bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quality of life (QOL) companion to CALGB 9840: A phase III study of paclitaxel (P) via weekly 1 hour (hr) versus standard 3 hour infusion every 3 weeks with trastuzumab in the treatment of patients with/without HER-2/neu-overexpressing metastatic breast cancer
Authors: Naughton M. J. , Gu L. , Wang X. F. , Seidman A. D. , Winer E. , Kornblith A. B. 
Published: March 2020

674 Background: This study determined if adding trastuzumab (Herceptin, T) to P modified the QOL of HER-2 non-overexpressors and examined QOL differences between patients treated with weekly versus standard P. Methods: Of the 585 patients treated in CALGB 9840, 394 provided QOL data. Eligibility criteria and main trial results were reported, indicating greater efficacy in weekly versus standard P, but no greater efficacy with T in HER-2 negatives (Seidman AD et al., Proc ASCO 2004, Vol. 22, No 14S, abstract 512). HER-2 non-overexpressors were randomized to 1 of 4 groups: 1) P 175 mg/m2 over 3 hrs every 3 wks; 2) P 80 mg/m2 over 1 hr weekly; 3) P 175 mg/m2 over 3 hrs every 3 wks + T 4 mg/kg load, then 2 mg/kg weekly; and 4) P l 80 mg/m2 over 1 hr weekly + T 4 mg/kg load, then 2 mg/kg weekly, all IV. All HER-2 overexpressors received T and were randomized to group 3 or 4. Patients completed QOL interviews prior to randomization, and at 3, 6, and 9 months. Main outcome measures were the EORTC-C30 with the Breast Module (QLQ-BR23). Data were analyzed using general linear models for repeated measures, with the following covariates: treatment arm, assessment point, patient age, race, education, marital status, performance status, prior chemotherapy, and prior radiation therapy. Results: HER-2 negative patients receiving weekly P with/without T as compared to standard P with/without T reported better global QOL (p=.022) and fewer cancer symptoms (p=.036). No QOL differences were observed among the HER-2 overexpressors. The use of T in the HER-2 negatives, regardless of P schedule, resulted in better role (p=.002) and emotional functioning (p=.039), and fewer arm (p=.045) and breast (p=.033) symptoms than HER-2 negative patients not receiving T. No differences in physical, social, and cognitive functioning were observed across any of these treatment groups. Conclusions: Both weekly P and T improved the QOL of HER-2 negative patients. There were no QOL differences by P schedule among the HER-2 overexpressors. The higher QOL in HER-2 negatives receiving T was unexpected, inconsistent with clinical data, and needs further exploration in the dataset. [Table: see text]
Eicosanoid modulation in advanced non-small cell lung cancer (NSCLC): CALGB 30203
Authors: Edelman M. J. , Watson D. M. , Wang X. , Kratzke R. A. , Mauer A. M. , Green M. R. , Vokes E. E. , Graziano S. L. , Masters G. A. , Bedor M. M. 
Published: March 2020

7025 Background: Increased expression of eicosanoids have been associated with adverse prognosis. Specific inhibitors of key enzymes of two eicosanoid pathways, COX-2 (celecoxib) and 5-LOX (zileuton) have been developed. In vitro, the addition of these inhibitors have demonstrated enhancement of cytotoxic chemotherapy. We hypothesized that the addition of eicosanoid inhibitors to standard chemotherapy of carboplatin (C) and gemcitabine (G) could improve outcome in advanced NSCLC. Methods: Patients (pts) with stage IIIb (pleural effusion)/stage IV NSCLC, PS 0–2, no prior therapy were eligible. All pts received up to six cycles of C AUC 5.5 d1 + G (1000 mg/m2) d1,8. Pts were randomized to three arms: A: Celecoxib (CEL) 400 mg po bid. B: Zileuton (Z) 600 mg qid po, C: CEL and Z at the same doses. CEL and Z were begun on the first day of therapy and continued until progression. In this randomized phase II trial, the objective was to demonstrate a 50% failure free survival (FFS) at 9 months. Serum and tissue samples were required. Results: Between 12/05/03 and 9/30/04, 140 pts were entered and 136 were eligible and treated (A: 44, B: 47, C: 45). M: 86, F: 50; PS 0,1,2 = 38,85,13. Toxicity was primarily hematologic with approximately 70% grade 3/4 toxicity on each arm. Response and survival with 95% CI (see table ). Arm C has superior FFS when compared to combined Arms A+B (p =.054, unstratified log rank test), however, this benefit decreases when adjusted for baseline PS (0 vs, 1,2) and stage (IIIB vs. IV) in a Cox model, p=.15, 2-sided Wald test. There was no difference in terms of OS (p=.96). Serum and tissue were submitted for >90%. Analysis of COX-2 and 5-LOX expression are pending. Conclusions: 1. The combination of C/G + eicosanoid modulators was well tolerated. 2. The trend towards improved FFS in Arm C is intriguing, however, did not achieve the primary endpoint. 3. Correlative studies which may be able to identify pts likely to benefit from this approach are in progress. [Table: see text] [Table: see text]
Phase II trial of amrubicin in patients with previously treated small cell lung cancer (SCLC)
Authors: Kato T. , Nokihara H. , Ohe Y. , Yamamoto N. , Sekine I. , Kunitoh H. , Kubota K. , Nishiwaki Y. , Saijo N. , Tamura T. 
Published: March 2020

7061 Background: Amrubicin, a totally synthetic 9-amino-anthracycline, has been shown to have excellent antitumor activity as a single agent against previously untreated extensive-stage SCLC. The objective of this study was to assess the efficacy and safety of amrubicin in patients with refractory or relapsed SCLC. Methods: Patients with histologically or cytologically confirmed SCLC, 20 to 74 years in age, performance status 0–2, with a history of receiving first- or second- line chemotherapy were eligible for the study. Amrubicin (45mg/m2/day) was administered on Days 1–3 every 3 weeks for four to six courses. The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 33 patients (Simon’s two-stage minimax design). Results: From June 2003 to January 2005, 35 patients (26 males/9 females, median age, 64 years) were enrolled, and 34 of these patients were treated with the study drug. Four courses or more were administered in 59% (20/34) of the patients, and dose reduction was required in 52% (15/29) of the patients who had received 2 courses or more. Four complete responses and 14 partial responses were observed among the 34 treated patients, yielding a RR of 53% (95% confidence interval: 35.1%–70.2%). The median survival duration in the patients was 8.8 months, and the 1-year survival rate was 26%. Grade 3/4 leukopenia, neutropenia, and thrombocytopenia were observed in 76%, 97% and 38% of the patients, respectively. Febrile neutoropenia occurred in 12 patients (35%), and one patient died from treatment related pneumonia. Conclusion: Amrubicin (45mg/m2/day) was effective in patients with previously treated advanced SCLC, however, severe hematological toxicities occurred in some patients. No significant financial relationships to disclose.
Randomized phase III study of high-dose sequential chemotherapy (CT) supported by peripheral blood progenitor cells (PBPC) for the treatment of small cell lung cancer (SCLC): Results of the EBMT Random-ICE trial
Authors: Leyvraz S. , Pampallona S. , Martinelli G. , Ploner F. , Aversa S. , Rosti G. , Brunsvig P. , Montes A. , Yilmaz U. , Perey L. 
Published: March 2020

7064 Background: EBMT has defined in a phase II trial (JCO 1999, 3531) feasibility and activity of high-dose sequential CT for SCLC increasing 3 fold the dose-intensity and significantly the peak-dose and the total dose of CT. Methods: Randomized prospective study aiming to improve the 3-year survival from 12% in the standard (S) to 24% in the high-dose (H) arm, for a total accrual of 340 patients. Limited or extensive ≤ 2 metastatic sites, age ≤ 65 y.o., PS 0–1. Arm S/Arm H: ifosfamide 5 g/m2 d1/2.5 g/m2/d × 4; carboplatin 300 mg/m2 d1/AUC = 5/d × 4; etoposide 180 mg/m2/d. × 2/300 mg/m2/d × 4, every 28 days, for 6 cycles in Arm S. Three cycles were given in Arm H supported by PBPC collected after 2 courses of epirubicin 150 mg/m2/paclitaxel 175 mg/m2. Due to low accrual, a formal stopping rule was introduced with boundaries for early stopping in favour of a difference (O’Brien-Fleming) or of lack thereof (Pocock). The present analysis has been done with 110 deaths. Results: Since June 1997, 145 patients have been accrued (evaluable =140, S = 71, H = 69), median age 53, prognostic factors balanced. Mobilization toxicity ≥ 3: neutropenia 61%, thrombopenia 11%, anemia 7%, infection 6%, mucositis 9% and 2 toxic deaths. Toxicity ≥ 3 among 353 cycles of S and 152 of H respectively: neutropenia 26%/100%, thrombopenia 12%/100%, anemia 8%/69%, infection 1%/15%, fever 11%/72%, toxic death 1/8. Response rate of S and H: 67% (CR 32%)/77% (CR 37%) (p = 0.188). Median follow-up 4.9 years. Progression free survival 8.8 and 12 months (p = 0.737, unadjusted) and median overall survival 15 and 19.1 months (p = 0.659, unadjusted) for S and H respectively. At 3 years, 19% of the patients were alive in both arms. Conclusions: Random-ICE was designed with strong statistical power and shows no evidence that the treatment of SCLC can be improved by increasing the dose-intensity, the peak-dose or the total dose of ICE and that such intensification strategy should probably be abandoned. No significant financial relationships to disclose.
Analysis of c-erb-1 (EGFR) and c-erb-2 (HER2) expression in bronchial dysplasia: Evaluation of potential targets for chemoprevention of lung cancer
Authors: Merrick D. T. , Kittelson J. , Winterhalder R. , Kotantoulas G. , Ingeberg S. , Keith R. L. , Kennedy T. C. , Miller Y. E. , Franklin W. A. , Hirsch F. R. 
Published: March 2020

7070 Background: Lung cancer is preceded by a premalignant phase during which intervention could decrease associated morbidity and mortality. Molecular characterization of factors involved in controlling progression of bronchial dysplasia (BD) will provide markers of premalignant change and identify targets for chemoprevention. Methods: Immunohistochemical (IHC) analysis of EGFR, HER2, Ki67 and MCM2 expression in BD was undertaken in 268 bronchoscopically obtained biopsies from 134 consecutive subjects recruited to University of Colorado protocols as study subjects with prior sputum atypia and >20 pack years tobacco use or FEV1 < 75% predicted or as never- or healthy-smoker controls. IHC on the worst and best histologic biopsies from each subject were scored and linear regression tests were used to determine significance of correlation between marker expression and histology or proliferation. Results: Analysis of biopsies with the most severe diagnosis from each subject showed a linear relationship between increasing marker expression and severity of dysplastic change for EGFR (p < 0.001), Ki67 (p < 0.001) and MCM2 (p = 0.001) but not HER2 (p = 0.102). Increased expression of either EGFR or HER2 was associated with increased expression of proliferation markers Ki67and MCM2, and combined overexpression of these receptors was associated with the highest levels of proliferation. Finally, in a comparison of subjects that were grouped according to the degree of difference between their best and worst biopsy histology, the absence of an associated trend toward increased EGFR expression with increased difference in histology suggested a field effect in the induction of EGFR expression. Conclusions: Our results 1) demonstrate a direct correlation between levels of EGFR expression and degree of BD, 2) suggest a field effect in the induction of EGFR expression in the airways of subjects with BD and 3) indicate a potential synergistic effect on epithelial proliferation in lesions with increased expression of both EGFR and HER2. These findings suggest that EGFR plays a prominent role in the development and progression of BD and could provide a promising target for chemoprevention of lung cancer. [Table: see text]
Predicting clinical benefit from EGFR TKIs: Not all EGFR mutations are equal
Authors: Hirsch F. R. , Franklin W. A. , McCoy J. , Cappuzzo F. , Varella-Garcia M. , Witta S. E. , Gumerlock P. , West H. , Gandara D. R. , Bunn P. A. 
Published: March 2020

7072 Background: EGFR mutations are associated with better response and in some studies (mainly Asian) also with prolonged survival after gefitinib therapy in patients with advanced NSCLC. Although a number of mutations have been reported, most frequent are exon 19 or exon 21 mutations of the EGFR tyrosine kinase domain.Whether clinical outcomes differ by subtype of EGFR mutation has not been previously reported. Methods: Mutation analysis (as previously described) was performed in 157 of 204 patients with advanced NSCLC treated with gefitinib (250 mg or 500 mg) in 2 study cohorts (Italian study of Iressa Expanded Access Program and SWOG 0126). Fifty nanograms of genomic DNA was isolated from pretreatment tumors, amplified for EGFR exons 19 and 21 by touchdown hemi-nested polymerase chain reaction and sequenced in both sense and antisense directions. Results: EGFR mutations were found in 43 pts (27%). Overall, patients with EGFR mutations had a response rate of 39% versus 7% for those without (p ≤ 0.001), disease control rate of 52% versus 37% (p = 0.14), time to progression of 3 months in both groups and median survival of 13 months versus 11 months (p = 0.14). Patients with exon 19 mutations exclusively (N = 11) had better outcome than those with exon 21 mutations exclusively (N = 31), with response rates of 67% versus 20% (p = 0.02), median time to progression of 15 months versus 2 months, and median survival of 26 months versus 10 months. There was a difference in time to progression (11 months versus 3 months) and overall survival (median 26 months versus 11 months) between patients with and without exon 19 mutations, while no difference was apparent in these outcome measures in patients with and without exon 21 mutations. Sample size provided insufficient power for significance tests of differences in survival outcomes. Conclusions: Not all EGFR mutations are created equal. Mutations in exon 19 are more predictive of response and survival after gefitinib than exon 21 mutations. [Table: see text]
Mutational analysis of the EGFR gene in lung cancer with acquired resistance to gefitinib
Authors: Mitsudomi T. , Kosaka T. , Endoh H. , Yoshida K. , Hida T. , Tsuboi M. , Tada H. , Kuwano H. , Yatabe Y. 
Published: March 2020

7074 Background: Non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) gene is usually highly sensitive to EGFR tyrosine kinase inhibitors (TKI), gefitinib or erlotinib. However, it is common to develop acquired resistance to TKI after presenting an initial striking response. It has been reported that secondary mutation of threonine to methionine at codon 790 (T790M) of the EGFR gene is related to this acquired resistance. Methods: We sequenced exons 18–21 of the EGFR gene in 14 NSCLC patients exhibiting acquired resistance to gefitinib following the initial good response. This region of the EGFR gene corresponds with that of the ABL gene where various secondary mutations have been reported in patients with chronic myelogenous leukemia (CML) with acquired resistance to imatinib. To raise sensitivity of the assay, we also subcloned the PCR products into plasmids and sequenced, or we used CyCleave method (real-time PCR combined with fluorescence labeled mutant specific probe) in addition to usual sequencing. We also searched for secondary K-ras mutations. Results: All the 14 patients had activating mutations of the EGFR gene (9 with exon 19 deletions, 5 with L858R). In addition, we found that 7 of 14 patients had a T790M mutation, but there were not any other novel secondary mutations. In these seven patients, T790M mutant bands were smaller than wild-type bands. Patients with T790M tended to be never smoking female, but there was no difference in the period of gefitinib administration by the presence or absence of T790M. We could not detect any T790M in tumors before gefitinib treatment at the sensitivity of 1%. There were no patients with acquired mutation of the K-ras gene. Conclusions: Secondary T790M mutation of the EGFR gene accounted for half of the cases with acquired resistance to gefitinib. Unlike the cases with CML, various kinds of secondary mutations were not likely to exist in the EGFR gene as a mechanism of acquired resistance. No significant financial relationships to disclose.
Phase II study of irinotecan (cpt-11) and cisplatin (cddp) regimen (IP) with concurrent thoracic radiotherapy (TRT) in limited-stage small cell lung cancer (LS-SCLC)
Authors: Castellano D. , Bartolomé A. , Font A. , Lopez-Martín A. , Diz P. , Lopez-Brea M. , Garrido P. , Lianes P. , Cortés Funes H. , Paz-Ares L. 
Published: March 2020

7084 Background: the combination of CPT-11 and CDDP (IP) is an active regimen for SCLC. (Noda et al NEJM ’02, Hanna et al ASCO 2005). We performed a multicenter phase II study to assess the efficacy and toxicity of IP regimen with concurrent TRT in previously untreated LS-SCLC pts. Methods: Eligible pts were required to have histologically confirmed SCLC, measurable disease, no prior therapy, ECOG PS of 0–2, adequate organ functions, and to give informed consent. Treatment consisted of: CDDP 60 mg/m2 D1, I 60mg/m2 IV D1, 8 Q 21D for 4 cycles, and concurrent TRT 2.0 Gy daily to a total of 60.0 Gy, beginning with the 2nd cycle. I was adjusted to 50 mg/m2 at 2nd and 3rd cycles (during TRT). Pts were restaged after 4 cycles. Pts without progression or undue toxicity received 2 additional cycles. PCI (2.0 Gy X 10) was offered to CR pts. The primary endpoints were response rate and OS. Results: Twenty-six pts were included and 25 pts were evaluable for response (median age 62; M/F, 22/4; PS 0/1/2, 9/17; T2–4N0,T2–4N+ 6/20pts). Among 126 cycles administered, the relative dose-intensities of I and CDDP were 80% and 92% respectively. Median number of cycles/pt was 5 (1–6), and 22 pts completed the IP + TRT program. Fifteen pts achieved a CR and 6 pts a PR, for an overall RR of 84%. Median TTP was 12 months. At a median follow-up of 14 months, 19 pts are alive, and estimated median survival is 17 months. Grade 3–4 (NCI-CTC 3.0) toxicity (per cycle) during concurrent therapy included: neutropenia (25%), anemia (3%), thrombocytopenia (3%), diarrhea (10%), vomiting (5%), esophagitis (10%). There were no treatment-related deaths. Two pts required hospitalization during the concurrent therapy due to g3 diarrhea (1 pt) and febrile neutropenia (1 pt). Conclusions: The concurrent regimen of IP + TRT is highly effective in pts with LS-SCLC. The associated toxicity profile is predictable and adequate. Further study is warranted. No significant financial relationships to disclose.
Dose escalation study of nab-paclitaxel followed by carboplatin as first line therapy in advanced non-small cell lung cancer (NSCLC)
Authors: Hawkins M. J. , Georgy M. , Makhson A. , Cheporov S. , Sergey O. , Yablonsky P. , Bhar P. , Socinski M. 
Published: March 2020

7132 Background: Paclitaxel for injection formulated in Cremophor® and ethanol (Taxol®, Cremophor paclitaxel) 225 mg/m2 and carboplatin area under the curve of 6 mg/min·ml (C6) administered every 3 weeks (q3w) has produced an overall response rate (ORR) of 17% in first line patients (pts) with NSCLC with a 1-year survival of 34% [Schiller et al., NEJM, 2002;346:92]. The aim of this phase II study is to obtain clinical experience with a 130-nanometer albumin-bound form of paclitaxel (Abraxane®, ABI-007, nab™ paclitaxel) followed by C6 in NSCLC to determine a dose that approximates the toxicity of Cremophor paclitaxel/C6. Methods: Pts with previously untreated, stage IIIB or IV NSCLC with measurable disease and a life expectancy of over 12 weeks were recruited. In a dose escalation schedule, 4 cohorts (n = 25 each) of successive pts received nab paclitaxel at doses of 225, 260, 300, or 340 mg/m2 as 30-minute IV infusions followed by C6 q3w. The primary endpoints were the ORR (pts with an objective, confirmed complete or partial response) and toxicity. The primary efficacy analysis was based on all pts who received at least 1 dose of nab-paclitaxel and C6. Stable disease (SD) at ≥16 weeks was also assessed. Results: One hundred pts (100% white; 78% male; median age, 63; performance status score: 0 [11%], 1 [89%] were enrolled from 15 March–28 June of 2005. Accrual was completed in each cohort and serious adverse events reviewed prior to accrual at the next dose level. The results for ORR and SD at ≥16 weeks currently available are shown in the Table . The most common toxicities (any grade) were neutropenia, 43%; fatigue, 37%; sensory neuropathy, 37%; nausea, 35%; thrombocytopenia, 33%; anemia, 24%; alopecia, 24%; and vomiting, 21%. Conclusions: The combination demonstrated antitumor activity and was reasonably well tolerated. Mature data will be presented. [Table: see text] [Table: see text]
Phase II trial with carboplatin/gemcitabine induction chemotherapy followed by radiotherapy concomitantly with paclitaxel/gemcitabine in stage III non-small cell lung cancer (NSCLC)
Authors: Hirsh V. , Duclos M. , Souhami L. , Del Vecchio P. , Ofiara L. , Faria S. , Ayoub J. , Charpentier D. , Portelance L. , Soulieres D. 
Published: March 2020

7139 Background: The optimal combination of concomitant thoracic radiotherapy (TRT) and CT in stage III unresectable NSCLC remains unclear. The role of induction CT with Cb/G regimen, less toxic than Cisplatin/G, has not been established in stage III NSCLC. Methods: Forty-two patients (pts), 41 evaluable, entered this trial between January 2003 and November 2004, 27 males, 14 females, median age 60 (37–70), 19 pts with ECOG PS 0, 22 pts with PS 1, 22 pts with stage III A (N2), and 19 pts with stage III B (N2, N3). They received Cb AUC 5 i.v. on day 1 and G 1000 mg/m2 i.v. on days 1 + 8 every three weeks x 2 cycles, followed on day 50 by TRT, 60 Gy over 6 weeks, concomitantly with P 50 mg/m2 i.v. and G 100 mg/m2 i.v. on days 1 + 8 every three weeks x 2 cycles. Results: After induction CT, partial response (PR) was 73.1% (30 pts), stable disease (SD) 24.4% (10 pts), and 2.5% (1 pt) had progressive disease. After TRT and P/G, 19.5% (8 pts) had CR, 75.6% (31 pts) PR, and 4.9% (2 pts) PD. Median time-to-disease progression was 11.5 months. Median survival has not been reached yet, but surpassed 16.5 months; one-year survival is 71% (29 pts). Twenty three patients are still alive, after minimal follow-up of 13 months. First site of PD was in lungs in 7 pts, in brain 5 pts, in bones 4 pts; 2 pts died without PD, of cardiovascular disease. Toxicity of induction CT was minimal. During TRT and CT, grade 3 neutropenia, thrombocytopenia, and anemia occurred in 8 pts, 3 pts, and 3 pts respectively, grade 4 neutropenia and thrombocytopenia in one pt each. Nine pts received red cell transfusions, one pt platelet transfusion. One patient developed esophageal fistula with grade 4 toxicity, 3 pts had grade 3 esophagitis, 2 pts grade 3 infections, and one pt grade 3 dermatitis and elevation of liver enzymes. Conclusions: This regimen is effective, well tolerated, and appears to be an excellent choice for stage III NSCLC. Sponsored by Eli Lilly Canada. [Table: see text]