tbuckley/cabot-search huggingface dataset:
Randomised phase II study evaluating weekly docetaxel in combination with cisplatin and 5FU or capecitabine in metastatic oesophago-gastric cancer
Authors: N. Tebbutt, V. Gebski, A. Strickland, D. Gibbs, E. Walpole, V. Ganju, D. Goldstein, S. Munro, M. Harrod, G. Van Hazel
Journal: Journal of Clinical Oncology (2006)

4067 Background: Docetaxel (T), cisplatin (C) and 5FU (F) are active agents in oesophago-gastric cancer. A recent phase III study using TCF achieved a survival advantage but was associated with high rates of haematological toxicity (30% incidence of febrile neutropenia/neutropenic infection) as well as non-haematological side effects (Moiseyenko et al, 2005 Pr ASCO abstr 4002). Weekly docetaxel is associated with a lower incidence of haematological toxicity. This randomised phase II study aimed to test weekly docetaxel based combination chemotherapy regimens with the aim of maintaining the activity of docetaxel based combination regimens but reducing toxicity. Methods: Eligibility included; histologically confirmed, metastatic oesophageal or gastric (OG) carcinoma, measurable disease, PS0–2, adequate organ function, no prior treatment, informed consent. Pts were randomised to receive weekly (w) T 30 mg/m 2 d1, 8 C 60 mg/m 2 d1 F 200 mg/m 2 /d continuously q 3w or wT 30 mg/m 2 d1, d8 and capecitabine (×)1600 mg/m 2 /d d1–14 q3w. The primary endpoint is confirmed response rate (RR), with each arm analysed independently. Simon’s 2 stage design was used, with 5/21 responses required in the first stage to allow continuation to 48 pts per arm. Results: 79 pts enrolled to date. Protocol specified interim analysis of efficacy after 21 pts per arm and of toxicity after 25 pts per arm ( Table ). In the first 21 pts per arm; 12 responses (11 confirmed) in wTCF arm, 6 responses (5 confirmed) in wTX arm. Trial continues accrual to target of 48 pts per arm. Complete accrual expected by April 2006. Updated data will be presented at the meeting. Conclusions: wTCF and wTX have encouraging activity and and a more favourable toxicity profile than TCF administered 3-weekly. [Table: see text] [Table: see text]
Phase I trial of belinostat in combination with cisplatin (Cis) and etoposide (Etop).
Authors: Sanjeeve Balasubramaniam, Christina Bryla, Christophe E. Redon, Min-Jung Lee, Cody Peer, Jane B. Trepel, Arun Rajan, William Bonner, William Douglas Figg, Antonio Tito Fojo, Richard Piekarz, Giuseppe Giaccone, Susan Elaine Bates
Journal: Journal of Clinical Oncology (2013)

2527 Background: Histone deacetylase inhibitors (HDIs) are epigenetic therapies in development. To exploit the unique activity in impairing DNA repair, HDIs have been combined with chemotherapy. Belinostat is a potent HDI combined with Cis and Etop based on enhanced DNA damage and apoptosis in small cell lung cancer (SCLC) cells. Methods: Patients with relapsed/refractory cancer or previously untreated advanced stage SCLC were eligible. Belinostat was administered by continuous infusion (CIV) over 48h, from 400 mg/m 2 /24h, in cohorts of 3. Cis was administered on day 1 and Etop daily X3. Belinostat pharmacokinetics (PK) and several pharmacodynamic (PD) measures were assessed, including lysine acetylation in peripheral blood mononuclear cells (PBMCs) and γH2Ax staining in PBMCs and in hair follicles. Results: Five dose levels were explored in 20 patients with solid tumors, including 5 patients with SCLC, two who had no prior therapy. At the first dose level, dose-limiting toxicities (DLT) of gr 4 ANC in 1, and gr 3 HTN in 1 were observed. Cis and Etop were reduced to 60 mg/m 2 and 80 mg/m 2 , respectively, and the dose level repeated without DLT. At the next dose level, 800 mg/m 2 /24h belinostat, grade 3 HTN and grade 4 pneumonitis were observed. At the MTD of 600 mg/m 2 /24h belinostat, DLT was seen in 1 of 6 pts; however, all 6 pts required later dose reductions. We thus considered 500 mg/m 2 /24h in combination with Cis and Etop to be the recommended Phase II dose; confirmation ongoing. PKs show belinostat levels at 1 uM over the 48h infusion, decreasing rapidly to the 60h timepoint. In total 11 pts, 3 with SCLC, completed 6 cycles. PR was seen in 6 pts (3 with SCLC). PD studies confirmed γH2AX staining in PBMCs and hair follicles, peaking at 36h and 60h, respectively. Tubulin and lysine acetylation (Ac-K) in PBMCs peaked at 36h; Ac-K recovered more rapidly than tubulin, mirroring γH2AX. Conclusions: The MTD of belinostat over 48h by CIV was 600 mg/m 2 /24h, in combination with Cis 60 mg/m 2 on day 1 and Etop 80 mg/m 2 on days 1 - 3. PD endpoints indicate that belinostat is active in promoting both acetylation and DNA damage. The HDI combined with chemotherapy requires dose reduction and likely represents an on-target increase in DNA damage. Clinical trial information: NCT00926640.
Spanish experience with the ipilimumab Expanded Access Program.
Authors: Alfonso Berrocal, Jose A. Lopez-Martin, Ana Maria Arance, V. Soriano, Enrique Espinosa, M Pilar Lopez Criado, Eva Muñoz, Jose Pablo Berros, A Soria, I Marquez, P Sancho, I Gil
Journal: Journal of Clinical Oncology (2012)

e19023 Background: Second line ipilimumab has proven efficacy in clinical trial but few is known outside this setting. Methods: We have retrospectively reviewed experience with the Expanded Access Program for Ipilimumab in Spain. We have collected data on demographics, response survival and toxicity. Ipilimumab was administered at a 3 mg/kg dose for four induction courses. Results: We have retrieved 99 expanded access ipilimumab applications that represent 40% of all possible applications. Five patients are not evaluable because they never received ipilimumab 4 due to progression and 1 declined consent. Median age is 58.5 years (30-81) and 54.3% of the patients are males. 59.6% have 3 or more metastatic locations, 50% have liver metastases, 16% have CNS metastasis and 74.6% have elevated LDH. ECOG performance status was 0 to 1 in 91.9%. Previous adyuvant treatment was received by 43.6% of the patients and consisted in high dose interferon in 85.4%. All except one patient have received previous first line chemotherapy and 34.2% have received 2 or more chemotherapy lines. Medium time from the start of metastatic disease to the start of ipilimumab was 11.2 months. 58.5% of the patients completed 4 doses of ipilimumab main reason for not completion was death or progression in 84.6% and toxicity in 5.1%. 8 patients are not evaluable for response, 5 have just completed the treatment and 3 are still on treatment. Responses are 1 (1.1%) CR, 6 (6.4%) PR, 6 (6.4%) PR with previous progression or new lesions, 13 (13.8%) SD, and 60 (63.8%) progressive disease. Reinduction treatment was offered to 5 patients 2 PR patients achieved a new PR, one PR patients a SD and 2 SD patients progressed after reinduction. Kaplan and Meier median survival is 150 days (95% CI 110,5-189.4). One year survival is 32.4% and 18 months survival 21.6%. Toxicity has been mild, skin, 20.2% grade I and 5.3% grade II, liver 7.4% grade I, 2.1% grade II, 3.2 grade III, and diarrhea 19.1% gI, 3.2% grade II and 1.1% grade IV. Only 7 patients experienced toxicity grade III to IV. Conclusions: Ipilimumab efficacy when it is used outside clinical trial is similar to the reported. There is room for improvement in patient selection as 40% of them did not completed treatment. Toxicity of the 3 mg/kg schedule is mild.
Clinical or survival benefit to routine surveillance imaging for classical Hodgkin lymphoma patients in first complete remission.
Authors: Sai Ravi Pingali, Sarah Jewell, Luiza Havlat, Martin Bast, Jonathan Thompson, Daniel Eastwood, Nancy Bartlett, James O. Armitage, Nina Wagner-Johnston, Julie Vose, Timothy S. Fenske
Journal: Journal of Clinical Oncology (2013)

8505 Background: Routine surveillance imaging (RSI) for patients in complete remission from classical Hodgkin lymphoma (cHL) is common practice. RSI offers the theoretical benefit of detecting asymptomatic relapse, which may allow for more successful second-line therapy. Despite this, evidence for a clinical benefit of RSI is lacking. We compared outcomes in cHL patients undergoing RSI versus clinical surveillance (CS) in which scans are only obtained to evaluate concerning signs or symptoms. Methods: Patients with cHL diagnosed at three tertiary care centers from 2001-2010, who achieved complete remission (CR) following frontline therapy, were analyzed retrospectively. Patients were stratified into two groups based on the surveillance strategy employed. Baseline patient characteristics, prognostic features, treatment records, and outcomes were collected. The primary objective was to compare overall survival for patients undergoing RSI versus CS. As a secondary objective we compared the success of second-line therapy for relapsed patients in each group. Results: 207 patients met eligibility criteria, with 131 RSI patients and 76 CS patients. Patient characteristics (age, gender, stage, sedimentation rate, Hasenclever index, bulky disease and B symptoms) were similar in each group. Chemotherapy consisted of ABVD in 79% and Stanford V in 15%. Patients in the RSI group more commonly received ABVD (91% vs. 57%) and less often radiation therapy (38% vs. 68%). Mean number of scans was 4.77 in RSI and 1.11 in CS groups, respectively. With a median follow up of 4 years, the overall survival was similar in both groups (p=0.74), with 5 (3.8%) deaths in the RSI group and 4 (5.3%) in the CS group. Six (4.6%) relapses occurred in the RSI group (4 of which were detected by RSI), and 5 (6.6%) in the CS group (p=0.64 for relapse at 5 years). All relapsed patients achieved second CR with second-line therapy. Conclusions: RSI did not yield a survival advantage in cHL patients who achieved CR after frontline therapy.Given the radiation exposure, cost, and risk for additional procedures associated with RSI, we conclude CS is the preferred strategy in cHL patients in first complete remission.
Association of chromosome complexity with age and metastasis in synovial sarcomas: Validation of expression and genomic prognostic signatures.
Authors: Fred Chibon, Pauline Lagarde, Joanna Przybyl, Celine Brulard, Antoine Italiano, Daniel Orbach, Binh Bui Nguyen, Philippe Terrier, Raf Sciot, Maria Debiec-Rychter, Jean-Michel Coindre
Journal: Journal of Clinical Oncology (2012)

9536 Background: Synovial sarcoma (SS) is one of the rare sarcomas that occurs in adolescents as well as in adults. Nevertheless, metastasis occurs with a lowest frequency in the former, 10 vs 50% respectively. In almost all cases, a characteristic translocation t(X;18)(p11.2;q11.2) exists and the importance of this translocation in SS oncogenesis is well established, but the genetic basis of SS metastasis is still poorly understood. We recently published expression (CINSARC) and genomic (GI) signatures related to chromosome integrity control that predict outcome in undifferentiated sarcomas and GIST and ask whether these signatures could also predict outcome in SS. Methods: To asses this issue we selected in the European sarcoma database CONTICABASE 92 primary untreated SS for expression and genomic profiling. Results: As demonstrated by metastasis-free survival, CINSARC and GI have strong and independent prognostic values (p = 1.6 x 10 -5 and p = 4 x 10 -6 , respectively). Comparing expression profiles of tumors with or without metastasis in a training series of 58 SS, a 52-genes signature was identified and validated in an independent series of 34 SS. Fourteen of these genes are common with CINSARC and these 52 genes are involved the same pathways than CINSARC, mitosis checkpoints and chromosome integrity. Comparing genomic profiles of adult versus pediatric SS we show that in both situations metastasis is associated to genome complexity and that the adult genome is highly more frequently rearranged. In line with this, the pediatric good-prognosis patients, according to GI, do not develop metastasis. Conclusions: Results clearly indicate that SS metastasis development is strongly associated with chromosome complexity and that CINSARC and GI are powerful prognostic factors. Data also mean that the metastasis frequency difference between adult and children likely is associated to the genome instability which is highly more frequent in adults. Finally, among these tree signatures, GI is potentially the best overall and clearly the most clinically relevant considering that CGH from FFPE samples is already used in the daily practice of pathology.
Mechanisms of elevated serum creatinine in patients receiving vemurafenib for advanced melanoma.
Authors: Charlotte Hurabielle, Evangeline Pillebout, Thomas Stehle, Cécile Pagès, Jennifer Roux, Pierre Schneider, Sylvie Chevret, Samia Mourah, Nicole Basset-Seguin, Cendrine Chaffaut, Emmanuelle Vidal-Petiot, Martin Flamant, Celeste Lebbe
Journal: Journal of Clinical Oncology (2015)

e20022 Background: We and others have observed elevated serum creatinine levels (sCr) in patients receiving vemurafenib (V), yet the prevalence and mechanism of this adverse event is unknown Methods: We designed a retrospective, monocentric study including patients receiving V for advanced melanoma. We collected clinical and biological data concerning renal impairment before V initiation and during monthly follow-up from 2010 to 2014 Results: 68/70 patients (97%) had an immediate increase in sCr after V initiation, of 22.8% on average, which remained stable thereafter. In case of V stop (mostly due to progression of the melanoma), sCr returned to pre V level (±5µmol/L) in 44/52 patients with available data (84.6%). There was no significant influence of cardiovascular risk factors (p = 0.27) or of recent contrast product infusion (p = 0.9). Renal biopsies were performed in 2 patients with acute renal failure (sCr increase > 50%), showing discreet proteic clusters in the cytoplasm of proximal tubular epithelial cells, but no glomerular or vascular lesions. Immunofluorescence and electronic microscopy were normal. To better define the mechanisms underlying sCr increase under V, in 11 patients, the decrease in GFR after V initiation was assessed by cystatin C variation (Cys GFR), as Cys has no tubular secretion, and was compared with that derived from sCr variation (sCr GFR). sCr GFR decreased by 16.7% when Cys GFR decreased only by 9.4% (p = 0.06), suggesting that the increase in sCr under V is partly due to an inhibition of tubular secretion of Cr, independently of an effect of GFR itself. To test this hypothesis, we measured GFR (urinary clearance of 51CrEDTA), clearance of Cr and tubular secretion of Cr in 3 patients pre and post V: tubular secretion of Cr was diminished in all 3 patients, by 60, 68 and 21%. 2 patients showed signs of proximal tubular lesions, but measured GFR was altered in only 1 patient Conclusions: V induced an immediate, steady and usually reversible increase in sCr, which we believe is the combination of a true renal function impairment (with signs of tubular damages in some cases), but also of a partial inhibition of Cr tubular secretion. Thus, renal function should be monitored both with sCr and Cys in patients treated with V.
A phase II study of ziv-aflibercept (Z) + FOLFIRI in Japanese patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Taroh Satoh, Tadamichi Denda, Tetsuya Hamaguchi, Naotoshi Sugimoto, Takashi Ura, Kentaro Yamazaki, Hirofumi Fujii, Takeshi Kajiwara, Takako Eguchi Nakajima, Shin Takahashi, Satoshi Otsu, Yoshito Komatsu, Toru Sasaki, Yoshinori Sunaga, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2017)

707 Background: VEGF promotes tumor angiogenesis and metastasis. Z blocks the activity of VEGF-A/-B, and placental growth factor and was shown in the VELOUR phase III study (NCT00561470) outside of Japan to significantly improve overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in mCRC pts as a second-line treatment given with FOLFIRI. Goals of the current open-label, multicenter phase II study were to assess the efficacy and safety of Z + FOLFIRI in a post-oxaliplatin setting in mCRC pts in Japan. Methods: Pts received Z (4 mg/kg) + FOLFIRI (400 mg/m 2 bolus 5-fluorouracil [FU]; 2400 mg/m 2 continuous infusion 5-FU; 200 mg/m 2 levofolinate; 180 mg/m 2 irinotecan) every 2 weeks until progression, unacceptable toxicity, or study withdrawal. Primary endpoint: ORR (required 60 pts in order to obtain a 95% CI width of 16–20%, assuming an ORR of 10–20%). Secondary endpoints: PFS, OS, and safety. Tumors were assessed by independent reviewers every 6 ± 1 weeks until progression. Results: Study enrolled 62 pts; 50 pts (83.3%) had received prior bevacizumab. Of 60 pts evaluable for response, 5 had a partial response and none had a complete response, resulting in an ORR of 8.3% (95% CI: 1.3–15.3%). The median PFS was 5.42 months (95% CI: 4.140–6.702), and the median OS was 15.59 months (range 11.20–19.81). Forty-one pts (66.1%) died due to progression; none died due to study treatment. Pts underwent a median of 8 treatment cycles (range 1–31) lasting a median of 21.8 weeks (range 2–73). The median relative dose intensity was 0.99 (range 0.2–1.0) for Z, 0.87 (range 0.4–1.0) for irinotecan, and 0.96 (range 0.7–1.0) for 5-FU. All pts had ≥1 treatment emergent adverse event (TEAE; see table). Conclusions: The ORR was 8.3% (95% CI: 1.3–15.3%), and the median OS was 15.59 months. The safety profile was consistent with that reported previously. Registered as NCT01882868. Clinical trial information: NCT01882868. [Table: see text]
Association of preoperative neutrophil-to-lymphocyte ratio with survival outcomes in patients undergoing radical cystectomy, regardless of neoadjuvant chemotherapy status.
Authors: Janet Baack Kukreja, Jason M Podolnick, Xuemei Wang, Hsiang-Chun Chen, Neema Navai, Ashish M. Kamat, Colin P.N. Dinney, Jay Bakul Shah
Journal: Journal of Clinical Oncology (2017)

352 Background: Pre-operative neutrophil-to-lymphocyte ratio (NLR) has been found to be associated with adverse pathological results and poor long-term outcomes in patients treated with radical cystectomy (RC) for urothelial bladder carcinoma (BC). Prior studies have determined inclusion based on neoadjuvant chemotherapy (NAC) status. This study aimed to evaluate pre-operative NLR in a large cohort without exclusion as a predictor of long-term outcomes in patients undergoing RC for BC. Methods: A retrospective cohort study was performed of 1243 patients undergoing RC between 2000 and 2011. NLR was summarized using descriptive statistics. Univariate classification and regression trees analysis (CART) was applied to identify subgroups of patients using pre-surgery NLR as the covariate and overall survival (OS) or disease specific survival (DSS) as the outcome of interest. The probabilities of OS and DSS were estimated using the Kaplan-Meier method. Results: The median follow-up time among survivors was 7 years. 863 (69%) patients died and 380 (31%) were alive at last follow-up. The median OS was 5.2 years (95% CI: 4.9-5.5 years). Using CART analysis, the strongest association with OS was the cutoff point 3.09. 767 (62%) patients had pre-surgery NLR &lt; 3.09 and 475 (38%) had pre-surgery NLR ≥ 3.09. The overall survival was found to be significantly associated with NLR &lt; 3.09 vs. ≥ 3.09 (p &lt; 0.001). The median OS for patients with NLR &lt; 3.09 and ≥ 3.09 was 5.9 years (95% CI: 5.3-6.3 years) and 4.2 years (95%:3.3-4.7 years), respectively. Patients with NLR &lt; 3.09 and ≥ 3.09 had 5-year OS of 56% and 44%, respectively. DSS was found to be significantly associated with NLR ≥ 3.09 vs. &lt; 3.09 (p &lt; 0.001). The median DSS for patients with pre-surgery NLR &lt; 3.09 and ≥ 3.09 were 15.6 years and 7.5 years, respectively. Conclusions: The NLR significantly predicts OS and DSS in RC patients. NLR should be taken into consideration as NAC and adjuvant treatments are considered in BC patients to help improve survival.
A single team experience of adjuvant radiation therapy in adults with intermediate or high-grade limb soft tissue sarcoma
Authors: O. Merimsky, V. Soyfer, F. Kovner, I. Meller, Y. Kollender, J. Issakov, M. J. Inbar
Journal: Journal of Clinical Oncology (2006)

19509 Background: Limb Soft tissue sarcomas (STS) are currently treated with limb sparing surgery (LSS) followed by radiation therapy (RT). This paper summarizes a one-team experience with homogenous population of adult patients, with intermediate or high grade STS confined to a limb, who were approached by LSS and postoperative RT. Methods: From October 1994 through October 2002, 133 adult patients (75 males, 58 females, age range 18–88 years, median 54) with biopsy-proven intermediate or high-grade limb STS were approached by LSS followed by RT. Their files were retrospectively reviewed for treatment outcome: local control, RT side effects, and time to progression. Tumor site was classified according to its proximal border. STS that involved the arm and the upper axilla was classified as axillary STS. Results: RT related toxicity was manageable, with a low rate of severe effects. At 4-year median follow up, there were 48 recurrences of any type, 23 of isolated local failure, and 35 of systemic spread w/o local failure. DFS and OS were influenced by disease stage II versus I, primary site in the upper limb versus lower limb, MPNST versus other types, induction therapy versus no induction, adequate resection Vs marginal resection or involved margins, and good response to induction therapy versus bad response. DFS and OS were Patient’s age and sex, tumor depth, acute or late toxicity of RT, or the interval of time between the date of definitive surgery and the start of RT did not affect DFS and or OS. Conclusions: The RT protocol is applicable in the era of complicated, expensive and time-consuming 3-D therapy. Our results of LSS + RT in adults with limb HG STS are satisfactory. No significant financial relationships to disclose.