tbuckley/cabot-search huggingface dataset:
Randomized, phase II trial comparing amrubicin with topotecan in patients (pts) with previously treated small cell lung cancer (SCLC)
Authors: S. Sugawara, A. Inoue, K. Yamazaki, Y. Saijo, K. Gomi, O. Ishimoto, F. Hommura, M. Maemondo, T. Suzuki, T. Nukiwa
Journal: Journal of Clinical Oncology (2008)

8042 Background: Amrubicin (A), a new anthracycline agent, and topotecan (T) are both active for previously treated SCLC. No comparative study with these two agents has been reported. This randomized phase II study was conducted to select A or T for future evaluation in a phase III setting. Methods: Previously treated SCLC pts were randomized to receive A (40 mg/m2, day1–3, every 3weeks) or T (1.0 mg/2, day1–5, every 3 weeks). The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS) and toxicity profile. Assuming that ORR of 40% in eligible pts would indicate potential usefulness while ORR of 20% would be the lower limit of interest, with alpha = 0.05 and beta = 0.10, the estimated accrual was 27 pts in each arm. Results: From February 2004 to July 2007, 60 pts were enrolled from 12 institutions. One patient in A arm did not receive any protocol treatment due to rapid disease progression and 59 pts were evaluable for efficacy and safety. Patient characteristics were: Male/Female 49/10; median age 67 (range 32–78); Performance status 0/1/2 31/19/9; Sensitive relapse (S) / Refractory relapse 36/23. The median numbers of treatment cycles were 3 (range 1–7) in A arm and 2 (range 1–4) in T arm. ORRs and disease control rates (DCRs) were 38% (95%CI: 20–56) and 79% (95%CI: 64–94) for A, and 13% (95%CI: 1–25) and 47% (95%CI: 29–65) for T, respectively. In subset analysis on type of relapse, ORRs and DCRs were 53% and 88% for A, and 21% and 63% for T in S pts, and 17% and 67% for A, and 0% and 18% for T in R pts. Median PFS on A arm was 105 days and on T arm was 60 days. Neutropenia was significantly severe in A arm. One treatment related death due to infection was observed in A arm. Conclusions: A is more active agent than T with acceptable toxicity for previously treated SCLC pts, especially for pts with R. Further evaluation of A as a single agent or in combination is warranted in SCLC. No significant financial relationships to disclose.
Evaluating the agreement between the empirical volumes of tumor lesions and the estimated volumes of tumor lesions based on the longest diameter.
Authors: Ruediger P. Laubender, Michael Schlichting, Ute Sartorius, Dominik Paul Modest, Ulrich Robert Mansmann, Volker Heinemann, Anno Graser
Journal: Journal of Clinical Oncology (2012)

635 Background: Tumor lesions are commonly evaluated by RECIST or WHO criteria, which involves reducing the development of a three-dimensional tumor to a two-dimensional process. However, volume measurements might reflect the clinical impact of the disease process more precisely. Therefore, we investigated if the volume of a tumor lesion can be reconstructed from RECIST- or WHO-based measurements. Methods: 20 colorectal cancer patients underwent routine staging MDCT examinations as part of the multicenter phase II CIOX trial comparing cetuximab + XELOX versus cetuximab + XELIRI. Two hepatic target lesions per patient were defined at baseline and measured using 1) semi-automated volumetry (Siemens Syngo Via Oncology, Siemens Healthcare) with manual correction and 2) semi-automated measurement of the longest diameter (LD) according to RECIST 1.1 and the corresponding longest orthogonal diameter (LOD). Patient lesions were followed over time using the same measurement strategies. An algorithm was developed for reconstructing the volume of a lesion based on the LD and the corresponding LOD. Agreement of the volume data generated by both methods was analyzed by a Bland-Altman plot. The limits of agreements were calculated using a variance components model considering repeated tumor assessments based on the log-transformed sum over the volume of a patient’s lesions. Results: 151 lesions from the 20 patients were measured at 73 tumor assessments. Volume was slightly overestimated by the algorithm compared to the volumetric measurements (p = 0.07). The Bland-Altman plot showed good agreement (mean difference −0.05, limits of agreement [−0.40, 0.30]). As expected, three out of the 73 measurements fell outside the limits of agreement. Conclusions: The proposed algorithm for the WHO-based reconstruction of the tumor volume provides a good approximation to the true sum of the volumes of the lesions. In future studies, volumetric tumor information can be included even if not all centers have full volumetric software available. This enables further research on the impact of changes in tumor volume on disease prognosis and/or prediction of treatment efficacy.
Esophageal cancer in young patients: Is aggressive treatment associated with better outcomes?
Authors: Alexander D Glaser, Miles Cameron, Khaldoun Almhanna, Sarah E. Hoffe, Jacques Fontaine, Jessica M. Frakes, Jose Mario Pimiento
Journal: Journal of Clinical Oncology (2016)

54 Background: Recent studies suggest that survival in young patients with esophageal cancer (EC) is worse than their older counterpart, secondary theoretically to more aggressive disease and late stage at diagnosis. The aim of this study is to compare stage at diagnosis, patterns of treatment and outcomes of young patients with EC at Moffitt Cancer Center (MCC). Methods: Patients with EC treated surgically between 1996 and 2014 at MCC were recorded at an IRB approved database. We divided the patients into two cohorts, those younger or older than 50 years of age. Demographics, pre-treatment clinical data, therapeutic courses and treatment outcomes were analyzed. We compared clinical variables and defined p &lt; 0.05 as statistically significant. Overall survival was examined using the Kaplan-Meier method. Results: Of the 816 patients treated surgically for EC 86 (10.5%) were &lt; 50 years old. The majority of patients were male 622(85.2%) vs. 67(77.9%) in the younger group (p =.084). Of the 816 patients, 569 had pre-treatment staging information available. Pre-treatment clinical staging for the older and younger cohorts was, Stage0/TIS = 13(2.2%) vs. 1(1.4%); Stage I = 90(15.3%) vs. 6(8.3%); Stage IIA = 119(20.3%) vs. 16(22.2%); Stage IIB = 88(15.0%) vs. 8(11.1%); Stage III = 269(46%) vs. 40(55%); Stage IV = 8(1.4%) vs. 1(1.3%)(p =.44). Younger patients were more likely to receive neoadjuvant therapy (75.6% vs.62.1%)(p =.013), and also neoadjuvant combined with adjuvant therapy, 24(41.4%) compared to 48(12.1%) in the older cohort (p =.001). Pathological complete response (pCR) rate was higher in older patients (43.2% vs 32%)(p =.204); Median survival was higher in younger cohort 64.3 vs. 56.4 months. Neither of these were statically significant (p =.516). Conclusions: This retrospective study with several variables only included surgical patients. In our experience, younger age was not associated with late stage presentation. Younger patients were more likely to be treated with neoadjuvant therapy, and despite similar pathologic response rates they were more likely to receive adjuvant therapy. Although younger patients received more aggressive treatment, their overall survival did not differ from their older counterparts.
Does overexpression of VEGFR and TIMP2 predict survival in primary cervical cancer (CC) patients? Results of a companion protocol of the randomized, phase III adjuvant trial of simultaneous cisplatin radiochemotherapy versus sequential carboplatin and paclitaxel followed by radiotherapy.
Authors: C. Fotopoulou, E. I. Braicu, R. Chekerov, R. Richter, M. Mentze, K. Pietzner, C. Pop, O. Camara, G. Oskay-Özcelik, S. Kuemmel, J. U. Blohmer, W. Lichtenegger, J. Sehouli
Journal: Journal of Clinical Oncology (2011)

e15507 Background: Aim of the study was to analyse the expression-profile of IGF1, IGFBP3, sICAM1, sVCAM1, MMP2, MMP9, TIMP2, VEGF, VEGFD, VEGFC and VEGFR in patients with FIGO-stage high-risk Ib-IIb CC. Methods: Serum from 68 high-risk CC patients primarily operated and subsequently treated within a phase-III-trial with either simultaneous cisplatin radiochemotherapy or sequential systemic carboplatin and paclitaxel followed by percutaneous irradiation were analysed using the ELISA method following a standard protocol. Results: Median age at time of diagnosis was 46 years (range 30-70 years). The most common histological types were squamous cell (72.1%) and adenocarcinoma (25%). All patients underwent a primary radical hysterectomy with pelvic and/or paraaortic lymphadenectomy. Overexpression of VEGFR, MMP2 and IGFBP3 were significantly associated with suboptimal surgical results in terms of microscopic positive tumor margins (p = 0.02, p=0.022 and p=0.027, respectively). For the cut-off value of 100pg/ml, an overexpression of VEGFR was associated with poor OAS and PFS (p=0.017 and p=0.015, respectively). Decreased concentration of TIMP2 was also associated with a poor OAS and PFS (p=0.045 and p=0.043, respectively). In the multivariate analysis, TIMP2 expression in serum was the only independent prognostic factor for OAS (HR= 6.51; 95%CI=1.17-36.01; p=0.032). Conclusions: Overexpression of targets associated with tumor invasion, cell migration and angiogenesis seems to be of prognostic value regarding survival in patients operated due to primary high risk CC. Further analyses are warranted to allow an implementation of such markers into the daily clinical management of those patients.
Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab
Authors: J. Sperinde, S. Ali, K. Leitzel, E. Fuchs, W. J. Köstler, A. Paquet, J. Weidler, W. Huang, M. Bates, A. Lipton
Journal: Journal of Clinical Oncology (2009)

1059 Background: Many HER2-positive patients with metastatic breast cancer (MBC) fail to respond to trastuzumab. We previously reported that precise quantitation of HER2 expression (H2T) by the HERmark assay identified a sub-population of IHC 3+, FISH(+) (positive) patients with low H2T levels that responded poorly to trastuzumab (Lipton, San Antonio Breast Cancer Symposium 2008, abs #32). Here we identify a sub-population of FISH(+) patients with very high H2T levels, that experience clinical outcomes that are indistinguishable from those of FISH(-) (negative) patients with low H2T levels. Methods: The HERmark assay was used to measure H2T in formalin-fixed, paraffin-embedded (FFPE) primary breast tumor specimens from 99 women treated with trastuzumab for MBC. Specimens were also tested by central FISH. A sub-population treatment effect pattern plot (STEPP) was generated to examine the progression-free survival (PFS) rate at 12 months after treatment with trastuzumab across the distribution of H2T. Kaplan-Meier (KM) analyses were performed comparing the PFS of FISH(-), H2T low (log 10 H2T &lt; 1.25) patients with those of FISH(+), H2T high (log 10 H2T ≥ 1.95) and FISH(+), H2T intermediate (1.25 &lt; log 10 H2T &lt; 1.95) groups. Cutoffs were identified by lowest p-value in a positional scanning analysis. Results: The PFS rate improved gradually with increasing H2T in STEPP analyses. At the highest levels of H2T, an abrupt decrease in the PFS rate was observed, consistent with a reduction in susceptibility to trastuzumab. KM analyses demonstrated that patients who were FISH(+), H2T intermediate had a significantly longer PFS than patients who were FISH(-), H2T low (median PFS 12.6 vs. 4.5 mos; HR = 0.34; p &lt; 0.0001). Patients that were FISH(+), H2T high experienced a PFS that was no better than patients that were FISH(-), H2T low (median PFS 4.6 vs. 4.5 mos; HR = 0.87; p = 0.68). Conclusions: Precise quantitation of HER2 expression levels allows the identification of multiple sub-populations of HER2(+) patients that have different clinical outcomes on trastuzumab. MBC patients with very high levels of H2T could represent a sub-group with de novo resistance to trastuzumab who may benefit from combined therapy. [Table: see text]
Relationship between components of the comprehensive geriatric assessment (CGA), chemotherapy dose intensity, and overall survival in a colorectal cancer (CRC) cohort age 65 and older.
Authors: E. E. Ramsdale, B. N. Polite, K. A. Bylow, H. L. Kindler, W. Dale
Journal: Journal of Clinical Oncology (2011)

9000 Background: 75% of CRC patients (pts) are >65 years. Age and ECOG PS alone may be insufficient to predict chemotherapy tolerance and clinical outcomes. This prospective trial investigates the efficacy of CGA for predicting these endpoints. Methods: CRC pts ≥65 years and eligible to receive chemotherapy were enrolled between Feb. 2006 and Feb. 2009 (n = 38). Baseline ECOG PS and CGA measures, including functional status, performance status, cognition, comorbidities, and nutrition were collected using validated tools. Chemotherapy administration was standardized using ‘relative dose intensity’ (RDI), a ratio of received to expected doses for the first 2 months of therapy. Overall survival (OS) data was collected through Dec. 2010. Results: Median age was 72 (range: 65-89); 63% male; 50% African American, 47% white, 3% Hispanic; 79% with stage IV disease at time of enrollment. RDI was most correlated with performance status as measured by short physical performance battery (SPPB, r2=0.25, p=0.003) and total comorbidities (r2=0.20, p=0.006). ECOG PS had the strongest correlation with RDI>0.85 (p=0.02). OS was associated with ECOG PS (HR 1.8, p=0.05), ADL impairment (HR 5.6, p=0.005), and Vulnerable Elders Survey (VES-13, HR 5.3, p=0.002), but only VES-13 (HR 15.61, p=0.016) was significant in a backward stepwise multivariate regression model. Age was not associated with either RDI or OS. Conclusions: ECOG PS was associated with completing RDI>85%. SPPB may help further risk-stratify. VES-13, a validated 13-item questionnaire which is easily administered in clinic, was the strongest correlate of OS, stronger than age or ECOG PS. Age was not correlated with completion of full dose chemotherapy or OS in this older cohort. Geriatric screening measures including SPPB and VES-13 should be used in addition to ECOG PS to risk-stratify older patients with CRC.
Primary and secondary endpoint analysis of N08C9 (Alliance): A phase III randomized study of sulfasalazine versus placebo in the prevention of acute radiation enteritis.
Authors: Matthew J. Iott
Journal: Journal of Clinical Oncology (2015)

562 Background: An interim futility analysis at ASTRO 2013 led to early closure of N08C9 (Alliance), a randomized controlled trial (RCT) comparing sulfasalazine (SSZ) versus placebo (PBO) in the prevention of radiation enteritis during pelvic RT. This is the full analysis of the primary endpoint (PE) and secondary endpoints (SEs) of the trial. Methods: A multi-institutional RCT conducted by the Alliance for Clinical Trials in Oncology assessed the effect of 1000 mg SSZ b.i.d. versus PBO b.i.d. in the treatment of pelvic RT related enteritis. Study participants (SPs) received the study agents during RT and for 4 weeks afterwards. The PEwas the maximal severity of diarrhea toxicity (CTCAE version 4.0) during and up to 6 weeks after RT. SEs, including the maximum severity of diarrhea (MSD) and the duration of MSD, rectal bleeding, abdominal cramping, tenesmus, and constipation, were graded weekly during RT by a health care provider. Bowel function was assessed using a self-administered bowel function questionnaire weekly during RT, afterwards at 6 weeks, and at 12 and 24 months. A two-sided 0.05-level Wilcoxon rank-sum test was used to test the equality of the distributions of MSD grades. The planned study size was 128 SPs. Results: 87 SPs were enrolled in the study between 4/29/2011 and 5/13/2013, with evenly distributed baseline factors. Toxicity data were available in 84 SPs during RT and in 54 SPs in the 6 weeks following RT. There was no significant difference in the distribution of MSD grades between the SSZ and PBO arms (p=0.41 regardless of attribution; p=0.09 at least possibly attributed to the study agent). No significant differences were observed in SEs during RT and after RT, except the abdominal pain occurring after completion of RT was higher in SPs receiving SSZ (p=0.02). More SPs required antidiarrheal agents on the SSZ arm (49% vs. 29%, p=0.06). Conclusions: Despite prior single institution RCT’s suggesting a benefit for SSZ (Kilic 2001; Pal 2013) in this clinical context, the results of this large, multi-institutional trial demonstrate that SSZ does not reduce the risk of enteritis and may worsen acute GI toxicity during pelvic RT. Clinical trial information: NCT01198145.
Prediction of prognosis in patients treated with everolimus for extrapancreatic neuroendocrine tumors by a single nucleotide polymorphism in PHLPP2.
Authors: Seth Albert Bellister, Yunfei Zhou, Eric Sceusi, Lee M. Ellis, James C. Yao
Journal: Journal of Clinical Oncology (2013)

163 Background: Rapamycin analogs (rapalogs) have improved outcomes in patients with neuroendocrine tumors (NETs). Few factors affecting response to rapalogs have been characterized. PHLPP2 is a phosphatase that inhibits PI3K-Akt-mTOR signaling. We hypothesized that an inactivating single nucleotide polymorphism (SNP) in PHLPP2 may affect outcomes in NETs treated with the rapalog everolimus. Methods: Blood was collected from 32 patients enrolled in a Phase 2 single arm trial of single agent everolimus in patients with NETs. DNA was extracted and RT-PCR products were sequenced to detect the L1016S SNP in PHLPP2. Outcomes analyses determined the role of the SNP in predicting progression-free survival (PFS), overall survival (OS), and response rates (RR) in patients with NETs treated with everolimus. Response rate (RR) assessed by RECIST criteria was evaluated as a binomial endpoint. A subset analysis was conducted to evaluate the NET site-specific role of the SNP. Results: Overall median PFS was 15.2 months (95% Confidence Interval (CI)=11.5 -18.7). The PHLPP2 SNP did not predict for a significant difference in PFS (Median PFS; wild type vs. SNP 16.8 (95% CI=14-20) vs. 11.3 (95% CI=4-19) mos., respectively, Hazard Ratio (HR)=1.2 (95% CI=0.5-3.1)), p=0.154). In a subset analysis, patients with extra-pancreatic NETs treated with everolimus with wild type PHLPP2 demonstrated increased PFS compared to patients with the SNP (Median PFS = 16.8 (95% CI=7-26) vs. 7.7 (95% CI=6-9) mos., HR=10.8 (95% CI=2-67), p=0.002). OS and RR were unaffected by the presence of the SNP in all analyses. Conclusions: In this preliminary study, the L1016S SNP in PHLPP2 may be prognostic for poorer PFS in patients with extrapancreatic NETs treated with everolimus. This study is hypothesis generating and requires validation in larger retrospective and randomized, placebo controlled studies in patients with NETs treated with everolimus.
HDAC Inhibitors, FK228 and Valproic Acid, Enhance the Effects of IL-3 or GMCSF on the Generation of Early Megakaryocytic as Well as Erythroid Precursors from Human Hematopoietic Precursors
Authors: Kohshi Ohishi, Hyou Ryuu, Kentaro Yamamura, Masahiro Masuya, Yuji Heike, Yoichi Takaue, Naoyuki Katayama
Journal: Blood (2008)
BASAL immunologic response and its modifications after treatment with ANTI-EGFR in patients with advanced colorectal cancer.
Authors: Jose M Vieitez, Marco Moro-Garcia, Paula Jiménez-Fonseca, Carlos A Echeverria de, Mar Iglesias Escudero, Luisa Sánchez Lorenzo, Maria Del Pilar Solis Hernandez, Rebeca Alonso
Journal: Journal of Clinical Oncology (2016)

626 Background: CRC patients treated with anti-EGFR having skin reactions tend to have a better outcome regardless of the presence of mutations in the RAS. This fact, repeated with various antibodies makes us think that the basal immunology, or its ability to react to these proteins is actually responsible for this phenomenon. We initiated an exploratory study to identify which parameters/immunological pathways might be related to skin reactions. Methods: Seric levels of immunoglobulins (IgG, IgA, and IgM) and complement factors (c3 and c4) were measured. Leukocyte and lymphocyte subsets were also quantified in peripheral blood. We evaluated cytotoxic activity of NK lymphocytes (CD107a expression in response to K562 cells) and activation of CD4+ and CD8+ T-lymphocytes in response to anti-CD3 stimulation (expression of CD38, HLA-DR, CD25 and CD69). Results: 17 consecutive patients were included from 29/08/2012 to 17/11/14. Median age was 66 (range 50-80), median number of organ affected 1 (range 1-3), liver affected in 8 patients. 9 Patients were treated with folfiri/panitumumab, 4 cpt11/panitumumab, 4 with panitumumab monochemotherapy. Two patients presented a partial response, median days to progression were 176 days (range 15-652). Levels of immunoglobulins, complement factors, and leukocyte subsets showed no differences between both groups of patients (with or without skin reactions). Increased T-lymphocyte percentages were found in patients without skin reactions, mainly explained by higher levels of CD8+ T-lymphocytes but with a more differentiated phenotype. Neither frequencies nor cytotoxic activity of NK-lymphocytes showed differences between patients. However, anti-CD3 stimulation induced higher activation status in CD4+ and CD8+ T-lymphocytes in patients having skin reactions, with increased levels of activation marker expression of CD38, HLA-DR, CD25 and mainly CD69. Conclusions: T-lymphocytes of CRC-patients having skin reaction in response to anti-EGFR treatment seem to have a less differentiated status and a higher ability to be activated by anti-CD3 stimulation in vitro.
Phase II study of short-course CHOP-rituximab followed by <sup>90</sup>y ibritumomab tiuxetan as first-line treatment for follicular lymphoma: Analysis of FcγR variants.
Authors: D. R. Mehta, V. Reichert, M. E. Lewis, D. E. Lenzner, J. A. Kant, S. A. Jacobs
Journal: Journal of Clinical Oncology (2011)

e18526 Background: Independent studies have suggested follicular lymphoma (FL) patients who are homozygous for 158V and 131H alleles in the FcγRIIIa and FcγRIIa genes respectively, achieve higher response rates with rituximab monotherapy. We previously reported complete response rate (CR) of 89% in 60 untreated patients with stage II-IV symptomatic or bulky FL who received short-course CHOP-rituximab (R) x 3 cycles followed by ibritumomab tiuxetan (IT) and extended R as first-line treatment (SA Jacobs, et al. Clin Cancer Res 2008) and presented follow-up results (DR Mehta, et al. ASCO 2010). This abstract reviews a subgroup of 32 such patients genotyped for these polymorphisms. Methods: Previously collected bone marrow samples from 32 patients were tested for FcγRIIIa 158 V/F (valine/phenylalanine) genotype using the PGxPredict:RITUXIMAB test and FcγRIIa 131 H/R (histidine/arginine) genotype by standard methods. Determination of response and duration of response included a fusion [18 F] fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) imaging performed at baseline, after the third cycle of CHOP-R, 12 weeks after IT, then at 6-month intervals for the first three years, and then yearly or at physicians’ discretion. Results: At median follow-up of 45 months, 18 patients are in remission and 14 have relapsed. Among relapses, 11 patients had bone marrow involvement at diagnosis. The table shows remission (CR) and relapse (RL) status (p=NS) versus genotype results. Conclusions: No significant trend was noted between genotype and clinical response, although the sample size is small. Specifically, of 10 patients homozygous for the 158V or 131H variants, 7 were in remission, and 3 had relapsed. IT and/or chemotherapy may have overcome relative resistance to rituximab in unfavorable FcγRIIa/FcγRIIIa genotypes. Given options of rituximab maintenance or radioimmunotherapy (RIT) as consolidation, a prospective, randomized trial stratifying for genotype seems warranted to personalize therapy. Genotype variant H/H H/R R/R V/V NA 1 1 NA 1 NA F/V 3 2 3 5 3 2 F/F 2 NA 1 2 4 2 No. of patients CR RL CR RL CR RL