tbuckley/cabot-search huggingface dataset:
The efficacy and tolerability of modified docetaxel, cisplatin, and 5FU in patients with advanced or recurrent gastric cancer: A retrospective analysis.
Authors: J. Kim, K. Park, S. Yi, H. Lee
Journal: Journal of Clinical Oncology (2011)

146 Background: Docetaxel, cisplatin, and 5FU (DCF) significantly improved TTP, OS, and response rate in gastric cancer patients, but resulted in some increase in toxicity compared with cisplatin and 5FU (CF) in multinational study such as V325 report. The main goal of this study is to report the experience of a single center about efficacy and tolerability of modified DCF in advanced or recurrent gastric cancer patients. Methods: A total of 23 patients with advanced or recurrent gastric cancer who had been treated with modified docetaxel, cisplatin and 5FU (mDCF) at Seoul Paik Hospital between Feb 2009 and June 2010 were included. Treatment protocol was 60 mg/m 2 of docetaxel, 50 mg/m 2 of cisplatin on D1, and 950 mg/m 2 /day of 5FU continuous infusion on D1-3 until disease progression or intolerance to chemotherapy. Clinical data were collected retrospectively. Results: Twenty-one patients were assessable for response. The ORR was 34.8% (8/23), and DCR 69.6% (16/23). Median PFS and OS were 6.8 months (95% CI, 3.8-9.8) and 11.9 months (95% CI, 6.6-17.2). The main toxicities were anorexia, diarrhea, and neuropathy. Grade 3 or 4 hematologic toxicities were neutropenia in 4 patients (17.4%), leukopenia in 5 patients (21.7%), anemia in 2 patients (8.7%) and thrombocytopenia 1 patient (4.3%). The treatment related death occurred in 1 patient (4.3%) due to febrile neutropenia. The median cycle was 5. Ten patients (43.5%) received chemotherapy more than 8 cycles with tolerable toxicities. Conclusions: Compared with previous studies, the presented mDCF showed a lower ORR, but more acceptable toxicities profiles, and similar PFS and OS in patients with advanced gastric cancer. No significant financial relationships to disclose.
The impact of modified Glasgow Prognostic Scale as a predictor of survival advantage by FOLFIRINOX in metastatic pancreatic cancer.
Authors: Ikuhiro Yamada, Masato Ozaka, Ryo Kanata, Kei Saito, Takashi Sasaki, Masato Matsuyama, Kouichi Takano, Naoki Sasahira
Journal: Journal of Clinical Oncology (2016)

440 Background: The superiority of FOLFIRINOX (FFX) therapy over gemcitabine (Gem) alone in patients with metastatic pancreatic cancer (mPC) has been demonstrated in ACCORD11. However, this combination regimen is associated with relevant toxicity and predictors for response to therapy are warranted. The aim of this study is to determine the prognostic factors associated with an indication for FFX therapy in patients with mPC. Methods: The current study included data from all consecutive patients who were diagnosed as mPC at our hospital between September 2007 and December 2014. Selection criteria were as follows: patients who 1) had histologically confirmed pancreatic adenocarcinoma, 2) were diagnosed as having metastatic disease, and 3) received first-line chemotherapy with Gem alone or FFX. We examined the prognostic markers, such as derived neutrophil–lymphocyte ratio, platelet–lymphocyte ratio, modified Glasgow prognostic scale (mGPS), ECOG Performance Status (PS), CA19-9 level and number of metastatic sites from the medical records and analyzed their survival data by chemotherapy regimen subgroups. Results: There were 187 patients who met the selection criteria. 159 (85%) received Gem alone, 28 (15%) received FFX. Univariate and multivariate regression analyses revealed that mGPS (1≦), number of metastatic sites (2≦) and high level of CA19-9 level (1000 U/ml≦) were significantly associated with worse prognosis in Gem group. PS (1≦) and mGPS (1≦) were significantly associated with worse prognosis in FFX group. Since mGPS was the only significant prognostic marker in both groups, we analyzed survival data stratified by regimen in both mGPS 0 or 1≦ cohort. In mGPS 0 cohort, the median survival time was 17.9 months in the FFX group as compared with 8.5 months in the Gem group (hazard ratio, 0.27; 95% CI, 0.11 to 0.55; P = 0.004). However there was no significant difference in mGPS 1≦ cohort (P = 0.4). Conclusions: This data suggests that mGPS 0 is associated with better survival time, and suggests it may also be predictive of benefit for FFX in Japanese patients with mPC. Incorporating mGPS into the clinical context may better inform prognosis and chemotherapy decisions in mPC patients.
Bladder cancer: Predicting response to BCG.
Authors: Rafael Nunez-Nateras, Melissa L. Stanton, Erin N. Ferrigni, Cheryl A. Protheroe, Nancy A. Lee, James J. Lee, Erik P. Castle
Journal: Journal of Clinical Oncology (2013)

287 Background: Our preliminary immunohistochemical studies of bladder cancer patients have shown that the inflammatory/immune responses associated with bladder cancer appear to be Th2-polarized as judged by the preponderance of tumor infiltrating GATA-3 + (Th2) vs. T-bet + (Th1) T cells, as well as by evidence of tumor-associated eosinophil infiltration and activation. The standard-of-care treatment for Tis bladder cancer is intravesical administration of BCG, a Th1-polarizing immunomodulator. The aim of the present study was to assess the Th2/Th1 ratio correlation with response to BCG therapy in patients with Tis bladder cancer. Methods: Two groups of patients were studied. Group A included 20 patients that responded to BCG, and Group B included 20 patients that did not respond to therapy. Response to BCG was determined as presence/absence of disease at 6 months post-BCG therapy. The initial diagnostic biopsies of these patients were subjected to immunohistochemical analysis using commercially available antibodies specific for Th2 (GATA-3 + ) and Th1 (T-bet + ) lymphocytes, and our unique monoclonal antibody specific for eosinophil peroxidase (EPX-mAb). Ten random high powered (400X) fields at the maximum focus of mononuclear infiltration were examined and the number of GATA 3 + and T-bet + tumor infiltrating T cells were counted to define the G/T ratio for each patient sample. Eosinophils and their degranulation activity were counted in the same fields. Results: Patients with response to BCG therapy had a G/T ratio of ≥ 3 and patients with non-response to BCG therapy had a G/T ratio of ≤ 1.5. Correlation of these scores with subsequent patient outcomes following BCG immune therapy demonstrated that patient responsiveness (i.e., tumor elimination at 6 months) trended with the higher G/T ratio patients. In addition, initial biopsies of BCG responsive patients display a higher number of eosinophils and degranulation relative to BCG non-responsive patients. Conclusions: Evaluations of initial biopsies revealed a strong correlation between Th1 and Th2 immune response with BCG therapy outcomes. The development of specific and novel tools to identify/measure Th2 immune responses in Tis bladder cancer provides a unique opportunity to predict outcomes at the time of diagnosis.
Genomic classifier (ColoPrint) to predict outcome and chemotherapy benefit in stage II and III colon cancer patients.
Authors: Scott Kopetz, Zhi-Qin Jiang, Michael J. Overman, Robert Rosenberg, Ramon Salazar, Josep Tabernero, Lisette Stork, Ying Li, Iris Simon, George J. Chang, Dipen M. Maru
Journal: Journal of Clinical Oncology (2013)

3612 Background: Although benefit of chemotherapy in stage II and III colorectal cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and validated in independent validation studies (JCO 2011, Ann Surg 2013). Methods: In this study, ColoPrint was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center. Frozen tissue specimen, clinical parameters and follow-up data (median follow-up 64 months) were available. Stage II patients from this study were pooled with patients from previous studies (n=416) and ColoPrint performance was compared to clinical risk factors described in the NCCN Guidelines 2013. Results: In the MDACC patient cohort, ColoPrint classified 56% of stage II and III patients as being at Low Risk. The 3-year Relapse-Free-Survival (RFS) was 90.5% for Low Risk and 78.1% for High Risk patients with a HR of 2.42 (p=0.025). In uni-and multivariate analysis, ColoPrint and stage were the only significant factors to predict outcome. Low Risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (91% 3-year RFS for treated patients, 90% for untreated patients) while ColoPrint High Risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70% 3-year RFS in untreated patients (p=0.037). In the pooled stage II dataset, ColoPrint identified 63% of patients as Low Risk with a 3-year RFS of 93% while High Risk patients had a 3-year RFS of 82.3% with a HR of 2.7 (p=0.001). In the univariate analysis, no clinical factor reached statistical significance. Using clinical high risk factors as described in the NCCN guidelines as classification, 56% of patients were classified as low risk with a 3-year RFS of 90.3% while high risk patients had a 3-year RFS of 87.7% with a HR of 0.6 (p=0.63). Conclusions: ColoPrint significantly improves prognostic accuracy, thereby facilitating the identification of patients at higher risk who might be considered for additional treatment.
Ontario’s approach to tackling drug funding sustainability.
Authors: Rebecca Anas, Scott Gavura, Robin McLeod, Virginia McLaughlin, Craig Earle, Jessica Arias, Michelle Rey, Hasina Jamal
Journal: Journal of Clinical Oncology (2016)

38 Background: One of the challenges facing Ontario relates to managing the rising costs of cancer drug treatments. The annual growth rate of cancer drug spending has increased by 10-20% since 2010, exceeding other therapeutic categories and is expected to continue to grow significantly faster than expenditures in other areas. Paradoxically, the price of a drug seems to have little relation to its demonstrated efficacy ( http://www.asco.org/practice-research/cancer-care-america-2015/focus-cost ). The Cancer Quality Council of Ontario (CQCO) and Cancer Care Ontario (CCO) embarked on a journey to systematically address this challenge. Methods: The CQCO and CCO focused on identifying and reviewing the critical success factors of a sustainable drug reimbursement program with international, pan-Canadian and internal input. Recognizing that drug funding sustainability is a challenge faced by health systems worldwide, the scope of this work was broadened from a provincial focus to one that was relevant across the Canadian context. Results: Ultimately, this work resulted in CQCO providing a core set of recommendations for CCO that may also be relevant to other reimbursement programs, in order to maximize the effectiveness of cancer drug use and support overall system sustainability in a patient-centred way. The recommendations to address drug funding sustainability included: (1) Transparency in drug funding decisions; (2) development of process to incorporate current best evidence to support system sustainability; (3) development of a consistent approach to gathering and analyzing real world evidence (RWE); (4) development of a consistent process for disinvestment and renegotiation of prices with buy-in from public, patients and clinicians; (5) development of a provincial process to maximize harmonization in cancer drug funding coverage decisions; (6) refinement of the algorithm and priority setting for review of drug submissions; and (7) incorporating RWE into funding decisions and downstream re-evaluation. Conclusions: CCO is determining an action plan based on the above recommendations and developing partnerships to support successful implementation to improve sustainability in regards to cancer drug funding.
Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study
Authors: Signe Borgquist, Anita Giobbie-Hurder, Thomas P. Ahern, Judy E. Garber, Marco Colleoni, István Láng, Marc Debled, Bent Ejlertsen, Roger von Moos, Ian Smith, Alan S. Coates, Aron Goldhirsch, Manuela Rabaglio, Karen N. Price, Richard D. Gelber, Meredith M. Regan, Beat Thürlimann
Journal: Journal of Clinical Oncology (2017)

Purpose Cholesterol-lowering medication (CLM) has been reported to have a role in preventing breast cancer recurrence. CLM may attenuate signaling through the estrogen receptor by reducing levels of the estrogenic cholesterol metabolite 27-hydroxycholesterol. The impact of endocrine treatment on cholesterol levels and hypercholesterolemia per se may counteract the intended effect of aromatase inhibitors. Patients and Methods The Breast International Group (BIG) conducted a randomized, phase III, double-blind trial, BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor-positive invasive breast cancer from 1998 to 2003. Systemic levels of total cholesterol and use of CLM were measured at study entry and every 6 months up to 5.5 years. Cumulative incidence functions were used to describe the initiation of CLM in the presence of competing risks. Marginal structural Cox proportional hazards modeling investigated the relationships between initiation of CLM during endocrine therapy and outcome. Three time-to-event end points were considered: disease-free-survival, breast cancer-free interval, and distant recurrence-free interval. Results Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen-letrozole (n = 189), letrozole-tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer-free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence-free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03). Conclusion Cholesterol-lowering medication during adjuvant endocrine therapy may have a role in preventing breast cancer recurrence in hormone receptor-positive early-stage breast cancer. We recommend that these observational results be addressed in prospective randomized trials.
Conatumumab (CON) plus FOLFIRI (F) or ganitumab (GAN) plus F for second-line treatment of mutant (MT) <i>KRAS</i> metastatic colorectal cancer (mCRC).
Authors: Allen Lee Cohn, Josep Tabernero, Juan Maurel, Elzbieta Nowara, Sarita Dubey, Nigel Baker, Yong Jiang Hei, Francesco Galimi, SuPin Choo
Journal: Journal of Clinical Oncology (2012)

534 Background: EGFR inhibitors are not an option for patients (pts) with MT KRAS mCRC; therefore, there is an unmet medical need for novel agents to treat this pt population. CON (agonist) and GAN (antagonist) are investigational, fully human monoclonal antibodies to death receptor 5 and type 1 insulin-like growth factor receptor, respectively. In colorectal xenografts, CON enhanced the activity of 5FU, and both agents enhanced the activity of irinotecan. A 3-arm, placebo (pbo)-controlled, double-blind, double dummy, randomized phase 2 study evaluated both agents in MT KRAS mCRC. Methods: Planned sample size = 150. Eligibility: MT KRAS mCRC; disease progression on 1 prior oxaliplatin and fluoropyrimidine therapy. Randomization was 1:1:1 to Arm 1: CON 10 mg/kg + GAN pbo + F Q2W; Arm 2: CON pbo + GAN 12 mg/kg + F Q2W; Arm 3: CON pbo + GAN pbo + F Q2W. Randomization was stratified by PS (0 vs 1) and prior anti-VEGF therapy (yes vs no). Pts received CON, GAN, or pbo IV day (D)1 and 15; irinotecan 180 mg/m 2 D1; leucovorin 400 mg/m 2 over 2 h D1; 5FU bolus 400 mg/m 2 over 2-4 min D1 then 5FU 2400 mg/m 2 over 46-48 h. Primary endpoint: PFS by investigator assessment. Results: 155 pts (Arms 1/2/3: 51/52/52 pts) were randomized between 3/09 and 2/11; 50/50/52 received ≥ 1 dose of study drug. Median age, 59/58/59 years; women, 47/54/56%; colon cancer, 75/65/83%; PS 1, 37/42/40%; prior anti-VEGF therapy, 43/40/42%. See table for efficacy. % pts with grade 3-5 adverse events (Arms 1/2/3) included: neutropenia 30/25/18%; diarrhea 18/2/10%; intestinal obstruction 4/6/8%. There was 1 treatment-related death of unknown cause on Arm 1. Conclusions: CON + F and GAN + F were tolerable in this pt population. CON + F, but not GAN + F, improved PFS. ORR was increased vs pbo. OS data are immature. Further study of CON may be warranted in mCRC. [Table: see text]
Preoperative radiation with concurrent daily tegafur-uracil plus leucovorin for locally advanced rectal cancer: Results of a phase II multicenter prospective study
Authors: P. Cellier, B. Leduc, L. Martin, B. Vie, V. Vendrely, C. Carrie, P. Burtin, L. Campion, V. Berger, C. Chevelle
Journal: Journal of Clinical Oncology (2008)

4092 Background: This two-stage phase II multicenter trial was designed to assess the efficacy and tolerability of pre-operative tegafur-uracil (UFT) plus leucovorin (LV) and radiotherapy (RT) in patients with locally advanced T3 rectal cancer (LARC). Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency was assessed prior to treatment. Methods: Eighty-five patients with potentially resectable cT3 LARC (<15 cm from anal verge) with no total DPD deficiency were to be enrolled (UH2/U ratio < 1). Chemoradiotherapy consisted of UFT (300 mg/m²/d), LV (75 mg/d), and pelvic RT (1.8 Gy/d, 45 Gy total) 5 days/week for 5 weeks. Surgery was performed 5- 6 weeks after chemoradiotherapy. Node-positive patients received adjuvant chemotherapy. Primary endpoints included echo-endoscopic tumor downstaging and pathologic complete response (pCR) rate. ITT analysis was performed. Results: Eighty-five patients (T3N0 55%; T3N1 39%; T3N2 2%; unknown 4%) were included, 8 of whom were ineligible none of them, with either partial nor DPD deficiency. Preoperative grade 3/4 adverse events included diarrhea (n=18; 21%) and nausea/vomiting (n=5; 6%); there was no hand-foot syndrome. No dose adjustments were planned even for gene variations. Forty five patients were heterozygous for the DPD gene. Two of them who were treated with full dose, experienced early grade 4 neutropenia (variant IVS14+1G>A) and diarrhea (variant 2846A>T). A third one experienced grade 4 diarrhea at week 3 (variant 1679T>G). Downstaging occurred in 44% of patients, pCR in 20% (including cellular variability criteria) with no tumor cells in 8.2% and sphincter-sparing surgery in 64%. Adjuvant chemotherapy was administered to 36 patients (mean duration 118 days). With a mean follow-up of 40 months, local failure occurred in 5% of patients and distant metastasis in 21%. Overall and recurrence-free survival at 2 years were 80% and 75%, respectively. Conclusions: Preoperative chemoradiotherapy using concomitant tegafur-uracil with LV plus RT is well tolerated and effective and represents a convenient alternative to 5-fluorouracil-based chemoradiotherapy for the treatment of resectable rectal cancer. No significant financial relationships to disclose.
EGFR polymorphisms as predictors of clinical outcome in patients with advanced colorectal cancer (ACRC) treated with cetuximab and panitumumab
Authors: E. Carcereny, S. Castellvi-Bel, V. Alonso, X. Garcia-Albeniz, J. Muñoz, R. Gallego, C. Hondler, A. Castells, P. Gascón, J. Maurel
Journal: Journal of Clinical Oncology (2008)

4124 Background: To evaluate EGFR polymorphisms as predictors of clinical outcome in patients (pts) with ACRC treated with cetuximab or panitumumab. Methods: 84 pts with ACRC who received cetuximab or panitumumab in second and third line therapy were included. We analyze three polyphormisms: a single nucleotide polymorphism (SNP) in codon 216 (216 G/T), a SNP in codon 497 (497 G/A), and a dinucleotide repeat polymorphism in intron 1. DNA was extracted from paraffin-embedded tissue using the QiaAmp DNA Mini kit. The sAVH3, - 216G>T and R497K polymorphisms were genotyped in each pts. In order to differentiate genotypes, a specific PCR amplification was followed by an electrophoresis on an Applied Biosystems ABI310 genetic analyzer to detect a FAM-labeled PCR product (sAVH3), a restriction endonuclease enzyme digestion and a 4% agarose electrophoresis (-216G>T), or a detection on a Applied Biosystems 7300 RT-PCR System using the TaqMan technology (R497K). The number of the CA repeats (sAVH3) and genotype assignment (-216G>T and R497K) were confirmed by direct sequencing. Results: Polymorphisms analysis could be performed in 65 of 84 pts (77%). Overall response rate (ORR) was 21.7%, median progression-free survival (PFS) 3.7 months (m) (2.8–4.5) and median overall survival (OS) 7.1 m (5.6–8.6). Polymorphism in intron 1 (>18 vs <18) and promoter SNP -216G>T were not associated to ORR, PFS and OS. SNP R497K (GA/AA vs GG) was significantly associated with a lower ORR (33.3% vs 66.7% p=0.08), and a shorter PFS (1.6 vs 4.27 m p= 0.0052) and OS (5.25 vs 10.28 m p=0.0068). By multivariate analysis CEA (1.003 IC95% 1.001–1.004 p=0.0001), LDH (1.001 IC95% 1–1.002 p=0.001) and polymorphism R497K (3.295 IC95% 1.7–6.2 p=0.0001), were identified as an independent prognostic factors for PFS and OS. Conclusions: SNP in codon 497 of EGFR, by reducing EGFR activity, could be a determinant of resistance in ACRC, treated with anti- EGFR monoclonal antibodies. No significant financial relationships to disclose.