tbuckley/cabot-search huggingface dataset:
Improved survival in an exhaustive population based on a cohort of liposarcoma (LPS) patients treated in expert centers according to clinical practice guidelines (CPG'S): Experience from Rhone Alpes (RA) region.
Authors: Olfa Derbel, Pierre Heudel, Claire Cropet, Pierre Meeus, Gualter Vaz, Philippe Cousin, Louis Tassy, Olivier Collard, Eric de la Roche, Philippe Thiesse, Dominique Ranchere-Vince, Francoise Ducimetiere, Pierre Biron, Philippe Cassier, Jerome Garret, Francois N. Gilly, Fadila Farsi, Dominique Cellier, Jean-Yves Blay, Isabelle Laure Ray-Coquard
Journal: Journal of Clinical Oncology (2014)

10581 Background: Liposarcoma (LPS) represents the most common soft-tissue sarcoma.The aim of this prospective and exhaustive population-based study is to explore the impact of medical practices conformed to CPG's on survival of patients with localized LPS in a region of 6 million inhabitants. Methods: Between 2005 and 2007, 133 patients out of 141 with an initial diagnosis of localized LPS and residing in the RA region (France), were enrolled. The prognostic impact of adherence to CPGs on progression-free survival (PFS) and overall survival (OS) was assessed with a multivariate Cox model analysis including all potential prognostic factors (PF). Results: The median age was 61 years (range 26-89). Sex ratio: M/F was 1.5; the histological subtypes were: well differentiated LPS (n=86, 64.5%), dedifferenciated LPS (n=29, 22%), myxoid (n=12, 9%) and pleiomorphic (n= 6, 4.5 %). Histological grade was low in 96 patients (73%), intermediate in 16 (17%) high in 12 (9%) and unknown in 2 (1%), 48.8% of tumors were localized in limbs (n=65), 44.3% in retroperitoneum (n=59) and 6.8% in other sites (n=9). The adherence to CPGs for patients with localized LPS was 53%, for initial surgery. In multivariate analysis, adherence of surgery to CPGs was the strongest independent prognostic factor (PF) of PFS (HR: 0·32; 95% CI [0·16-0·61]), along with age at diagnosis ≤60 years (HR: 0·42; 95% CI [0·21-0·83]), grade (low vs. high, HR: 0.16, 95% CI [0.07-0.37]; intermediate vs. high, HR: 0.8, 95% CI [0.34-1.85]) and tumor site (limbs vs. retroperitoneal tumors HR: 0·49, 95% CI [0·24-1·01]; head, neck and thoracic vs. retroperitoneal tumors HR: 0·12, 95% CI [0·02-0·93]). For OS, independent PF were adherence to CPGs for surgery (HR: 0.36 95% CI [0.15, 0.84]), age at diagnosis ≤60 years (HR: 0·34; 95% CI [0·14-0·85]) and grade (low vs. high, HR: 0.05, 95% CI [0.02-0.15]; intermediate vs. high, HR: 0.53, 95% CI [0.22-1.29]). Conclusions: In this exhaustive population-based study, adherence to CPGs is one of the major significant PF of survival for localized LPS patients. Organization of rare cancer care and physician's education are urgently needed.
<i>RAS</i> heterogeneity as a prognostic marker in metastatic colorectal cancer.
Authors: Jonathan M. Loree, Michael Lam, Jeffrey Morris, Michael J. Overman, Kanwal Pratap Singh Raghav, Cathy Eng, A. Dasari, Bryan K. Kee, David R. Fogelman, Robert A. Wolff, Zhiqin Jiang, Jennifer S Davis, Kenna Rael Shaw, Russell Broaddus, Mark Routbort, Rajyalakshmi Luthra, Dipen M. Maru, David Menter, Funda Meric-Bernstam, Scott Kopetz
Journal: Journal of Clinical Oncology (2017)

586 Background: The impact of intratumor heterogeneity on prognosis in metastatic colorectal cancer (mCRC) is unclear, however relative variant allele frequency (rVAF) of key mutations within a tumor may impact outcomes. Therefore, we sought to determine whether rVAF of RAS ( KRAS &amp; NRAS) mutant (mt) clones impacts overall survival (OS) in mCRC patients (pts). Methods: Using a next generation sequencing panel of 201 cancer related genes, we tested 200 mCRC tumors / matched normals. Mutations, indels, and copy number variant (CNV) information were obtained. An rVAF of RAS clones was determined by dividing RAS mt VAF by the VAF of the mutated gene with the highest allele frequency. This truncal gene served as a marker of the total malignant population in a specimen. Pts were stratified at an rVAF of 50%. OS was compared with Kaplan-Meier curves, the log-rank test, and Cox regression. We assessed the impact of CNV on our findings by correcting the rVAF for CNVs in RASand truncal mutations. Results: Of 200 pts, 15% had RAS mt rVAF &lt; 50%, 40.5% had rVAF ≥ 50%, and 44.5% were RAS wild type (WT). Age, gender, MSI status, histology, and stage at diagnosis were similar between groups. More RAS WT pts had BRAF mutations (19.1% vs 1.2% and 3.3%, P&lt; 0.0001), left sided (78.7% vs 56.8% and 60%, P= 0.02), or poorly differentiated tumors (27.3% vs 8.6% and 13.3%, P= 0.003) compared to pts with rVAF ≥ 50% or rVAF &lt; 50%, respectively. Mean coverage was 807x for RAS and 602x for truncal mutations. OS was better in pts with an rVAF &lt; 50% compared to pts with rVAF ≥ 50% regardless of whether rVAF was corrected for CNV (HR 0.6; 95% CI 0.39-0.93, P =0.029) or not (HR 0.48; 95% CI 0.31-0.82, P= 0.010). mOS for pts with WT, rVAF &lt; 50% and rVAF ≥ 50% tumors were 65.8, 55.7, and 38.6 months ( P= 0.0025). In multivariate models controlling for stage at diagnosis and BRAF mutation, pts with rVAF &lt; 50% (HR 1.75; 95% CI 1.03-2.97, P = 0.04) and rVAF ≥ 50% (HR 2.46; 95% CI 1.66-3.65, P&lt; 0.0001) had worse OS compared to WT pts. When rVAF was used as a continuous variable, every 1% increase in rVAF RAS mt resulted in a 1% increased hazard of death ( P &lt;0.0001). Conclusions: Our findings suggest that clonal proportion of a tumor with a RAS mutation may impact OS and suggest the prognostic impact of RAS mutations is not an “all or none” phenomenon.
Textbook of Uncommon Cancer
Authors: Daniela Dornelles Rosa
Journal: JAMA (2007)

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Does second-line therapy for non-small cell lung cancer (NSCLC) result in symptom palliation? Analysis of 484 patients from a randomized trial of pemetrexed vs docetaxel
Authors: F. De Marinis, J. R. Pereira, K. Park, S. S. Leong, C.-M. Tsai, T. Ansari, M. C. Perry, A. M. Liepa, S. Paul, R. J. Gralla
Journal: Journal of Clinical Oncology (2004)

7035 Background: Second-line treatment for NSCLC patients (pts) with good performance status improves survival. Using the recent trial comparing survival with pemetrexed (500 mg/m2 q3wks) vs docetaxel (75 mg/m2 q3wks) we evaluated the benefit of second-line treatment in terms of palliation, and whether it occurs with less than a major response. Methods: 571 previously treated advanced NSCLC pts, randomized from 3/01 to 2/02, completed the Lung Cancer Symptom Scale (LCSS) which assesses quality of life and 6 symptoms with scores from 0 to 100. Analysis was performed on pts who had data from baseline and ≥1 treatment cycle. Pts were grouped by best overall response: complete or partial, or stable disease (CR/PR/SD) vs progressive disease (PD). A two-factor interaction model with treatment and tumor response as factors was used for analysis. Results: Baseline characteristics were well-balanced between treatment arms with 75% Stage IV and 88% ECOG PS 0/1. Survival time and response rate with pemetrexed were similar to docetaxel (median 8.3 vs 7.9 months [HR 0.99 (95% CI 0.82, 1.20)]; 9.1 vs 8.8%). SD rate was 46% for each arm. 484 pts were included in the LCSS analyses. Baseline LCSS scores were similar between arms. All within-arm improvements were significant except for hemoptysis in docetaxel arm; all between-arm comparisons were not. When pts with CR/PR were divided from those with SD and treatment groups were pooled, mean maximum improvement of Average Symptom Burden Index (average of 6 symptoms) was greater for those CR/PR than those with SD (9.9 vs 4.3); those with PD worsened (-3.7). Conclusions: We conclude that: 1) Symptomatic benefit is achieved in pts with advanced NSCLC receiving second-line single-agent chemotherapy; 2) Pts achieving tumor response or stable disease have a greater likelihood of pt-reported benefit than pts with progressive disease; and 3) Pemetrexed and docetaxel are similarly effective in palliating symptoms. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. AstraZeneca; Eli Lilly & Co. Eli Lilly & Co. Bristol-Myers Squibb; Eli Lilly & Co.
Impact of treatment breaks on vismodegib patient outcomes: Exploratory analysis of the STEVIE study.
Authors: Reinhard Dummer, Nicole Basset-Seguin, Johan Hansson, Jean-Jacques Grob, Rainer Kunstfeld, Brigitte Dréno, Laurent Mortier, Paolo Antonio Ascierto, Lisa F. Licitra, Caroline Dutriaux, Thomas Jouary, Nicolas Meyer, Bernard Guillot, Kate Fife, D. Scott Ernst, Sarah Williams, Alberto G. Fittipaldo, Ioannis Xynos, Axel Hauschild
Journal: Journal of Clinical Oncology (2015)

9024 Background: Vismodegib (VISMO) is the first Hh pathway inhibitor approved for use in adults with advanced BCC (aBCC) that is inappropriate for surgery or radiotherapy. While most VISMO-related adverse events (AEs) are mild to moderate, the presence of multiple chronic AEs may lead to treatment interruption or discontinuation. Treatment breaks are allowed in the STEVIE study (NCT01367665) for the management of toxicity, among other reasons. Herein we present an exploratory analysis assessing the safety and efficacy profile in patients (pts) with treatment breaks on study. Methods: STEVIE is an ongoing study focusing on safety of VISMO in pts with aBCC. Pts receive VISMO 150 mg once daily until progressive disease, unacceptable toxicity, or withdrawal. The primary objective is safety; efficacy is a secondary end point. Tumor response assessments are performed using RECIST 1.1 as assessed by the investigator. Exploratory analyses were performed using data from a planned interim analysis (data cutoff Nov 6, 2013). Results: 499 pts were included in the safety population and analyzed according to number of treatment breaks received. The median duration of treatment was 223.5, 299.0, 399.0, and 454.0 days in pts with 0, 1, 2, or ≥ 3 treatment breaks, respectively. Median dose intensity was 97%, 89%, 86%, and 81%, respectively. Median treatment break duration was 22 days (SD 13.92). Safety and efficacy results are presented in the Table. Patients with more treatment-emergent AEs (TEAEs) including those experiencing more grade ≥ 3 TEAEs had more treatment breaks. These were AEs known to be commonly associated with VISMO use. The most common grade ≥ 3 TEAE was muscle spasm. Conclusions: Increased number of treatment breaks was associated with longer median duration of VISMO treatment and did not appear to compromise efficacy. Clinical trial information: NCT01367665. Number of treatment breaks Result 0 1 2 ≥ 3 n (%) 368 (74) 76 (15) 41 (8) 14 (3) Any TEAE, % 98 100 100 100 Dysgeusia 51 58 63 93 Muscle spasms 59 70 81 93 Alopecia 59 63 78 79 Grade ≥ 3 TEAEs, % 39 45 66 79 Deaths due to TEAEs, n (%) 19 (5.2) 4 (5.3) 0 1 (7.1) Best overall response rate, % 61 65 95 85 Complete response, % 30 33 51 39 Partial response, % 31 32 44 46 Median progression-free survival, mo 19.8 19.0 Not estimable Not estimable
Are validated symptom assessment instruments comprehensive? “Orphan” and “champion” symptoms.
Authors: Shirley Thomas, Declan Walsh, Aynur Aktas
Journal: Journal of Clinical Oncology (2013)

e20597 Background: Cancer patients experience multiple symptoms which vary in prevalence, severity, distress and negative impact on life. Comprehensive assessment is essential. Many validated assessment tools are used. They have limitations; varied content, clinical utility, completion rates, and acceptability. The objectives of this study were: Compare common cancer multisymptom assessment instruments to a comprehensive checklist. Identify commonly assessed (“champions”) and frequently neglected (“orphans”) symptoms. Examine the clinical importance of “orphan” symptoms. Methods: A 46-symptom checklist was developed from available evidence. This was compared against the content of 6 commonly used, validated, multisymptom instruments. Those with ≤ 2 symptoms, cancer site-specific, and tumor response instruments were excluded. Results: Symptom numbers varied in the 6 instruments; median (range) 19 (3-32). Of the 46 checklist symptoms, only 28 were present in 1 or more of the instruments. “Orphans”: 18 of the 46 were not evaluated in any of the 6 (e.g., confusion, agitation, early satiety, indigestion, tremors). 12 of the 18 had prevalence rates &gt;10%. These symptoms are also often rated moderate/severe and distressful. “Champions”: Only four checklist symptoms (pain, fatigue, dyspnea, anorexia) were present in all 6 instruments. Conclusions: Eighteen “orphan” symptoms (severe/distressing) were not captured by any tool. Only four “champion” symptoms were present in all validated tools. Unreported and misdiagnosed symptoms can bias our view of the cancer symptom experience. Validated cancer symptom assessment tools do not capture accurate, reliable comprehensive data on the cancer symptom experience. These challenge the validity and reliability of current symptom assessment tools in clinical research.
Combined abiraterone, salvage prostate bed radiotherapy and LH-RH agonists (CARLHA) in biochemically-relapsing prostate cancer patients following prostatectomy: A phase I study of the GETUG/GEP.
Authors: Stephane Supiot, Loic Campion, Pascal Pommier, Melanie Dore, Severine Racadot, Emmanuel Rio, Gerard A. Milano, Celine Mahier - Ait Oukhatar, Christian Carrie
Journal: Journal of Clinical Oncology (2017)

45 Background: Salvage radiotherapy (RT) plus 6 months LH-RH therapy (ADT) improves biochemical relapse free survival in men with rising PSA following prostatectomy. Abiraterone acetate (Aa) increases overall survival in metastatic prostate cancer. We aimed to establish the toxicity of adding Aa combined with salvage RT and 6 months goserilin (Gos). Methods: We enrolled pT2-pT4a pN0 prostate cancer patients (pts) with rising PSA (0.2 to &lt;2.0 μg/l) following radical prostatectomy. The primary endpoint was to determine the Maximum Tolerated Dose and recommended dose of Aa during RT plus Gos, two dose levels tested : 1 (750mg) and 2 (1000 mg). Two different schemes were explored: Sheme A: Aa (1000 mg) and predisone (10 mg) were given orally during 1 month to salvage IMRT (66 Gy in 33 fractions). The first day of irradiation, Aa is reduced to level 1 or 2 and 10.8 mg Gos is injected (sc). In sheme B, Gos is injected the first day (1 month before starting RT). Results: We recruited 9 + 9 pts in scheme A and B respectively. In scheme A, Testosterone (Tst) levels declined to castration level (&lt;0.5ng/ml) after 10 days . Two/9 pts did not achieve castration levels at 30 days. Median LH levels increased to 10.4 (D10) and 12.5 IU/l (D20). At dose level 1, 4/9 pts (44%) experienced grade 3 hepatitis, occurring prior to RT or during RT (8 Gy, 36 and 54 Gy). We hypothesized that this unexpected liver toxicity was related to the LH increase during the first month (Aa administration without Gos). Therefore, we modified LH-RH administration (scheme B) and recruited 9 more pts. Tst levels dropped to undetectable at day 6, while median LH levels decreased to 6.1 (D10) and 1.7 IU/l (D20). At dose level 1 (3 + 3 pts), no grade 3 liver toxicity was reported. No other grade 3 toxicity was recorded. At dose level 2, 2/3 pts had grade 3 hepatitis occurring during RT. CYP17 polymorphism did not correlate with liver toxicity. Conclusions: The recommended dose of Aa combined to short-term androgen deprivation and salvage RT is 750 mg. Aa alone did lead to castration levels in 22% of pts.An unexpected high frequency of grade 3 liver toxicity was observed. Clinical trial information: NCT01780220.
A randomized, parallel-dose phase 1 study of onapristone (ONA) in patients (pts) with progesterone receptor (PR)-expressing cancers.
Authors: Paul H. Cottu, Andrea Varga, Sylvie Giacchetti, Eric Leblanc, Marc Espie, Anas Gazzah, Veronique Dieras, Catherine Lhomme, Francois Marc Lokiec, Keyvan Rezai, Alice Susannah Bexon, Erard M. Gilles, Joseph Bisaha, Alexander Zukiwski, Jacques Bonneterre
Journal: Journal of Clinical Oncology (2014)

TPS2643 Background: ONA is a type I PR antagonist, which prevents PR-induced DNA transcription. Presence of transcriptionally activated PR (APR), could indicate potential for ONA anticancer activity and could be used as a predictive biomarker. Development of an IHC companion diagnostic which identifies distinct subnuclear PR distribution patterns is ongoing, and could help select patients with PR-positive cancers most likely to respond to ONA, including endometrial and breast cancers. ONA anti-cancer activity has been documented in multiple preclinical models. Prior ONA clinical studies led to objective responses in pts with hormone therapy-naïve or tamoxifen-resistant breast cancer. ONA appeared well tolerated with the exception of LFT abnormalities, which would not preclude development in oncology. An extended-release (ER) tablet formulation of ONA was designed to address the LFT elevations seen with immediate-release (IR) ONA, by reducing the Cmax. Methods: This is a multi-center, open-label, randomized, parallel-group, 2-stage phase 1 study with an expansion component (total n~60). Female pts ≥18 years with tumors expressing PR are eligible. Tumor tissue is required to determine PR (both A and B isotypes) and APR status. The primary endpoint is determination of the recommended phase 2 dose (RP2D) of ER ONA, with a 57-day period for observation of dose-limiting toxicity (DLT). Secondary endpoints include safety/tolerability, efficacy, and real-time PK. Tissue specimens will be used to determine relationship of APR to preliminary efficacy. Six pts per cohort are receiving ONA ER tablets 10, 20, 30, 40 or 50 mg BID, or ONA IR tablets 100 mg QD until progressive disease or intolerable safety Stage 1: Six dose cohorts are randomized in parallel. A data review committee (DRC) monitors/reviews safety signals and all DLTs. Stage 2: when sufficient pts have been treated for 8 weeks, the DRC will review all safety, PK and efficacy data to determine the RP2D. The RP2D dose cohort will be expanded by enrolling 24 additional pts to confirm the safety profile and provide a preliminary assessment of anti-tumor activity. Stage 1 is open for accrual. Clinical trial information: NCT02052128.
Impact of neoadjuvant chemotherapy plus HER2-targeting on breast conservation rates: Surgical results from CALGB 40601 (Alliance).
Authors: David W. Ollila, Donald A. Berry, Constance Cirrincione, Lisa A. Carey, Keith D. Amos, Norah Lynn Henry, Eric P. Winer, Clifford Hudis, Mehra Golshan
Journal: Journal of Clinical Oncology (2013)

501 Background: Neoadjuvant systemic therapy improves breast conserving therapy (BCT) rates, but the magnitude of this benefit is unknown in operable breast cancer. We sought to quantify this benefit in CALGB 40601, a phase III trial of paclitaxel (T) + HER2 blockade with either trastuzumab (TH), lapatinib (TL), or both (THL), by requiring the treating breast surgeon to determine BCT eligibility before and after neoadjuvant therapy and examining surgical results. Methods: Eligible patients (pts) had operable, newly diagnosed, noninflammatory stage II-III HER2+ breast cancer randomized to receive TH, TL or THL. Prior to, and again after neoadjuvant therapy, the treating breast surgeon determined whether the patient was a BCT candidate based on clinical and radiographic criteria, but the subsequent breast cancer operation was at the discretion of the surgeon and patient. Two endpoints examined were: (1) the conversion rate from BCT-ineligible to BCT-eligible and (2) the rate of successful BCT as determined by tumor-free surgical margins. Results: Of 305 pts randomized (118 THL, 120 TH, 67 TL), 294 were evaluable. Prior to neoadjuvant therapy, 136 (46%) patients were candidates and 158 (54%) were non-candidates for BCT. 107/136 (79%) remained BCT candidates following neoadjuvant therapy and 78 chose BCT, of whom 69 (88%) were successful. 29 pts (21%) initially thought to be BCT candidates became non-candidates after neoadjuvant therapy. Conversely, 76/158 (48%) pts considered non-BCT candidates prior to neoadjuvant therapy down-sized sufficiently to be considered BCT candidates; 40 of these opted for BCT with a 75% (30/40) BCT success rate. In total, 183 pts were deemed BCT candidates after neoadjuvant therapy, yet 65 (36%) proceeded directly to mastectomy. Conclusions: This is the first neoadjuvant trial to prospectively quantify a nearly 50% conversion rate from BCT-ineligible to BCT-eligible in HER2+ breast cancer pts treated with modern systemic therapy. Neoadjuvant chemotherapy combined with targeted anti-HER2 treatment permits potential BCT in approximately 80% of properly selected patients. Clinical trial information: NCT00770809.