bluuebunny/crossref_metadata_2025 huggingface dataset:
Updated results from a phase II study of sequential treatment epirubicin, cyclophosphamide (EC), surgery and docetaxel (DTX) in stage II and III breast cancer
Authors: Grecea D. , Neamtiu L. , Tanasescu R. , Rancea A. , Resiga L. , Galatar M. , Postescu D. , Daicoviciu D. , Popita V. , Ghilezan N.
Published: March 2020

11096

Background: The study was designed to evaluate the efficacy and safety of sequential administration of epirubicin plus cyclophosphamide (EC) followed by surgery and docetaxel (DTX). Methods: All patients (74) with untreated breast cancer stage II and III received epirubicin (E) 100mg/m2 given in 30 min followed by cyclophosphamide (C) 600mg/m2(q3w).After four cycles of neoadjuvant chemotherapy, the pts were evaluated for response: 46 ( 62.1%) presented PR, 2 (2.7%) CR and 26 ( 35.2%) SD and then they underwent surgery: conservative (17.57%) or radical mastectomy (82.43%).After surgery, the patients received four cycles of docetaxel (DOC) 100mg/m2 (1 hour , q3w). The median age was 46 ( 24–66) years, with 51 ( 69%) premenopausal and 23 (31%) postmenopausal patients. Results: The pathological response was pT1 lower to 2 cm, 41 patients ( 55.41%), pT 2–5 cm, 33 pts ( 44. 59%); pN+ 1–3: 13 pts ( 17.56%); pN+ = 4 and more than four: 61 pts ( 82.44%). Overall survival at 60 months was 59. 57% and DFS was 41.25%. For patients with pN+1–3 , at 5 years DFS was 46.35% and for those with pN+ = 4 and more 4, DFS was 38.25% (p=0.045).Overall survival at 5 years follow-up was 65.74% for pts with pN+ 1–3 and 57.36% for those with pN+=4 and more than 4. Conclusions: Previous interim analysis results of sequential chemotherapy with DTX demonstrate the efficacy and safety of these treatment in breast cancer stage II and III. At 5 years follow-up, we conclude that the use of four cycles of EC followed by sugery and then four cycles of DTX is a reasonable treatment choice for at least some patients with breast cancer st II and III.

No significant financial relationships to disclose.
Clinical outcome of node-negative (NN) breast cancer (BC) patients
Authors: Atalay Basaran G. , Cabuk D. , Dane F. , Teomete M. , Iyikesici S. , Meltem E. , Gulluoglu B. , Kaya H. , Abacıoglu U. , Yumuk F. , Turhal S.
Published: March 2020

11102

Background: Breast cancer patients (pts) with NN disease have diverse clinical outcomes. An optimal treatment decision- making tool has not been defined for this heterogeneous group. Methods: We identified pts with NN disease who have been treated between 1998–2006 in our department. We recorded the clinical/pathological, treatment characteristics and analyzed their survival outcome. High risk (HR) was defined as having at least one of the following features: age<35 yr-old, pts with grade 3 tumors (tms), ER and PR negative tms, tm size >2 cm. Results: Out of 597 early BC pts, 275 pts with NN disease were identified, 190 pts with HR, 85 with low risk (LR) features.The median age was 51 (26–83). The median follow up was 40 months (4–120 months). 47% pts were premenopausal. 31% pts had breast conserving surgery (BCS).58/29% pts had grade 2/3 tms. 34% pts with BCS or T3 tms received adjuvant radiotherapy. All receptor positive pts received adjuvant endocrine therapy (ET). In the HRNN group, 5% pts had tms>5cm, 51/40% pts had grade 2/3 tms, 43% pts had ER/PR negative tms. In the LRNN group 25/74% pts had grade 1/2 tms, no pt had receptor negative tm. 86%/51% pts received adjuvant chemotherapy (CT) in the HR and LRNN groups. 12%/48% pts received adjuvant ET alone in the HR and LRNN groups. 5pt in the HR and 1 pt in the LR group received no adjuvant systemic therapy due to their comorbidities and/or negative receptor status. So far, 14 pts had relapsed (8 from the HR, 6 from the LR group) and 3 pts died due to BC (1 from the HR, 2 from LR group). The 5-yr DFS was %94 in the HR and was %90 in the LR groups. HRNN pts had %98 and LRNN pts had %95 5-yr OS. Conclusion: It seems that prognostic information based merely on clinical/pathological characteristics might not accurately quantify the risk of recurrence and death, so that the decisions about adjuvant chemotherapy in NN breast cancer patients. Prospective evaluation of the performance of the new genomic prognostic tools compared to traditional prognostic factors is needed in order to more clearly define the HR vs LR subsets of NNBC pts.

No significant financial relationships to disclose.
Heterogeneity in disease-free survival in breast cancer patients
Authors: Yahyazadeh Jabbari S. , Khodabakhshi R. , Gohari M. R. , Mortzavi S. , Alidoosti A. , Shahidi J. , Moradi A. , Bahoor F.
Published: March 2020

11106

Background: Breast cancer is the most common cancer and women’s health problems in Iran. There are some known prognostic factors for occurrence of metastasis after surgery. However, there are some other unknown factors affect the risk of metastasis. The purpose of this study was to determine the value of known prognostic factors by accounting for patient-specific effect, the rate metastasis in breast cancer patients who received surgical treatment followed by adjuvant treatment in Iran. Methods: Among 174 women whom have been undergone surgery followed by adjuvant therapy at three hospitals in Tehran, Iran during 3 years 117 have met the including criteria. Women with defined breast cancer with no distant metastases in time of diagnosis whom have been undergone MRM or BCS were enrolled. Tumors were classified according to the TNM system of the American Joint Committee on cancer (AJCC). Grading was performed according to Scarff-Bloom-Richardson method. ER and C-erb2 was measured by immunohistochemistry (IHC) method. The patients have been followed regularly by routine clinical, lab profile, serologic markers (CEA,CA15–3) and Para clinical examinations. Results: The median relapse- free survival for patients in study was 49.6 month. The median time to experience second metastasis was 22.5 month. 44 (38% ) patients developed metastasis. 20 (45%) of those experienced second metastasis. the Frailty model showed that age, size of tumor, number of positive lymph nodes and histologic grade had a significant effect on the risk of metastasis (p<.05) and there was a heterogeneity between patients after adjusting for covariates. Conclusion: Many patients who referred to cancer centers were not detected at early stage and they will meet more risk for relapse. The known risk factors describe the risk of metastasis partly and other unknown or unmeasured factors, such as environmental or genetics, are important to describe the risk of metastasis in breast cancer. Family history has no significant effect on event- free survival.

No significant financial relationships to disclose.
Phase II evaluation of liposomal doxorubicin combined with docetaxel in patients with metastatic breast cancer
Authors: Fasano J. , Hershman D. , Novik Y. , Blozie K. , Tiersten A.
Published: March 2020

1112

Background: The combination of anthracyclines and taxanes are effective in the treatment of metastatic breast cancer. Liposomal doxorubicin has been shown to be as effective as doxorubicin with less toxicity and it can be combined safely with docetaxel. Methods: Monthly liposomal doxorubicin (30 mg/m2) in combination with weekly docetaxel (30 mg/m2) was evaluated in women with metastatic breast cancer. Cycles were continued until disease progression or unacceptable toxicity. Radiologic assessment was performed every two months. The primary outcome was time to progression. Secondary endpoints included overall response rate, median survival and toxicity. Results: Between 12/2002 and 9/2005, 12 women were enrolled and received this combination as front- line chemotherapy for metastatic breast cancer. The mean age was 46.5 (31–60) years. Nine (75%) patients had tumors that were ER+ or PR+. Five (41.7%) women had tumors that over-expressed her-2/neu. Ten women had an EGOG performance status of 1. Two women had an ECOG performance status of 2. The median number of cycles received was 4 (1–12). Four (25%) women were taken off study due to intolerable toxicity and 7 (58.3%) due to progressive disease. One (8.3%) woman remains progression free. Ten (83.3%) women had a partial response, one (8.3%) woman had a mixed response and one (8.3%) was not evaluable for response to chemotherapy. The median time to progression was 21 (6–52) weeks. Three women remain alive with disease. One woman remains alive and progression-free. Ten (83%) patients experienced Grade 3/4 toxicities, including: stomatits 6 (50%), nausea/vomiting 1 (8.3%), neutropenia 3 (25%), infection 3 (25%), dyspnea 2 (16.7%), and PPE 1 (8.3). Conclusions: Monthly liposomal doxorubicin plus weekly docetaxel in women with metastatic breast cancer resulted in an encouraging response, but was difficult to tolerate. Further evaluation of this combination with improved supportive care may be warranted.

[Table: see text]
Bisphosphonate-induced osteonecrosis of the jaw: Incidence and risk factors in patients with breast cancer and gynecological malignancies
Authors: Beck V. , Solomayer E. , Krimmel M. , Reinert C. , Fehm T.
Published: March 2020

1113

Background: Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. They are successfully used in conditions of increased bone turnover such as osteoporosis or bone metastases. Since 2003 multiple cases of bisphosphonate-induced osteonecrosis of the jaw (ONJ) were reported. Our purpose was to describe the incidence and risk factors of ONJ in patients with breast cancer or gynecological malignancies. Patients and Methods: ONJ was assessed retrospectively for all patients with breast cancer or gynecological malignancies treated with bisphosphonates at the Department of Gynecology and Obstetrics, University Hospital Tuebingen during April 1999 until May 2006. Results: 10 of 310 (3%) patients with breast cancer or gynecological malignancies developed ONJ while receiving bisphosphonate therapy. All patients with ONJ were treated for bone metastases. Except one all patients with ONJ had a history of recent dental procedures. All patients had received zoledronic acid as part of their bisphosphonate regimen. In 4 of 10 patients this was the only bisphosphonate given. The remaining 6 patients had received at least one of the other bisphosphonates (alendronate, ibandronate, clodronate or pamidronate) before or after zoledronic acid therapy during their course of disease. Time of exposure to bisphosphonates and the number of treatment cycles were significant risk factors for the development of ONJ (p<0.001). In patients diagnosed with ONJ the mean number of treatment cycles was 27 ±18 cycles (median: 21 cycles, range 6–62 cycles) and the mean duration of bisphosphonate therapy was 29 ±20 months (median: 22 months, range 1–67 months). In contrast, the mean number of treatment cycles in patients without manifestation of ONJ was 11 ±12 cycles (median: 6 cycles, range 1–90 cycles). The mean duration of therapy was 12 months (median: 7 months, range 1–81 months). Conclusion: Osteonecrosis of the jaw is regarded a major side effect of bisphosphonate therapy. Length of exposure to bisphosphonates and the number of treatment cycles seem to be the most important risk factors for the development of ONJ. In addition, recent dental procedures favours the development of an ONJ.

No significant financial relationships to disclose.
Improved renal function in patients switched from zoledronic acid to ibandronate: A retrospective review of medical records
Authors: Diel I. J. , Weide R. , Köppler H. , Antràs L. , Smith M. , Green J. , Wintfeld N. , Neary M. , Duh M.
Published: March 2020

11500

Background: The renal safety profile of ibandronate (IA) was assessed retrospectively across a spectrum of oncology patients including multiple myeloma, breast, prostate, and non-small cell lung cancer. Patient groups were classified as IA switchers (with prior zoledronic acid (ZA) therapy) (n=34) or early IA (without prior ZA therapy) (n=72). Renal impairment rates and trends in renal function were compared during ZA and IA treatment periods in patients switching from ZA to IA (n=32 observable in both treatment periods). Methods: Medical records from two German oncology clinics, spanning May 2001 to March 2006, were reviewed. Serum creatinine (SCr) was analyzed from baseline to last evaluation. Renal impairment was defined as a SCr increase of =0.5mg/dL or =1.0mg/dL from baseline values of <1.4mg/dL or =1.4mg/dL, respectively; or =25% decrease in glomerular filtration rate (GFR) from baseline. Results: Both groups had similar baseline renal function. Physicians reported that renal-related problems led to 22 patients (69%) switching from ZA to IA. Patients switched from ZA therapy to IA showed a significant trend towards renal function deterioration during the ZA treatment period (p=0.016) but experienced a trend towards improved renal function after switching to IA (p=0.082). Patients receiving IA with prior ZA therapy exhibited significantly higher renal impairment rates versus those without prior ZA therapy (50.0% versus 11.1%, relative risk (RR)=4.5, p<0.0001 [SCr] and 70.6% versus 38.9%, RR=1.8, p=0.0024 [GFR] for patients with and without prior ZA therapy, respectively). Cox proportional hazards models, adjusted for significant covariates, found significantly higher hazards ratios (HRs) in the IA switchers group versus the early IA group (HR=7.7, p<0.01 [SCr] and HR=4.3, p<0.01 [GFR]). Conclusions: ZA naïve patients had a significantly lower renal impairment risk compared to those who received ZA followed by IA. Patients switching from ZA to IA showed recovery of renal function, suggesting that patients may benefit from IA early in the treatment cycle or by switching to IA treatment. A prospective randomized study is warranted.

No significant financial relationships to disclose.
Diabody vinorelbine conjugate (DVC) composed of vinorelbine-tartrate conjugated to anti-DNMT1/SHH di-diabody induce ADCC, CDC, AMP and inhibit DNA methylation
Authors: John G. N. , Giannios J. , Seraj E. , Kanelopulos G. , Ginopulos P. , Alexandropulos N.
Published: March 2020

11503

Background: Hormone refractory breast cancer (HRBC) is incurable due to malignant stem cells,which represent a potential nidus for the recurrent cancer that arises after treatment failure. Methods: From 126 metastatic HRBC patients,we obtained CSCs from recurrent tumor reservoirs missed from current chemotherapy,which had eradicated bulky tumor foliage.HRBC-CSCs were treated with DVC composed of vinorelbine linked onto anti-DNMT1/anti-SHH di-diabody. Results: Post treatment ,we observed antibody dependent cellular toxicity (ADCC),complement dependent cellular toxicity (CDC) ,and antibody mediated phagocytosis (AMP) mediated by the di-diabody.Next,we observed inhibition of SHH, which is overexpressed in CSCs,blocking HH binding to PTCH,and signaling from SMO and GLI. DNMT1 was downregulated blocking DNA methylation.This inhibited hTERT transcription blocking the telomerase activity of CSCs. DNA demethylation reactivated DEAF-1 upregulating PTEN,which antagonised PKB/mTOR,PI3K/AKT,src/VEGF , HIF-1a/survivin angiogenic and antiapoptotic pathways leading to synergistic inhibition of telomerase activity. RKIP was re-expressed inhibiting Raf-1/MEK1–2/ERK1–2,NFkB and STAT3 leading to downregulation of CD46 mediating CDC. PTEN by inhibiting AKT,it upregulated Drg-1.Also,PTEN re-expression inhibited synergistically with vinorelbine,the oncogenes bcl-2,bcl-xL and mcl-1 leading to upregulation of bid,bax and bak. DNA demethylation reactivated CDH1,RASSF1A,EDNRB,Kip1/p27,RhoE,NKX31,DLC-1,GSTP1, TIG1,TAP,Necl-1,RARb,NTRK2,MFPC7–8,p16/Rb,p53/p21,DOC- 2/DAB2,BTG2,maspin and DEFB1. Ki67,BrdU and MTT exhibited inhibition of CSC proliferation. DFF,PARP,TUNEL,SEM and TEM exhibited PCD type I,II and III in CSCs.We observed aponecrosis based on lysosomal damage independent of caspases.PCR exhibited inhibition of CSC markers CD44/a2b1/CD133,b-catenin,Sca1,Notch-1 and methylation marker SCNN1B. Conclusions: DVC eradicated efficiently HRBC-CSCs.

No significant financial relationships to disclose.
Survival differences in patients with brain metastases according to breast cancer subtypes
Authors: Nam B. , Lee K. , Kim T. , Ro J.
Published: March 2020

11507

Background: Brain metastases (BM) occur in as many as one-third of patients with metastatic breast cancer (MBC). Incidences and prognoses by triple receptor subtypes in BM have not been well delineated. Methods: Retrospectively, prognoses were assessed according to clinical characteristics, triple receptor subtypes, and receipt of trastuzumab therapy by univariate and multivariate analyses. ER/PR/HER2 were tested by IHC with HER2 FISH for IHC 2+ and for all 118 consecutive primary BC. Results: Between 8/2001 and 4/2006, 138 of 805 pts (17.1%) with MBC presented with BM at NCC Korea. More pts with triple negative and HER2+ tumors developed BM (see table ). The median age was 47 years. They were single (9%), multiple (80%), or leptomeningeal disease with or without multiple BM (11%). As initial therapy, 104 pts received WBRT, 8, intrathecal therapy (IT), 9, WBRT with IT, and 17 others. Of 56 HER2+ pts, 45 received trastuzumab either before (n=25) or after (n=13), or continuously before and after BM diagnosed (n=7). By 10/2006, 117 pts died with a median survival of 4.5 months. Multivariate analyses indicated age, tumor receptor subtypes, leptomeningeal presentation and number of extracranial disease sites as significant factors. Receipt of trastuzumab therapy after BM was a significant variable for survival in HER2+ diseases (3.8 vs. 13.4 mo, p=0.0000). Pts with triple negative subtype lived shortest compared with other types (p=0.0035). Conclusions: More pts with triple negative and HER2+ disease developed BM. HER2+ disease gained a significant survival benefit by trastuzumab therapy. Supported by NCC Grant 0610240 and 0510520.

[Table: see text]

No significant financial relationships to disclose.
Cardiotoxicity of weekly trastuzumab (T) plus epirubicin (E) and paclitaxel (P) for HER2-positive locally advanced (LA) and/or metastatic (M) breast cancer (BC): A feasibility phase II study
Authors: Nisticò C. , Bria E. , Cuppone F. , Carpino A. , Vaccaro V. , Barberi S. , Sperduti I. , Giannarelli D. , Cognetti F. , Terzoli E.
Published: March 2020

11509

Background: The introduction of T for patients (pts) overexpressing HER-2 changed the natural history of BC. The adjunction of T to anthracyclines and taxanes for both LABC and MBC provided a significant incidence of unexpected cardiotoxicity. Given the low cardiac toxicity in our previous experience with weekly ET in unselected MBC pts, a feasibility phase II study aimed to cardiotoxicity was planned. Methods: Pts affected by untreated LABC/MBC overexpressing HER-2 by FISH/CISH amplification or 3-positive Dako- Test, underwent weekly T (4–2 mg/kg/week), day 1, and E (25 mg/m2/week) plus P (80 mg/m2/week), day 2, plus G-CSF support, for 16/24 consecutive weeks in absence of progression or toxicity, in LA/M pts, respectively. Pts with significant cardiac disease/L-FEV<50% were excluded. Primary endpoint was the rate of pts with L-FEV reduction >10% after 12 weeks. An optimal 2-stage Simon design was applied. With a power of 90% at a 5% significance level, assuming a toxicity rate of 30% as unacceptable, and less than 10% as acceptable, an initial group of 15 pts was required; with 11 pts with no toxicity, a second step with further 21 pts (total 36) was planned. Non-cardiac toxicity and activity were evaluated as secondary end-points. Results: From May 2004 to November 2006, 15 pts entered the study. Patient characteristics: median age=47 (range 37–69); LABC/MBC=4/11; positive hormonal receptor 8/7; menopausal pre/post=7/8; PS 0/1=14/1; number of met sites 1/2/3=7/6/2. Median baseline- and post-week-12-L-FEV was 69% (range 64–77) and 65% (range 61–76), respectively. With a median number of courses of 13 (range 8–24), 3 pts had a >10% L-FEV reduction (20%), with an overall median L-FEV reduction of 5.2%. No EKG alteration or specific symptoms were registered. With a 17-months median follow-up, 13 pts were evaluable for response. Eight response (61.5%, 95% CI 9- 87) were documented, with a median response duration of 9 months. No grade 3–4 toxicity were registered, with the exception of severe alopecia. Conclusions: The weekly administration of T plus E and P is extremely tolerable, also with regard to L-FEV reduction. The low L- FEV reduction rate allowed entering the second step of the study.

No significant financial relationships to disclose.
Longitudinal analysis of trastuzumab use in metastatic breast cancer
Authors: Hammerman A. , Klang S. , Liebermann N. , Ben-Baruch N.
Published: March 2020

11513

Background: Six years after including Trastuzumab in the Israeli ‘National Health Basket‘ (NHB) for metastatic breast cancer (MBC), we evaluated its ‘real-life‘ use in terms of duration of treatment (DOT) and survival after initiation of treatment. Methods: The computerized database of Clalit Health Services’ (CHS), the largest Israeli sick fund, was used to determine DOT and survival (at Dec. 31, 2005), in all CHS patients with MBC that started Trastuzumab therapy during years 2000–2003. Results: * At Dec. 31, 2005. ** However, most received AC as adjuvant. Conclusions: A longitudinal analysis of Trastuzumab use shows a difference of 40–100% between the median and mean DOT. This difference is attributed to a sizeable proportion (∼15%) of patients that are “long-term responders” and are treated for more than 24 months. In these patients, we can assume that the HER-2 amplification is an essential transforming event. We recommend investigating the molecular characteristics of long-term responders.

[Table: see text]

No significant financial relationships to disclose.
Single-agent docetaxel (TXT) as first-line treatment in metastatic breast cancer (MBC)
Authors: Guarneri D. , Ratti R. , Venturino A. , Addamo G. , Coccorullo Z. , Colloca G. , Campora E.
Published: March 2020

11515

Background: Historically anthracyclines have been considered the most active agents in metastatic breast cancer (MBC). Docetaxel (TXT) has challenged this belief. Aims: Evaluate response rates, toxicity and time to progression in patients with MBC receiving single agent TXT as first line treatment. Methods: MBC patients received first line single agent treatment according to one of the following schedules: TXT 35 mg/m2 iv weekly for 6 wks q 8 wks (Group 1) or TXT 100 mg/m2 iv day 1 q 3 weeks (Group 2). Adjuvant chemotherapy was FAC (600,50,600) day 1 q 21 days for 6 courses in all cases so treated. Results: Conclusions: It appears that results with single agent TXT obtained in clinical practice are comparable to those reported in Phase II-III trials (Group 1 and Group 2, respectively ) using the same regimens.

[Table: see text]

No significant financial relationships to disclose.
Fixed dose rate (FDR) gemcitabine as radiosensitizer for newly diagnosed glioblastoma multiforme (GBM): Preliminary results of a phase II study
Authors: Fabi A. , Felici A. , Mirri M. A. , Metro G. , Vidiri A. , Pace A. , Carosi M. A. , Cognetti F. , Occhipinti E. , Carapella C. M.
Published: March 2020

12502

Background: In a previous phase I study (ASCO 2006), where FDR Gemcitabine at 10/mg/m2/min was tested in association with radiotherapy (RT) for the treatment of newly diagnosed GBM, a maximum tolerated dose of 175 mg/m2/wk was identified. Methods: After surgery for GBM (either citoreduction or sterebiopsy), patients were treated with fractionated focal RT at a daily dose of 2.0 Gy per fraction, five days per week for six weeks (total dose of 60 Gy). FDR Gemcitabine at 175 mg/m2/wk was given concomitantly starting 24–72 hours prior to RT and then for the whole duration of RT. An MRI performed at 7 and 40 days from the end of chemo-radiotherapy was used for activity assessment. Standard oral temozolamide 150–200 mg/m2 was administrated following the combined treatment. Results: From 07/2004 16 patients (9 male, 7 female) have been enrolled. Characteristics of patients were: median age 57 years (42–72), median KPS at baseline 90 (70–100), surgery/stereobiopsy 14/2. Median time from diagnosis to initiation of Gemcitabine was 45 days (28–54). Among the 14 evaluable patients 3 (21.4%) partial responses, 7 (50%) stable disease and 4 (28.5%) progressive diseases were recorded. At a median follow up of 18 months (2–33) time to progression was 6 months (1.5–24). Toxicity was manageable with only one G3 neutropenia and hypertransaminasemia in two patients respectively. Grade 1 hypertransaminasemia was registered in 6 patients (43%). Conclusions: These preliminary results show that in patients with newly diagnosed GBM, radiosensitizing FDR Gemcitabine at 175 mg/m2/wk is a well tolerated regimen with an interesting activity. Accrual is ongoing and final results will be presented at the meeting.

No significant financial relationships to disclose.
The role of MGMT promotor hypermethylation as a predictive factor for response to temozolomide in recurrent high-grade glioma
Authors: Sadones J. , Michotte A. , Chaskis C. , In ’t Veld P. , Califice S. , Bierau K. , Svensson C. , De Grève J. , Neyns B.
Published: March 2020

12509

Background: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promotor hypermethylation (MGMT-meth) compromises DNA repair of high-grade glioma (HGG) and has been associated with a survival benefit in patients treated with temozolomide (TMZ) for newly diagnosed glioblastoma multiforme (GBM). It remains undetermined if the MGMT-meth status correlates with response to temozolomide at recurrence and whether extended dosing of TMZ (known to deplete MGMT in peripheral blood mononuclear cells) can overcome resistance in unmethylated HGG. Methods: We are investigating the MGMT-meth status on glioma tissue samples collected at diagnosis from 64 patients (pts). Fifty pts were treated at the time of recurrence with conventional TMZ (5 out of 28d regimen) and 14 pts with extended dosing of TMZ (100 mg/m2/d, 21 out of 28d regimen). Following DNA isolation from archival glioma tissues by phenol/chloroform extraction and a bisulphite conversion of genomic DNA, real-time methylation-specific PCR quantification of the methylation status of the MGMT promotor region is performed by OncoMethylome Sciences S.A. (according to OMS proprietary methodology). Results: At present, results have been obtained for 15 pts (13 M/ 2 W, median age: 46y). From 3 pts a biopsy at recurrence was available for analysis. The result was discordant with the MGMT-meth status at diagnosis in 2 pts (1x meth to unmeth and 1x unmeth to meth). Of the 6 (40%) pts with MGMT-meth gliomas, none had immediate progression on TMZ (respectively 4x SD, 1x CR, 1x PR). Of the 9 pts with an unmethylated MGMT promotor, 4 pts had immediate progression on TMZ and 5 pts had SD (of which 4 had been treated with the 21/28d regimen). All pts, except one, with MGMT-meth had a TTP that was above the median of our study population. The two pts with an MGMT-unmeth status that had a TTP above the median had received the extended dosing regimen. Conclusions: Our preliminary data indicate that MGMT promotor hypermethylation at diagnosis might correlate with sensitivity to TMZ in the recurrent setting. Extended dosing of TMZ might be more active against MGMT-unmethylated glioma. Final data from this study will be available for presentation at the meeting.

No significant financial relationships to disclose.
Can a conventional schedule of radiation therapy be administered to elderly patients with glioblastoma multiforme?
Authors: Manfrida S. , D’Agostino G. R. , Anile C. , Mantini G. , Colicchio G. , Gambacorta M. A. , De Renzi F. , Valentini V. , Smaniotto D. , Balducci M.
Published: March 2020

12516

Background: We retrospectively evaluate the tolerance and the efficacy of a conventional schedule of radiotherapy in elderly patients with glioblastoma multiforme (GBM). Methods: Eighty-three consecutive patients affected by glioblastomas were treated between 2001 and 2006. We divided our series in two groups: patients under 65 years (n=52) and patients ≥ 65 years old (n=31). In the elderly group, median age was 68 years (range, 65–80). 17 patients (54,8%) were female, 14 male (45,2%); 20 patients (64,5%) <70 years, 11 patients (35,5%) ≥70 years. Among the younger patients, median age was 51 years (range 25–64), male/female ratio 32/20 (61.5%/38.5%).Twenty-seven out of 31 elderly patients (87,1%) were treated with conformal radiotherapy (CRT, 5940 cGy, 180 cGy/day; CTV2: tumor bed + residual tumor if present + oedema, 3960 cGy; CTV1: tumor bed + residual tumor if present + margins, 1980 cGy). Four out of 31 patients received an intensification dose of xxxx cGy by stereotactic conformal radiotherapy (SRT, 12,9%); among the younger patients, 25/52 were treated with CRT (48,1%) and 27/52 with SRT (51,9%). Concomitant and adjuvant chemotherapy was administered by temozolomide (TMZ).Toxicity was evaluated according to RTOG score. Survival analysis were performed using Kaplan-Meier method and log-rank testing was used for comparison of groups. Results: In the elderly group, neurological acute toxicity was observed in 6/31 patients (19,4%), with grade 3 in two patients. In the under 65 group, 5/52 patients (9,6%) had neurotoxicity (Grade 3 in two patients).This difference was not statistically different.At a median follow-up period of 28 months (range, 3–61), median progression-free survival (PFS) was 11 months in the ≥65 group and 10 months in the under 65 group; median overall survival (OS) was respectively 17 months and 22 months. 1- year survival was respectively 77.6% and 74.5%. Conclusions: In our analysis age did not seem to be a limiting factor in the choice of the therapeutic strategy for patients with glioblastoma multiforme.

No significant financial relationships to disclose.
Re-irradiation using high precision radiotherapy and concomitant temozolomide in patients with recurrent glioma: Re- challenge with radio-chemotherapy
Authors: Combs S. E. , Schulz-Ertner D. , Welzel T. , Bischof M. , Debus J.
Published: March 2020

12517

Background: This study was aimed to assess the toxicity and efficacy of radiochemotherapy (RCHT) with temozolomide performed as re-irradiation in patients with recurrent glioma. Patients and Methods: We treated 17 patients with RCHT for recurrent glioma between July 2005 and December 2006. Nine patients were female, eight were male. Pathology evaluation revealed WHO grade II astrocytoma in 5, anaplastic astrocytoma in 4 and glioblastoma multiforme (GBM) in 7 patients. One patient suffered from gliosarcoma. Median age at primary diagnosis was 33 years (range, 6–60 years). In 4 patients surgery had been performed as total resection, subtotal resection in 9 and as a biopsy in 4 patients. Median doses of radiotherapy (RT) of 60 Gy had been applied. Prior treatment with temozolomide either as RCHT or as chemotherapy alone for tumor progression had been performed in 8 patients. The median time interval between primary RT and re-irradiation was 29.5 months (range 5–180 months). Re-irradiation was performed as high precision radiotherapy using fractionated stereotactic radiotherapy (FSRT) in 16 patients with a median total dose of 36 Gy (range, 28–36 Gy); in one patients stereotactic radiosurgery (SRS) was applied for a very small lesion with a single dose of 18Gy/80% isodose. The target volume was defined as the area of contrast enhancement on T1-weighed MRI-scans including a safety margin of 0.5 to 1 cm. Chemotherapy was applied concomitantly in a median dose of 50 mg/m2 per day (median of 100mg TMZ qd); in 14 patients RCHT was followed by adjuvant cycles of temozolomide. Results: Treatment could be completed in all patients without interruptions due to side effects; no severe acute or long-term toxicities were observed. One patient with recurrent GBM showed tumor progression during therapy and treatment was stopped at 32 Gy out of 36 Gy. Progression-free survival was 56% at 6 months after FSRT; survival after FSRT was 75% at 6 months. Median overall survival was 39 months, with 92% at 1 and 2 years. Conclusions: High-precision RT and concomitant temozolomide is safe and effective when performed as re-irradiation in recurrent glioma. The data demonstrate that re-challenge with temozolomide justifies further evaluation.

No significant financial relationships to disclose.
Efficacy of different regimens of adjuvant radiochemotherapy for glioblastoma
Authors: Scheda A. , Finjap K. , Lohr F. , Tuettenberg J. , Brockmann M. , Wenz F. , Wenz F.
Published: March 2020

12531

Background: Purpose/Objective(s): We retrospectively analyzed the impact of different temozolomide (TEM) regimens in a group of patients treated for glioblastoma compared to patients only receiving postoperative radiotherapy. Methods: Between 01/2000 and 12/2003, 75 consecutive patients underwent radiotherapy. 52 patients received exclusively radiotherapy, 17 patients radio-chemotherapy with low-dose TEM (20 mg/m2) given in 2 daily single doses in combination with an inhibition of cyclooxygenase-2, 6 patients radio-chemotherapy with high-dose TEM (50mg/m2) followed by adjuvant TEM (150–200mg/m2) for 5 days during each 28-day cycle up to 6 cycles. Patients were monitored with MRI every 8 weeks. Aggressive treatment for recurrent disease consisted of re-operation, re-irradiation (fractionated stereotactic radiotherapy 12 x 3 Gy) and/or chemotherapy. Results: The groups treated with high-dose TEM and low dose TEM showed the longest overall survival (OS) (median OS 21 months and 17 months, respectively). Median OS of 9 months for the radiation alone group was condiserably shorter. The same positive trend on prolonged OS was confirmed when either only patients submitted to maximally radical resection or for patients with KPS>70 were considered. No statistically significant difference was observed in terms of progression free survival (PFS). Conclusions: Patients treated with adjuvant TEM either inside or outside study protocols had survival times similar to other reports or randomized studies. The absence of influence of TEM on PFS could either depend on the unavoidable drawbacks and bias of retrospective investigations or on the definition of relapse used. Aggressive and early treatment for recurrent disease results in median survival times approaching 2 years.

No significant financial relationships to disclose.
Second surgical intervention and continuous adjuvant therapy with temozolomide improved survival time in patients with GBM
Authors: Urs Sebastian H.
Published: March 2020

12536

Background: GBM is among the most debilitating malignant disease. A combination of surgery followed by concurrent radiochemotherapy (RCT) followed by adjuvant TMZ improves overall survival (OS) & progression-free survival (PFS). This retrospective exploratory analysis evaluated the effect of different TMZ treatment regimens & repeated surgical interventions on clinical outcome in patients with GBM. Methods: 28 pts with WHO Grade IV GBM diagnosed between 1998–2005 (age: 27–68 years) underwent maximum resection feasible, followed by RT (40–80Gy). 18 pts received standart adjuvant TMZ 150–200 mg/m2 /d, d1–5/ 28d (TMZ-S) after initial surgery. 10 patients received no further treatment, until relapse. Results: 2/28 pts have not yet relapsed and continue to receive adjuvant TMZ-S (>40 cycles, PFS 5.2 + yrs & >73 cycles; PFS 7.5+ yrs). In the 26 relapsed pts, PFS was 13.1 ± 13.0 mos (n=16, range: 2 - 48 ) in pts receiving TMZ-S compared to 9.5 ± 11.7 mos (n=10; range: 0.5 - 41) in pts with no adjuvant TMZ. At relapse, 12 had a second surgery with additional TMZ-S or TMZ 75 mg/m2/d, d1–14/21days (TMZ-LD) . 14 pts did not have a second surgery and were further treated with either TMZ-S or TMZ-LD. OS was 30.6 ± 13.7 mos in pts who received adjuvant TMZ-S followed by a change to TMZ-LD at relapse (n=5) compared to 18.3 ± 20.0 mos in pts who continued TMZ-S after relapse (n=6). Overall, the longest OS was observed in pts who received adjuvant TMZ-S with a second surgery followed by TMZ-LD at relapse (n= 2: PFS 57 & 59 mo). The shortest OS was observed in pts who had neither adjuvant TMZ-S nor additional surgery (n=5; 3–15 mos). A single outlier in this group was a pt with an OS of 58 mos. Conclusion: Best outcome in our pts with relapsed GBM was observed in those who received initial resection/RT followed by adjuvant TMZ-S with subsequent re-resection and TMZ- LD at relapse. Pts unable to undergo re-resection appeared to still benefit from a change to TMZ-LD at relapse.

No significant financial relationships to disclose.
Open-label study to assess effect of omeprazole (O) on pharmacokinetics of bortezomib (B) in subjects with advanced solid tumors, NHL, or multiple myeloma
Authors: Quinn D. I. , Nemunaitis J. , Fuloria J. , Britten C. D. , Gabrail N. Y. , Yee L. , Acharya M. , Chan K. C. , Bishop P. , Dudov A. P.
Published: March 2020

13000

Background: Omeprazole (O), an over-the-counter proton pump inhibitor, is also a potent inhibitor of cytochrome P450 (CYP) 2C19, an enzyme responsible for the metabolism of many drugs including bortezomib (B; VELCADE®). This study sought to evaluate potential drug interactions between omeprazole and bortezomib. Methods: Between January 2005 and August 2006, 18 men and 9 women were randomized to receive B 1.3 mg/m2 iv alone on Days 1, 4, 8, and 11 of a 21-day cycle or B + O 40 mg (2 x 20 mg capsules) on the mornings of Days 6–10 and the evening of Day 8 in Cycle 1, crossing over to receive the other treatment in Cycle 2. Baseline plasma samples were collected before B administration on Day 1 Cycle 1 and Day 8. Results: 17 patients completed both cycles and were evaluable for pharmacokinetics (PK) analysis. The PK of bortezomib with and without omeprazole overlapped and the peak concentrations and time to reach peak concentrations were similar (Table). As observed in other studies of B, there was a high degree of inter-subject variability (B alone, %CV = 64.7; B + O %CV = 60.3); however, differences in mean exposure values between treatments were within the degree of inter- subject variation. There was no increase in adverse events related to bortezomib as a result of treatment with O. In both groups over 95% of patients had over 80% 20S proteasome inhibition. No meaningful relationships were apparent among CYP gene polymorphisms (2C19, 2D6, 3A4, 3A5) and PK endpoints (AUC8 and Cmax) or pharmacodynamic (PD) endpoints (AUE72 and Emax) in either group or both groups combined. Conclusion: Addition of O to B did not alter PK, PD or safety parameters. Clinically significant drug interaction is unlikely when B is co-administered with O or other CYP2C19 inhibitors.

[Table: see text]

No significant financial relationships to disclose.
Phase I trial of fenretinide (4-HPR) intravenous emulsion for hematologic malignancies
Authors: Mohrbacher A. , Gutierrez M. , Murgo A. J. , Kummar S. , Reynolds C. P. , Maurer B. J. , Groshen S. , Vergara L. , Yang A. S.
Published: March 2020

13007

Background: 4-HPR is a retinoid cytotoxic for cancer cell lines. In clinical trials, oral capsule 4-HPR had limited bioavailability and activity. An intravenous intralipid emulsion formulation of 4-HPR (ILE 4-HPR) was developed to increase bioavailability. The objectives of this phase I trial were to determine a maximally tolerated dose (MTD) of ILE 4-HPR, and to assess toxicities, pharmacokinetics (PK), and preliminary response data. Methods: We used an accelerated titration Simon design 2 dose escalation schema with 100% increase in ILE 4-HPR per dose level tested until moderate toxicity was observed in 2 patients or DLT in one. Ten dose levels were planned with a starting dose of 80 mg/m2/day (continuous i.v. x 5 days q 3 weekly), increasing until Dose level 10 at 1,810 mg/m2. A De-escalation to 1,240 mg/m2/day Dose level 9 was added when DLT was observed in 2 patients at 1,810 mg/m2 dose level 10. Results: To date, 11 patients have been enrolled. At dose level 10 (1,810 mg/m2/day), 2 pts experienced a DLT of grade IV hypertriglyceridemia with grade 2 pancreatitis. A de-escalation to dose level 9 (1,280 mg/m2/day) has enrolled 4 pts, 1 had grade IV hypertriglyceridemia; enrollment is ongoing. We observed a transient response in a patient with NHL at 320 mg/m2 and a continued partial response in one patient with NHL on dose level 10 (1,810 mg/m2). PK showed a linear relationship of dose to plasma level, with steady-state levels of 54 μM (1,280 mg/m2)and 62 μM (1,810 mg/m2). Conclusions: ILE 4-HPR was given via continuous infusion to a dose of 1,810 mg/m2/day x 5 days. 1 patient with NHL had a transient partial response and a second patient with chemotherapy-refractory NHL had a partial response sustained on treatment for > 6 months. The DLT of hypertriglyceridemia is likely related to the intralipids delivered. Enrollment continues at a dose of 1,280 mg/m2/day. ILE 4- HPR can be safely administered and obtained plasma levels 6 to 7 times higher than previously obtained by oral capsule 4-HPR, with clinical activity in hematologic malignancies.

No significant financial relationships to disclose.
Pharmacokinetic study of a combination chemo-endocrine treatment of paclitaxel and toremifene
Authors: Saeki T. , Okita A. , Aogi K. , Kakishita T. , Okita R. , Taira N. , Takashima S. , Fujita K. , Nishikawa K.
Published: March 2020

13017

Background: The mechanism of paclitaxel (PXL) resistance has been investigated. P-glycoprotein (P-gp) on cell membrane could be an important target for improving efficacy of PXL. Toremifene (TOR) may moderate P-gp-related drug resistance in vitro. To determine safety and efficacy of PXL and TOR, we conducted a pharmacokinetic study for a combination chemo-endocrine treatment of PXL plus TOR for metastatic breast cancer. Methods: Patients with metastatic breast cancer, who were previously treated with a standard chemotherapy without PXL, were eligible. Patients received PXL 80 mg/m2(i.v.) weekly on days 1, 8, and 15 in a cycle. Concurrently, toremifene 120mg/body (p.o.) was given dairy from day 1–28 in a cycle. For pharmacokinetic study, single agent of PXL was initially administrated on day 1, 8, and 15. From day 18, TOR 120mg/body was given dairy. On day 22, PXL administration in second cycle was skipped. On day 32, blood samples were collected from the patients received PXL 80 mg/m2 + TOR 120 mg/day/body. Samples were analyzed by HPLC (Unisil Q 5CN). Response was evaluated by WHO criteria and adverse events were evaluated by NCI•CTC Ver.2. Results: Nineteen patients were enrolled. Out of 19, 15 patients had measurable disease, and 1 partial response, 8 stable disease, and 6 progressive disease were observed. The addition of TOR caused in no specific adverse events more than grade 3 and toxic profile in combination was similar that in PXL monotherapy. Pharmacokinetic profile of PXL was similar with/without TOR. In addition, Cmax of TOR was 1.85±0.71 mg/mL. Tmax was 2.9±1.8 hr were observed. AUC0–8 of TOR was not affected in the presence of PXL. AUC0- 8 of TOR-1, metabolite of TOR, also demonstrated the similar pharmacokinetic profile. Pharmacokinetic parameters of PXL did not reveal intra-patient variability in previously treated metastatic breast cancer patients. Conclusions: Pharmacokinetic profile in a combination of PXL and TOR was similar that in PXL monotherapy. The addition of TOR to PXL for previously treated metastatic breast cancer patients might be safety.

No significant financial relationships to disclose.
Population pharmacokinetics of docetaxel in elderly patients
Authors: Uriens S. , Rezai K. , Girre V. , Dieras V. , Lokiec F.
Published: March 2020

13020

Background: Elderly patients (>70 years) may present different pharmacokinetic profile for many drugs , mainly because of altered elimination due to renal function or metabolic decreases. Methods: Docetaxel, 50 to 85 mg/m2, median 70 mg/m2, was infused during 1 hr to 44 patients, aged 70 to 83 years, median 76.5 years. Three blood samples per patient were obtained according to a limited sampling strategy (Baille et al. Clin Cancer Res 1997, vol. 3, 1535–38). Covariates of interest were carefully recorded, age, body weight, body surface area, gender, serum creatinine, orosomucoid, serum albumin. These data were then analysed using NONMEM V to a) obtain individual Bayesian estimates of docetaxel clearance, b) re-analyse the data in order to estimate population parameters for this elderly population, c) show possible covariate effects on the pharmacokinetic parameters. Results: Median docetaxel CL from Bayesian estimation was 29.1 (2.5–97.5% quantiles 12–49) L/h. When the population was re-analysed per se, docetaxel CL was 29.2 (2.5–97.5% quantiles 17–35) L/h. The inter- subject variability for CL was 25% (precision 32%).. No covariate effect was observed on CL. Conclusions: Docetaxel clearance in elderly patients is slightly decreased, 29 L/h versus 36.8 L/h (reported in 547 patients, mean age 56 years, 5–95% quantiles 39–71 years). The inter-subject-variability of CL in elderly patients was decreased to 25% versus 47.5% in the 547 patients population. A pharmacokinetic- pharmacodynamic modelling of neutrophil counts versus time will be performed in these elderly patients in order to point a possible different sensitivity of this population to the myelosuppressive effects of docetaxel.

No significant financial relationships to disclose.
Immunological and clinical effects of a multiple peptide vaccine and low-dose cyclophosphamide in prostate carcinoma patients
Authors: Marrari A. , Iero M. , Squarcina P. , Villa S. , Salvioni R. , Parmiani G. , Valdagni R. , Rivoltini L.
Published: March 2020

13502

Background: Despite effective therapeutic strategies for the treatment of prostate cancer (PC), patients still recur and progress in a significant percentage. Here we describe the preliminary clinical and immunological data of a peptide-based strategy of vaccination in biochemical relapsed PC patients. Methods: We planned to enroll 30 HLA-A*0201 patients with biochemical failure after surgery, radiation or androgen deprivation therapy (ADT), according to the ASTRO criteria. On entering the study, patients discontinue ADT. No selections were made based on PSA levels at diagnosis, Gleason pattern score or other pathological features. Vaccination includes three peptides derived from proteins highly expressed in PC, PSMA (PSMA-P14–12 and PSMA-P2711–719) and Survivin (SVV96- 104/97M). Peptides, emulsified in Montanide ISA 51, are administered subcutaneously (8 injections) at two-weeks intervals. Vaccine is preceded by systemic administration of low dose cyclophosphamide (300 mg/m2/four weeks), aimed at selectively down- modulating regulatory T cells (Treg). Immunological monitoring includes evaluation of peptide and tumor-specific CD8+T cells in peripheral blood (IFN?-Elispot and HLA/multimer staining) and analysis of the frequency and suppressive activity of CD4+CD25+Foxp3+Treg. Results: So far, ten patients have been enrolled. Treatment is well tolerated, with mild cutaneous toxicity due to Montanide injection. A significant increase in the frequency of antigen-specific CD8+ T cells was observed in 8/10 patients. Treg, only marginally expanded in these patients, do not seem to decrease by cyclophosphamide treatment, although studies on the potential modulation of their suppressive activity are in progress. After a follow-up of 6–12 months, PSA stabilization was observed in 7 patients, 2 of which entered the trial after maximal androgen blockade discontinuation. Interestingly, PSA stabilization appears to directly correlate with the induction of antigen-specific T cell responses. Conclusions: Our vaccination strategy proved to be safe, non toxic and well tolerated. Initial monitoring data show an expansion of antigen specific T cells, with an apparent correlation between immunological and biochemical responses.

No significant financial relationships to disclose.