tbuckley/cabot-search huggingface dataset:
Primary chemotherapy in breast cancer shows excellent clinical and pathological response with docetaxel and epirubicin
Authors: H. R. Marana, J. M. Andrade, D. G. Tiezzi, F. E. Zola, H. H. Carrara, F. C. Reis, S. Bighetti
Journal: Journal of Clinical Oncology (2006)

10779 Background: Primary chemotherapy is becoming the standard of care for locally advanced breast cancer. Recently tested regimens using new drugs have been showing better results than usual anthracycline based treatments. Methods: From April 1998 through April 2004, 104 patients (18 stage IIA; 36 stage IIB; 13 stage IIIA; 33 stage IIIB; 4 stage IV) were included in the trial and received three cycles of docetaxel 75 mg/m 2 and epirubicin 50 mg/m 2 (q3w). Patients with stable or progressive disease were excluded from the trial, receiving alternative treatment. Those with partial response after three cycles but still not suitable for conservative surgery received up to 3 additional cycles. Following completion of the chemotherapy regimen, tumour response was assessed and appropriate surgery performed. Pathological response was evaluated in excised specimens. Results: According to the UICC criteria for clinical evaluation, 79 pts (76%) had objective regression (14 CR and 65 PR); 21 resulted in stabilised disease and 4 showed progression (24%). There was no toxicity in 62 patients, grade I/II in 4 and grade III/IV in seven patient. Ninity-nine patients became eligible for surgery (95%); 60 underwent conservative surgical treatment (60.6%) and in 39 patients a modified radical surgery was done (39.4%). No axyllary involvement were detected in 22 patients, other 23 had 1–3 positive nodes and 54 had 3 or more positives node in axillary dissection. 338 chemotherapy cycles were given, with an average of previously expected 3.25 cycles per patient. Conclusions: Our study demonstrates a high response rate with primary docetaxel and epirubicin chemotherapy in locally advanced breast cancer and high axillary envolvement group, enabling conservative surgery to take place and carrying no significant toxicity. Survival rate was directly linked to pathological response and complete response was associated to highest rate of survival in the group. No significant financial relationships to disclose.
A pilot study of transarterial injection of <sup>166</sup>Holmium-Chitosan complex in the treatment of single and small hepatocellular carcinoma (HCC)
Authors: B. C. Cho
Journal: Journal of Clinical Oncology (2005)

4172 Background: Percutaneous treatments have been the best option for small unresectable HCC. New technologies to improve the efficacy have been needed so far. We have previously reported transarterial administration of 166Holmium-Chitosan complex as a novel and effective modality in the treatment of single and large (tumor size ≥3 cm in diameter) HCC (JH Sohn, ASCO, 2004, # 4023). Now, here is the report of clinical trial that was performed in patients (pts) with single and small (<3 cm) HCC to explore its potential as a therapeutic modality. Methods: 166Holmium-Chitosan complex at a dose of 20 mCi per cm of tumor mass-diameter was administered through the artery that directly fed the tumor. Eligibility criteria were: pts who refuse or are poor candidates for surgery, single HCC (<3 cm), no vascular shunt. Results: Twelve pts were treated with a median follow-up duration of 26 months. The median dose of 166Holmium-Chitosan complex administered was 30 mCi (range, 30–50 mCi). The median tumor size was 2.0 cm (range, 1.5–2.5 cm). Ten pts (83%) had CR and 2 (17%) had PR. The median CR duration was not reached. The median AFP level dropped from 83.8 to 8.3 ng/mL within 3 months after the treatment. No grade III-IV toxicity was observed. Grade I-II toxicities were observed in 4 patients (2 abdominal pain, 1 fever and 1 AST/ALT elevation). No toxic death occurred. Conclusions: These preliminary results are showing a promising and durable complete response rate with acceptable safety profiles of transarterial injection of 166Holmium-Chitosan complex for a small HCC. Further studies with more accrual of pts are warranted. No significant financial relationships to disclose.
Phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients (pts) with non-Hodgkin lymphoma (NHL) in Japan
Authors: K. Tobinai, T. Watanabe, Y. Kobayashi, S. Yamasaki, Y. Morita-Hoshi, H. Yokoyama, Y. Morishima, H. Kato, S. R. Frankel, T. Otsuki
Journal: Journal of Clinical Oncology (2007)

18521 Background: Vorinostat (Zolinza™), a potent histone deacetylase inhibitor, has demonstrated clinical activity in pts with cutaneous T-cell lymphomas (CTCL) and other NHL subtypes. However, the clinical activity and PK profile in Japanese pts with NHL was unknown. Methods: Japanese pts with NHL were sequentially enrolled in two dose levels ranged from 100 (Level 1) - 200 mg (Level 2) BID, PO for 14 consecutive days every 3 wks. Higher doses were not tested as other phase I studies had established that 300 mg BID for 14 consecutive days every 3 wks exceeded the MTD. PK profiles were analyzed in serum and urine samples. Response was also evaluated according to the international workshop criteria. Results: Ten pts were enrolled: 9 were evaluable for toxicity. One was excluded due to noncompletion of the 1 st cycle. All were evaluable for PK. Median age was 60 yrs (range 52–74). Four pts had follicular lymphoma (FL), 2 mantle cell lymphoma (MCL), 2 diffuse large B-cell lymphoma and 2 CTCL. Median no. of prior regimens was 3 (1–4). In the 1 st cycle, none of 3 pts at Level 1 and 1 of 6 pts at Level 2 developed DLTs (anorexia and hypokalemia of grade 3), indicating Level 2 to be the MTD in this setting. PK was not greatly affected by multiple doses. Intact drug was hardly excreted in urine (&lt;1% of dose). PK profile is similar to that established in US pts. As of Dec 2006, 4 pts were continuing treatment (median 5 mos [1–15]). Two pts with FL showed PR for 8+ and 2+ mos, respectively, and the remaining 1 pt with FL and 1 of 2 pts with MCL showed tumor reduction greater than 30%. Conclusions: Oral vorinostat was well tolerated up to 200 mg BID for 14 consecutive days every 3 wks in Japanese pts with NHL. Preliminary observations of clinical efficacy warrant further investigations for NHL focusing on FL and MCL. No significant financial relationships to disclose.
Antitumor activity and pharmacology of TT-232 (a novel somatostatin structural derivative) in malignant melanoma patients
Authors: F. Gyergyay, M. Gödény, G. Sármay, J. Kralovanszky, E. Papp, M. Gergye, B. Vincze, G. Kéri, I. Bodrogi
Journal: Journal of Clinical Oncology (2004)

3151 Background: TT-232 (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) is a structural derivative of natural signal inhibitory peptide somatostatin. It has been shown to bind to SSTR1 and 4 (somatostatin receptors) and pyruvate kinase M2 receptor, with selective anti-proliferative and anti-inflammatory properties. Methods: Patients with histologically proven metastatic malignant melanoma had been treated with 480 μg/kg TT-232, daily 4-hour infusion on days 1–7, every second week. Serum level of TT-232 has been measured with an enzyme immunoassay (ELISA) method. On days 1, 7, and 56. the following hormones were measured: FSH, LH, prolactine, TSH, fT4, oestradiole, progesterone, and testosterone Results:. Between August 2001 and September 2002 twelve patients (male:6, female:6) were enrolled in the study. The median age was 52 yrs. (range 27–72). The primary tumour localization was the following: trunk:7, head:1, ocular:1, upper extremity:1, lower extremity:2. All pts had previous surgery, 8 had radiotherapy, all received chemotherapy and 11 had immunotherapy as well. Altogether 49 cycles had been given (range 2–8, median 4). One patient had partial remission (lymphnodes) and 3 pts had stable disease (hepatic, mediastinal, rertoperitoneal lymphnodes and pulmonary metastases).Out of 343 days of treatment fever (gr.1–2) has been observed on 8 days. No other significant side effect occurred. The mean steady state concentration was 3.42 μg/mL, the mean elimination half-life was 1.71 hours and the clearence was 2.91 hours/L. The TSH level has doubled by day 7 and remained high on day 56 as well (p>0,05). Other hormones have showed no significant changes. Conclusion: TT-232 seems to be a promising new agent in the treatment of malignant melanoma with no obvious toxicity. No significant financial relationships to disclose.
The optimization of 5-fluorouracil (5FU) dose by pharmacokinetic (PK) monitoring in Asian patients with advanced-stage gastrointestinal (GI) cancer.
Authors: I Peng Thomas Soh, Maria Jannet Mogro, Ross A. Soo, Angela Pang, Chee Seng Tan, Benjamin Chuah, Ying Kiat Zee, Andrea Li Ann Wong, Samuel Guan Wei Ow, Raghav Sundar, Joline Si Jing Lim, Yiqing Huang, Winnie Hui Yee Ling, Wei-Peng Yong
Journal: Journal of Clinical Oncology (2015)

770 Background: PK guided dose management and systemic plasma levels of 5FU have shown correlation with both reduced toxicity and improved efficacy. However, data for Asian patients are lacking. Levels are highly variable with doses based on body surface area. Methods: Area under the curve (AUC) was estimated using a nanoparticle immunoassay from Saladax Biomedical (My5-FU). Patients with GI cancers receiving de Gramont, FOLFIRI or mFOLFOX6 regimens had 5 PK sampling time points obtained (reduced to 2 samplings after first 15 patients). If target AUC (18-28 mg.h/L) was reached for 2 consecutive cycles, monitoring is performed for alternate cycles. With dose adjustments, PK sampling will be done in the next cycle. Results: 50 patients (33 males, 17 females) enrolled, with 349 PK samplings done, and 291 analyzable. 31 (62%) had mFOLFOX6, 18 (36%) FOLIRI and 1 (2%) de Gramont. Colorectal cancer (76%) and gastric cancer (12%) were the most common cancer types. Median AUC (35 evaluable) was 24.2 in C1, 23.65 in C2 (n=38), 20.6 in C3 (n=38) and 22 mg.hr/L in C4 (n=35). Proportion of patients achieving target AUC were 54.3%, 32%, 39.5% and 51% respectively and did not change significantly despite PK guided doses adjustments (C1 vs. C4 p=0.81, C2 vs. C3 p= 0.63, C2 vs. C4 p=0.085, C3 vs. C4 p=0.31). Higher than expected rate of G3/4 neutropenia (52%) and fewer mucositis (0%) and diarrhea (8%) were observed. Other toxicities (all grades) were fairly consistent with historical data. There were no inter-cycle differences in rates of toxicity, and no relationship with G3/4 toxicities and high AUC levels were observed. Correlation of response rates, efficacy with AUC were omitted due to heterogeneous tumor types. Conclusions: Contrary to past studies, PK guided 5FU did not result in a greater number of patients achieving target AUC in Asian patients. Furthermore, AUC levels of 5FU did not correlate with toxicity. Larger numbers are needed to confirm the clinical utility and benefit of PK guided 5FU in Asian patients. Clinical trial information: NCT00943137.
Phase II study of the EGFR tyrosine kinase erlotinib in patients ≥ 70 years of age with previously untreated advanced non-small cell lung carcinoma
Authors: D. Jackman, J. Lucca, P. Fidias, M. S. Rabin, T. J. Lynch, P. Ostler, A. T. Skarin, J. Temel, B. E. Johnson, P. A. Janne
Journal: Journal of Clinical Oncology (2005)

7148 Background: Chemotherapy for patients ≥ 70 with advanced NSCLC is associated with survival benefits but with increased toxicity compared with younger patients. Erlotinib has shown promising activity and a tolerable side effect profile, and it has been approved in the treatment of patients who have failed prior chemotherapy. We have conducted a single center, phase II trial of erlotinib in patients ≥ 70 years with previously untreated advanced NSCLC. Methods: Patients who were chemotherapy-naïve, IIIB/IV, PS 0–2, were enrolled and treated with erlotinib, 150 mg p.o.q.d, until evidence of disease progression or toxicity. Median survival is the primary endpoint. Secondary endpoints include response rate, toxicity, quality of life (measured by LCSS), and gene sequencing for EGFR and K-ras mutations, and EGFR copy number (CN). Results: From 3/03 to 8/04, 58 patients were treated; all were evaluable for survival and toxicity; 55 were evaluable for response. Demographics: median age 76 (range 70–91); 55% male; 91% PS 0/1; 73% adenocarcinoma or BAC; smoking status: current/former/never: 3/49/6. Toxicity: Rash (81%) and diarrhea (69%) were the most common toxicities. Toxicity ≥ grade 3: 5 rash, 3 interstitial pneumonitis, 2 anorexia, 2 hand-foot syndrome, 2 elevations in PT/PTT, 1 GI bleed, 1 hemoptysis, 1 diarrhea, and 1 glossitis. Eight patients were discontinued from study due to toxicity. There was one treatment-related death (pneumonitis). Response: CR 0, PR 6 (10.9%), SD 30 (54.5%), and PD 19 (34.5%). Median survival for all patients was 10.5 months. Median duration of PR and SD was 13.75 and 3.5 months, respectively. In 21 pts with available tissue, EGFR mutations were found only in 3/5 responders. K-ras mutations were found in 1/7 with stable disease and 2/9 with disease progression. EGFR CN did not correlate with treatment outcome. Conclusions: Erlotinib appears to be relatively well tolerated and demonstrates encouraging activity and median survival in patients ≥ 70 years of age with previously untreated advanced NSCLC. Accrual is continuing to 80 patients, and updated response, survival, quality of life, and EGFR/K-ras sequencing will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Genentech
β-catenin interacts with heat shock protein Hsp27 and heat shock transcription factor 1 and it is a useful prognostic marker in breast cancer patients
Authors: F. E. Gago, M. A. Fanelli, M. M. Montt-Guevara, A. M. Diblasi, O. Tello, F. D. Cuello-Carrión, E. Callegari, D. R. Ciocca
Journal: Journal of Clinical Oncology (2007)

10593 Background: We examined in breast cancer the possible interactions between heat shock proteins (Hsps) and the cadherin- catenin cell adhesion proteins, which have important roles in signaling pathways and tumor cell invasion. The cadherin-catenin proteins, like Hsps, have the capacity to bind other proteins. Moreover, there are common molecular pathways for the Hsp response and for the cadherin- catenin protein system. Methods: β-catenin was immunoprecipitated from breast cancer biopsies and the resulting product was probed with antibodies against Hsp members. LC-ESI-MSMS analysis was performed. Immunohistochemistry was used on paraffin sections. Statistical analyses were performed (Prism computer program): Kaplan-Meier, difference between curves evaluated with the log-rank test for censored survival or event observations, contingency tables analyzed by the Fisher`s exact test and Chi-square. Results: β- catenin interacted with Hsp27 and HSF1 (heat shock transcription factor 1), this is the first demonstration of these specific interactions, β- catenin did not interact with Hsp60, Hsp70, Hsp90, gp96 and CHOP. To confirm this finding, the 27 kDa band was excised and submitted to LC- ESI-MSMS, the band was identified as Hsp27. In addition, β-catenin interacted with P-cadherin and caveolin-1. In the co-localization studies, β- catenin was observed in the same tumor areas and cells that expressed Hsp27. This association was strong when β-catenin was expressed in the cytoplasm, not when β-catenin was expressed at the cell membrane. In addition, β-catenin co-localized with HSF1. Finally, the prognostic significance of cadherin-catenin proteins was examined in breast cancer patients (n=215, follow-up: &gt;10 years). Conclusions: We found that cytoplasmic β-catenin interacted with Hsp27 and HSF1, and that the survival (disease free and overall) was significantly shorter for patients with P-cadherin + and cytoplasmic β-catenin + tumors. The interactions of β-catenin with Hsp27 and with HSF1 may explain some of the molecular pathways that influence tumor cell survival and the clinical significance in the prognosis of the breast cancer patients. No significant financial relationships to disclose.
A phase I study of a second generation antisense oligonucleotide to clusterin (OGX-011) in combination with docetaxel: NCIC CTG IND.154
Authors: K. N. Chi, E. Eisenhauer, L. Siu, H. Hirte, S. J. Hotte, S. Chia, J. Knox, E. Guns, J. Powers, M. E. Gleave
Journal: Journal of Clinical Oncology (2005)

3085 Background: The clusterin gene encodes a cytoprotective chaperone protein that promotes cell survival, is expressed in a variety of cancers, and increases in response to apoptotic stimuli. OGX-011 (OGX, Oncogenex Technologies Inc) is a 2’methoxyethyl antisense complimentary to clusterin mRNA that inhibits expression with a tissue t1/2 >7 days in pre-clinical studies. A phase I trial of OGX in men prior to prostatectomy identified biologically active doses of 480 and 640mg as determined by clusterin suppression effects. The objective of this phase I study was to define a phase II dose of OGX in combination with docetaxel. Methods: The study was conducted at 3 centers in Canada. Patients (pts) with cancers known from the literature to express clusterin were eligible. OGX was given by 2 hr IV infusion at fixed doses starting at 40mg weekly after loading on days 1, 3, and 5. Docetaxel was given IV 30 mg/m2/week (w) for 5 out of 6w or 75 mg/m2 every 3w. Serial samples of peripheral blood mononuclear cells and serum were assessed for clusterin as were accessible malignant tissues. Results: 26 pts (9 prostate, 8 ovary, 3 NSCLC, 4 renal, 1 breast and other) have been enrolled to 6 cohorts with doses of OGX up to 640mg delivered with weekly docetaxel. 24 pts are evaluable for toxicity. Toxicity was typical for docetaxel with 3 pts having grade 3 treatment related toxicity (allergic, gastrointestinal, fatigue). OGX attributable adverse events were grade 1/2, including fevers, rigors, fatigue and transient AST and ALT elevations. OGX AUC and CMAX increased linearly with dose with no apparent effect on docetaxel pharmacokinetics. Serial baseline serum clusterin levels were consistent, but by treatment day 8 decreased in 3/3 pts by a mean of 52% (SD=26%) at the 640 mg dose level. Of 18 pts with measurable disease, there has been 1 partial response and 5 patients with stable disease. Conclusions: OGX can be given at biologically active doses with standard doses of weekly docetaxel. Accrual continues and additional cohorts are evaluating OGX with docetaxel q3w. Phase II trials of this combination are planned in pts with breast and prostate cancer. Supported by a grant from the NCIC and a grant in aid from Aventis Pharma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OncoGeneX Technologies OncoGeneX Technologies
Phase II study of sequential administration of vinorelbine -capecitabine combination followed by weekly docetaxel as first line chemotherapy for advanced breast cancer
Authors: M. Ghosn, G. Chahine, J. Kattan, F. Farhat, F. Nasr, W. Moukaddem, E. Tueni, J. Dagher, F. Younes, J. Gasmi
Journal: Journal of Clinical Oncology (2004)

817 Background: The combination of vinorelbine (N) and capecitabine (C) has demonstrated to be active and safe regimen for advanced breast cancer (ABC) (Ghosn; ASCO 03); capecitabine and docetaxel (D) combination in anthracycline failure has demonstrated an interesting outcomes, but with high toxicity profile. In order to improve patient clinical benefit by minimizing toxicity, we conducted a phase II trial with these 3 agents in sequential schedule. Methods: Eligible patients (pts) had ABC (locally advanced or metastatic), measurable disease, no prior chemotherapy for ABC, WHO PS<2, adequate bone morrow, renal and hepatic functions and written informed consent. Pts received 4 cycles of N: 25 mg/m2 on day 1 & day 8 in combination with C: 825 mg/m2 twice a day from day 1 to day 14 every 3 weeks. Pts with objective response or stable disease received twelve consecutive weeks of D: 25 mg/m2. Results: Between July 02 and Sept 03, forty-two consecutive pts were enrolled into the study; median age: 58 years (36–79), median WHO PS: 1 (0–2), 7 pts were stage IV at diagnosis. Sites involved; visceral: 78.5%, bone: 33%, adjuvant chemotherapy: 67% (anthracycline: 57%, anthra + taxane: 9.5%), prior hormonal therapy: 62%. Up to day, so far thirty pts were evaluable for efficacy and 36 pts for toxicity. Twenty-four pts achieved an objective response (ORR: 80%) including one complete response, 3 pts had a stable disease and disease progression occurred in 3 pts. The treatment was well tolerated, WHO grade 3–4 neutropenia (14% pts) and febrile neutropenia (8% pts), grade 3–4 thrombocytopenia and anemia were seen in one pt respectively. No severe clinical toxicity was reported, Grade 1–2 hand-foot syndrome (7% pts), nausea/vomiting (8%), asthenia, diarrhea, edema and nail disorders were occurred in 3% of pts respectively. Conclusions: The sequential treatment of N+C followed by weekly D as first line chemotherapy is highly active and well tolerated regimen, response rates were not affected by prior adjuvant chemotherapy or visceral involvement. Final results will be presented at the meeting. No significant financial relationships to disclose.
Standard (SIDR) and intensive ifosfamide and doxorrubicin (IIDR) regimen in advanced soft tissue sarcoma (ASTS)
Authors: M. Chacon, C. Coronado, J. M. O’connor, A. Nervo, C. Pupareli, V. Costanzo, F. Nasroulah, M. Varela, J. P. Sade, R. Chacon
Journal: Journal of Clinical Oncology (2005)

9076 Background: Doxorrubicin (D) and Ifosfamide (I) are the most active agents in STS. A dose-response effect for this drugs has been established. Despite multiples randomized trials of D-I as single or combination, it still difficult to determined the most effective systemic treatment for ASTS. Objetive: To evaluate Rate Response (ORR) Time to Progression (TTP) and Toxicity from two consecutives D- I regimens for ASTS pts. Material and Methods: We conducted a retrospective analysis in pts with ASTS who received: GROUP A (Jan /94 - Jan /2000) SDIR: D at doses < 75 mg/ m2 and I < 10 gm/m2. GROUP B (Jan 2000- March 2004) IIDR: D 75 mg/m2 in 72 hs continuous infusion (c.i.), I 10 g/m2 (5 doses of 2 g/m2 each 12 hs.) MESNA and G-CSF. every 21 days. Results: GROUP A: 31 pts were included, median dose: D 50 mg/m2 and I 5 g/m2; 24 pts were assessed for response; male/female 18/ 13; median age 44 years (18–61) Primary Tumor: extremities 35%, visceral 30%; leiomiosarcomas 16%. sites of recurrence: lung 10 pts, others 9 pts. The ORR was 21%; TTP 5 months, SD 21%, PD 58% after 2 cycles. 10 episodes of febrile neutropenia (8%) were registered and 1(3,2%) sepsis death. GROUP B: 42 pts; 27 male, 15 female, median age 42 years (17–66). Primary tumor: extremities 43%, Visceral 12%, leiomiosarcoma 19%.Sites of recurrence: lung 9 pts; others 16 pts; multiple sites 14 pts. 37 pts were evaluable for response. 179 cycles were administered, median 4 (2–7). 41 episodes of febrile neutropenia (22%) in 25 pts were observed and 1 dead (2,3%) sepsis related. Neurotoxicity Grade 3 in 5 pts. Response: CR 5/37 (13, 5%), RP 11/37 (30%) SD 37, 5% and PD 19%. 11 pts (26%) underwent to resection of residual metastatic sites. Median TTP was 10 months (r 2–39). Conclusion: in our serie of ASTS IIDR showed higher RR, TTP and RO resections than historical regimens with SIDR. Due to the risk of substantial toxicity IIDR should be appropriate for pts whit the possibility of long term control or borderline resectables. No significant financial relationships to disclose.