bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of the novel oral camptothecin gimatecan (G) in women with anthracycline (A) and taxane (T) pre-treated advanced breast cancer
Authors: Mariani P. , Moliterni A. , Da Prada G. , Hess D. , Gamucci T. , Zaniboni A. , Malossi A. , Barbieri P. , Marsoni S. , Gianni L. 
Published: March 2020

662 Background: Gimatecan (G) is a new oral camptothecin with a favourable therapeutic index in several tumor xenograft models and with documented antitumor activity in breast, endometrial and NSCLC cancer in Phase I. A Phase II trial was implemented to determine the antitumor activity of G in women with pre-treated metastatic breast cancer (MBC). Methods: A Simon 2-step design was used: patients with MBC who failed A & T were eligible. Treatment failure was defined as disease progressing after receiving both A and T (adjuvant or metastatic setting). All patients had ECOG 0–1. Baseline neuropathy > gr 1 or CNS metastases were criteria of exclusion. G was administered for 5 days every week on weeks 1 & 2 q4weeks at 4–5 mg/m2 total dose per cycle. Results: To date, 21 patients have received 67 cycles of G (median 3); 18 are evaluable for the 1st step analysis. Median age was 53 years (range, 32–70), all had received A & T prior treatment. The initial dose of 5 mg/m2 was reduced to 4 mg/m2 after treating the first 7 cases due to hematological toxicity (thrombocytopenia G3 30% and neutropenia G3–4 40%) that prevented the planned monthly retreatment. The toxicity at 4 mg/m2 included thrombocytopenia (% of cycles with any grade: 36%, G3 9%); neutropenia (G3 18%), diarrhea (1 case), nausea (81%, G3 18%), vomiting (G1 18%), and asthenia (G1 36%). To date, three confirmed partial responses (PR) lasting respectively 5.5, 5.7+, and 9.4+ months and two unconfirmed PR were observed in visceral and nodal sites. Accrual into step 2 is proceeding. Conclusions: Gimatecan at a dose of 4 mg/m2 is well tolerated and active. The antitumor activity of 27% observed in the first step of the study is unusual for camptothecins and prompted to continue to the second step and complete the ongoing enrolment of 43 patients overall. [Table: see text]
Phase II study of capecitabine (X) + docetaxel (T) as neoadjuvant treatment in patients (pts) with locally advanced breast cancer (LABC) including biological correlates
Authors: Bellet M. , Muñoz M. , Bellosillo B. , Corominas J. , Pena T. , Suárez M. , Maristany M. , Perich J. , Tusquets I. , Fabregat X. 
Published: March 2020

664 Background: X and T have demonstrated synergy in preclinical studies and survival benefits in metastatic BC. We aimed to determine whether the high efficacy of XT could translate into the neoadjuvant setting. Methods: Expression levels (mRNA) of 3 enzymes involved in X intratumoral activation and metabolism (thymidylate synthase [TS], thymidine phosphorylase [TP] and dihydropyrimidine dehydrogenase [DPD]), were determined in tumor biopsies before treatment and their relationship with clinical and pathological response analyzed using Fisher’s Exact Test. Pts with stage IIIA/IIIB LABC, adequate organ function and KPS ≥80 received 4 cycles of X 1250mg/m2 (1000mg/m2 for age >60) bid d1–14 and T 75mg/m2 d1 q3w followed by surgery, adjuvant AC q3w × 4 ± tamoxifen according to ER and PR status. The primary endpoint was pCR. Results: We enrolled 34 pts with LABC IIIA (44%)/IIIB (56%): median age 52y (30–72); KPS ≥90 (76%); median tumor size 6.8cm (2–20); N0 (20%), N1 (41%), N2/3 (35%); ER+PR-/p53+/HER2+ (23/24/28%). 128 cycles of X and T were administered (median 4, range 1–5). Main G3/G4 toxicities were: HFS 32%, diarrhea 15%, asthenia 9%, stomatitis 6% and neutropenia 71%. There were no treatment-related deaths. 2 pts were withdrawn prematurely due to adverse events. The overall response in 32 evaluable pts was 78%, including 5 CRs and 20 PRs. 6/29 pts evaluable for pathological response had pCR (20%), and 10 (33%) had ≤10mm residual tumor (3 microscopic RD) in breast. Nodal involvement after chemotherapy was N0 (33%), N1 (33%), N2 (27%), N3 (7%), and the rate of breast-conserving surgery was 17%. High TP/DPD ratio was associated with CR (p=0.037) and both high TP/DPD and low TS/DPD ratio appeared to correlate with residual tumor ≤10 mm (p=0.028). Conclusions: Neoadjuvant XT appears to be highly active. Safety was similar to that reported in anthracycline-pretreated pts but with less stomatitis. In this small sample, a high TP/DPD ratio appears to correlate with clinical response and a favorable enzymatic profile (high TP/DPD and low TS/DPD ratio) may predict for high pCR. A further prospective study is required to validate this hypothesis. No significant financial relationships to disclose.
Clinical response assessment after 2 cycles of neoadjuvant chemotherapy for primary breast cancer fails to predict for final clinical response, but does predict for pathological complete response
Authors: Beresford M. J. , Chin Y. , Burcombe R. , Ah-See M. , Makris A. 
Published: March 2020

667 Background: Neoadjuvant chemotherapy (NC) is increasingly being used for large primary breast carcinomas. Clinical trials have established its role in improving breast-conserving surgery (BCS) rates and have shown that complete pathological response (pCR) is associated with improved survival. Early evaluation of response is important for selecting patients with possible worse outcomes, who may benefit from alternative treatments. Methods: 107 women received NC for large operable breast cancers (T2–4, N1–2, M0). Patients received 6 cycles of FEC chemotherapy (5-FU 500mg/m2, epirubicin 75mg/m2, cyclophosphamide 500mg/m2 every 21 days) prior to a planned operation. Clinical response was recorded at baseline, after 2 cycles of NC and on completion of 6 cycles. Baseline and completion ultrasound and/or mammography were performed and a pathological assessment of response was made in those patients who underwent surgery. Results: Median age was 50 (range= 29–78). Overall clinical response rate after 2 cycles of chemotherapy was 59.8% (64/107) and after 6 cycles was 84.1% (90/107). 56 patients (52.3%) underwent BCS, 37 (34.6%) mastectomy and 14 (13.1%) no operation. Overall pCR rate was 15.0% (16/107). Of the 43 patients who failed to respond clinically after 2 cycles, 27 (62.8%) went on to exhibit a clinical response on completion of chemotherapy. 3 (7.0%) patients went on to have a complete clinical response and 21 (48.8%) underwent BCS. However, none of these 43 patients demonstrated a pCR. Conclusions: Lack of clinical response after 2 cycles of neoadjuvant chemotherapy does not preclude clinical response after further treatment with the same schedule, and many women will have sufficient down-staging to enable breast-conserving surgery. However, a pathological complete response is unlikely if no clinical response is observed after 2 cycles. No significant financial relationships to disclose.
Impact of symptoms and toxicity on quality of life: Exploratory analysis of gemcitabine plus docetaxel vs capecitabine plus docetaxel in metastatic breast cancer
Authors: Fumoleau P. , Romieu G. , Chan S. , Huober J. , Tubiana-Hulin M. , Schneeweiss A. , Lluch A. , Bougnoux P. 
Published: March 2020

682 Background: A recent phase III trial comparing gemcitabine-docetaxel (GD) with capecitabine-docetaxel (CD) for metastatic breast cancer (MBC) found comparable progression-free survival but patients (pts) on GD had less toxicity (Chan, ASCO 2005). To better understand how quality of life (QoL) is impacted by toxicity and symptoms, we conducted an exploratory analysis. Methods: The study had 305 pts who relapsed after anthracycline-based treatment either in (neo)adjuvant or first-line MBC. Pts were randomized to GD or CD for 21-day cycles until PD or unacceptable toxicity. QoL was assessed every cycle with Rotterdam Symptom Checklist (RSCL). Only pts with RSCL data were included in the QoL analysis. Comparison between arms of changes from baseline in RSCL dimensions at each cycle were analyzed using analysis of co-variance (ANCOVA). Because the physical symptom distress scale (PSDS) includes symptom- and toxicity-related items, distributions of responses to each item were explored. Results: 302 pts received treatment (GD 152; CD 150); median number of cycles was 6 for both arms. 267 pts (88%) had baseline RSCL data; compliance ranged from 79%-88% for the first 6 cycles. Baseline RSCL scores were comparable between arms. No statistical differences between arms were seen for any of the RSCL dimensions (p>.05 at all cycles). Both arms had worsening in the PSDS (median increases of 3–6.8 on 69-point scale). Numerical differences were seen in some PSDS items rated as “quite a bit” or “very much.” By cycle 3, more GD pts reported tiredness (58% v 47%), lack of energy (45% v 38%), back pain (19% v 9%), and by cycle 2, alopecia (76% v 66%). By cycle 1, more CD pts reported tingling hands/feet (15% v 7%) and burning/sore eyes (14% v 3%). Conclusions: Preliminary analysis indicated no QoL differences between GD and CD; however, further exploration shows that physical distress is explained by different symptoms and toxicities in each arm. Results, particularly at later cycles, should be cautiously interpreted because of pt attrition and different reasons for discontinuation (eg, more CD than GD pts discontinued due to serious adverse events [28% v 13%]). Further analysis incorporating clinical outcomes may better explain QoL outcomes [Table: see text]
Prevalence and correlates of fatigue and depression in breast cancer survivors: Breast cancer quality care study
Authors: Kim S. H. , Park B. W. , Ahn S. H. , Noh D. Y. , Nam S. J. , Lee E. S. , Yun Y. H. 
Published: March 2020

683 Background: Fatigue and depression may persist for months or even years after completion of breast cancer treatment. We investigated the prevalence and correlates of fatigue and depression in disease-free breast cancer survivors. Methods: 1,933 breast cancer survivors recruited from five large hospitals in Korea completed standardized questionnaires as part of a survey study, including the patient demographics, Brief Fatigue Inventory, Beck Depression Inventory, European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and QLQ-BR23. Women were eligible to participate if they had a past diagnosis of breast cancer (stage 0, I, II, or III) and were currently free of the disease more than one year. Eligible patients were contacted by telephone, and those who agreed to participate were sent the questionnaire with consent forms and a postage-paid return envelope. Multivariate logistic regression models were used to identify factors associated with fatigue and depression. Results: Sixty six percent of the breast cancer survivors reported moderate to severe fatigue, which was defined as a “fatigue worst” rating of 4 or greater, 24.9% reported clinical moderate to severe depression, which was defined as a rating of 19 or greater. Fatigue and depression were highly correlated (Pearson r=.593). Fatigue was associated with significantly employment status (OR=1.58), low income (OR=1.29), having gastrointestinal disease (OR=1.94), dyspnea (OR=2.15), appetite loss (OR=3.02), insomnia (OR=2.72), breast symptoms (OR=1.82), and hair loss (OR=1.75). Depression was strongly related to low income (OR=2.50), fatigue (OR=4.52), insomnia (OR=1.98), appetite loss (OR=2.24), constipation (OR=2.12), and financial difficulties (OR=1.89), systemic therapy side effect (OR=3.12). Fatigue and depression were negatively associated to QOL. Conclusion: There were subgroups of survivors who report more severe and persistent fatigue and depression. This information may be helpful in elucidating the mechanisms underlying fatigue and depression in this population, as well as directing intervention efforts. No significant financial relationships to disclose.
Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma
Authors: Gatzemeier U. , Blumenschein G. , Fosella F. , Simantov R. , Elting J. , Bigwood D. , Cihon F. , Reck M. 
Published: March 2020

7002 Background: Sorafenib, an oral multi-kinase inhibitor, targets the Raf/MEK/ERK pathway at the level of Raf kinase and receptor tyrosine kinases, and has shown efficacy against several tumor types in phase I/II trials. Non-small-cell lung cancer (NSCLC) is associated with mutations in k-ras, upstream of Raf/MEK/ERK. Methods: This multi-center, uncontrolled, phase II trial evaluated efficacy (every 8 weeks using RECIST) and safety of sorafenib (400 mg bid, continuous) in patients with relapsed or refractory advanced NSCLC. Plasma for proteomic biomarker analysis (ELISA [n=44]; mass-spectrometry [n=43]) was taken at screening, Day 21 of Cycle 1, and Day 1 of Cycle 3. Results: Fifty-two of 54 patients enrolled received sorafenib. Most (49/52) patients who received sorafenib had stage IV NSCLC. Thirty patients (59%) out of 51 evaluable for efficacy had SD. Although there were no confirmed PRs, tumor shrinkage was observed in 15 (29%) patients (four had ≥30% shrinkage). Patients with SD had a median progression-free survival (PFS) of 23.7 weeks, while all evaluable patients (n=51) had a median PFS of 11.9 weeks and median overall survival of 29.3 weeks. The most frequent drug-related adverse events observed in 52 patients were diarrhea (21 [40%] patients), hand-foot skin reaction (HFS; 19 [37%]), fatigue (14 [27%]), and nausea (13 [25%]). Frequent drug-related adverse events ≥ grade 3 included HFS (n=5 [10%]) and hypertension (n=2 [4%]). Three patients discontinued due to adverse events (HFS, elevated lipase, and myocardial infarction). There were nine deaths within 30 days of discontinuation of sorafenib (n=5 PD; n=2 cardiopulmonary arrest; n=1 hemoptysis; and n=1 unknown cause). The levels of five proteins measured by ELISA, either at screening or change over treatment duration, correlated significantly with time to progression (TTP) or maximum tumor shrinkage. Levels of five additional proteins, identified by mass-spectrometry, also correlated with TTP. Conclusions: Identified biomarkers may help assess efficacy of sorafenib in NSCLC patients. Sorafenib 400 mg bid is generally well tolerated and shows promising efficacy in patients with advanced, progressive NSCLC, with approximately 60% of pts achieving disease stabilization. [Table: see text]
Prediction of clinical outcome in non-small cell lung cancer (NSCLC) patients treated with gefitinib using Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) of serum
Authors: Solomon B. , Gregorc V. , Taguchi F. , Kasahara K. , Nishio M. , Roder H. , Hirsch F. R. , Duncan M. W. , Bunn P. A. , Carbone D. P. 
Published: March 2020

7004 Background: Assessment of epidermal growth factor receptor (EGFR) gene copy number, mutational status, and protein levels may predict response and possibly survival following treatment with EGFR tyrosine kinase inhibitors, but all these methods require tumor tissue, highlighting the need for a non-invasive predictive test. We evaluated the ability of MALDI-TOF MS profiling of serum to predict which patients (Pts) with NSCLC were likely to benefit from gefitinib treatment. Methods: Serum from Pts with NSCLC, collected prior to treatment with gefitinib, was subjected to MALDI-TOF MS using Voyager DE-STR or DE-PRO instruments. Replicate mass spectra obtained at two institutions were submitted to a third party for processing (background subtraction, noise estimation, normalization, spectral alignment and peak identification) and selection of discriminating mass/charge (m/z) values from a training cohort of 70 Caucasian Pts. The predictive capability of the profile was then assessed in independent cohorts of NSCLC Pts. Results: Intra- and inter- laboratory reproducibility of MALDI spectra were excellent. A set of 11 m/z values (mass range 5 - 12.5 kDa) predictive of clinical benefit were identified in the training cohort and confirmed by leave-one-out cross validation. Spectra from 19/70 Pts in the training cohort were unclassifiable. For the remaining 51 Pts the algorithm discriminated groups more or less likely to benefit with respect to time to progression (median 3.0 vs. 1.5 mo., p = 0.0325) and overall survival (median 14.6 vs. 2.3 mo., p = 0.0128). Validation was performed in an independent cohort consisting of serum from 69 Japanese Pts. Spectra from 13/69 Pts were unclassifiable. For the remaining 56 Pts it was possible to identify a group with superior time to progression (median 14.8 vs. 2.1 mo., p = 0.0012) and overall survival (median 19.1 vs. 7.9 mo., p = 0.0102). Conclusions: MALDI-TOF MS of pretreatment serum may aid with the identification of subsets of NSCLC Pts that will benefit from treatment with gefitinib. This algorithm is currently being evaluated in an expanded cohort of Pts receiving gefitinib treatment and in Pts treated with erlotinib. [Table: see text]
A phase III randomised trial comparing sequential to standard chemotherapy in advanced non-small cell lung cancer (NSCLC)
Authors: Sculier J. , Lafitte J. , Lecomte J. , Alexopoulos C. , Van Cutsem O. , Giner V. , Efremidis A. , Scherpereel A. , Paesmans M. , Berghmans T. 
Published: March 2020

7012 Background: Cisplatin-based chemotherapy and taxans are effective treatments for advanced NSCLC. We performed a phase III randomised trial to determine if the sequential administration of cisplatin-based chemotherapy followed by paclitaxel is superior to a cisplatin-based standard chemotherapy, with the use of paclitaxel as salvage treatment. Methods: Untreated advanced NSCLC with adequate PS, hematological, hepatic, cardiac and renal functions were treated by 3 courses of GIP (cisplatin 50 mg/m2, ifosfamide 3 g/m2, gemcitabine 1 g/m2). Patients with a non-progressing tumour were randomised between 3 further courses of GIP or 3 courses of paclitaxel (225 mg/m2). To detect an increase in the survival rates (primary endpoint) from 20% in the GIP arm to 35% in the sequential arm, with 80% probability using a two-sided logrank test with a significance level of 5%, we needed to observe 178 events, requiring to randomise 123 patients in each arm. Results: From January 2000 to February 2004, 485 patients received 3 courses of induction GIP of which 140 were randomised in the GIP arm and 141 in the paclitaxel arm. Median survival times were 14.1 (95% CI: 12.0–16.3) and 16.4 (95% CI: 14.0–18.8) months for the paclitaxel and the GIP arms, respectively (p = 0.17). When treatment comparison was adjusted for the two independent prognostic factors (sex and haemoglobin) revealed by a Cox multivariate analysis, the observed HR was 0.81 (95% CI: 0.63–1.09) in favour of the GIP arm (p = 0.10). There were more grades III/IV thrombopenia with GIP (p< 0.01) and more alopecia with paclitaxel (p = 0.04). Conclusion: Sequential cisplatin-based chemotherapy by paclitaxel does not result in better survival than standard chemotherapy, with the use of paclitaxel as salvage treatment. No significant financial relationships to disclose.
Bortezomib + gemcitabine (Gem)/carboplatin (Carbo) results in encouraging survival in advanced non-small cell lung cancer (NSCLC): Results of a phase II Southwest Oncology Group (SWOG) trial (S0339)
Authors: Davies A. M. , McCoy J. , Lara P. N. , Gumerlock P. H. , Crowley J. , Gandara D. R. 
Published: March 2020

7017 Background: Bortezomib (PS-341), a small molecule proteasome inhibitor, has single agent activity in NSCLC and potentiates Gem/Carbo in pre-clinical models in a sequence-specific manner (Mortensen, Cancer Chem Pharm, 2004). A phase I trial of Gem/Carbo + PS-341 in patients (pts) with advanced NSCLC yielded an encouraging response rate of 48%. Here we describe the results of a SWOG phase II study of this regimen in advanced NSCLC. Methods: 114 eligible chemonaive stage IV and selected stage IIIB (pleural effusion) NSCLC pts received Gem 1000 mg/m2 on days 1, 8 and Carbo AUC 5 on day 1, followed 1 hour later by PS-341 1.0 mg/m2 on days 1, 4, 8, 11, with cycles repeated every 3 weeks. Non-progressing pts could continue PS-341 alone after 4 cycles. Results: Pt characteristics: Median age: 64 years; Sex M/F = 68/46; Performance status 0/1 = 50/64; stage IIIB/IV = 13/101. Response rate: 20% (95% CI 13–29%); 66% (95% CI 56–75%) had stable disease. At a median follow-up of 13 months, progression free and median survival times were 5 months (95% CI 3.5–5.3) and 11 months (95% CI 8.2–12.5). One-year survival was 46% (95% C.I. 37–55%). Most common grade 3/4 toxicities: neutropenia (52%), thrombocytopenia (63%), and fatigue (13%). Ongoing correlative studies are examining markers of proteasome inhibition (Bcl2 family, NFKB, IKB) and hypoxia (PAI-1, VEGF, OPN, HIF-1) in tumor tissue and surrogate specimens. Conclusions: The 11 month median survival achieved with the addition of PS-341 to Gem/Carbo in this phase II study is unprecedented in prior SWOG trials in advanced NSCLC, and does not appear to be explained by altered patient characteristics. The toxicity profile of this regimen is favorable. A phase III trial of Gem/Carbo ± Bortezomib in advanced stage NSCLC is under development. Supported by CA38926, CA32102. No significant financial relationships to disclose.
Clinical and biological effects of gefitinib in EGFR FISH positive/phospho-akt positive or never smoker non-small cell lung cancer (NSCLC): Preliminary results of the ONCOBELL trial
Authors: Cappuzzo F. , Toschi L. , Trisolini R. , Bemis L. , Sujita M. , Domenichini I. , Franklin W. , Crino L. , Ciardiello F. , Varella-Garcia M. 
Published: March 2020

7023 Background: Effectiveness of gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), in never smokers and/or EGFR FISH positive NSCLC patients has been evaluated only in retrospective studies and few data exist on the biological effects of gefitinib therapy in tumor samples. Methods: The ONCOBELL trial is a multicenter prospective phase II study designed to include 39 patients EGFR FISH positive/phospho-Akt (p-AKT) positive and/or never smokers with advanced or metastatic NSCLC. Gefitinib is given at the daily dose of 250 mg. When feasible, primary tumor biopsy was repeated immediately before therapy, during therapy and at progression. Specimens were evaluated for EGFR and HER2 gene copy number by FISH, EGFR gene mutation by DNA sequencing, and EGFR and p-AKT protein expression by immunohistochemistry. Results: Data from the first 28 enrolled patients are available: median age was 60 years (range, 43–80); male/female: 7/21; stage IIIB/IV: 2/26; ECOG PS 0/1/2: 18/6/4; 25 patients had a diagnosis of adenocarcinoma and/or bronchioloalveolar carcinoma; 13 patients had brain metastases, and in 10 cases gefitinib was offered as first-line therapy. Twenty-four patients were never smokers and 19 were EGFR FISH positive. Overall response rate was 54%, including 1 complete and 14 partial responses. Median time to progression was 6.45 months, and median survival was not reached. Response to therapy was not influenced by previous therapies or presence of brain metastases. Toxicity was mild, and consisted in grade 1–2 skin rash (68%) and diarrhea (57%). One patient developed grade 3 diarrhea and another patient was hospitalized for acute interstitial lung disease. In patients exposed to previous chemotherapy, no difference in EGFR or HER2 FISH results were observed in specimens collected at the time of original diagnosis compared to specimens collected immediately before gefitinib therapy. In 14 cases primary tumor biopsy was repeated during gefitinib therapy. Conclusions: These preliminary data indicate that gefitinib is highly effective in patients with trial characteristics. Clinical and biological data for the entire cohort will be available in June 2006. No significant financial relationships to disclose.