bluuebunny/crossref_metadata_2025 huggingface dataset:
HER2-negative metastatic breast cancer patients receiving first-line docetaxel: Survival data and prognostic factors
Authors: Deblock M. , Esterni B. , Tarpin C. , Charaffe-Jauffret E. , Extra J. M. , Viens P. , Goncalves A.
Published: March 2020

1105

Background: Modern management of metastatic breast cancer (MBC) patients (pts) is currently based on molecular stratification according to HER2 status and first-line taxanes. We sought to examine outcome data and prognostic factors in a prospectively characterized cohort of HER2 negative MBC pts receiving first-line docetaxel in a routine setting. Methods: Medical records from 162 HER2-, MBC pts treated at the Institut Paoli-Calmettes with first-line docetaxel-based regimen between 1997 and 2005 were reviewed. These patients had been treated with docetaxel single-agent or in combination according to standard institutional protocols. Univariate and multivariate analysis according Cox regression model were employed to identify prognostic factors for progression-free survival (PFS) and overall survival (OS). Results: Pt characteristics were the following: median age (ys), 51 (24 -75); Histological type (ductal/lobular/other, %) 81/15/4; Grade (1/2/3, %); Hormonal Receptivity (HR) (yes/no, %) 83/17; Adjuvant chemotherapy (CT) (yes/no; %) 66/34; Disease-free interval (DFI) (<24 months/>24 months, %) 47/53; visceral disease (yes/no, %) 46/54; number of metastatic sites (<3/>3,%) 78/22; liver metastasis (yes/no, %) 31/67; bone metastasis (yes/no, %) 65/35. After a median follow-up of 33 months, median PFS and OS were 11.7 months (95%CI , 9.7 -14.8) and 35 months (95%CI, 28.1–52.1), respectively. By univariate analysis, HR- (p=7.9 e-06), visceral disease (p=0.015), shorter DFI (p=0.027) and previous adjuvant CT (p=0.0038) were negatively associated with PFS, while HR- (p=6.3e-07), visceral disease (p=0.0094) and shorter DFI (p=0.01) were also negatively associated to OS. 14. These parameters retained independent prognostic significance by multivariate analysis, the strongest being HR-(p=2.4e-5) for OS. HR- pts had a PFS of 6.87 months [95%CI, 4.27 - 11.0] Vs 14 months [95%CI, 11.84 - 18.5] in HR+ pts (log-rank test p= 3.16e-06). 2-year OS were 38% [95%CI, 21.9–65] and 76%[95%CI, 68.7–84.4] (p = 6.52e-08) in HR- and HR+ pts, respectively. Conclusions: In the taxane era, median OS of HER2- MBC pts is nearly 3 yrs. Triple negative pts (HER2-, HR-) are a very poor-risk group requiring innovative therapeutic strategies.

No significant financial relationships to disclose.
Phase II trial of neoadjuvant exemestane [EXE] and celecoxib [CELE] in breast cancer: Results of biomarkers
Authors: Shapiro C. L. , Povoski S. P. , Jiminez R. , Dehart J. , Ottman S. , Shiels D. R. , Xiaobia L. , Brueggemeier R.
Published: March 2020

11056

Background: Aromatase [CYP19] activity and expression is increased by prostaglandin E2, thus providing a rational for combining the COX-2 inhibitor, CELE, with an aromatase inhibitor. To evaluate the effects of these drugs on proliferation and other biomarkers, we conducted a neoadjuvant trial of EXE alone followed by the combination of EXE and CELE. The primary endpoint was the assessment of biomarkers and the secondary endpoint was toxicity. Methods: Clinical stages II/III, postmenopausal, estrogen [ER] and/or progesterone receptor [PR] positive, previously untreated, ECOG 0–1 were eligible. Excluded were inflammatory breast cancer, history of myocardial infarction, and documented allergy to aspirin, NSAIDs, or sulfonamides. After initial core biopsy pts received 8 weeks (wks) of EXE 25 mg daily. They then received a second core biopsy followed by 8 wks of EXE and CELE 400 mg twice daily. After 16 wks, pts had definitive surgery. Compliance was assessed by pill counts at study visists every 4 wks. At baseline, 8, and 16 wks, pts had tumor measurements by physical exam, mammogram, and ultrasound. A tissue microarray [TMA] was contructed and immunohistochemical [IHC] staining with commercially available antibodies for Ki-67, COX-2, HER-2, ER, and PR was performed. Two independent pathologists scored intensity and percentage of cells staining and were blinded to treatment and the timimg of specimen acquistion. Statistical analyses were performed using Wilcoxon signed-rank test Results: Twenty pts with a median age 62 (range 56–87) were enrolled. CELE was discontinued in 3 (15%) pts for grade 1 rash-1 pt; grade 1 creatinine elevation-1 pt; and grade 1 melena-1 pt. Three (15%) pts-partial response, 16 (80%)-stable disease, and 1 (5%)-progressive disease. None of the differences in biomarkers between 0 and 8 wks and 8 and 16 wks were significant. A trend toward decreasing mean Ki 67 was observed from 0 to 8 wks (20% vs 9%, p=0.19) and 8 to 16 wks (9% vs 7%, p=0.7) Conclusions: Neoadjuvant EXE followed by EXE/CELE was well tolerated with anti-tumor activity. Tumor cell proliferation decreased by about 50% during EXE, but small sample size precluded reaching statistical significance. Frozen tissue was collected and the results of CYP 19 mRNA expression will be presented.

[Table: see text]
Biweekly neoadjuvant gemcitabine, epirubicin, and nano-particle albumin bound (nab) paclitaxel (GEA) with tumor SPARC analysis correlated with pathologic responses: Results of a multicenter phase II trial
Authors: Daniel B. R. , Doss H. , Gian V. , Meluch A. A. , Murphy P. B. , Peacock N. W. , Raefsky E. , Yardley D. A. , Simons L. , Inhorn R. C.
Published: March 2020

11060

Background: The triplet combination of gemcitabine (G), anthracyclines and taxanes have demonstrated significant activity in the metastatic as well as neoadjuvant breast cancer setting with objective response rates of 90% and pathologic CRs of 20–25% with a variety of schedules. SPARC, a poor prognostic indicator, is a glycoprotein expressed in many solid tumors, including breast cancer, and is thought to mediate active tumor transport of nab paclitaxel resulting in high intratumoral concentrations. The present tumor analysis correlates SPARC expression with pathologic responses to neoadjuvant GEA. Methods: Patients with clinical T1c-T4d and/or N0–3, M0 (T1N0M0 excluded) breast cancer, chemo naive, ECOG PS 0–2, normal LVEF, adequate organ function were treated with neoadjuvant G 2000 mg/m2, epirubicin 50 mg/m2, nab paclitaxel (A)175 mg/m2 IV q14 x 6 cycles followed by surgery. Postoperative therapy: G 2000 mg/m2 and A 220 mg/m2 q14 x 4 cycles. Neulasta 6 mg sc D2 was given with all cycles although alternative granulocyte stimulating factors was permitted. Enrollment planned for 120 pts. Results: 72 pts are enrolled, 48 patients evaluable for toxicityand pathologic responses available for 35 pts. Median age: 48 years (29–73), ECOG PS 0 - 45 pts (96%), 1 - 3 (6%), median tumor size 4.5 cm, 79% ductal, 4% lobular, 13% inflammatory. 54% ER-/PR-, 81% HER2 negative. 21 (60%) were triple negative, basal subtype. Heme toxicity was minimal: G3/4 neutropenia: 4 (8%) pts, thrombocytopenia: 3 (6%) pts. There were no episodes of febrile neutropenia. Nonheme toxicity significant for G3/4 arthraglias: 5 (10%) pts & fatigue in 3 (6%) pts. 3 pts hospitalized (infection, PE, abd pain). 1 pt developed PD during neoadjuvant therapy; 5 pts did not complete post op chemo (pt compliance: 2, PD: 2, MD discretion: 1). pCR was noted in both breast and LNs in 7 pts (20%) and pPR in 26 (74%). Conclusions: Neoadjuvant dose dense GEA is feasible and extremely well tolerated. Significant activity with a pCR of 20% is evident with the basal subtype of breast cancer. SPARC tumor analysis correlations with observed pathologic responses will be presented and updated with the continuing accrual to this trial.

No significant financial relationships to disclose.
Ductal carcinoma in situ (DCIS) breast specimens need to be embedded completely in order to determine the correct extent of the disease
Authors: Bendrat K. , Georgiev G. , Corterier H. , Friedrichs K. , Lindner C. , Niendorf A.
Published: March 2020

11061

Background: The processing of breast specimens suspicious of ductal carcinoma in situ (DCIS) is hampered by the fact that DCIS is not regularily visible at the gross level. There is no general consensus as how to process those breast specimens. Suggestions lead from examination of the entire tissue sample with a special focus on the resection margins to algorithms such as cutting only those paraffin blocks containing calcifications. Methods: In order to identify the influence of the diagnostic method on the measured extent of a DCIS lesion we compared two approaches. One was based on the examination of a single section and the other on examination of the entire specimen, i.e. cutting multiple 0.5 cm slices to be analyzed as max. 52 x 76 mm whole mount sections. 187 consecutive breast specimens from 186 patients (median patient age 60 years, range 31 to 87 years) from three gynecological institutions between Jan 2004 and Nov 2006 were searched for DCIS. We compared the largest tumor diameter from a single section of a specimen (‘apparent diameter‘, AD) with a ‘reconstructed diameter‘ RD calculated on the basis of the number of 0.5 cm slices taken from a sample and the number of slices containing the DCIS lesion. Results: Complete histological examination of these 187 cases (90 high and 97 low grade DCIS lesions) revealed a statistically significant difference (p=7.5E-9) between the apparent diameter AD (mean 22.4 mm, range 2 to 80 mm) and the reconstructed diameter RD (mean 31.6 mm, range 6 to 76 mm). In 138 cases (73.8%) the true extent of the disease would have been underestimated (RD > AD) if the diagnosis had been based only on a single exemplary section, the mean difference RD-AD being 14.8 mm (range 1–50 mm). In addition, we found 40 invasive cancers (multifocal inside the DCIS lesion, unifocal inside the DCIS and unifocal outside the DCIS). Conclusions: We conclude that the complete examination of a breast specimen helps to determine the true extent of DCIS and additionally helps to identify cases that turn out to be already invasive. Both findings may have important impact on the patients’ further treatment and outcome.

No significant financial relationships to disclose.
Concurrent chemoradiotherapy (CRT) following neoadjuvant chemotherapy (NACT) in locally advanced breast cancer (LABC)
Authors: Alvarado-Miranda A. , Morales-Barrera R. , Arrieta O. , Zinser-Sierra J. , Gamboa-Vignole A. , Maafs-Molina E. , Ramirez-Ugalde T. , Lara-Medina F.
Published: March 2020

11063

Background: Despite broad advances in the treatment of LABC, 30 to 40% of patients responding to NACT develop locoregional relapse. We performed a retrospective analysis of the experience obtained so far in patients with LABC who were treated with CRT after NACT in terms of pathologic complete response (pCR), relapse-free survival (RFS) and overall survival (OS) at our institution. Methods: One hundred and twelve patients with LABC (Stage IIB-IIIB) were treated between January 2000 and December 2003 with NACT with 5FU 500mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500mg/m2 (FAC) or doxorubicin 50 mg/m2 and cyclophosphamide 500mg/m2 (AC) administered i.v. in four 21-day cycles. CRT with 60 Gy whole-breast irradiation and concurrent weekly mitomycin 5mg, 5FU 500mg and dexamethasone 16 mg or cisplatin 30 mg, gemcitabine 100 mg and dexamethasone 16 mg. Subsequently they underwent surgery and 6 to 8 weeks later received 2 additional courses of FAC, AC or paclitaxel 90mg weekly for 12 weeks and in estrogen receptor (ER) positive patients hormone therapy. Results: Median tumor size 5 cm; stages IIB, IIIA and IIIB were 21.4%, 42.9% and 35.7% respectively. pCR was 42% (CI 95% 33.2 - 50.5) in breast and 29.5% (CI 95% 21.4 - 37.5) in breast and axillary lymph nodes. Multivariate analysis showed the main determinant of pCR was negative ER (P 0.016). Median RFS has not been reached. The 5 year RFS is 76.9% (CI 95% 68.2 - 84.7). No relationship between pCR and RFS was found. Multivariate analysis showed the main determinant of RFS was the clinical stage (p=0.03). Only one patient had local recurrence. The 5 year OS is 84.2% (CI 95% 75 - 93.2). Toxicity during CRT: grade 1–2 neutropenia 32.2%, grade 1–2 anemia 5.2%, grade 3 radioepithelitis 22.4% Conclusions: This modality has good locoregional control for locally advanced breast cancer with an acceptable toxicity profile. Futher investigation of concurrent chemoradiotherapy should be explored in LABC.

No significant financial relationships to disclose.
The role of MRI in therapy management in triple-negative (TN) breast cancer
Authors: Lex B. , Russu V. , Popovich M. , Gilster T. , Pfaffenberger K. , Volkholz H. , Tulusan A.
Published: March 2020

11079

Background: Triple-negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) is a high-risk breast cancer that lacks the benefit of specific therapy which targets these proteins. TN is associated with decreased survival. Data for defining the optimal systemic therapy in patients with TN are still missing. Reported clinical and pathological response rates in TN due to different chemotherapy schedules are rare and data are inconsistent. Our study group showed that MRI is an effective method to monitor the tumour-response in PST (Russu V et al. Proc Am Soc Clin Oncol 2004, abstract 9704). The aim of this study was to clarify the accuracy of MRI in monitoring the tumor-response to PST in TN. Methods: 43 female patients (range of age: 29a-67a) with TN (cT2 â€“ cT4) were examined with dynamic contrast enhanced MRI after PST. 34 patients were examined with MRI before and after PST. 12 patients were treated with sequential anthracyclin and taxan based chemotherapy and 31 with only anthracyclin based chemotherapy. 22 patients were premenopausal. 34 patients had ductal-invasive carcinomas, 9 lobular-invasive The measure of tumour-response to PST was graded in partial response (PR: > 50% of tumour reduction mm2), no change (NC: < 50%) and complete response (CR: no evidence of residual tumour-cells). Results: Comparing tumour-size measured by MRI before and after PST 22 patients had PR and 7 CR. NC had 5. The histological tumour-size after PST strongly correlated with the size measured by MRI r = 0,931(pâ€ 0,001). Conclusions: MRI seems to be a useful method in monitoring the tumour-response to PST in TN. Further studies could find out if MRI is a suitable tool to detect chemotherapy-resistance very early in TN.

No significant financial relationships to disclose.
Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 for improved management in node-negative (N0) breast cancer: Experiences from the ongoing multicenter trial NNBC 3-Europe
Authors: Persing M. M. , Paepke D. , Schmidt M. , Veyret C. , Augustin D. , Guerts A. , Martin P. M. , von Minckwitz G. , Thomssen C. , Harbeck N.
Published: March 2020

11081

Risk-assessment in N0 breast cancer is still controversial. In line with St. Gallen, only few patients (pts) are considered at such low risk of relapse, that adjuvant chemotherapy could be avoided. Various groups have started clinical trials aimed at improved risk-assessment by gene or protein analysis of the primary tumor. We launched the NNBC 3-Europe trial asking the following questions: Is the identification of low- risk pts by the invasion markers uPA and PAI-1 more effective than by St. Gallen criteria? Is adjuvant chemotherapy using an anthracycline- taxane sequence superior to standard FEC in N0 high-risk pts? The centres of the NNBC 3 trial had to choose their mode of risk- assessment (either St. Gallen criteria or uPA/PAI-1) prior to recruitment. High-risk pts receive chemotherapy randomly assigned to FEC-100*3 followed by Docetaxel-100*3 (FEC-Doc), or FEC-100*6. No adjuvant chemotherapy is given to low-risk pts. Pts with hormone receptor positive tumors receive standard endocrine therapy. To date, 1206 pts in 57 centres have been registered. Using fresh frozen tumor tissue, uPA and PAI-1 are tested in nine laboratories; inter-laboratory quality assurance is performed. In 141 of 1188 evaluable pts, St Gallen criteria were used. In the biological risk-assessment group, 150 of 1047 tumors (14.3%) were well differentiated, thus regarded as low-risk. Using both, tumor grade and uPA/PAI-1, 35.3% of the pts were considered low-risk, whereas the remaining 64.7% high-risk pts received adjuvant chemotherapy (FEC-Doc, n=334, or FEC, n=343). Multicenter prospective risk assessment based on testing of fresh frozen (or paraffin- embedded) tumor tissue is sophisticated. All trials with similar approach (MINDACT, TAILORx) had a long preparation phase including thorough assay validation. The ongoing NNBC-3 trial demonstrates that inclusion of pts based on testing of fresh frozen material is feasible in a routine setting. Risk-group distribution is as expected. The study is planned to recruit 5,700 pts and it is performed in cooperation with the EORTC Patho-Biology Group, the German AGO Breast Group, and the German Breast Group (GBG). Unrestricted grants by Sanofi-Aventis and Pfizer.

[Table: see text]
Evaluation of clinicopathological features from core needle biopsy and CT imaging as predictors of response to primary systemic therapy for operable breast cancer
Authors: Shien T. , Akashi-Tanaka S. , Shimizu C. , Hojo T. , Seki K. , Kohno T. , Ando M. , Katsumata N. , Fujiwara Y. , Kinoshita T.
Published: March 2020

11086

Background: Primary systemic therapy (PST) is standard therapy for patients with locally advanced breast cancer and increasingly used for early-stage operable disease. Clinical and pathologic responses are important prognostic parameters and clinicopathological markers to predict response to PST are needed to individualize treatment. Methods: From 1998 to 2005, 403 primary breast cancer patients were underwent curative surgical treatment after PST (Anthlacycline and/or Taxane) at NCCH. We retrospectively evaluated the clinicopathological features (age, histological type, histological grade, ER, PgR and HER-2) and classification of tumors using CT (localized tumor type and diffused tumor type) at before PST and analyzed the correlation with clinical response and pathological complete response (pCR). The log-rank statistic was used for univariate comparisons and multivariate analysis performed using Cox hazard model. Results: Overall response and pCR rate were 87% and 18%. Breast conserving surgery was performed 37% patients. Histological grade 3 (p<0.0001), ER negative (p<0.0001), PgR negative (p<0.0001), solid-tubular type (p=0.0006), age (>50) (p=0.008) and localized tumor type (p=0.02) correlated with pCR. In multivariate analysis, Histological grade 3 (p=0.01) and localized tumor type (p=0.036) were independent predictors for pCR. ER positive, histological grade 2 or 1, invasive lobular carcinoma and diffuse tumor type associated with low chemosensitivity and low breast conserving surgery rate. Conclusions: Clinical and pathological response significantly associated with ER status and histological grade. Furthermore the classification of tumor type using CT was effective to predict of response to PST.

No significant financial relationships to disclose.
Phase II study of neoadjuvant docetaxel (T), doxorubicin (A) and capecitabine (X) in locally advanced or inflammatory breast cancer (LABC)
Authors: Perez-Manga G. , Mendez M. , Palomero M. I. , Quiben R. , Belon J.
Published: March 2020

11092

Background: Studies suggest that chemotherapy + surgery + radiotherapy gives a high survival rate in patients with LABC. Primary objective was to evaluate response rate. Secondary endpoints were time to progression and toxicity profile of neoadjuvant T, A and X in LABC. Methods: Eligibility: histologically confirmed LABC, ECOG PS =2, age =75 years, LVEF >50%, and adequate bone marrow, renal and hepatic function. Prior systemic therapy, surgery or radiotherapy for breast cancer was not allowed. Patients with invasive bilateral breast cancer were not included. Treatment: T (30 mg/m2) iv day 1, 8 and 15, A (50 mg/m2) iv day 1 and X (1500 mg/m2 o.d.) days 1–14, in a 4-week course repeated for up to 4 cycles followed by surgery. According to investigator criteria patients received a maximum of 6 cycles. Radiotherapy and hormone therapy were allowed after surgery. Expression of markers was determined by immunohistochemistry before chemotherapy. Results: 43 patients were included in this analysis, median age 48 years (25–73). ECOG PS was 0 in 37% of patients and 1 in 63%. Hormonal receptor status was ER+ 44%, PR+ 34% and C-erb2+ 59%. In total, 157 cycles (median 4, range 2–4) were given. Median relative dose intensity was 86% for T, 92% for A and 88% for X. Of 43 patients evaluable for efficacy, 13 achieved CR, 24 PR and 1 PD resulting in an ORR of 97% (CI 95%: 92–100). Surgery was performed in 40 patients: 4 (10%) achieved pathologic CR and one additional patient had non-invasive carcinoma. Grade III/IV toxicity per patient was neutropenia (74%), leukopenia (56%), febrile neutropenia (9%), mucositis (12%), diarrhea (12%), nausea/vomiting (5%), dysgeusia (2%) and asthenia (2%). Median follow-up time was 19.5 months. Conclusions: Neoadjuvant T, A and X every 28 days for 4 cycles is an active regimen in LABC with a manageable toxicity profile before surgery.

No significant financial relationships to disclose.
Phase I study of preoperative chemoradiation therapy in unresectable locally advanced breast cancer (LABC)
Authors: Conzen S. , Hahn O. , Vanderpuye V. , Fleming G. , Olopade F. , Haraf D. , Jaskowiak N. , Heimann R.
Published: March 2020

11097

Introduction: Therapy of unresectable LABC is challenging due to the need to resect local disease and prevent distant metastases. We conducted a phase I trial to determine the maximum tolerated dose of preoperative vinorelbine (VIN) combined with paclitaxel (P) and radiation (XRT). Methods: Eligible patients (pts) had unresectable LABC, ECOG performance 0–2 and adequate organ function. Prior chemotherapy and metastatic disease were permitted. All pts received weekly bolus P 80 mg/m2 and concurrent XRT at 2.0 Gy daily for 5 days in a week-on/week-off (WO/WO) schedule for 12 weeks. A planned 59 -70 Gy were delivered to the breast, chest wall and supraclavicular regions. In dose level 2, VIN 15 mg/m2 /week was added. Results: Twenty-six pts were enrolled from July 1999-July 2005 with a median age of 51 years (range 24–69); 9 pts had stage IV disease, 17 pts had stage IIIB disease, and 13 pts had received prior chemotherapy. VIN was not tolerated due to grade (G) 4 neutropenia despite GCSF; however single-agent P and concurrent XRT was well-tolerated. Thus, 7 pts in the final cohort received P/XRT without GCSF. This regimen was well-tolerated; toxicities seen included: G3 in-field skin desquamation 4/7; G4 lymphopenia 7/7, G3 infection 1/7; G3 wound dehiscence 1/7. After therapy, 20/26 pts underwent mastectomy: 6 pts had a pathologic complete response (no invasive disease), 12 had a pathologic partial response (scattered microscopic disease), and 2 pts had no response. Overall pathologic response rate was 90% for pts undergoing mastectomy; only 3 of the 20 resectable pts are alive without relapse a mean of 19.5 months after mastectomy. Conclusions: Neoadjuvant P 80 mg/m2 with full dose XRT in a WO/WO schedule is tolerable and effective allowing 20/26 unresectable pts to undergo successful mastectomy. Pts do not require routine GCSF support. Although most pts eventually relapse distantly, this regimen does render some pts not responding to initial doxorubicin-based therapy resectable.

[Table: see text]

No significant financial relationships to disclose.
Concomitant chemoradiotherapy in adjuvant treatment of breast cancer: A retrospective study of 296 cases
Authors: Errihani H.
Published: March 2020

11099

Background: Concomitant chemo-radio-therapy in adjuvant treatment of breast cancer is an attractive method which is under ongoing research program. We are trying by this retrospective study to document and support the feasibility of concomitant methods at the Oncology Institute in Rabat. Methods: Two hundred ninety six patients having breast cancer were investigated in a retrospective study. All patients were either treated by radical chirurgy (86.5%) or conservative treatment (13.5%). The study compares two adjuvant treatments associating concomitant chemotherapy and radiotherapy. In the first treatment (first brace) the patients were treated by chemotherapy and radiotherapy in concomitant way using anthracycline [(doxorubicine 60mg and cyclophosphamide 600mg/m2 (AC60), 5-fluorouracile 500mg/m2, doxorubicine 50mg/m2, and cyclophosphamide 500mg/m2 (FAC50), 5- fluorouracile 500mg/m2, epirubicine 75mg/m2, and cyclophosphamide 500mg/m2 FEC75)] (N=123). In the second treatment (second brace) the chemotherapy was CMF type (cyclophosphamide 500mg/m2, methotrexate 60mg/m2 and 5-fluorouracil 500mg/m2) (N=173). Chemotherapy was administered in six cycles, one each 3 weeks. Radiotherapy delivered a radiation dose of 50 Gy on the breast (or on the external layer) Results: With an average time of 37 months after the end of the treatment, only one patient was recidivist of the breast cancer disease as a loco regional breast cancer when the treatment was based on anthracycline. So in 3 years the rate of recidivism of the disease was 0.6%. All the other recidivists were metastasic. The survival rate without disease, after 3 years, in the anthracycline brace was 87% compared to 86.5% in the CMF brace (p> 0,5). The global survival probability after 3 years was 93% in the anthracycline brace and was 90.84% in the CMF treatment. Conclusions: From the three year retrospective investigation we showed a similarity of the two cancer treatment results with higher haematological toxicity in the concomitant treatment based on anthracycline. Waiting for the results of ongoing research we recommend the use of adjuvant treatments in sequential mode by using the chemotherapy prior to radiotherapy.

No significant financial relationships to disclose.
Randomized controlled comparative clinical pharmacokinetic study of nab-paclitaxel and solvent-based paclitaxel in Chinese patients (pts) with metastatic breast cancer (MBC)
Authors: Li S. , Guan Z. , Yao Z. , Teng X. , Liao H. , Deng L. , Pan Y. , Yao Q. X. , Hawkins M. J.
Published: March 2020

11505

Background: nab-paclitaxel is a novel solvent-free, 130-nM albumin-bound (nab™) formulation of paclitaxel. In previous studies, nab-paclitaxel demonstrated higher volume of distribution and clearance than that of paclitaxel formulated with Cremophor (Cr-PAC) in Caucasian patients (Sparreboom, Clin Cancer Res 2005;11:4136) and had greater response rate and favorable safety profile in pts with MBC (Gradishar et al., JCO, 2005;23:7794) . The aim of this study was to evaluate nab-paclitaxel blood pharmacokinetics (PK) and compare it with that of Cr-PAC in Chinese MBC patients.Methods: In this randomized controlled, open-label study, patients were assigned to either nab-paclitaxel 260 mg/m2 intravenously (iv) over 30 minutes q3w or Cr-PAC 175 mg/m2 iv over 3 hours q3w. At cycle 1, 12 patients in each treatment group participated in the PK study and then continued treatment until PD or unacceptable toxicity. Plasma samples from pts were analyzed for PK parameters. The primary clinical endpoints were ORR and toxicity (Guan et al; submitted, ASCO, 2007). Results: 24 female pts (median age 44.5 years) participated. No statistically significant between group differences were noted in age, height, weight, or baseline liver function. Paclitaxel blood PK parameters in 2 treatment groups are summarized in the Table. ORR: nab-paclitaxel, 75%; Cr-PAC, 25% (P = 0.018). The maximum grade (G) of neutropenia and neuropathy in the nab-paclitaxel and Cr-PAC groups were G3 and G2, respectively, with no significant between-group difference. Conclusion: nab-Paclitaxel had a greater distribution volume, clearance, and smaller dose adjusted AUC0-inf compared with that of Cr-PAC. There was no significant difference in T1/2 in the 2 groups. PK results in Chinese pts are identical to data reported in Caucasian pts. The lower CL and Vz for Cr-PAC are probably related to sequestration of paclitaxel in the blood by Cremophor. * dose adjusted AUC0-inf

[Table: see text]

[Table: see text]
Trastuzumab and paclitaxel or vinorelbine for HER2+ metastatic breast cancer: A retrospective study and analysis of economic cost
Authors: Scola A. , Koussis H. , Jirillo A. , Ghiotto C. , Lonardi S. , Bortolami A. , Monfardini S.
Published: March 2020

11517

Background: We analyses a mono institutional series of patients treated with metastatic breast cancer (MBC). Methods: From 2000 to 2006 forty consecutive patients affected by MBC were evaluated. The average age was 50 years (range: 30–79). All patients had HER2+ tumors (IHC 3+ or FISH+) and LVEF > 50%. Metastatic sites were: liver 18, lymph nodes 10, bone 9, skin 7, lung 5 pts. In 11 cases the sites of metastases were multiple (1–3). All patients were treated with Trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly thereafter with weekly Paclitaxel 80 mg/m2 or weekly Vinorelbine 25 mg/m2; specifically, Paclitaxel was used in 26 patients and Vinorelbine in 14 patients. The endpoints were time to progression (TTP), duration of response, toxicity (including cardiologic) and overall survival. Results: A total of 1271 courses of weekly Trastuzumab were administered (average 28 courses per patient: range 8–72). There were 22 complete and partial responses (CR+PR=55%). In the association of Trastuzumab and Paclitaxel were seen :11 CR, 6 PR, 3 SD and 6 PD, (RR 65.3%). In the combination of Trastuzumab and Vinorelbine: 2 CR, 3 PR, 4 SD and 5 PD (RR 35.7%) . The most responsive sites were: liver 15 CR+PR (37.5%), lung 11 CR+PR (27.5%), lymph nodes 8 CR+PR (20%), and skin 6 CR+PR (15%). TTP was 7 months (2–27 months) and response duration 6.7 months (2–26 months). Overall survival at 5 years was estimated at 26.4 months. Toxicity rates were: hematological grade 4 in 2 pts, grade 3 in 3 pts, neurological grade 3 in 19 pts. No important cardiologic toxicity was observed: LVEF was reduced to 40% in 4 pts. Seven patients developed brain metastasis during therapy. The patients in PD continued Trastuzumab with other chemotherapy, no responses were observed. The median cost of treatment with Trastuzumab for patient was 16.147 € (range 3.987–39.959 €. Conclusions: Treatment with Trastuzumab plus chemotherapy has been shown to be effective and well-tolerated providing a good quality of life. The economic impact is important and is to define. The cost/benefit in this cohort of the patients is ongoing.

No significant financial relationships to disclose.
Radiographic evaluation of recurrent glioblastoma multiforme (GBM) in patients treated with bevacizumab and irinotecan
Authors: Andre J. , Spearman K. , Lu S. , Hwang S. , Dorsett L. , Raval S.
Published: March 2020

12512

Background: Recurrent GBM carries a poor prognosis after first-line therapies have been exhausted, even in the setting of gross total resection. Bevacizumab and Irinotecan have shown promising results in patients with recurrent GBM (Stark-Vance, et al. Neuro- Oncol, 2005). We sought to retrospectively document the short-term effects of this chemotherapeutic regimen on recurrent GBM, as evidenced by comparative MRI brain scans obtained prior to, and one-month following initiation of treatment. Methods: We collected brain MRI data from August 2005 to December 2006, in which post-contrast spin-echo T1-weighted images demonstrated measurable enhancement and/or GBM tumor mass. Having failed temozolomide and radiation therapy, 14 consecutive patients’ MRI scans were available for review at this institution by a neuro-radiologist, in which both pre- and post-treatment hard and/or soft copy MR images were available for direct measurement. Each was treated with Bevacizumab 5 mg/kg IV and Irinotecan 125 mg/m2 IV infusion every 2 weeks until disease progression, or development of unacceptable toxicity. We measured pre- and post-treatment recurrent GBM bulk tumor in anteroposterior, transverse, and cranio-caudad dimensions, and calculated volumetric data, assuming an ellipsoid tumor configuration. Results: Pre-treatment MRI scans were performed 2 weeks prior to initiation of therapy (Mean: 13 days; Median: 10 days). Post-treatment scans were performed at approximately one month following initial treatment (Mean: 30 days; Median: 28 days). All patients witnessed significant decrease in tumor bulk volume ranging from 15.3 to 89.8%, having received an average of two cycles of chemotherapy. We observed a mean decrease in tumor volume of 46.6% (SD = 22.6%; SEM = 6.0%; 95% CI = 33.6 - 60.0 % decrease). Conclusions: We report 46.6% mean reduction in recurrent GBM tumor bulk at an average of 1-month post-treatment in patients treated with an average of two cycles of Bevacizumab and Irinotecan therapy. These promising initial results necessitate further long-term prospective evaluation of this chemotherapy.

No significant financial relationships to disclose.
Low protracted dose of temozolomide (TMZ) and concurrent radiotherapy for brain metastasis of solid tumors
Authors: Addeo R. , Faiola V. , Cennamo G. , Guarrasi R. , Montella L. , Del prete S.
Published: March 2020

12525

Background. Whole brain radiotherapy (WBRT) remains the mainstay of therapy for brain metastasis of solid tumours not amenable to surgical resection. Chemotherapy with temozolomide (TMZ) has emerged as an alterative approach for recurrent brain metastases. It has been already used alone or in combination with radiotherapy in the treatment of primary brain tumours. Protracted administration of TMZ, even at relatively low daily doses, leads to significant and prolonged depletion of enzyme O6-alkylguaninae-DNA alkyltransferase (AGAT) activity, with may enhance the antitumor activity of the agent. Methods. Patients with histologically or cytologically confirmed breast cancer and NSCLC and inoperable brain metastasis were eligible for the study .We have treated 29 consecutive patients (16 F and 13 M, mean age: 55, range 46–76) affected by brain metastases ( 16 non-small-cell lung cancer and 13 breast cancer) with WBRT at 3 Gy/day administered over a two-week period (on wks 1–2), total dose 30 Gy, and an induction with TMZ 50 mg/m2/day during this period, following TMZ 50mg/m2 fractionated in 21 days every 28 days, for up to 12 cycles. Pts who received at least one cycle of TMZ were assessable for response. Results. Twenty-four patients were subjected to the induction therapy and 124 cycles were performed. TMZ was generally well tolerated, and the main toxicities seen were hematologic. The toxicities were generally between grade 1 or 2 in severity although two patients had grade 3 events. Two CR, in patients with breast cancer and NSCLC. Nine partial responses were recorded in 5/11 patients with breast cancer, 4/13 patients with NSCLC, while a stable disease was achieved in other 5 patients. Eight patients showed progressive BM growth during the treatment. The overall response rate was 45.5% (C.I. 38.7–56.9%), while the disease control rate was 77% (C.I. 61.7–82.4%). At the present, the overall survival at 12 months was 64%. Conclusions. We developed a new regimen based on a different strategy: the utilization of a more intensive TMZ dosing schedule that would permit the concomitant use of a second cytotoxic agent on the primary cancer. Final data analysis will be presented. The schedule was safe and well tolerated and has suggested an encouraging activity in brain metastases.

No significant financial relationships to disclose.
Salvage chemotherapy with CPT-11 for recurrent temolozomide-refractory anaplastic oligodendroglioma
Authors: Chamberlain M. C.
Published: March 2020

12526

Background: There is no standard therapy for alkylator-resistant AO and hence a need exists for new therapies. Methods: Twenty patients (10 men; 10 women) ages 27–47 (median 38), with radiographically recurrent AO were treated. All patients had previously been treated with surgery, involved-field radiotherapy, and adjuvant chemotherapy (TMZ in 14; BCNU in 6). 13 patients were treated at first recurrence with an alternative chemotherapy (TMZ in 6 all previously treated with BCNU; 5 with PCV and 1 each with carboplatin, sorafenib, or cyclophosphamide). 11 patients underwent repeat surgery. All patients were treated at either first or second recurrence with CPT-11 administered intravenously once every 3 weeks (350mg/m2 in patients on non-enzyme inducing anticonvulsants or no anticonvulsant; 600mg/m2 in patients on enzyme inducing anticonvulsants), operationally defined as a single cycle. Neurological and neuroradiographic evaluations were performed every 8–9 weeks. Results: All patients were evaluable for toxicity and response. A total of 129 cycles of CPT-11 (median 4.5 cycles; range 3–18) was administered. CPT-11 related toxicity included diarrhea (4 patients; 2 [10%] grade 3), neutropenia (3; 3 [15%] grade 3), fatigue (3; 3 [15%] grade 3), and delayed nausea/vomiting (1; 1 [5%] grade 3). 5 patients (25%) demonstrated a partial radiographic response, 7 (35%) demonstrated stable disease and 8 (40%) had progressive disease following three cycles of CPT-11. Time to tumor progression ranged from 2 - 13.5 months (median: 4.5 months). Survival ranged from 3 - 21 months (median: 6 months). 6-month and 12-month PFS were 30% and 25% respectively. Conclusions: CPT-11 demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent AO all of whom had failed prior TMZ chemotherapy.

No significant financial relationships to disclose.
Hypofractionated therapy versus conventional fractionated radiotherapy in elderly patients with glioblastoma multiforme
Authors: Elshenshawy H. , Abd El-Razek A. , Bader H.
Published: March 2020

12529

Background: To evaluate efficacy of short- course radiotherapy(RT) in elderly (>60years) patients with glioblastoma multiforme(GBM), and compare this biological similar short -course radiotherapy with a standard radiotherapy Methods: Forty-four elderly patients with GBM were randomly assigned after surgery to receive either a short-course of radiotherapy (45 Gy in 15 fractions over 3 weeks ) or standard radiotherapy (60 Gy in 30 fractions over 6weeks) to a target volume described as tumor visible on CT scan and a 2- cm margin . The primary end point was overall survival. Results: The overall response rate and median duration of response were 60%and 8.5 months in short- course RT versus 65% and 8 months in standard RT . Improvement in pretreatment performance status and increase in post- treatment corticosteroid dosage were observed in 50% and 25% in short- course RT versus 40% and 50% in standard RT (P=0.09, P=0.031) respectively. Median survival time was 5.9 months in short-course RT versus 5.6 months in standard RT . Six months, 1-year survival and progression-free survival rates were 40%, 15% and 30% ,10% in short- course RT versus 45%, 10% and 35% , 5% in standard RT , respectively. In both treatment groups, females did significantly better than males, patients with KPS 60–70 did significantly better than those with KPS 50 , patients having tumors 4–5 cm did significantly better than those with tumors 6–8 cm as well as did those with more radical surgery when compared to those with biopsy only. On multivariate analysis , only tumor size and extent of surgery were found to independently influence survival. Acute toxicity was generally assessed as mild in the two treatment groups. While RT -induced brain necrosis appeared only in one patient received short- course RT, but this patient died from tumor recurrence. Conclusions: Hypofractionated RT is feasible and safe treatment for elderly patients with GBM.

No significant financial relationships to disclose.
Intracerebral presentation of Hodgkin’s disease mimicking meningioma
Authors: Apollonsky N. , Karayalcin G.
Published: March 2020

12533

A 23-year-old woman presented with headaches, diplopia, nausea and vomiting. CT scan revealed frontal extradural mass consistent with meningioma. After excision of the mass light microscopic evaluation revealed a polymorphous variably cellular neoplasm with a background of normal small lymphocytes, eosinophils, histiocytes with large, atypical, often multinucleated cells. Immunohistochemical studies demonstrated large cell strongly positive for CD 30 and focally positive for CD 15 and negative for EMA and ALK1. The morphology, architectural features, and immunohistochemical findings were consistent with Hodgkin disease, the nodular sclerosing type. Systemic work up revealed stage IV disease. Patient was successfully treated with chemotherapy for Advance Stage HD and involved field RT, involving brain. The patient remains disease free 4 years after completion of treatment. Intracranial involvement (IC) of the Hodgkin disease (HD) is a rare entity. In the majority of cases intracranial involvement has been seen during relapsed and progressive disease. Until now nine cases of initial presentation of the HD as a brain tumor with appropriate morphological and histochemical confirmation were reported. Among those patients six patients had isolated primary IC HD and three patients after further investigation were found to have extracranial involvement. Seven of the nine patients had nodular sclerosing histology, one had mixed cellularity and in one case histology was not reported. All patients following resection of the IC mass received cranial RT. Two patients also received intrathecal chemotherapy. Patients with the extracranial involvement received systemic chemotherapy. All patients responded to the treatment and were disease free on the subsequent follow up 6–48 months after the completion of the therapy.

No significant financial relationships to disclose.
The influence of radiotherapy and chemotherapy on survival and quality of life of patients with cerebral metastases
Authors: Markulin-Grgi L. , Santek F.
Published: March 2020

12535

Background: The problem of cerebral metastases is a great one and seams to become more and more important thanks to the earlier diagnosis of malignant tumors and to the possibility of effective treatment of carcinomas which leads to prolongation of life of patients with malignant disease. Although many patients with malignant tumors develop symptoms of cerebral metastases in course of their disease, even more cerebral metastatses are found at the post mortem. Because autopsies are undertaken very rarely, the true incidence of cerebral metstases can only be estimated. Surgery is indicated in patients with solitary or 2 adjacent metastases. Radiotherapy is the most common method of treatment, sometimes after surgery, but mostly as the only method and in combination with chemotherapy. Methods: 165 patients with cerebral metastases treated at the Clinic of Radiotherapy and Oncology, School of Medicine, University Hospital Center Zagreb from 1995 to 2000 are discussed. The commonest primary tumor was bronchial carcinoma in 87/165 of patients (52,8%) followed by breast carcinoma in 36/165 (21,8%). In 10/165 (6,1%) of the patients the primary tumor was unknown. The patient were treated by radiotherapy, chemotherapy and surgery in various combinations. Results: The survival was significantly better in younger patients taking into account the median of age as 56 years (p<0,05). In the group of 78/165 patients who were treated only by radiotherapy (47,2%) the median survival was 6 months (1–38 months). In the group of 87/165 (52,8%) treated by radiotherapy and chemotherapy the median survival was 8 months (1–48 months) (p<0,001) There was no influence of duration of the symptoms on survival of our patients (p>0,05) Conclusions: According to treatment modalities, the best survival results were observed in patients treated by a combination of surgery, radiotherapy and chemotherapy (p<0,001).

No significant financial relationships to disclose.
Addressing BCR/Abl resistance: Evolving dasatinib to a novel inhibitor of the T315I BCR/Abl mutation
Authors: Zhu H.
Published: March 2020

13004

We have previously shown that inhibition of the BCR/Abl.T315I mutation can be achieved by using a benzotriazine small molecule in both enzymatic and cell proliferation assays. We have further evolved the benzotriazenes into a class of structurally simplified BCR/Abl inhibitors with enhanced pharmaceutical properties. A representative of this new class, TG101114, inhibits Abl and Abl.T315I enzyme as well as proliferation of cells expressing either BCR/Abl or BCR/Abl.T315I. It displays desirable pharmaceutical properties (e.g. oral bioavailability>20% and T1/2>5 h). Consistent with its potency and PK, orally administered TG101114 inhibits the growth of BCR/Abl-driven tumors in a SCID mouse xenograft model and BCR/Abl.T315I-induced STAT5 phosphorylation in the spleens of mice implanted with BCR/Abl.T315I cells. In an ex vivo assay, TG101114 normalized colony formation of stem cells isolated from a BCR/Abl.T315I+ CML patients. To further expand upon the themes of these structurally simplified scaffolds, we have transformed dasatanib into a potent and selective T315I inhibitor, thus inhibiting both abl and T315I.abl with equal nM potency in enzymatic and cellular assays. TG101477, an exemplary compound from this class, has shown potency in both enzyme and cell proliferation assays as well as appealing PK properties in mice (e.g. oral bioavailability>20% and T1/2>5 h). Furthermore, TG101477 has exceptional selectivity as was demonstrated in a commercial kinase assay in which TG101477 potently inhibited only 6 of 76 kinases in a panel of phylogenetically diverse kinases. We conclude that these classes of BCR-abl inhibitors present new themes for circumventing gatekeeper mutations and represent new prototypes for the treatment of drug resistant forms of CML.

No significant financial relationships to disclose.
Population pharmacokinetic and pharmacodynamic (PK-PD) parameters of Erwinia Chrysanthemi (ERW) asparaginase (ASNase) using the fused first-order elimination and Michaelis-Menten (MM) limited physiological model
Authors: Avramis V. I. , Fu C.
Published: March 2020

13010

Background: Using the linear PK first order (FO) compartmental approach, the methodical and computational uniformity in modeling various linear systems (ERW) is the dominant characteristic of the population PK analyses. However, saturation of the enzymatic reaction results in nonlinear kinetics based on the MM equation, i.e., the deamination of ASN by ERW, which complicates the PK-PD model. The PK with FO & the MM PK-PD model is theoretically better when single dose of ERW is given. To simulate the PK-PD data and to project patient (pt) data using this model, we used simultaneous integration of the FO+MM equations. Methods: In the 1990’s, ERW was used in pediatric ALL pt (n=23, 1st cohort evaluated for PK-PD). The current study was started to assess if the parallel MM+FO (MM+FO) PK-PD model fit the limited ERW (25K) data better than the MM model, and to validate the MM+FO model and its population parameter estimates. Results: The population PK-PD model best-fitted serum ERW & ASN-time pairs obtained in 23 and from 5 pediatric pt with ALL, using nonlinear mixed-effects modeling (NONMEM). The validity of the MM+FO population PK-PD model and the estimated parameters were tested using the naive prediction method. Patients were administered ERW 6K or 25 K IU/m2 when allergy to E. coli formulations appeared. High correlation between ERW peak serum levels calculated from limited individual pt’ KM (900 μM) & Vmax values in 5 pediatric pt (2nd cohort) and the observed ERW trough levels & its substrate (ASN) were found. The T1/2 averaged 16 hr (25K ERW), and the trough level of 0.1–0.2 IU/ml was correlated with ASN <3 μM. These PK-PD parameters validated those obtained from the 1st cohort. When simulations on population parameters were conducted, the MM+FO predicted the multiple dose steady-state serum ERW & ASN levels nicely. Therefore, the MM+FO model was clearly superior to either the FO or the MM PD models. Moreover, simulations compared favorably ERW 25K Q2 days x3 doses & x2 weeks vs. Pegaspargase 2,5K Q2 weeks. Conclusions: The NONMEM PK-PD model for ERW fitted the simultaneous analyses of data from different doses and regimens better than either standard Two-stage or MM could.

No significant financial relationships to disclose.