tbuckley/cabot-search huggingface dataset:
Optimum timing of gefitinib therapy in metastatic non-small cell lung cancer (NSCLC) patients
Authors: J. Ayllon, V. Plazanet, E. Fabre Guillevin, E. Banu, B. Bonan, S. Oudard, F. Le Pimpec Barthes, N. Theou, H. Sors, J. M. Andrieu
Journal: Journal of Clinical Oncology (2005)

7323 Background: Gefitinib (IressaTM) is approved in for use as monotherapy for the treatment of patients (pts) with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapy (CT). CT that include a taxane, vinorelbine or gemcitabine remains the alternative for the second- and third-line CT. The modality of combining these CT in a sequential manner and the place of target therapies could have a major impact on survival. Methods: The present analysis evaluates the efficacy of Gefitinib for metastatic NSCLC pts. The primary outcome measure was the impact of the moment of gefitinib initiation on Time from Primary Diagnosis (TPD). TPD was calculated from primary diagnosis until death or last follow-up. Cox hazard regression analysis was performed, stratified according the initial stage of disease (AJCC 1997) and baseline ECOG performance status (PS). Progression-free survival (PFS), overall survival (OS) and TPD were estimated by Kaplan-Meier method. Gefitinib was given at a dose of 250 mg daily until disease progression in an expanded access program. Results: A retrospective analysis was performed on 71 pts, treated with gefitinib from August 2001 to October 2004 in a single institution. Median age was 59 year (range 44–85), sex M/F: 52/19 pts, ECOG PS: 0–1/2–3: 20/44 pts. Pts distribution according to treatment line was:17 pts (24%) receiving gefitinib as second-line, 16 pts (23%) as third-line, 23 pts (32%) as fourth-line CT. There were 4 pts (6%) with partial response, and 15 pts (21%) with stable disease. The median PFS and OS were 2.6 months (95% CI,1.8–3.4 months) and 5 months (95% CI,3–7 months), respectively, independently of CT line number. The median TPD for our cohort was 18.5 months (95% CI, 15.7–21.2 months). A negative and strong association (Cox coefficient = -0.6) between TPD and the moment of gefitinib initiation was observed (P=0.006, two-sided), demonstrating a major impact of precocity of treatment initiation. Conclusions: Our analysis demonstrates that the prognosis in these patients depends on the precocity of gefitinib initiation. These data may be useful in the design of clinical trials to earlier introduce target therapy, combined with chemotherapy. No significant financial relationships to disclose.
Randomized, double blind, phase II trial: Epigenetic therapy (valproic acid and hydralazine) plus chemotherapy versus placebo plus neoadjuvant chemotherapy in operable and locally advanced breast cancer.
Authors: C. Arce, A. Duenas-Gonzalez, A. Mohar, F. U. Lara Medina, V. Perez-Sanchez, E. Bargallo Rocha
Journal: Journal of Clinical Oncology (2011)

e13550 Background: Epigenetic regulation is critical in normal growth and development. In breast cancer, epigenetic changes are involved in pathogenesis and progression. Those epigenetic changes are potentially reversible. In a proof-of-concept study of demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, added to neoadjuvant AC in locally advanced breast cancer shows gene reactivation in primary tumors, with safe profile. The aim of this study was to evaluate the efficacy of epigenetic therapy plus chemotherapy vs. placebo plus chemotherapy in terms of pathologic complete response (pCR). Methods: We conducted a double blind, randomized, phase II trial; we included patients with operable and locally advanced breast cancer, with ECOG 0-1. Patients with HER2 overexpression were excluded. Patients received epigenetic therapy or placebo for 1 week, after that 4 cycles of FAC followed by weekly paclitaxel for 12 weeks. At the end of chemotherapy surgery was done. Protocolo was approved by local ethics committee. Results: 33 patients were included, 16 patients received chemotherapy plus placebo and 17 received chemotherapy plus epigenetic therapy, median age at diagnosis was 47 years-old (range 33-65), they were well balanced according clinical stage, hormone receptors status and histological characteristics. After neoadjuvant therapy, four patients were considered inoperable, one in placebo arm and 3 in experimental arm (NS), pCR was reached in 7 patients (70%) in placebo arm vs. 3 patients (30%) in experimental arm without statistical significance. None of them developed serious adverse events. Conclusions: The addition of epigenetic therapy to conventional chemotherapy does not increase the pCR. We need to identify responders patients according epigenetic profile.
Modified high-dose melphalan and autologous stem cell transplantation (mHDM/SCT) in the treatment of AL amyloidosis (AL) and/or high-risk myeloma (hM): Analysis of a Southwest Oncology Group trial.
Authors: V. Sanchorawala, V. Bolejack, J. Crowley, A. Hoering, K. T. Finn, S. Fennessey, D. C. Seldin, B. Barlogie
Journal: Journal of Clinical Oncology (2010)

8022 Background: Intensive treatment for AL and hM with HDM/SCT is effective; however, benefits have not been explored in a multi center study. We designed a trial of two cycles of mHDM/SCT at 100mg/m2 through Southwest Oncology Group (S0115). Methods: The primary objective was overall survival and secondary objectives were hematologic responses, tolerability and feasibility. Eligibility for patients with AL required tissue diagnosis, underlying plasma cell dyscrasia, performance status of ≤2, and adequate cardiopulmonary function. Eligibility for hM patients required age ≥ 70 years and/or serum creatinine of > 2 mg/dL or calculated creatinine clearance of < 50 ml/kg/min. Results: From 2004 to 2009, 70 patients with AL and 30 patients with hM were enrolled at 16 centers. The median age was 63 years (range; 32-79), and the median number of organs involved for AL was 2 (range, 0-8). There were 21 patients (30%) with cardiac involvement with AL. The median serum creatinine level was 1.7 mg/dL (range 0.8-10) for patients with hM. There are 65 patients with AL and 25 patients with hM eligible for survival and adverse event analysis at this time. The treatment-related mortality (TRM), defined as deaths within 100 days of registration (even without protocol-directed treatment) was 10% (n=7, 5 removed from study after registration) for AL and 11% (n=3, 2 removed from study after registration) for hM. Grade 3 and higher non-hematologic adverse events by CTCAEv3.0 were experienced by 71% (n=46) of AL and 68% (n=17) of hM patients. The median survival is 54 months for AL and is not reached for hM with a median follow up for surviving patients of 27.1 months (range; 0.3-60.5). Three year survival is 63% and 60% for AL and hM respectively. Median progression-free-survival is 38 months for AL and not reached for hM. Hematologic response was 35% (n=11) for AL and 56% (n=5/9) for hM. Conclusions: This experience demonstrates that careful selection of patients as well as using mHDM for SCT in patients with AL and hM, even in the setting of a multi-center study, can lead to prolonged overall survival with an acceptable morbidity and TRM. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene, Johnson & Johnson, Millennium
Long term efficacy of rituximab in follicular lymphoma (FL) and polymorphism in IgG Fc receptor FcγRIIIa/FcγRIIa genes
Authors: G. Cartron, M. Orhesser, P. Solal-Celigny, G. Salles, P. Colombat, N. Varoqueaux, H. Watier
Journal: Journal of Clinical Oncology (2005)

6598 Background: FCGR3A coding for the FcγRIIIa receptor displays a functional dimorphism (FCGR3A-158V/F) and human IgG1 have a higher affinity for FCGR3A-158VV NK cells and increased ADCC compared to FCGR3A-158FF NK cells (Dall’Ozzo et al. 2004). We and others have previously demonstrated that FCGR3A-158VV genotype was associated with a higher rate of clinical and molecular response to rituximab in 49 patients receiving rituximab (anti-CD20 chimeric IgG1) alone for previously untreated low-tumor burden FL (Cartron et al. 2002). We have recently reported (Solal-Celigny et al. 2004) that 28% of all these patients and 34% of responders remain free of relapse more than 5 years after treatment. Weng et al. (2003) have also reported that FCGR2A-131HH patients have a better response and PFS after treatment by rituximab. The aim of this study was to determine the influence of FCGR3A and FCGR2A polymorphisms on the clinical outcome in the long-term responders. Methods: The FCGR3A and FCGR2A genotypes were determined by a nested PCR (PCR-ASRED) in the 49 patients who have been treated with rituximab (375 mg/m2 x 4) for FL. Results: FCGR3A-158VV patients represented 20% of the population, FCGR3A-158FF 35% and heterozygous patients 45% (FCGR3A-158F carriers). FCGR2A-131HH patients represented 20% of the population, FCGR2A-131RR 31% and heterozygous patients 49% (FCGR2A-131R carriers). The median PFS was 18 months for the whole population and was 25 months and 16 months for FCGR3A-158VV and FCGR3A-158F carriers patients (log-rank test, p = 0.8), and 23 months and 16 months for FCGR2A-131HH and FCGR2A-131R carriers, respectively (log-rank test, p = 0.7). Among, the 14 patients free of relapse more than 5 years after rituximab treatment, 2 (15%) and 12 (85%) were FCGR3A-158VV (p = 0.7) and FCGR3A-158F carriers, and 3 (20%) and 11 (80%) were FCGR2A-131HH and FCGR2A-131R carriers, respectively (p = 1.0). Conclusions: After a long term follow-up, neither FCGR3A-158VV nor FCGR2A-131HH genotype are significantly associated with a longer PFS, despite the fact that FCGR3A-158V homozygosity is associated with a higher rate of clinical and molecular response to rituximab in low-tumor burden FL patients. No significant financial relationships to disclose.
Outcome of chemoradiotherapy followed by surgery for locally advanced T4 thoracic esophageal squamous cell carcinoma.
Authors: Yasunori Akutsu, Tsuguaki Kono, Masaya Uesato, Isamu Hoshino, Kentaro Murakami, Hisahiro Matsubara
Journal: Journal of Clinical Oncology (2014)

170 Background: Chemoradiotherapy (CRT) is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC). The outcome of CRT with/without following surgery for locally advanced ESCC was demonstrated. Methods: 1,235 new ESCC patients from 2001 to 2012 were obtained. From these, locally advanced thoracic ESCC was selected. If the patients showed resectability with down-staging after CRT, a subsequent surgery was performed. For the remaining cases, an additional CRT was prescribed, following by a re-evaluation for surgery. If down-staging and resectability were achieved, the patients underwent surgery. In the surgery group, pathologic effectiveness in the primary tumor and lymph nodes was observed and survivals both in surgery and non-surgery group were calculated. Results: From 1,235 new ESCC patients, 153 patients (12.4%) were of locally advanced thoracic ESCC. Among these, 28 patients (18.3%) showed finally down-staging of the primary tumor and could undergo following surgery. 12 patients (7.8%) could obtain down-staging and underwent surgery (surgery H group). In total, 40 patients (26.1%) could undergo surgery (surgery group). The rate of residual tumor in the primary tumor was detected in 32 cases (80%). The 5-year overall survival was 33.0% in the surgery group and 10.0% in the non-surgery group (P=0.002). The 5-year cause-specific survival was 65.0% in the surgery group and 18.1% in the non-surgery group (P=0.002). Conclusions: CRT for locally advanced thoracic ESCC is the standard modality and following surgery have benefits. However, the outcome is not satisfactory and further improvements of treatments for such cases are requested.
Psychosocial distress in vulnerable patient populations: What happens after screening?
Authors: Theora Cimino, Margot Albert, Leslie Safier, Heather A. Harris, Anne Kinderman
Journal: Journal of Clinical Oncology (2016)

114 Background: The Commission on Cancer mandates psychosocial distress screening for patients with cancer, as well as documentation of referrals made to address sources of distress. Patients in safety net settings, who are vulnerable to significant economic and social stressors, may benefit from such screening; however, it is unclear if patients can access needed services and if their needs change over time. We examined the experience of cancer patients in an urban safety-net healthcare system to identify areas of improvement in the provision of support services. Methods: We performed a retrospective cohort analysis of patients screened for psychosocial distress during 2015. We reviewed medical records from initial oncology visits for results of screening and referrals made at that time. Those who reported a distress score of ≥ 4 were eligible for telephone follow up, which occurred 1-12 months after initial screening. Patients who agreed to participate completed a telephone survey that assessed current distress and referral status. Results: Of 113 patients who completed a psychosocial distress screen, 60% (n=68) reported a distress score of ≥ 4 and were called for follow up. Of these 68 patients, 17 (25%) had died or enrolled in hospice, 16 (25%) could not be reached after 3 attempts, 7 (10%) had transferred care, and 1 declined to participate. 26 patients (38%) completed telephone follow up. Patients reported an average distress score of 3.8, compared to 6.2 at their first visit. While “worry” was the most commonly reported problem at baseline, “pain” was the most common problem at follow up. For these 26 patients, a total of 69 referrals were made at their first visit, 59% of which were not accessed. 58% of the reasons given for not accessing referrals cited factors other than lack of interest, including requiring more information, not hearing back from the organization, and transportation issues. Conclusions: Significant barriers, such as difficulty with referrals and follow up, may interfere with providing care to a diverse, underserved population of patients who report high levels of distress at their first oncology visits. Alternative approaches, including primary or specialty palliative care, may be needed in this population.
Concordance among gene-expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen.
Authors: A. Prat, J. S. Parker, C. Fan, M. C. U. Cheang, L. D. Miller, J. Bergh, S. K. L. Chia, P. S. Bernard, T. O. Nielsen, M. J. Ellis, L. A. Carey, C. M. Perou
Journal: Journal of Clinical Oncology (2011)

502 Background: ER-positive (ER+) breast cancer includes all of the intrinsic molecular subtypes, although the luminal subtypes predominate. In this study, we evaluated the prognostic ability and biologic significance of 6 independent gene-expression signatures in patients (pts) with ER+ tumors treated only with adjuvant tamoxifen. Methods: Four public microarray data sets and added clinical data were combined. Signatures evaluated: OncotypeDX, Mammaprint, PAM50, Rotterdam 76-gene, endocrine sensitivity index (SET) and the estrogen-induced gene set. We also included qRT-PCR PAM50 data from another large cohort (Nielsen et al. 2010). Distant relapse-free survival (DRFS) at 8.5 yrs was estimated by Kaplan-Meier and log-rank tests. Multivariable analyses were done using Cox regression analysis. Risk scores across the PAM50 subtypes were compared using a student's t-test. Mean Harrell's C-index after 200 repetitive cross-validations was used to evaluate the performance prediction. Results: 686 node- and 731 node+ pts were identified. PAM50 subtype distribution was LumA (46%), LumB (39%), HER2-enriched (7%), Basal-like (2%) and Normal-like (6%). Most signatures discriminated the relatively good prognosis LumA tumors from the poorer prognosis LumB/HER2-enriched/Basal-like tumors and were prognostic in all pts (p<0.001), in pts with node- (p<0.001) and node+ disease (p<0.05). In terms of performance, the majority showed similar C-Index scores in node- (∼0.73) and node+ (∼0.60) disease. A small increase in prognostic capacity in node- disease (∼0.75) was observed when these signatures were combined into a multivariable Cox model. Low-risk tumors (>90% DRFS at 8.5 yrs) were only identified within node- disease, and these were mostly (81-100%) of the LumA subtype. Conclusions: In a large ER+ patient cohort, prognostic and ER-regulated gene signatures are tracking similar biology and show significant agreement in outcome predictions; however, their performance in node+ appears minimal. From a clinical perspective, these signatures should specifically aid in identifying pts with node-negative LumA breast cancers that might be considered for adjuvant endocrine therapies alone.
EF5 as a predictive biomarker for activation of the new hypoxia-targeting prodrug SN30000.
Authors: J. Wang, A. Foehrenbacher, J. Su, R. Patel, M. P. Hay, K. O. Hicks, W. R. Wilson
Journal: Journal of Clinical Oncology (2011)

e13597 Background: SN30000 (CEN-209), a benzotriazine-N-oxide, is a second generation analogue of tirapazamine (TPZ) and is currently in late stage preclinical development as a hypoxia-targeted prodrug. Here we test the hypothesis that the 2-nitroimidazole imaging agent EF5, currently in clinical development for both immunohistochemical and PET imaging of hypoxia, can also detect the one-electron reductases required for activation of this class of bioreductive prodrug. Methods: Aerobic and hypoxic covalent binding of 14C-EF5, and reductive metabolism of TPZ and SN30000 by LC/MS/MS, was determined in 14 human tumor cell lines and in SiHa and HCT116 transfectants that over-express NADPH:CytP450 oxidoreductase (CYPOR). The DNA damage response to the bioreductive prodrugs was measured by γH2AX formation, and cell killing by clonogenic assay. Bioreductive metabolism was modulated in HCT116 tumor xenografts either by over-expression of CYPOR or breathing of hyperbaric oxygen, air, or 10% oxygen following SN30000 administration. Results: Over-expression of CYPOR induced similar increases in EF5 binding and reduction of TPZ and SN30000, and similar enhancement of γH2AX formation in response to the bioreductive prodrugs in isogenic paired cell lines. Hypoxic EF5 binding and reduction of TPZ and SN30000 were highly correlated in the panel of human tumor cell lines (r2 = 0.65, p = 0.0005) suggesting that EF5, TPZ and SN30000 share one-electron reductases. In HCT116 xenografts, CYPOR over-expression also significantly increased EF5 binding and SN30000 reduction, and modification of tumor hypoxia caused similar changes to the bioreductive activation of both agents. This resulted in a strong correlation between EF5 binding and SN30000-induced γH2AX formation (r2 0.68, p < 0.0001) at the individual tumor level. Conclusions: EF5 binding is a promising stratification biomarker for benzotriazine-N-oxide bioreductive prodrugs because of its potential for interrogating one-electron reductase activity as well as hypoxia in individual tumors.
Economic evaluation of adjuvant hormonal options in postmenopausal women with breast cancer: Tamoxifen vs tamoxifen then exemestane vs anastrazole
Authors: C. Skedgel, D. Rayson, R. Dewar, K. Potvin, T. Younis
Journal: Journal of Clinical Oncology (2005)

6040 Background: Adjuvant anastrazole (ANA) for 5 years or tamoxifen followed by exemestane (TAM-EX) for 2.5 years each have become acceptable alternatives to tamoxifen (TAM) for 5 years in postmenopausal women with breast cancer. An economic evaluation was undertaken to compare the cost-effectiveness (CE) of ANA and TAM-EX relative to TAM alone. Methods: A Markov model was developed to calculate cumulative costs and disease free survival years (DFSY) for each alternative over 5- and 20-year time horizons. The analysis took a direct payer perspective. Drug costs were based on average wholesale prices in Canada in 2004. Costs of adverse events and relapses were not included in the primary analysis. The baseline TAM DFS rate and hazard ratios associated with ANA and TAM-EX were taken from the published ATAC and IES trials. Beyond the 5-year treatment period, hazard ratios for ANA and TAM-EX were set to 1.0, reflecting conservative estimates of benefit. Both costs and benefits were discounted at 3%. Results: Both ANA and TAM-EX were associated with gains in DFS. Per 1,000 patients treated, ANA resulted in an incremental gain of 56.4 DFSY after 5 years and 162.3 DFSY after 20 years relative to TAM alone. TAM-EX had an incremental gain of 31.6 and 164.9 DFSY per 1,000 treated relative to TAM alone after 5 and 20 years, respectively. Incremental costs were $6.35 million per 1,000 treated with ANA and $2.90 million per 1,000 treated with TAM-EX. The CE of ANA relative to TAM alone was $112,510 per DFSY after 5 years and $39,124 per DFSY after 20 years. The CE of TAM-EX relative to TAM alone was $91,604 and $17,570 per DFSY after 5 and 20 years. Comparing TAM-EX and ANA directly, ANA had an incremental cost of $139,174 per DFSY gained at 5 years and was dominated by TAM-EX at 20 years. Conclusions: Although the short-term CE of ANA and TAM-EX is unfavourable, projecting the benefits over a longer horizon results in CE ratios well below $50,000 per DFSY gained. Both alternatives appear to be cost-effective options for postmenopausal women with breast cancer. These results will be updated based on the recently reported DFS and adverse events rates of the ATAC and IES trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Pfizer
A novel prognostic classification for overall survival in Japanese patients with untreated metastatic renal cell carcinoma.
Authors: N. Shinohara, S. Maruyama, T. Abe, A. Sazawa, T. Kamai, M. Takahashi, K. Tatsugami, S. Yokoi, H. Kanayama, T. Deguchi, S. Naito, K. Oba, K. Nonomura
Journal: Journal of Clinical Oncology (2011)

e15051 Background: Although MSKCC risk classification is standard prognostic criteria for Caucacian patients (pts) with metastatic renal cell carcinoma (mRCC), it is questionable whether this classification is suitable for Japanese pts with mRCC who are more sensitive to immunotherapy. The present study was conducted to define outcome data and prognostic classification for Japanese pts with mRCC. Methods: Baseline characteristics and outcomes on 473 pts with untreated mRCC were collected from Hokkaido university hospital and our affiliated hospitals between 1995 and 2005. 361 (76%) pts received IFN and no pt was treated with molecular-targeted drugs. Cox proportional hazards model, followed by bootstrap internal validation, was used to identify independent prognostic factors for overall survival (OS). Furthermore, independent dataset from four university hospitals in Japan was used for external validation. The predictive accuracy was measured by c-index. Results: Median OS for all pts was 22.2 months (95%CI 18.7-27.6). From the univariate and multivariate analysis, three of the five adverse prognostic factors according to the MSKCC risk classification were independent predictors for the OS; time from RCC diagnosis to metastasis (<12 months), LDH (>1.5X the upper limit), and corrected Ca (> 10). Each patients was assigned to one of three risk groups: the low-risk (0 factor; n=119), in which median OS was 65.2 months and 3-year OS (3y OS) was 65.6%; the intermediate-risk (1 factor, n= 242), in which median OS was 19.5 months and 3y OS was 34.4%; and the poor-risk (2 or 3 factors, n=59), in which median OS was 8.7 months and 3y OS was 10.4% (log-rank P <0.0001). The c-index of the prognostic classification was 0.794 in original dataset and 0.795 in 400 random bootstrap samples. Patients was clearly classified in specific population (IFN-treated pts, pts with lung metastasis or osseous metastasis). In the independent data set for the external validation, the c-index was 0.816. Conclusions: The novel prognostic classification is easily applicable for Japanese patients with previously untreated metastatic RCC and would be incorporated into patient care and into clinical trials performed in Japan.