tbuckley/cabot-search huggingface dataset:
The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model as a prognostic tool in metastatic renal cell carcinoma (mRCC) patients previously treated with first-line targeted therapy (TT).
Authors: Jenny J. Ko, Wanling Xie, Daniel Yick Chin Heng, Nils Kroeger, Jae-Lyun Lee, Brian I. Rini, Jennifer J. Knox, Georg A. Bjarnason, Lauren Christine Harshman, Sumanta Kumar Pal, Takeshi Yuasa, Martin Smoragiewicz, Frede Donskov, Aristotelis Bamias, Lori Wood, D. Scott Ernst, Neeraj Agarwal, Ulka N. Vaishampayan, Sun Young Rha, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2014)

398 Background: Prior prognostic models for 2nd-line systemic therapy have not been studied in the setting of contemporary sequential targeted therapy (TT). We sought to validate the IMDC prognostic model in patients with mRCC receiving next-line TT after progression on 1st-line TT. Methods: Patients who received 2nd-line TT after progressing on 1st-line TT for mRCC at 19 centres were analyzed. For the patients who had immunotherapy (22%) prior to their 1st TT, we examined their second TT (ie 3rd-line therapy). The endpoint was median overall survival (OS) since the initiation of 2nd-line therapy. Additionally, we compared the IMDC model with the 3-factor-MSKCC model (Motzer et al JCO 2004) used for previously-treated patients. Results: 1,021 patients treated with a second TT were included. Median time on 2nd-line TT was 3.9 months (range 0-76+). 871 (85%) of patients had stopped 2nd-line TT by the time of analysis. Median OS since 2nd-line TT was 12.5 months (95% CI: 11.3-14.3 months), with 369 (36.1%) of patients remaining alive. 5 out of 6 pre-defined factors in IMDC model (anemia, thrombocytosis, neutrophilia, KPS &lt;80%, and &lt;1 year from diagnosis to treatment) measured at the time of 2nd-line TT were independent predictors of poorer OS (HR between 1.39 and 1.58, p&lt;0.05). Hypercalcemia was not statistically significant in multivariable analysis (p=0.3008) likely due to the low incidence of hypercalcemia (9%). The concordance index using all 6 prognostic factors was 0.70, and was 0.66 with the 3-factor-MSKCC model. When patients were divided into 3 risk categories using IMDC criteria, median OS was 35.8 months (95% CI 28.3-47.8) in the favorable risk group (n=76), 16.6 months (95% CI 14.9-17.9) in the intermediate risk group (n=529), and 5.4 months (95% CI 4.7-6.8) in the poor risk group (n=261). Conclusions: The IMDC prognostic model has been validated in and can be applied to patients previously treated with TT, in addition to previously validated populations in 1st-line TT and non-clear cell setting.
Intravenous and intraperitoneal paclitaxel with S-1 for refractory pancreatic cancer with malignant ascites: An interim analysis.
Authors: Naminatsu Takahara, Hiroyuki Isayama, Yousuke Nakai, Takashi Sasaki, Hironori Ishigami, Hironori Yamaguchi, Hirofumi Kogure, Natsuyo Yamamoto, Naoki Sasahira, Kenji Hirano, Minoru Tada, Joji Kitayama, Toshiaki Watanabe, Kazuhiko Koike
Journal: Journal of Clinical Oncology (2013)

267 Background: Here we reported an interim analysis of feasibility and safety in the first 10 cases of 30 cases in a phase II trial of intravenous and intraperitoneal paclitaxel combined with S-1 for gemcitabine-refractory pancreatic cancer with malignant ascites. Methods: Paclitaxel was administered intravenous at 50 mg/m 2 and intraperitoneal at 20 mg/m 2 on days 1 and 8 every 3 weeks, and S-1 was administered at 80 mg/m 2 /day for 14 consecutive days, followed by 7 days rest. Results: Between April 2011 to February 2012, 10 patients were enrolled. A partial response was achieved in two (20%) and a disease control rate of 50%. The median time to progression and overall survival were 3.2 and 5.9 months, respectively. Malignant ascites was completely resolved in two (20%). Major grade 3/4 adverse events weremyelosuppression including neutropenia (50%) and catheter-related infection (10%). Conclusions: This novel combination chemotherapy was feasible and showed promising results in pancreatic cancer patients with malignant ascites. Clinical trial information: UMIN000005306.
Hair depigmentation as an indicator of durable response to CTLA-4 therapy.
Authors: A. C. Pavlick, P. A. Ott, R. Kannan, K. M. Madden, C. Sorlie, C. Escano, J. Escalon, E. Hernando-Monge, I. Osman, N. Bhardwaj
Journal: Journal of Clinical Oncology (2010)

8571 Background: Treatment with CTLA-4 monoclonal antibodies for metastatic melanoma has been known to induce immunologically related adverse events. It is unclear if these events correlate with clinical responses. We report here, for the first time, the occurrence of hair depigmentation following therapy with CTLA-4 monoclonal antibodies that correlate with durable clinical responses. No non-responders developed any hair depigmentation. Methods: Patients (pts) enrolled onto 2 clinical trials at NYU using either ipilimumab (ipi) or tremelimumab (treme) for metastatic melanoma were evaluated. 43 pts were accrued (33-ipi and 10-treme). 11 pts achieved long-term, durable responses (3 complete responses and 8 partial responses) lasting over a median of 24 months. 5F:6M Age range: 37-78. All had normal baseline LDH levels. Results: Six pts developed sudden hair depigmentation starting with the eyebrows. Median time to depigmentation was 10 months. All 6 pts have continued to have either complete depigmentation of all body hair or the development of diffuse vitiligo. All of these pts have remained with stable disease or complete resolution of disease ranging from 24-36 months. Five of 6 had normal baseline total lymphocyte counts. One with low baseline lymphocyte counts normalized following therapy. All pts had prior therapies including biologics, immunotherapy and/or chemotherapy. All 6 pts also developed other immunologic-related toxicities including rash (6), pruritis (4), diarrhea (4), grade III hypophysitis (2). The remaining 5 pts without hair depigmentation remain with stable disease ranging from 24-48 months. Immune related toxicities in these include rash (4), pruritis (3), diarrhea (2) and myalgias (1). Tumor tissue from all 11 responders are being analyzed for tumor infiltration with CD3 T cells, infiltrating TILs, microRNA and SNPs. Blood samples drawn before and after response to therapy will be evaluated for anti-NY-ESO-1 antibodies. Conclusions: To our knowledge, this is the first report of immune related hair depigmentation in metastatic melanoma patients treated with CTLA-4 monoclonal antibodies who achieve durable responses. Scientific correlates being performed on blood and tissues and will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Pfizer
Impact of pretreatment systemic inflammatory response on survival in AGC patients receiving first-line chemotherapy.
Authors: Kazumasa Fujitani, Hiroya Takiuchi, Naotoshi Sugimoto, Hiroshi Imamura, Shohei Iijima, Motohiro Imano, Yutaka Kimura, Yukinori Kurokawa, Toshio Shimokawa, Toshimasa Tsujinaka, Hiroshi Furukawa
Journal: Journal of Clinical Oncology (2013)

88 Background: Systemic inflammatory response plays an important role in cancer progression. However, little is known about how it affects the advanced gastric cancer (AGC) patients receiving first-line chemotherapy. We assessed the impact of pre-treatment systemic inflammatory response on survival in AGC patients receiving S-1 based first-line chemotherapy. Methods: OGSG 0402 multi-institutional phase II trial randomly assigned 102 patients with previously untreated, locally advanced and/or metastatic measurable gastric adenocarcinoma to receive S-1 plus irinotecan (SI arm) (n=51) or S1 plus paclitaxel (SP arm) (n=51) to evaluate these two S-1 based regimens as first-line treatment for AGC [ASCO-GI 2009: abstract 9.]. Among these patients, 99 patients were identified in this study excluding 2 patients who had died before receiving the allocated treatment and one patient who was lost to follow-up. All patients had performance status (PS) of 0-1 except for one with PS of 2. Pre-treatment clinical findings, such as gender, age, body mass index (BMI), tumor status (unresectable vs. recurrent, intestinal vs. diffuse), number of metastatic sites, serum levels of albumin (Alb) and C-reactive protein (CRP), neutrophil lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR), were assessed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses. Results: Median OS and PFS were 390 days and 175 days for SI arm, and 363 days and 140 days for SP arm, respectively. Multivariate analysis identified the CRP level of 0.5 mg/dl or above (hazard ratio 1.96, 95% confidence interval 1.08 to 3.55, P=0.026) as a significant prognosticator for poor OS, and age of 60 years or greater (hazard ratio 1.92, 95% confidence interval 1.06–3.47, P=0.032) for shorter PFS. Conclusions: Pre-treatment CRP level was a most potent prognosticator for OS, reflecting the impact of systemic inflammatory response on survival, in AGC patients receiving first-line chemotherapy.
KW-2449, a Novel Multi-Kinase Inhibitor, Suppresses the Growth of Imatinib-Resistant Ph+ Leukemia Including BCR-ABL/T315I Both in Vitro and in Vivo.
Authors: Yukimasa Shiotsu, Hitoshi Kiyoi, Ryohei Tanizaki, Yosuke Minami, Akihiro Abe, Yuichi Ishikawa, Kenichi Ishii, Makiko Shimizu, Yutaka Kanda, Yuko Sato, Shiro Akinaga, Jorge Cortes, Tomoki Naoe
Journal: Blood (2008)
Phase II trial of paclitaxel, ifosfamide, and cisplatin (TIP) for previously untreated patients (pts) with intermediate- or poor-risk germ cell tumors (GCT).
Authors: Darren Richard Feldman, James Hu, Tanya B. Dorff, Sujata Patil, Lindsay Joy Van Alstine, Lamia Momen, Maryann Carousso, Amanda Hughes, Jolie Snively-Solomon, Charlean Ketchens, Joel Sheinfeld, Manjit S. Bains, Dean F. Bajorin, George J. Bosl, Robert John Motzer, David I. Quinn
Journal: Journal of Clinical Oncology (2013)

336 Background: Durable progression-free survival (PFS) rates for pts with intermediate- and poor-risk GCT approximate only 75% and 50%, respectively with standard BEP chemotherapy. This phase II study investigated first-line TIP in this population. Methods: Pts age ≥18 with previously untreated poor-risk or modified intermediate-risk (LDH ≥3x upper limit of normal [ULN]) GCT were eligible. Four cycles of TIP were given every 21 days, consisting of paclitaxel 120mg/m 2 on days 1-2; ifosfamide 1200mg/m 2 (with mesna support) on days 1-5; and cisplatin 20mg/m 2 on days 1-5. Peg-filgrastim was given on day 6 and levofloxacin on days 7-13 for prevention of neutropenic fever. The primary endpoint was the complete response (CR) rate; secondary endpoints included PFS and toxicity. A Simon’s two-stage design was used: if ≥11 CRs were observed in the first 18 pts, a total of 41 evaluable pts would be accrued with the trial considered positive if ≥27 CRs were achieved. Results: Of 44 men (median age 27 [range 18-56]) enrolled; 38 had nonseminoma and 6 had seminoma; 29 were poor-risk and 15 intermediate-risk. Primary site was testis in 30, mediastinum in 11, retroperitoneum in 3. Most pts had lung (n=31) and abdomen/pelvis (n=29) metastasis, and 14, 6, and 1 had liver, bone, and brain metastasis, respectively. Markers were elevated in 42 pts. Forty pts received all 4 TIP cycles; 3 pts were withdrawn after 2 cycles for allergic reactions to paclitaxel and were inevaluable for response, and 1 pt completed only 3 cycles in order to undergo surgery for growing teratoma syndrome (evaluable). Of 41 evaluable pts, 29 (72%, 90% CI: 60% – 78%) achieved a CR and 5 (all seminoma) achieved a PR with negative markers (PR-); 7 pts had incomplete responses and 2 pts relapsed from PR- or CR. With a median follow-up of 2.1 years, estimated 1-year PFS was 79% (95% CI: 64% – 89%) and 3-year overall survival 97% (95% CI: 83% – 100%). There were no toxic deaths. Grade 3/4 toxicities were primarily hematologic but only 7 (16%) pts developed neutropenic fever. Conclusions: TIP demonstrated promising efficacy and was tolerable in intermediate- and poor-risk GCT pts. A randomized trial of TIP versus BEP is being planned. Clinical trial information: NCT00470366.
A phase I study of lenalidomide in combination with liposomal doxorubicin in recurrent epithelial ovarian cancer.
Authors: J. S. Carter, M. A. Geller, P. L. Judson, P. Argenta, R. Ghebre, A. L. Jonson, L. F. Carson, L. S. Downs
Journal: Journal of Clinical Oncology (2011)

e15545 Background: Lenalidomide (CC-5013) is an anti-angiogenic and immunomodulatory (IMiD) drug. The objective of this phase I clinical trial was to determine the maximum-tolerated dose (MTD), safety, and tolerability of lenalidomide in combination with liposomal doxorubicin in patients with recurrent epithelial ovarian cancer. Methods: Eligible patients had recurrent or progressive epithelial ovarian, fallopian tube, or primary peritoneal cancer. Dose escalation through five dose levels (10 mg, 15 mg, 20 mg, 25 mg, 30 mg) was planned with lenalidomide on days 1-28 of a 28 day cycle in combination with liposomal doxorubicin at a fixed dose (40 mg/m2) on day 1. Dose escalation was scheduled in cohorts of 3 patients enrolled at each dose level. Dose-limiting toxicity (DLT) was defined as grade 4 hematologic toxicities, or grade 3 or 4 non-hematologic toxicities which prevented the completion of cycle 1 or inability to start cycle 2 within 7 days of the scheduled start. Results: Eleven of 13 enrolled patients were eligible to participate in the trial. Five were enrolled at dose level 1 and 6 were enrolled at dose level 2. No DLTs occurred at level 1. Two DLTs occurred at level 2 due to urticaria and neurologic side effects (blurred vision, ataxia, and dizziness). At dose level 1, one patient had grade 3 neutropenia. At dose level 2, one patient had grade 4 neutropenia, one patient had grade 3 anemia, two patients had grade 3 or 4 fatigue, and one patient had grade 3 neurologic side effects. MTD was reached at dose level 1 of lenalidomide (10 mg) in combination with liposomal doxorubicin (40 mg/m2). There were no clinically significant drug-drug interactions. Conclusions: The combination of lenalidomide at 10 mg on days 1-28 and liposomal doxorubicin at 40 mg/m2 on day 1 resulted in an acceptable safety profile for the outpatient treatment of women with recurrent or progressive epithelial ovarian cancer. Further evaluation of lenalidomide at the MTD in combination with liposomal doxorubicin is warranted in a phase II trial.
Embedded integration of palliative care in an academic outpatient cancer center.
Authors: Christian T Sinclair
Journal: Journal of Clinical Oncology (2015)

158 Background: Palliative care is no longer reserved for ICUs and inpatient settings, since it can be delivered at any age and any stage regardless of goals of care. Oncologists are beginning to embrace more upstream palliative care but translating that to the long term setting has unique difficulties. Outpatient palliative care is a vital component to quality oncology care, but few examples of successful integration have been demonstrated. Methods: Data was collected from the palliative care clinic at the University of Kansas Medical Center Westwood Cancer Center. Descriptive analysis of the initial and current programs as well as successful outreach and education projects will be discussed. Quantitative analysis of number of initial and follow-up outpatient visits, cancer type, referring service and referring physician are all included. Hospice utilization was also recorded as well as length of time from initial consult to either death, discharge or calendar date June 30, 2015. Results: Since the pilot clinical program of outpatient palliative care in 2012 with two half day clinic sessions focused on BMT patients, the program has expanded to 5 half-day sessions and includes medical oncology, surgical oncology and gynecologic oncology. Referrals to palliative care have grown consistently covering multiple cancer diagnosis and including the entire oncology staff instead of a few champions. Increase in outpatient utilization has also spurred more early and appropriate inpatient palliative care utilization. Staff have moved from crisis-only use of outpatient palliative care to a co-management model. Conclusions: Outpatient palliative care can be successfully integrated into an NCI academic medical center oncology practice. (Note: More detailed data will be presented at the conference on all of the trends mentioned above.)
Combination strategy of gemcitabine with the dual PI3K/mTOR inhibitor NVP-BEZ235 in pancreatic cancer cells.
Authors: E. Hausmann, W. Glienke, L. Bergmann
Journal: Journal of Clinical Oncology (2011)

e14562 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumor with poor prognosis. Currently, gemcitabine still remains the chemotherapeutic agent of choice for the treatment of PDAC. However, treatment with gemcitabine has a response rate of less than 20%. Combining two compounds acting via different ways of action may result in a better effectiveness. Methods: To analyze the outcome of a combination therapy, we have incubated four human pancreatic cancer cell lines (Panc-1, BxPC-3, MiaPaCa-2 and AsPC-1) with Gemcitabine (20, 50 and 100µM) and NVP-BEZ235 from Novartis Pharma (500nM, 1 and 5µM). The cells were analyzed with MTT assay for cell viability, FACSscan for cell cycle distribution and Real-time RT-PCR for Survivin mRNA expression. Results: Stand alone application of NVP-BEZ235 and Gemcitabine influenced cell viability in a concentration-independent manner. Combined treatment of Gemcitabine and NVP-BEZ235 lead to a synergistic effect on cell viability of all pancreatic cancer cell lines tested. This effect was enforced by time-delayed usage of these compounds. In these cases, the strongest effect was achieved by a pretreatment with Gemcitabine followed by administration of NVP-BEZ235 24 hours later. Cell cycle analysis revealed, that pretreatment with Gemcitabine before NVP-BEZ235 administration maintained a part of the cells at the S-phase (15-20%), where gemcitabine acts preferentally. An increased gene expression of Survivin mRNA (2-4 fold increase) was observed after treatment with Gemcitabine, while treatment with NVP-BEZ235 decreased the expression of Survivin mRNA. Survivin is involved in DNA strand break repairing so down-regulation of Survivin by NVP-BEZ235 may prolongue the time of DNA strand break repairing leading to a decrease of cell viability. Conclusions: Combining Gemcitabine with dual PI3K/mTOR inhibitors like NVP-BEZ2235 may improve the efficacy of PDAC treatment.
Relationship of incomplete inhibition of PI3K pathway signaling and efficacy of cetuximab in KRAS wild-type colorectal cancers.
Authors: Ryan Bruce Corcoran, Hiromichi Ebi, David P. Ryan, Jeffrey A. Meyerhardt, Jeffrey A. Engelman
Journal: Journal of Clinical Oncology (2012)

462 Background: Therapies targeting receptor tyrosine kinases (RTKs) are typically effective only when they lead to simultaneous downregulation of PI3K-AKT and MEK-ERK signaling. Cetuximab is a monoclonal antibody directed against EGFR that has been approved for the treatment of metastatic colorectal cancer, and several studies have suggested that its benefit is restricted to patients with KRAS wildtype cancers. However, even in KRAS wildtype colorectal cancers, the response rate to single-agent cetuximab is low, and the mechanistic basis for this is not well-understood. Methods: The ability of cetuximab to downregulate PI3K-AKT and MEK-ERK signaling in a panel of KRAS wildtype colorectal cancer cell lines was assessed by immunoblotting. We preformed immunoprecipitations of the regulatory subunit of PI3K on lysates derived from cell lines and primary colorectal tumor specimens to identify the RTKs involved in PI3K activation. Cetuximab-based therapeutic combinations were evaluated in KRAS wildtype cell lines and tumor xenograft models. Results: Cetuximab led to effective inhibition of MEK-ERK signaling (&gt;75% reduction in phospho-ERK), but led to incomplete inhibition of PI3K-AKT signaling (0-50% reduction in phospho-AKT) in all KRAS wildtype colorectal cell lines tested. PI3K regulatory subunit immunoprecipitations revealed multiple RTK inputs to PI3K in cell lines and primary tumors, most notably from IGFIR. Combined treatment with cetuximab and an IGFIR inhibitor or a PI3K inhibitor led to improved efficacy in vitro and in tumor xenograft models. Conclusions: Cetuximab fails to completely downregulate PI3K-AKT signaling in KRAS wildtype colorectal cancer cell lines. Biochemical analysis of cell lines and primary colorectal tumors reveals that additional RTKs other than EGFR play a role in PI3K activation in these cancers. Therefore, combining cetuximab with targeted therapies directed against the PI3K pathway may lead to improved efficacy in KRAS wildtype colorectal cancers.
Sunitinib scheduling in metastatic renal cell cancer: A single-center experience.
Authors: Sarah Louise Picardo, Dearbhaile Collins, Amnah Al Khamis, Victoria Teresa Mallett, Niamh M. Keegan, Irnani Ismail, Bryan Hennessy, Oscar S. Breathnach, William Grogan, Patrick G. Morris
Journal: Journal of Clinical Oncology (2016)

554 Background: Sunitinib is a receptor tyrosine kinase inhibitor that has proven activity as first line treatment for metastatic renal cell carcinoma (mRCC). The recommended dose is 50mg once daily in a 4 week on 2 week off schedule. However this regimen has a significant side effect profile and alternative schedules have been used to minimize dose reductions and maintain dose intensity. We sought to identify the incidence of dose modifications and assess toxicity in patients treated with two sunitinib schedules in a National Cancer Center. Methods: Patients with mRCC who had sunitinib as first line treatment were identified retrospectively and patient data reviewed. Two patient groups were identified: those who received sunitinib 50mg day 1-28 in 6 week cycles (cohort 1) and those who received sunitinib 50mg day 1-14 in 3 week cycles (cohort 2). Primary end point was incidence of dose modification. Secondary end points included incidence of common sunitinib-related side effects. Known prognostic variables, including prior nephrectomy, body mass index (BMI) and use of angiotensin system inhibitors (ASI) were correlated with time to disease progression (TTP). Results: Between 2009 and 2014, 28 patients were identified. Of those, 23 (83%) patients were treated in cohort 1, and 5 (17%) patients in cohort 2. Dose modifications were required in 13 (56.5%) patients in cohort 1, but only 2 (40%) patients in cohort 2. Common sunitinib-related side effects in cohort 1 included hypertension in 19 (79%), weight loss in 10 (41.6%), fatigue in 9 (37.5%) and nausea in 8 (33.3%) patients respectively. Overall, the use of ASIs correlated significantly with longer median TTP (10.5 months) compared to non-users (4 months) (p = 0.04). BMI ≥ 25 (TTP 9 vs. 3 months, p = 0.008) demonstrated a similar correlation. However, no difference in median TTP was noted between patients who had prior nephrectomy compared to those who had not (5 vs. 4 months) (p = 0.18). Conclusions: In this small retrospective study, standard sunitinib scheduling was associated with a high incidence of dose modifications and side-effects. Consistent with previous studies, we identified known prognostic variables. The use of sunitinib 50mg day 1-14 in 3 week cycles may be more tolerable for patients.