

Background: Cinical studies have confirmed that gefitinib, an EGFR-TKI, is effective for some advanced NSCLC patients. Patients with Asian ethnicity are reported to have a higher response rate with gefitinib monotherapy. However, a higher incidence of interstitial lung disease, sometimes lethal, is also found. The combination of gefitinib and radiotherapy has been observed to have a synergistic, anti-proliferative effect against NSCLC in vitro. This phase I study assessed the safety, clinical feasibility and optimally tolerated regimen (OTR) of this combination in patients with pretreated locally advanced or metastatic (IIIB/IV) NSCLC. Methods: Patients with stage IIIB or selected stage IV, failure of platinum-based chemotherapy regimen NSCLC were eligible. Four Cohorts of eight patients each were planned to be treated with escalating doses from 54 to 60 Gy of conformal or intensity- modulated radiotherapy (2Gy/Fx) administered in combination with gefitinib 250mg daily during RT and 60 days after the completion of RT to determine the OTR. Results: Since June 2007, 2 cohorts, a total of 16 patients, were enrolled and treated: 8 stage IIIB and 8 stage IV; 2 squamous-cell carcinoma and 14 adenocarcinoma; 8 smokers and 8 nonsmokers. Prior-chemotherapy regimen was consisted of NP, GP and TP for a median of 3.5 cycles (range, 1–5). Median follow-up time was seven months. Mean progression-free survival time was 5.2 months (median, 3.9; range, 1.7–12.3). Overall, adverse events were mild to moderate in severity. The most frequent grade 2 events included pneumonitis (31%) and dysphagia (19%). There were one treatment-related grade 3 event, which was nausea, and no grade 4 events. Most of the failure patterns were out-of-field (11/13) and the most common distant metastasis organ was the lungs. Three patients are progression-free to date. Conclusions: Thoracic radiotherapy up to 56 Gy concurrent with gefitinib 250 mg daily was well tolerated and clinically active in this group of pretreated Chinese NSCLC patients, including nonsmokers with adenocarcinoma. Accrual is continuing. Sponsorship: This work was partly supported by Program for New Century Excellent Talents in University (NCET), Ministry of Education.

No significant financial relationships to disclose.
Plasma levels of 4-OHT with topical tamoxifen gel (afimoxifene) and therapeutic local antiestrogenic effect in premenopausal women with cyclical mastalgia
Authors: Goyal A. , Baruah B. , Le Nestour E. , Masini-Etévé V. , Mansel R.
Published: August 2020

e14598

Background: 4-hydroxytamoxifen(4-OHT) is a potent anti-estrogenic metabolite of tamoxifen with a much higher affinity for estrogen receptors than tamoxifen. Methods: Plasma levels of 4-OHT in 19 premenopausal women taking 20 mg/d oral tamoxifen for at least 2 months were compared with those of 16 premenopausal women assigned to apply 4mg 4-OHT in a 0.228% Afimoxifene gel daily for 21 days in a pharmacokinetic(PK) study. To evaluate the clinical effectiveness of the gel, premenopausal women experiencing moderate-to-severe mastalgia were randomized to receive placebo, 2mg or 4 mg of Afimoxifene daily delivered as a transdermal hydroalcoholic gel for 4 menstrual cycles. The primary efficacy parameter was change in mean pain intensity, as measured by the VAS for the 7 worst pain score days within a cycle, from baseline to the 4th cycle. Results: In the PK studies, the 4-OHT plasma levels following oral tamoxifen were 16–18 times higher than 4-OHT levels following 4mg 4-OHT administration by topical gel. At steady state, mean Cmax levels in the Afimoxifene group and oral tamoxifen group were 149+99 pg/mL and 2398+901 pg/mL respectively. The Cave concentrations, derived from AUC0–24h/24, were 117+77 pg/mL (Afimoxifene) and 2078+811 pg/mL (oral tamoxifen). After 4 cycles of gel treatment, significant improvements relative to placebo were seen in mean VAS score in the 4-mg Afimoxifene group (-12.71 mm [95% confidence interval, -0.96 to -24.47; P = 0.034]). Patient global assessment of pain, physician assessment of pain, tenderness on palpation and nodularity following 4 cycles of treatment were significantly improved in the 4-mg group, compared with placebo (P = 0.010 [pain]; P = 0.012 [tenderness]; P = 0.017 [nodularity]). There were no changes in menstrual pattern or plasma hormone levels and no breakthrough vaginal bleeding in patients treated with Afimoxifene. Conclusion: Topical application avoids high systemic exposure to 4-OHT compared with oral tamoxifen, a 16–18-fold difference, thus reducing the risk of systemic side-effects. Afimoxifene is an effective treatment for moderate-to-severe mastalgia and potentially may be used for breast cancer chemoprevention and gynecomastia.

No significant financial relationships to disclose.
Effect of (-)-gossypol (AT-101) on transcriptional regulation of Noxa and Puma and on Mcl-1-mediated cancer cell resistance to apoptosis
Authors: Wang S. , Jiang F. , Bai L. , Long J. Jianting , Qiu S. , Chen J. , McEachern D.
Published: August 2020

e14611

Background: AT-101 is being evaluated in Phase II clinical trials for the treatment of human cancers and demonstrates anticancer activity as a single agent and in combination with docetaxel. Despite extensive investigations, the mechanism of action for its antitumor activity is not completely understood. In this study, we have performed detailed investigations using a panel of human cancer cell lines on the mechanism of action for AT-101. Methods: A series of human breast and prostate cancer cell lines were utilized to evaluate the antitumor activity of AT-101. Cell growth inhibition, cell viability and apoptosis were determined by WST assay, trypan blue assay and flow cytometry, respectively. Gene specific siRNAs were used to knockdown target gene expression. Quantitative RT- PCR was performed to detect the mRNA levels of Puma and Noxa. Co-immunoprecipitation was carried out to detect the association between Mcl-1 and Noxa or Puma. Results: AT-101 induced apoptosis in both Bax/Bak-dependent and -independent manners in a variety of human cancer cell lines concomitant with increased expression of Noxa and Puma in a p53-independent manner. The up-regulation of Noxa was not observed in normal primary breast epithelial cells or normal-like human breast epithelial MCF-12F cells. Transcription inhibitor actinomycin D blocked AT-101-induced up-regulation of Puma and Noxa. Knockdown of Noxa or Puma attenuated AT-101-induced apoptosis. Furthermore, AT-101 effectively overcame Mcl-1-mediated cancer cell resistance to apoptosis. Co-immunoprecipitation studies demonstrated that Mcl-1 specifically associated with Noxa but not Puma. Conclusions: Our findings suggest that transcriptional up-regulation of pro-apoptotic Noxa and Puma contributes to the antitumor activity of AT-101, which plays a dominant role in antagonizing Mcl-1 and overcoming Mcl-1-mediated resistance to apoptosis of cancer cells. AT-101 functions as an antagonist of Bcl-2, Bcl-xL and Mcl-1 through direct binding to these proteins, as well as through upregulation of Noxa and Puma.

[Table: see text]
Predictive values of intratumoral microvascular density (MVD) in the patients (pts) with advanced NSCLC and metastatic colorectal cancer (mCRC) receiving chemotherapy plus bevacizumab
Authors: Zhang L. , Jiang W. , Zhang Y. , Xu R. , Qian C. , Resau J. H. , VandenBeldt K.
Published: August 2020

e14618

Background: The using of bevacizumab (VEGFR inhibitor) combined with chemotherapy represents a most noticeable recent advance in clinical oncology for significantly improving pts’ survival in several tumor types. There is an unmet need for seeking biomarker(s) to predict the treatment response of bevacizumab and identify the pts sensitive to the treatment. Our study was designed to investigate the predictive value of intratumoral MVD in NSCLC and mCRC pts treated with bevacizumab. Method: Sixteen NSCLC (stage IIIB/IV) and 15 mCRC pts who underwent chemotherapy (paclitaxel+carbo for NSCLC and IFL for CRC, respectively) combined with Bevacizumab were included into this study. The paraffin-embedded tumor samples (13/16 NSCLC and all CRC samples were collected from primary tumor) were sectioned and stained immunohistochemically for blood vessel markers (CD34 and CD31) to identify the characteristics of intratumoral vasculature. A computerized image analysis program was used to quantitatively calculate the intratumoral MVD (Yao et al., Clin Cancer Res 2007). Treatment response was evaluated by computed tomography scanning. Results: Two types of blood vessel, undifferentiated (CD31+/CD34-) and differentiated (CD34+), were identified. For the 16 NSCLC pts, a positive correlation was found between the largest tumor shrinkage percentage (evaluate in the primary tumors and metastases) and the total (CD31+) MVD as well as the undifferentiated (CD31+/CD34-) MVD, with Spearman's correlation coefficients equaled to 0.567 (p=0.022) and 0.576 (p=0.019), respectively. However, no significant correlation between tumor shrinkage and MVD was found in CRC pts, in which the treatment response was evaluated in metastatic lesions while the MVD was calculated in primary tumor. Conclusion: This exploratory analysis suggests higher total vessel and undifferentiated vessel MVD appeared to be predictive of bevacizumab treatment advantage for advance NSCLC pts.Our study also indicated that the MVD of primary lesions did not correlate with the treatment response of metastatic lesions in CRC pts. Further studies are needed to verify the predictive role of MVD in the treatment of bevacizumab in NSCLC.

[Table: see text]
Impact of 18F-flurodeoxyglucose positron emission tomography in the staging and treatment response assessment of extrapulmonary small cell cancer
Authors: Brennan S. M. , Gregory D. , Stillie A. , Herschtal A. , MacManus M. P. , Ball D. L.
Published: August 2020

e14639

Background: To assess the frequency of use and impact of FDG PET in the management of extrapulmonary small cell carcinoma (EPSCC). Methods: Patients treated for EPSCC who had undergone FDG PET for staging or response assessment between 1985 and 2007 were identified from the institutional database and patient records. The PET result was compared to the conventional staging investigations and management decisions were recorded. Results: 22 patients had staging PET at diagnosis. All known disease was PET avid. Stage migration occurred in one patient. Additional disease without upstaging was noted in 3 patients. PET influenced management in 4/22 (18%) of cases, in one case changing from radical to palliative therapy, and in 3 cases altering radiation target volume. 21 patients had reassessment PET scans. There was disparity with conventional imaging in 8 cases. In 4 cases the PET was found to be correct, in 2 case the PET result was a false positive and 2 cases were not assessable. (Sensitivity 100%, specificity 80%.) PET resulted in a change in management in 25% of patients, in all cases discontinuing radical therapy in patients with persistent disease. Conclusions: PET contributes to both staging and restaging of EPSCC and may influence management in up to 25% of cases.

No significant financial relationships to disclose.
Antiproliferative, antiangiogenesis, and reversal of chemoresistance by specific cathepsin L inhibitors
Authors: Rebbaa A. , Dyskin E. , Dier E. , Gallati C. , Honko C. , Simone T. , Yalcin M. , Sudha T. , Mousa S. A.
Published: August 2020

e14643

Background: Uncontrolled proliferation, enhanced angiogenesis and the development of resistance to therapy are hallmarks of cancer; therefore, the development of approaches to simultaneously target these three processes would be the most desirable. Previous work from our laboratory has demonstrated that NapSul-Ile-Trp-CHO (NSITC), a specific inhibitors of cathepsin L, and its analogs strongly inhibited cancer cell proliferation and suppressed the development of drug resistance in vitro (Zheng X. et al., 2004 Cancer Res. 64:1773–80). In the present study, we sought to investigate the validity of these observations in vivo, and to dissect the underlying mechanism(s). Methods: Nude mice (Strain CD1) bearing xenografts of doxorubicin resistant neuroblastoma cell line SKN-SH/R were challenged with doxorubicin (1.5 mg/Kg) alone, NSITC (20 mg/kg) alone or the combination of both. The effect of NSITC on tumor angiogenesis was also investigated using the Chick Chorioallantoic Membrane (CAM). Putative mechanisms by which NSITC inhibits cellular proliferation, drug resistance and angiogenesis were studied using cancer and endothelial cells maintained in culture. Results: The in vivo data indicated that doxorubicin alone had no effect on tumor growth, however NSITC alone exerted 40% inhibition and the combination of both drugs reduced tumor growth by about 90%. NSITC also caused a 125% inhibition of blood vessel branching in the CAM model (at 1 μg/CAM). Investigation of the underlying mechanisms of its action revealed that at low concentration, NSITC forces cancer cells into senescence, preventing them from developing resistance to classical anticancer agents, and at high concentrations, it induced autophagic cell death. NSITC also strongly inhibited the proliferation and invasion of endothelial cells in a dose dependent manner with more than 90% inhibition at 20 μM. Conclusions: Overall, these findings suggest that NSITC has multi-anticancer functions and thus, may represent a potential drug candidate for the treatment of aggressive malignancies.

No significant financial relationships to disclose.
Long-term follow-up of endogenous erythropoietin, VEGF levels and red blood count in patients receiving different antiangiogenic treatment
Authors: Bloch J. , Mouawad R. , Spano J. , Vigniot S. , Magné N. , Khayat D.
Published: August 2020

e14648

Background: Anemia, commonly defined as a hemoglobin level of <12 g/dL, occurs in over 30% of cancer patients at any time point and its incidence increases with treatment. The concept of antiangiogenic treatment for solid tumors has recently emerged and we wondered why patients under such kind of treatment did not experience anemia requiring transfusion or the use of erythropoietin. The goal of this study is to follow-up endogenous serum EPO, VEGF concentrations, hemoglobin (Hb) and hematocrit (Ht) levels in various metastatic cancers patients receiving different anti-angiogenic treatment and to try to establish the possible relation between these parameters. Patients and Methods: 30 patients (20 men and 10 women) with different cancer type (20 RCC and 10 thyroids) with a median age of 56 year were included in this study. All of theme received a angiogenic therapy. The values of hemoglobin, hematocrit and platelet were determined in all patients Endogenous serum erythropoietin,VEGF serum concentrations were quantified using Elisa test and at day 0 and each 4 weeks. Statistical analysis of the results was performed using Mann-Whitney U test and the correlation analysis was performed using Pearson test. Results: At day 0, The mean level of endogenous EPO and VEGF serum concentration was significantly higher in patients as compared to healthy donors (p=0.005 and p=0.0001 respectively). Regarding anemia, 65 % of the patients had a mild grade of anemia with 11.5 g/l of hemoglobin (Hb) and 36.4 % of Ht. Patients with normal Hb values had a lower mean EPO serum concentration and high VEGF concentration as compared to patients with anemia. A negative correlation was observed between EPO serum concentration and Hb and Ht levels. In overall patients, the follow-up of these parameters showed an increase in endogenous EPO and VEGF concentrations which was confirmed during the subsequent cycles treatment without any increase in Hb and Ht count.The study of these parameters patient by patient and the relation with the clinical response is ongoing and will be more developed. Conclusions: In overall patients we were not able to find any correlation between Hb or Ht, levels and EPO concentrations but a relation between the production of EPO and VEGF is observed.

No significant financial relationships to disclose.
Comparison of l and dl forms of folinic acid in Gercor C96.1 trial (A phase III trial comparing bimonthly LV5FU2 to monthly high-dose 5FU-leucovorin in patients with Dukes’ B2 and C colon cancer)
Authors: Quinaux E. M. , Baumgaertner I. , Khalil A. , Louvet C. , Buyse M. E. , de Gramont A. , André T.
Published: August 2020

e15004

In C96.1 study (André T et al; J Clin Oncol. 2007 20;25:3732–8), patients were randomized to either monthly 5FU-LV hd (dl LV 200 mg/m2 or l LV 100 mg/m2 15 min iv followed by 5FU 400 mg/m2 15 min iv, d1–5 q4 wk) or LV5FU2 (dl LV 200 mg/m2 or l LV 100 mg/m2 2-hour infusion followed by iv bolus 5FU 400 mg/m2 and 22 hours continuous infusion 600 mg/m2, d1 and d2 q 2 wk). Form l LV was administered to 60% (n=519) of patients and dl LV to 40% (n=357) of patients. It was unknown in 29 patients. No randomization was made between form l or dl (It was the choice of each center). The aim of this analysis was to compare the 2 LV forms in term of safety and efficacy. Important prognostic characteristics were well balanced between the 2 groups. The proportion of any grade III-IV toxicity was 20% in l form and 17% in dl form. There was no difference in term of toxicity between the two groups, except a trend for more diarrhea grade 3–4 in form l (8% in l form vs 4% in dl form, p=0.07). The median follow-up time was 6.2 years in l form and 6.0 years in dl form. There were no statistically significant differences between l and dl forms in term of disease free survival (33.3% vs 32.8% of patients with at least one event in l and dl forms respectively, hazard ratio=1.03, 95% CI=[0.82–1.31], p=0.78). In term of overall survival, there was a trend without statistical significance in favor of l form (21.8% vs 25.5% of patients who died, hazard ratio=1.28, 95% CI=[0.97–1.69], p=0.078). We conclude that the toxicity profile is similar between the two forms (excepted diarrhea). The difference in overall survival should not be attributed to folinic acid form as no difference was observed on DFS.

No significant financial relationships to disclose.
Anti-VEGF and anti-EGFR monoclonal antibodies (Mabs) in the first-line therapy for metastatic colorectal cancer: A meta-analysis
Authors: Zhou Z. , Walsh W. V. , Bathini V. G. , Piperdi B.
Published: August 2020

e15012

Background: Anti-VEGF (VEGFi) and anti-EGFR (EGFRi) Mabs have increased options for patients with metastatic colorectal cancers (mCRC). The optimal class of antibody to combine with chemotherapy (Ctx) in the first-line treatment for mCRC remains less well defined. Results from randomized controlled trials (RCTs) are variable. Methods: Systematic review and meta-analysis were performed on the basis of previously released RCTs results. We searched the MEDLINE, Cochrane registry, proceedings from ASCO, ECCO, ESMO until 12/ 2008 for RCTs of Mabs in first-line mCRC. Summary statistics were pooled hazard ratio (HR) of progression-free survival (PFS), overall survival (OS) and odds ratio (OR) of Response rate (RR) and 60 day mortality (60d-M). Effect of k-ras wild type and mutation were stratified in trials involving EGFRi. Results: 7 trials with complete data were identified, including 3 Ctx ± VEGFi (AVF2107g, NO16966, JCO2005.05.122), n=2422; 2 Ctx±EGFRi (CRYSTAL, OPUS), n=1554; 2 Ctx/VEGFi ± EGFRi (PACCE, CAIRO-2), n=1789. Addition of VEGFi to Ctx offered 20–30% risk reduction in disease progression and overall mortality, a 30% higher RR and nonsignificant 60d-M. Benefit of EGFRi in addition to Ctx was seen only in k-ras wild type patients with 36% reduction in disease progression and doubling in RR. However, addition of EGFRi to Ctx+VEGFi caused increased risk of progression and death with no significant increase in RR and 60d-M. Conclusions: Benefit of VEGFi in addition to Ctx in first-line mCRC is well pronounced and persistent. In k-ras wild type patients, addition of EGFRi to Ctx results in significant increase in RR and PFS. Addition of EGFRi to Ctx+VEGFi appeared harmful regardless of k- ras status.

[Table: see text]

[Table: see text]
Pregabalin (PGB) in treatment of oxaliplatin-induced neuropathy
Authors: Isufi I. , James E. , Keley K. , Peccerillo J. , Saif M. W.
Published: August 2020

e15045

Background: Oxaliplatin is effective in many GI cancers, especially colorectal cancer (CRC); however, severe neuropathy develops frequently. PGB is a new antiepileptic drug approved as adjunctive therapy of partial seizures in adults, pain from diabetic neuropathy and post-herpetic neuralgia. PGB is structurally related to gabapentin, but unlike gabapentin, it is well absorbed (> 90%) and its absorption is dose independent. In this study, we evaluated the role of PGB in reduction of oxaliplatin- induced neuropathy. Methods: From Nov 2006 to Dec 2008, a total of 23 pts (age range: 50–71 yrs; M:F = 14:9) with GI cancers were treated with PGB upon development of oxaliplatin-induced neuropathy > G2 (NCI-CTC 3.0). Of these pts, 15 received FOLFOX for CRC, 2 EOX for gastric ca and 6 GemOx for pancreatic ca. Neurologic symptoms were evaluated prior PGB and then q 2 wks. PGB was started at 50mg PO tid, and if tolerated, dose was escalated by 50mg increments until symptoms improved up to a maximum of 150mg PO tid. Results: 5/23 pts (22%) were escalated to 150mg PO tid. 12 pts (52%) were escalated to 100mg tid, out of which 7 (58%) continued, 4 (33%) stopped due to no benefit and 1 (8%) stopped due to weight gain. 1/23 (4%) decided to follow 100mg bid. 5/23 (22%) could not be escalated above 50mg tid; 2 continued at this dose and 3 stopped due to CNS side effects. Onset of benefit was observed in 2 - 6 wks. In 3/23 pts (13%), neuropathy improved from G3 to G2, 2/23 (9%) from G3 to G1, 5/23 (22%) from G2 to G1, 6/23 (26%) remained stable at G2 and no pts remained at G3. Most pts continued PGB even beyond disease progression on oxaliplatin (15/23). Among those who continued (15), duration of therapy was 4 -24 months. The best benefit with PGB was seen at a dose of 150mg tid, followed by 100mg tid. The most common non-hematologic toxicities were dizziness (57%), headache (26%), somnolence (22%), dry mouth (17%), ataxia (17%), tremor (13%), peripheral edema (13%), weight gain (13%), blurred vision (13%) and constipation (9%). Hematologic toxicity (G1 thrombocytopenia) was seen in 1 pt (4%) but impact of chemotherapy could not be excluded. Conclusions: PGB significantly reduces the severity of oxaliplatin-induced neuropathy. Larger, placebo-controlled trials assessing safety and efficacy of oral PGB are warranted in pts treated with oxaliplatin.

[Table: see text]
Robotic radiosurgery of liver metastases of solid tumors
Authors: Stintzing S. , Hoffmann R. T. , Heinemann V. , Kufeld M. , Muacevic A.
Published: August 2020

e15049

Background: The number of patients (pts) suffering from isolated liver metastases is growing. Although surgical excision is the treatment of choice many pts do not qualify for surgery. So local ablative techniques like radiofrequency ablation, laser induced thermal ablation therapy, brachytherapy and different external beam radiation therapies have been employed. We here report the therapeutic efficacy of a robotic radiosurgery device for local control of liver metastases of solid tumors. Methods: Patients with liver metastases not qualifying for surgery were treated with single session radiosurgery (24 Gy) using robotic image-guided real-time tumor tracking. In a prospective analysis, follow-up was done by MRI scanning at two months after the treatment, and subsequently at 3-month intervals to evaluate local control. For inclusion into the radiosurgery treatment protocol, tumor volumes had to be smaller than 80cc. Results: 27 pts (median age 62 years) with a total of 43 target lesions were evaluated. 17 pts were treated with single, 10 pts with multiple targets. Metastases (n=27) originated from: colon (12), rectum (2), pancreas (2), lung (1), bladder (2), malignant melanoma (1), stomach (1), cholangiocellular carcinoma (2), breast (1), ovary (1), appendix (1) and endometrium (1). Median tumor volume was 21cc (range 2.2–79.3). Median KPS was 100% (range 80–100). The median follow up was 12 months. 23 pts (85%) reached local control of the disease, 4 pts (15%) had local recurrence. Grade 2–4 adverse events due to cyberknife treatment were not observed. Conclusions: Robotic radiosurgery with image-guided real-time tumor tracking of liver metastases is a new and promising treatment approach for pts not eligible for surgical resection and might enhance the possibilities of multidisciplinary oncological treatment concepts.

No significant financial relationships to disclose.
Chemotherapy-induced thymidine phosphorylase modulation in colorectal cancer
Authors: Aprile G. , Miscoria M. , Baldin P. , Casetta A. , Pandolfi M. , Di Loreto C. , Pizzolitto S. , Pizzolitto S. , Foltran L. , Fasola G. , Puglisi F.
Published: August 2020

e15050

Background: Thymidine phosphorylase (TP) is an inducible enzyme responsible for nucleoside metabolism, antiapoptosis activity, and promotion of angiogenesis. In addition, conversion of the prodrug capecitabine (C) to its active form depends on TP activity. Preliminary evidence suggests that TP immunohistochemical expression may predict benefit from first-line treatment of metastatic colorectal cancer (CRC) with C plus irinotecan. Several chemotherapeutic agents have been shown to modulate TP expression. The aim of the present analysis was to verify if TP expression differs among primary and paired metastases in CRC patients, or may vary depending on patients’ exposure to chemotherapy. Methods: TP expression was evaluated by immunohistochemistry (clone p-P-GF.44C, Abcam, Cambridge, UK) in a series of 120 primary CRC and their matched distant metastases. Tsuda's scoring system was adopted, defining TP expression as negative (score 0–1) or positive (score 2–3). Results: Data on the first 57 patients are here presented. Sites of biopsied metastases were liver (n=41), lung (n=10), and peritoneum (n=6). Metastases were asynchronous in 42% of patients. Higher TP expression was observed in primary cancers than in metastases (36.8% vs. 15.8%, p=0.007). Among patients who received at least one cycle of chemotherapy before metastasis sampling (38.6%), a TP expression decrease was demonstrated in only 13% of metastatic samples. Oppositely, a significantly higher proportion of untreated patients lost TP expression in metastasis sites (36%, p=0.01). Conclusions: In advanced CRC patients, TP expression tend to decrease in metastases, particularly in those patients who did not receive chemotherapy before metastatic sampling. Although intratumoral heterogeneity and other causes of discrepancy cannot be excluded, true chemotherapy-induced modulation of TP may be hypothesized.

No significant financial relationships to disclose.
The effects of Gosha-jinki-gan on oxaliplatin-related neurotoxicity: A prospective randomized study
Authors: Nishioka M. , Shimada M. , Kurita N. , Utsunomiya T. , Iwata T. , Yoshikawa K. , Higashijima J.
Published: August 2020

e15056

Background: Oxaliplatin is now considered a standard treatment for advanced or unresectable colorectal cancer, but sensory neurotoxicity is its dose-limiting toxicity. The OPTIMOX (stop and go) approach offers a reasonable strategy, but preventive agent is not established. It is reported that Gosha-jinki-gan (a blended herbal medicine) is recently considered as an effective agent for the neurotoxicity of taxanes and for vibration sensation in patients with diabetic neuropathy. Patients and Methods: From 2007, 32 patients treated with modified FOLFOX6 for advanced or unresectable colorectal cancer were randomized. Fifteen patients received oral administration of 7.5 g/day of Gosha-jinki-gan (G group) every days from first course and 17 patients (Control group) did not. Neurotoxicities were evaluated every course according to DEB-NTC (Neurotoxicity Criteria of DEBIOPHARM) and NCI-CTCAE Ver.3.0 using self-check sheet. Results: The median number of cycles of per patient of G group was 14 (range, 4–26), and that of C Group was 9 (range, 1–20). Cumulative dose of oxaliplatin of two groups was 1,190 mg/m2 (G group) and 765 mg/m2 (C Group). Peripheral neurotoxicity evaluated by DEB-NTC in Group G was grade 0 in 0 patients (0%), grade 1 in 11 (73%), grade 2 in 4 (27%) and grade 3 in 0 (0%) and, in C group, respectively, 1 (6%), 6 (35%), 7 (41%), 3 (18%). According to NCI-CTCAE, neurotoxicity was lower in G group than that of C group. Fifteen patients in G group were evaluated by RECIST criteria with a PR rate of 66.7%, SD rate of 20.0% and PD rate of 13.3%. Seventeen patients in C group were evaluated by RECIST criteria with a PR rate of 52.9%, SD rate of 35.3% and disease control rate of 11.8%. Conclusion: Gosha-jinki-gan is effective for preventing oxaliplatin-induced neuropathy in advanced or unresectable colorectal cancer patients.

[Table: see text]
Oxaliplatin/Capecitabine combination (Xelox) with or without targeted therapies in advanced colorectal cancer (ACRC) and pharmacokinetic analysis
Authors: Gil-Delgado M. , Bastian G. , Spano J. , Paule B. , Des-Guetz G. , Bardier-Dupas A. , Khayat D.
Published: August 2020

e15068

From 04/2002 to 12/2004, and 03/2006 to 08/2008, two consecutive steps were conducted in ACRC patients with chemotherapy alone for the step 1 and with Cetuximab and Bevacizumab for the step 2. Treatment schedule: oxaliplatin (0) 130 mg/m2 D1 over 4 to 6 hours, capecitabine (X) 1000 mg/m2 bi daily D2 to 15, 1 week rest. Cetuximab D1 at cyle 1 and at D2 at cycle 2(400 mg/m2 loading dose, then 250 mg/m2 every week), bevacizumab 7.5 mg/Kg D2 at cycle 1 and at D1 for the cycle 2. At cycle 3 cetuximab and bevacizumab were given at D1. PK analysis were performed at cycles 1 and 2, days 1,2,15,22 and 23. In the step 1, 23 pts were included, M/F = 9/14, M. age 57, PS 0–1-2 = 14/6/3, 1st line /2/3 = 18/4/1. Eleven responses were obtained (4 CR and 7 PR) 2 pts were in CR after hepatectomy, ORR = 48 %( intent to treat). In the step 2, 18 pts were included, M/F = 11/7, M. age = 55, PS 0–1-2 = 8/7/3, 1st line/2 = 17/1.Status K-RAS mutated/wild = 2/13.Seven pts responded to therapy: 1 CR, 6 PR and 1MR for an ORR of 38 %(intent to treat) 3 pts were in CR after hepatectomy and 6 pts were in SD, tumor control in 16/18 pts=88 %.Toxicity was mild, only 1 pt had G3 diarrhoea, 1pt G3 acne, 1pt had G3 neurotoxicity with need oxaliplatin discontinuation after 14 cycles. One pt had fatal pulmonary embolism at first cycle. PK results in plasma ( 14 pts in step 1 and 12 pts in step 2):no statistical differences between X and its metabolites on D2 and 15. Urinary elimination is about 2 % of total dose administered over 4 hours for 5- FU and 8 to 22% for Fluoro β Alanine (FBAL). Plasma clearance of 1.73±1.22ml/h/m2 for 5FU, 53.76±25.36ml/h/m2 for FBAL. For O, residual level at D15 higher in erythrocytes than in plasma suggest an important irreversible binding with red cells without blood toxicity. Conclusions: Xelox with and without targeted therapies is an active and safe combination in ACRC. When O is administered over a long period of time and X is given at least 12 h later, neurotoxicity was mild and no hand-foot syndrome was observed. Important PK parameters variability mainly for 5FU and FBAL suggest posology adaptation on the basis of concentration ratio 5FU/FBAL in blood. No PK interaction between monoclonal antibodies and X or O were observed whatever the schedule of drug administration.

No significant financial relationships to disclose.
Immune infiltrates in liver metastases of colorectal cancer and response to chemotherapy
Authors: Halama N. , Michel S. , Kloor M. , Zoernig I. , Pommerencke T. , Schirmacher P. , von Knebel-Döberitz M. , Weitz J. , Grabe N. , Jäger D.
Published: August 2020

e15069

Background: Colorectal cancer (CRC) is a major cause of death from cancer. Patients with irresectable or metastasized CRC usually receive chemotherapy in combination with a monoclonal antibody, median overall survival time is around 20- 21 months with response rates of around 50%. Almost half of the patients experience treatment related side effects without benefit. K-ras mutation is the only (negative) predictive marker for response to therapy (for EGFR-targeting antibody treatment), no biomarkers are available that help to select patients most likely responding to chemotherapy. In primary colon cancer immune infiltrates in the tumor represent an important prognostic factor. High densities of tumor infiltrating lymphocytes (TIL) were shown to be correlated with an improved survival in patients with primary CRC. TILs therefore represent a valuable prognostic tool, a high density of immune cells being associated with good outcome independently of other established prognostic markers. Little is known about an association between these immune cells and the response to chemotherapy. Methods: Here the relation between infiltrates of immune cells in liver metastases of CRC and the response to chemotherapy (using immunohistochemical staining against CD8, GranB, FOXP3, CD45RO, etc.) was investigated. Samples from 33 patients with metastasized colorectal cancer (samples from 22 patients were used as training set and samples from 11 patients as validation set) were analyzed. Results: The evaluation of positively stained TIL in the invasive margin of the liver metastasis allowed to predict response to chemotherapy. This was also observed in the analysis of the time to progression, where higher numbers of positively stained cells were associated with longer intervals. The difference between the groups with either response or no response to chemotherapy in time to progression was statistically significant in the analyzed sets (Mann-Whitney- U, p<0.001, two-tailed, z=-3,961, n=33). In primary tumors no association between TIL densities and response to chemotherapy was observed. Conclusions: Our results suggest that the immune system has an important impact on the efficacy of chemotherapy and the presented data will have implications for the assessment of therapy options.

No significant financial relationships to disclose.
Phase II study of bevacizumab in combination with capecitabine as first line treatment in elderly patients with metastatic colorectal cancer (MCC)
Authors: Vrdoljak E. , Omrcen T. , Hrabar A.
Published: August 2020

e15074

Background: The aim of this prospective study was to evaluate efficacy and safety of bevacizumab in combination with capecitabine as first line treatment in elderly patients with MCC. Methods: 40 elderly patients (median age 75 years) with MCC have been treated with bevacizumab in combination with capecitabine as their first line therapy. Regimen consisted of bevacizumab 7.5 mg mg/kg on day 1 plus capecitabine 1000 mg/m2 on day 1–14 followed by 7 days rest. Results: The median follow up time at time of ASCO will be 12 months. Median number of 9 cycles was administrated, ranging from 1 to 23. 3 patients (7.5 %) had complete response, 19 patients (47.5 %) had partial response, 11 patients (27.5 %) had stable disease, 1 patient (2.5 %) progressed according to RECIST criteria and 6 patients (15%) were not evaluated yet. Until this report 15 of 40 patients progressed and 9 of 40 patients died. Median time to progression is 6.37 months. Median overall survival will be reported at ASCO 2009 meeting. The most common hematological adverse events were mild (grade I and II): anemia (27.5%) neutropenia (22.5%), and thrombocytopenia (20%). The most common non-hematological toxicity were mild as well (grade I and II): hand-foot syndrome (70%), arterial hypertension (52.5%), proteinuria (45%), hyperbilirubinemia (45%), diarrhea (25%), loss of appetite (23.5%), fever (22.5%), fatigue (17.5%), tearing (17.5%), and nail changes (12.5%). Grade 3 and 4 adverse events occurred rarely: hand-foot syndrome (12.5%), deep vein thrombosis (7.5%), fever (5%), and arterial hypertension (2.5%). Conclusions: This prospective phase II study has demonstrated that bevacizumab in combination with capecitabine as first line treatment in elderly patients with metastatic colorectal cancer is an effective and well-tolerated regimen.

[Table: see text]
Capecitabine and irinotecan (XELIRI) in first-line treatment of metastatic colorectal cancer (mCRC): A systematic review of controlled clinical trials
Authors: Sukumaran S. , Pavlakis N. , Pittman K. B. , Patterson K. , Price T. J.
Published: August 2020

e15100

Background: Irinotecan and 5-Fluorouracil based combination is an effective regimen for mCRC. Capecitabine, an oral fluoropyrimidine, is a convenient alternative to intravenous 5- Fluorouracil. This study aims to systematically review all published and unpublished controlled phase II and III trials of XELIRI combination, used in first line treatment of mCRC, reported from 2000–2008, to describe its efficacy and safety. Methods: A literature search of MEDLINE, EMBASE, CINAHL and proceedings from ASCO, ESMO and WGIC was conducted. The primary end point was response rate (RR), secondary endpoints include: time to progression (TTP), overall survival (OS) and toxicity. Results: Thirty non-randomised phase II trials (n = 1380) along with 6 randomised phase II and 3 phase III trials, were included (pooled n = 1478). The daily dose of capecitabine ranged from 1,800 mg/m2 to 2,500 mg/m2 for 7 to 14 days per cycle and the dose of irinotecan varied from 180mg/m2 to 350 mg/m2, over a 3 week period per cycle. Amongst the non-randomised studies, the median patient age was 61 years (53–72).The median RR was 46.75% (25–78%). The median reported TTP was 7.9 months (mo) (5- 9.9 mo) and the median OS was 15.6 months (7–24.8 mo). Grade 3–4 toxicity incidence was: diarrhoea (21.5%), neutropenia (12%), vomiting (12.5%), fatigue (6%) and Hand-foot syndrome (6%). The pooled incidence of febrile neutropenia was 2.5%. Amongst the randomised trials, the comparator regimens were XELOX or FOLFIRI. Median age was 65 years (61–74). RR for XELIRI was 39% (34–56%) compared to 47% (27–61.8%) for the non XELIRI comparator arms. Median reported TTP was 8.2 mo (5.7–12.5 mo) for the XELIRI arms and 9.2 mo for the comparator arms. Conclusions: XELIRI is an effective and feasible regime in the first line management of mCRC. However the optimal role of this combination remains to be established.

No significant financial relationships to disclose.
Do predictive scoring systems have any role in determining treatment strategy for colorectal liver metastases at the individual patient level?
Authors: Malik H. , Poston G.
Published: August 2020

e15104

Background: the literature contains four prognostic scoring systems from large volume series predicting survival after resection for colorectal liver metastases. Our aim was to directly compare these systems in terms of accuracy in predicting survival, and evaluate the role of such systems in determining therapeutic strategies on intention to treat at the individual patient level. Methods: the original published data were reviewed and the median survivals plotted against each point in the scoring system. The best fit line was drawn and the resultant plots enabled calculation of slope of the linear regression line and the square of the Pearson product moment correlation coefficient through data points allowing all four prognostic scoring systems to be directly compared. Results: when the prognostic scores were compared on a common scale, the R-squared values of all the scoring systems were similar with R-squared values of greater than 0.94 in all cases. The Basingstoke Predictive Index however produced the steepest gradient suggesting it can better distribute patients along a wider range of survival. Conclusions: none of the four scoring systems was perfect in their predictive value. It is not surprising that the risk score from MSKCC and Leeds are not as good as the others since they are meant to be preoperative prognostic scores and postoperative scoring system by their nature of having more information should be better. Clearly, future developments in this field must incorporate advances in our understanding of tumor biology.

[Table: see text]
Evaluation of the distinction between responder and non-responder in FOLFOX/FOLFIRI based on the alteration of serum iron level
Authors: Ochiai T. , Nishimura K. , Watanabe T. , Kitajima M. , Nakayama N. , Mashiko S. , Yamazaki R. , Kaneko N. , Futagawa S. , Nagaoka I.
Published: August 2020

e15110

Background: The alteration of serum-iron level during chemotherapy is already reported (Follezou, NEOPLASMA 1985). However, the correlation to prognosis has not been evaluated. The aim of this study was to evaluate the correlation between prognosis and serum-iron level in advanced / metastatic colorectal cancer (aCRC / mCRC) patients treated by FOLFOX / FOLFIRI. Methods: Serum-iron levels, hemoglobin, AST and ALT serum levels in immediately pre and post chemotherapy were analyzed in 58 aCRC / mCRC patients received FOLFOX-4 / FOLFIRI therapy between April 2005 and September 2008. 26 patients received FOLFOX-4 / FOLFIRI therapy as the final chemotherapy died by the time of analysis. These patients were categorized into the high increase group and the low increase group using 200% increase as cut-off value and the prognosis was compared. Results: Mean serum-iron levels in immediately pre and post chemotherapy were 71.7±29.0μg/dl and 186.8±83.2μg/dl, respectively, and significant increase after chemotherapy was observed (p<0.001). This increase was transient and returns to pre chemotherapy level by the start of next course. This alteration was always observed on the chemotherapy. The median survival times from the initiation of FOLFOX-4 / FOLFIRI therapy for the high increase group (n: 5) and the low increase group (n: 21) were 487 and 182 days, respectively, and was significantly better in the high increase group (p=0.004). The alterations of hemoglobin, AST and ALT serum levels in immediately pre and post chemotherapy were not observed. Conclusions: It is suggested that serum-iron increase is a biological response not attributed to leakage from erythrocyte and hepatocyte. Significantly better prognosis in high serum-iron group may suggest the usefulness of serum-iron level to distinguish responder and non-responder in FOLFOX-4/FOLFIRI therapy.

No significant financial relationships to disclose.