tbuckley/cabot-search huggingface dataset:
Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: a regimen with high activity and low cardiotoxicity in advanced breast cancer.
Authors: P F Conte, E Baldini, A Gennari, A Michelotti, B Salvadori, C Tibaldi, R Danesi, F Innocenti, A Gentile, R Dell'Anna, O Biadi, M Mariani, M Del Tacca
Journal: Journal of Clinical Oncology (1997)

PURPOSE To determine the maximum-tolerated dose (MTD) of paclitaxel over 3 hours with a fixed dose of epirubicin, to investigate the plasma pharmacokinetics of this combination, and to evaluate the toxicity and the activity in previously untreated metastatic breast cancer patients. PATIENTS AND METHODS Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible. Epirubicin was administered as an intravenous (I.V.) bolus at the fixed dose of 90 mg/m2 before the infusion of paclitaxel over 3 hours. The initial dose of paclitaxel was 135 mg/m2 and was increased by 20 mg/m2 in subsequent cohorts of six patients until dose-limiting toxicity (DLT). Plasma pharmacokinetics of paclitaxel and epirubicin was performed at cycle 1 in at least two patients per dose level of paclitaxel (175 up to 225 mg/m2). RESULTS The DLT of this combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 micromol/L at doses of 175 to 225 mg/m2. The concentration of epirubicinol decreased from 47.3 +/- 9.4 to 37.9 +/- 7.5 ng/mL in patients treated with paclitaxel 175 and 225 mg/m2. The most relevant toxicity was grade 4 neutropenia (61% of all courses). The pharmacokinetic data of paclitaxel, in particular the time above the threshold level of 0.05 micromol/L, were not significantly related to myelosuppression. Cardiac toxicity was mild: three patients (6%) developed mild congestive heart failure that was responsive to therapy. Among 49 assessable patients, 41 responses (84%; 95% confidence interval [CI], 70% to 92%) were observed, and nine (18%) of these were complete. CONCLUSION Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer.
Recommendations for Cancer Prevention Trials Using Potentially Ototoxic Test Agents
Authors: Lawrence I. Shotland, Frank G. Ondrey, Kristen A. Mayo, Jaye L. Viner
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Preventive oncology applies pharmacologic agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy, a process that may require administration of agents over long periods of time. Although ototoxicity may be a tolerable side effect of anticancer or antimicrobial therapy, even modest ototoxicity may not be acceptable in agents developed for preventive oncology that are routinely administered to subjects who neither are, nor necessarily will become, clinically ill. MATERIALS AND METHODS: Age-related shifts in hearing may occur over the course of longterm or open-ended therapy; consequently, age-adjusted norms enable researchers to better distinguish hearing loss caused by drugs from that caused by aging. Norms for hearing sensitivity are derived from the Baltimore Longitudinal Study of Aging and are the basis for the proposed audiologic monitoring recommendations. RESULTS: Audiologic monitoring recommendations are presented that standardize patient selection, adverse event reporting, posttreatment follow-up, and audiologic testing for potentially ototoxic investigational agents. CONCLUSION: These recommendations are applicable to trials of investigational agents as well as various classes of drugs used in routine clinical care.
AIDS-related lymphoma (ARL): Efficacy of highly active anti retroviral therapy (HAART) on survival and prognostic factors in a general hospital in Peru
Authors: R. D. Reategui, B. Beltran, D. Morales, L. Vera, P. Quinones, K. Portugal, C. Desposorio, A. Capellino, J. Castillo
Journal: Journal of Clinical Oncology (2009)

e19545 Background: Since the introduction of HAART in 1996, the profile of ARL has shifted considerably. The impact of HAART on the survival of ARL in developing countries in the post-HAART era has not been clearly defined. The aims of this study were to evaluate efficacy of HAART on survival and prognostic factors in our population. Methods: The clinical records of 2,502 HIV-infected patients seen in our institution from March 1997 to March 2008 were reviewed. The survival was calculated using the Kaplan-Meier method and the prognostic factors were evaluated by chi square. Results: Forty-eight patients with HIV-associated lymphoma were identified. From the 48 ARL identified 44 were non Hodgkin lymphoma (NHL) and 4 were Hodgkin lymphoma. Two patients with CNS primary were excluded for analysis. From 42 systemic NHL: 38 (90,5%) were of B-cell and 4 (9,5%) were of T-cell. The 5-year overall survival (OS) was 27%. Three groups of patients were included: 13 patients (31%) received HAART previous the diagnosis of ARL, 21 patients (50%) initiated HAART after ARL diagnosis and 8 patients (19%) did not receive HAART. HAART treatment before the diagnosis of NHL increases the survival (54% versus 9,5% versus 25% respectively, p=0.048). Twenty of 42 patients (47,6%) received chemotherapy. This group had a better survival rate than those who did not receive chemotherapy (50% versus 4,5%, p&lt; 0.0001) The overall response to chemotherapy was 80% with CR (n=11, 55%), PR(n=5, 25%) and PD in four (20%). In a multivariate analysis, IPI score &gt; 2, presence of B symptoms and no HAART previous ARL diagnosis were statistically associated to worse survival with p-values of 0.0001, 0.018 and 0.048 respectively. Conclusions: In our study the use of HAART is effective when started before ARL diagnosis. IPI score &gt; 2, B symptoms and no HAART previous the diagnosis were unfavorable prognostic factors. These latest findings are in concordance with prior reports. This is the first Latinamerican report on the impact of HAART on the OS in ARL patients. No significant financial relationships to disclose.
A phase II trial of dasatinib in advanced melanoma
Authors: H. M. Kluger, A. Dudek, C. McCann, L. Rink, J. Ritacco, C. Adrada, N. Phouyaphone, N. Southard, M. Sznol
Journal: Journal of Clinical Oncology (2009)

9010 Background: Direct or indirect inhibition of Src kinases (non-receptor tyrosine kinase signaling intermediates) reduces melanoma cell proliferation in vitro. Dasatinib is a well tolerated, small molecule inhibitor of src kinase family members c-Src, c-Yes, Lck, and also inhibits c-KIT, PDGFβR and EPHA2. We initiated a CTEP-sponsored phase 2 trial of dasatinib in melanoma to assess response rate, PFS and toxicity. The secondary objective is to evaluate the association between clinical response and expression of dasatinib targets in tumors obtained pre-treatment. Methods: Adults with stage III/IV unresectable melanoma with a PS of 0- 1, who have not received prior chemotherapy are eligible. Dasatinib was administered at 100mg PO BID continuously to the first 18 patients. Subsequently, the starting dose was decreased to 70mg BID. Cycles are 4 weeks, tumor assessments occur q2 cycles. Results: Thirty patients have been accrued, five are too early to evaluate. Five, four and three patients had acral-lentiginous, ocular or mucosal primaries, respectively. Median age was 62, M:F 18:12, six received prior non-cytotoxic therapy. Three patients had confirmed partial responses lasting 16, 6, and 5 months, and one had a non-confirmed partial response, progressing after 4 cycles. One patient had a minor response and remains on study after 24 cycles. A patient with an exon 13 mutation in c-KIT responded to therapy, while another with a c-KIT exon 11 deletion mutation did not. Common toxicities are grade II fatigue, grade II-III dyspnea and pleural effusions. Chronic toxicities required reduction of the starting dose, and have been observed in all patients on dasatinib for over two months, all of whom required two dose reductions. Conclusions: Daily dasatinib has modest activity in melanoma. Accrual is almost complete. Toxicities are frequent, alternate schedules providing breaks in dosing might be better tolerated and should be evaluated. Combination studies may be warranted based on preclinical evaluation in molecularly defined subsets of patients. [Table: see text]
Pharmacodynamic case study of sunitinib/SU11248 in a gastrointestinal stromal tumor patient: Evidence toward a mechanism of effect
Authors: M. Seandel, J. Shia, I. Linkov, R. G. Maki, C. Antonescu, J. Dupont
Journal: Journal of Clinical Oncology (2006)

9526 Background: Despite abundant pre-clinical data, the mechanisms of action in humans of multi-targeted small molecule tyrosine kinase inhibitors against sarcomas remain unclear. Herein, we sought evidence from pre- and post-treatment biospies to suggest whether the primary mechanism of action of sunitinib/SU11248 is anti-angiogenic or rather a direct anti-tumor cell effect. Methods: We report data regarding a 59 year old woman with imatinib-resistant GIST who demonstrated a marked tumor response to sunitinib treatment. Her gastric primary GIST tumor was previously resected, followed by recurrence one year later. A complete remission lasting 24 months was then attained on imatinib therapy. After progression of disease, sunitinib was started at 50 mg orally per day. A major clinico-radiographic response was seen after 12 months of therapy, followed by resection. To assess the pharmacodynamic effects of sunitinib, we undertook immunohistochemical analysis of formalin-fixed tissue sampled immediately prior to treatment and just after completing sunitinib, using anti-CD117, anti-CD34, or anti-CD31 antibodies, respectively. Results: We found a dramatic effect of sunitinib on the tumor parenchyma. Whereas the pretreatment biopsy revealed viable, mitotically active, CD117+ and CD34+ tumor cells, the post-treatment specimen was &gt;90% sclerotic and necrotic. The CD31+ blood vessels appeared robust both pre- and post-treatment. Vessel counts did not differ significantly before and after treatment by CD31 staining (3.3±2.0 per field vs. 1.8±1.3, p= 0.09). Thus, the tumor cells were largely eliminated with sunitinib treatment, while blood vessels were still present after 12 months of therapy. Conclusions: This observation supports the assertion that the mechanism of sunitinib in GIST is predominantly cytotoxic against the tumor by directly targeting KIT and that an anti-angiogenic effect, either through the VEGF-R2 in endothelium or through the PDGF-R in pericytes, may be secondary. [Table: see text]
Phase II trial of linifanib in patients with advanced renal cell cancer (RCC) after sunitinib failure.
Authors: N. M. Tannir, Y. Wong, C. K. Kollmannsberger, M. S. Ernstoff, D. J. Perry, L. J. Appleman, E. M. Posadas, J. Qian, J. L. Ricker, D. Michaelson
Journal: Journal of Clinical Oncology (2010)

4527 Background: Linifanib (ABT-869) is a potent inhibitor of VEGF and PDGF receptor tyrosine kinases. Phase I study results suggested antitumor activity in advanced solid tumors including RCC. This study investigated the efficacy and safety of linifanib in patients with RCC following sunitinib failure. Methods: In this open-label, multicenter trial of oral linifanib 0.25 mg/kg (12.5-25.0 mg) daily, key eligibility criteria included PD within 100 days of enrollment after at least 2 cycles of sunitinib, prior nephrectomy, and adequate organ function. The primary endpoint was overall response rate (ORR) by central imaging. Secondary endpoints were PFS, OS, and TTP. Safety was assessed by NCI-CTCAE, v3.0. Results: 53 pts were enrolled from 8/07 to 10/08. The median age was 61 years. 81% of pts had clear-cell histology, and the median number of prior therapies was 2. All pts were previously treated with sunitinib. Response rate to prior sunitinib was 13.2%. Additional prior treatments included cytokines (23%), sorafenib (19%), temsirolimus (4%), and bevacizumab (17%). The ORR [95% CI] per RECIST was 9.4% [3.1, 20.7] (all responses confirmed on 2 visits >4 weeks apart), the median PFS was 5.4 months [3.6, 6.3], and the median OS was 13.3 months [10.8, not reached]. Pts with only 1 prior systemic therapy appeared to have PFS (HR 1.33, [0.71, 2.50], p=0.37) and OS (HR 0.9 [0.39, 2.09], p=0.81) that were similar to those with >1 prior therapy. The most common linifanib-related grade 3/4 adverse event (AE) was hypertension (HT) in 32% of pts. The most common linifanib-related any grade AEs were diarrhea, fatigue (74% each), HT (60%), nausea (51%), and hand-foot syndrome/skin reaction (40%). 46 pts had AE-related dose interruptions and 36 pts had AE-related dose reduction. At the time of analysis, 37 pts discontinued therapy due to PD (clinical, radiographic or AE related to PD), 8 discontinued due to AEs not related to PD, and 2 discontinued for other reasons. There were no deaths due to linifanib-related AEs. Conclusions: Linifanib demonstrated antitumor activity in RCC after sunitinib failure as assessed by ORR and PFS. Future monotherapy trials will utilize a fixed starting dose of 17.5 mg/day. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories, Genentech, Novartis, Pfizer, Wyeth Abbott Laboratories Pfizer, Wyeth Abbott Laboratories
Expression of the endothelin axis and microvessel density in bladder cancer
Authors: E. Herrmann, S. Bierer, M. Boegemann, E. Eltze, L. Hertle, C. Wülfing
Journal: Journal of Clinical Oncology (2006)

4583 Background: Endothelin-1 (ET-1) and its receptors ETAR and ETBR, referred to as the Endothelin (ET)-axis play an emerging role in cancer. The ET-axis has been shown to be involved in proliferation, angiogenesis and metastasis. We investigated the effect of the ET-axis on microvessel density (MVD) and on the clinical prognosis in patients with invasive carcinoma of the bladder. Methods: Archival tumor tissue of 157 consecutive patients was reviewed and representing tumor blocks were selected. Paraffin sections were assessed immunhistochemically using mono- and polyclonal antibodies for ET-1, ETAR,ETBR and CD34 (MVD). Staining intensities were analyzed semiquantitatively and the MVD was calculated as vessels per field. The results were correlated with various pathological and clinical factors, as well as with disease-free and overall survival. Results: Overexpression of ET-1, ETAR and ETBR was identified in 26.8%, 58.8% and 76.9% of cases, respectively. Normal urothelium was constantly negative. No association with TNM staging and histologic grading was found. However, patients with ETBR expression tended to have organ-confined tumors (P = 0.16) and no vascular invasion (P = 0.09), the latter being statistically significant in the subgroup of G3 tumors (P = 0.02). T1 and T2 (MVD = 32,2) tumors had greater MVD compared to T3 and T4 tumors (MVD = 21,2) (P = 0.02), showing an association of MVD and overexpression of ET-1 (P = 0.027). ETBR-positive tumors were associated with favorable disease-free survival (P = 0.04). In urothelial carcinomas the MVD was 23,7, whereas squamous cell carcinomas had a MVD of 17,8 (P = 0.04). Conclusion: The ET-axis is overexpressed in invasive bladder cancer. Urothelial carcinomas are significantly greater vascularized compared to squamous cell carcinomas. Organ-confined tumors showed more MVD than T3 and T4 tumors, which is related to ET-1 expression in this subgroup. ETBR appears to predominate in bladder cancer and is associated with a more favorable prognosis. No significant financial relationships to disclose.
Outcomes of patients with metastatic colorectal carcinoma (MCRC) treated with first and second line chemotherapy at a multicenter cancer clinic
Authors: H. J. Lim, C. Lohrisch, C. Kollmannsberger, S. Gill, H. Kennecke, A. Shah, N. Phillips, A. Coldman, B. Melosky
Journal: Journal of Clinical Oncology (2006)

13529 Background: In British Columbia (BC), FOLFIRI and FOLFOX were approved for the treatment of MCRC in 2002. The effect on survival of various treatment and patient related factors was determined for patients with MCRC treated with sequential doublet chemotherapy. Methods: Eligible patients received either FOLFOX or FOLFIRI first-line with a cross over to the alternative regimen for second-line therapy. Patient records were retrospectively reviewed for patient and disease characteristics, treatment, toxicity and survival. Analysis of survival was performed by the Kaplan-Meier method. Results: Between March 2002 and June 2004, 106 new patients met the criteria above. Sixty five patients were treated with a sequence of FOLFOX-FOLFIRI (Group A): 67% M, median age 57y, rectal 20%. Forty-one were treated with the sequence FOLFIRI-FOLFOX (Group B): 64% M, median age 58y, 27% rectal. Survival was statistically similar in both groups. Progression requiring second line chemotherapy within 4 weeks of a first line treatment was associated with inferior survival (13 months vs. 21 months (p&lt;0.018). Grade 3 or 4 toxicity was experienced in 27.5% of the patients treated with FOLFOX and 22% of the patients treated with FOLFIRI. Conclusions: In the general population with MCRC, the median survival achieved with sequential doublet therapy is consistent with that reported in clinical trials. A superior sequence was not identified. The median number of first line chemotherapy cycles with FOLFOX and FOLFIRI was similar, reflecting the general clinical practice in BC to give 10 - 12 cycles of therapy followed by a planned break. Patients who required initiation of second line chemotherapy within 4 weeks of stopping the first line therapy experienced an inferior prognosis. Univariate and multivariate analysis showed no significance of sex, age, site (colon versus rectal), and ECOG status as predictive factors. [Table: see text] No significant financial relationships to disclose.
Use of lymphopenia assessed during routine follow-up after immunochemotherapy (R-CHOP) to predict relapse in patients with diffuse large B-cell lymphoma (DLBCL).
Authors: L. F. Porrata, K. Ristow, D. J. Inwards, S. M. Ansell, I. N. Micallef, P. B. Johnston, T. M. Habermann, T. E. Witzig, J. Colgan, S. Markovic
Journal: Journal of Clinical Oncology (2010)

e18516 Background: A specific predictor during routine follow-up to ascertain risk for relapse after standard chemotherapy in non- Hodgkin lymphoma (NHL) has not been identified. Thus, we studied absolute lymphocyte count (ALC) as a marker of post-standard immunochemotherapy (R-CHOP) NHL relapse in patients with diffuse large B-cell lymphoma (DLBCL). Methods: From 2000 until 2006, 149 DLBCL consecutive patients were treated with R-CHOP, originally diagnosed, treated, and followed at the Mayo Clinic, Rochester, were included in this study from the Mayo Clinic Lymphoma Data Base. ALC was obtatined at the time of confirmed relapse and at last follow-up. Results: Patients at last follow-up without relapse (N=112) had a higher ALC compared with those with relapsed (N= 37) [median ALC × 109/L of 1.43 (range: 0.33-4.0) vs 0.67 (range: 0.18-1.98), p <0.0001, respectively]. ALC at the time of confirmed relapse was a strong predictor for relapse with an area under the curve (AUC) = 0.91 (p<0.0001). An ALC < 0.96 × 109/L (N = 46) at the time of confirmed relapse had a positive predictive value of 72% and a positive likelihood ratio of 7.4 to predict relapse post-R-CHOP in DLBCL. Patients with an ALC ≥ 0.96 × 109/L (N = 103) had a cumulative incidence of relapse of 6% versus 79% with an ALC < 0.96 × 109/L (N = 46) (p<0.0001). Conclusions: This study suggests that lymphopenia measured by ALC can be used as marker to assess risk of DLBCL relapse during routine follow-up after standard immunochemotherapy. No significant financial relationships to disclose.
Endoscopic skin-sparing breast-conserving surgery for breast cancer and immediate reconstruction with autologous tissue
Authors: N. Mizuta, H. Nakajima, I. Fujiwara, K. Sakaguchi, Y. Hachimine
Journal: Journal of Clinical Oncology (2008)

566 Background: Endoscopic breast-conserving surgery (E-BCS) for breast cancer has been developed in Japan and is indicated for breast cancer without skin involvement. The surgical incision is made at an inconspicuous site, and skin-sparing partial mastectomy and immediate reconstruction of the breast are performed. This technique affords good cosmetic results. The long-term results are reported herein. Methods: E-BCS was performed on 551 patients. The skin incision was put on a peri-areolar margin or on the mid-axillary line. Skin-sparing partial mastectomy was performed using an endoscope and the lifting and tunneling method. Deformity due to the loss of breast tissue is addressed immediately by reconstructing the breast using autologous tissues via mobilization of the remnant breast gland and fat tissue and use of a lateral tissue flap or latissimus dorsi adipose tissue flap. Morbidity, curability and degree of satisfaction of patients with regard to cosmesis were analyzed. Results: Skin necrosis in 22 patients (4.0%) and necrosis of fatty tissue-muscle flap in 17 patients (3.1%) were recorded as postoperative complications. There were none of other serious complications. Local recurrence occurred in 23 patients (4.2%) after a mean follow-up of 38.4 months. Distant metastasis-free survival rate at 66 months was 100% for Tis, 95.5% for T1 and 90.7% for T2. Overall survival rate was 100% for Tis, 97.3% for T1 and 95.7% for T2. Degree of satisfaction with surgery as investigated by questionnaire was “excellent” for 76.1% of patients. Conclusions: E-BCS for early stage breast cancer have shown none of association with increases in local or distant organ recurrence. The technique yielded improved cosmesis and a high degree of patient satisfaction. Although the observation of patients for a longer period is necessary, the E-BCS give big advantages on the breast cancer patients in terms of aesthetics and curability. No significant financial relationships to disclose.