tbuckley/cabot-search huggingface dataset:
Pre-treatment PSA doubling time (PSADT) predicts biochemical response to chemotherapy in patients with androgen sensitive PSA progression after local therapy
Authors: A. Mehta, M. Stein, S. Goodin, S. Yao, J. Shih, M. Todd, R. S. Dipaola
Journal: Journal of Clinical Oncology (2006)

14528 Background: As phase III studies are developed in patients with androgen sensitive (AS) PSA progression after local therapy, efforts to stratify patients based on likelihood of benefit is critical. In an effort to define a pretreatment PSADT cutoff that predicts chemotherapy response in AS patients for use in hypothesis testing in phase III studies, we assessed patients with pretreatment PSA data in two of our prior published phase II studies of docetaxel (D) or mitoxantrone (M) chemotherapy in patients with AS PSA progression without metastasis. Methods: A retrospective analysis of PSADT was performed on 36 pts with AS PSA progression following local therapy without metastasis with available pretreatment PSA values (23 pts with D and 13 pts with M). PSADT was calculated as [LN(2)]/b, where b is the slope of the regression of LN(PSA) vs time. A t-test was used to compare the PSADT of responders vs non-responders; ANOVA was used for the combined data. A logistic regression analysis with ROC curves was used to evaluate the value of PSADT in discriminating response. Results: Mean PSADT of patients with ≥50% decrease in PSA with therapy was 204 vs. 99 days (P = 0.02). For D only, mean PSADT of pts with any PSA decrease (mean 52%) vs. increase was 211 vs. 115 days (P = 0.04). The mean PSADT of pts with ≥50% PSA decrease only on D was 203 vs. 174 days (P = 0.31). Overall, logistic regression analysis showed that PSADT is a good test to discriminate which pts will have some decrease in PSA while on treatment (P = 0.03). ROC curves (AUC = 0.807) for pts with a decline in PSA on treatment showed that the best balance of sensitivity and specificity was for a PSA DT cutoff of 70 days (sens = 70.0%, spec = 71.4%). Sensitivity was highest at a DT of 50 days (85%), and specificity at 180 days (93%). Conclusions: This study suggests that pretreatment PSADT may be a useful predictor of response to therapy in patients with AS PSA progression after local therapy, but will require larger confirmatory studies. A PSADT cutoff of 70 days can be considered to stratify patients in future trials in this patient population. No significant financial relationships to disclose.
Phase I study of the safety and efficacy of atiprimod, a novel azaspirine, for patients with advanced cancer
Authors: F. S. Braiteh, J. Yao, L. H. Camacho, C. Ng, D. S. Hong, P. Harris, N. Dhillon, R. Kurzrock
Journal: Journal of Clinical Oncology (2006)

13050 Background: Atiprimod (N-N-diethl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) is an oral cationic azaspirane that suppresses angiogenesis by inhibiting both bFGF and VEGF induced proliferation and migration. Atiprimod has been shown to down-regulate multiple growth factors involved in tumor progressions and metastases, including IL-6, TNF-α, and VEGF. Methods: This is an ongoing, single-center, open-label, ascending dose (modified Fibonacci) Phase I trial of oral atiprimod in patients with advanced cancers (3+3 design). Atiprimod was given orally for 14 days every 28-day cycle. The primary objectives are to identify the MTD and to evaluate the safety of atiprimod; the secondary objectives include measuring PK and describing efficacy. Data from these patients enrolled are presented here. Results: Fourteen patients have been treated to date with 60 mg tablets (N = 3), 60 mg capsules (N = 3), 90 mg capsules (N = 3) and 120 mg capsules (N = 5). The most common side effects, which occurred in over half the patients, were related to the gastrointestinal system, and include nausea (11), diarrhea (7), vomiting (4) abdominal pain (2) and dyspepsia (2). These events were generally low-grade, occurred primarily during days of active drug administration and tended to resolve during off-drug days. Less common adverse events were sinus headaches, and elevated serum transaminases, alkaline phosphatase and creatinine. One patient who received prolonged therapy (7 months) developed fever and multi-organ failure of unclear etiology. One patient with uterine leiomyosarcoma experienced a DLT (syncope and hypotension) at 120 mg/day, and that dose level is therefore being expanded up to 6 patients. One patient with midgut carcinoid tumor and liver metastasis achieved a partial remission lasting 2+ months (50% decrease in maximum diameter by RECIST). Three patients (carcinoid = 2 and thymoma = 1) had stable disease for four, four and six months, respectively. Conclusions: Preliminary data indicate that atiprimod was reasonably tolerated, with predominantly gastrointestinal side effects. There is early evidence of anti-tumor activity in carcinoid tumors. Dose escalation continues. [Table: see text]
Patterns of relapse in patients treated with surgery followed by platinum based chemotherapy for advanced epithelial ovarian cancer
Authors: M. H. Tuthill, J. Borley, H. Gabra, S. Ghaem-Maghami, S. Blagden
Journal: Journal of Clinical Oncology (2008)

16562 Background: Although relapse is common after treatment for ovarian cancer there have been few studies on patterns of relapse. We sought to determine the commonest site or sites of relapse and to determine the influence of stage, histology, grade and sites of residual surgical disease on relapse. Methods: Medical, surgical and radiological records from patients who had undergone primary or interval cytoreductive surgery followed by platinum based chemotherapy for epithelial ovarian cancer between 2001 and 2006 at the Hammersmith Hospital were retrospectively reviewed. Data was collected for sites of residual disease at surgery, chemotherapy response and location of sites of relapse. Results: 145 patients were identified of whom 100 were evaluable for inclusion in the study. 66% were optimally or totally debulked with 59% (59/100) achieving a complete response to treatment by radiological and clinical criteria. 52 patients (52%) relapsed: median time to relapse was 7.4 months. Patients who had been totally macroscopically debulked had longer time to relapse than those who had undergone optimal or suboptimal debulking (10.9 vs 7.1 and 6.4 months respectively). The majority (58%) of patients presented at relapse with abdominal symptoms. 25% of patients relapsed at a single site: commonest site being the pelvis, 38% patients relapsed at two sites; commonest sites the liver and peritoneum, 25% relapsed at 3 sites: commonest site: peritoneum and 13% of patients relapsed at 4 sites: commonest site lymph nodes. 50% of patients that had less than complete macroscopic debulk at initial surgery but subsequent complete response to chemotherapy relapsed at sites of residual surgical disease. 50% relapsed with new sites of disease; commonest site being the lymph nodes. Higher grade and stage tumours relapsed more frequently and had a reduced time to relapse. Conclusion: These results demonstrate that ovarian cancer more commonly relapses at multiple sites. The majority of patients relapse within 1 year and present with abdominal symptoms. The finding that patients relapse at sites of surgically inoperable disease (despite a subsequent response to chemotherapy) re-enforces the need for a more aggressive surgical approach in treating ovarian cancer. No significant financial relationships to disclose.
Antitumor activity of imatinib mesylate in medulloblastoma cell lines and xenografts
Authors: R. Morosetti, D. Meco, C. Dominici, T. Servidei, A. Riccardi, A. M. Di Francesco, G. Cusano, R. Riccardi
Journal: Journal of Clinical Oncology (2004)

8554 Background. Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Its tendency to disseminate is the main cause of treatment failure. Recently PDGFRa has been suggested to play a role in MB metastasis. Imatinib mesylate (STI571, Gleevec) is an inhibitor of selected receptor tyrosine kinases, including PDGFRa/β and c-kit. Thus, we investigated the therapeutic potential of STI571 in MB, by evaluating its antitumor activity in vitro and in vivo. Methods. Expression of PDGFRa/β and c-kit was studied in 4 human MB/PNET cell lines (D283 Med, D341 Med, DAOY, PFSK) by RT-PCR and western blotting. We performed growth inhibition assays at different STI571concentrations (5 to 50 μM)and time-points. The antitumor activity of STI571 was studied in D283 Med xenografts in nude mice, either by treating palpable tumors or by trying to prevent tumor development after inoculation. STI571 was administrated p.o. (100, 200 and 400 mg/kg/day) twice a day for 5 consecutive days for two weeks. Results. All cell lines expressed PDGFRa and c-kit, while only DAOY and PFSK expressed PDGFRβ mRNA and protein. STI571 produced a dose- and time-dependent inhibition of growth of all the cell lines, although with a different sensitivity (IC50 ranging from 7 to 13 μM). In the therapeutic study, STI571 was inactive or marginally active against D283 xenografts, while in the prevention study a significant difference in tumor size was seen between treated and control animals on day 22 (TWI>60). No obvious toxicity was observed. Conclusions. STI571 was able to inhibit the in vitro growth of 4 MB cell lines and this was associated with a significant antitumor activity in vivo, thus suggesting a therapeutic potential of STI571 in MB. Whether these effects are mediated through inhibition of PDGFR or c-kit is under evaluation. (Supported by Italian Ministry of Health; AIRC; FOP and ALTI). No significant financial relationships to disclose.
Bevacizumab (BV) plus chemotherapy (CT) in second-line metastatic colorectal cancer (mCRC): Initial results from ARIES, a second BV observational cohort study (OCS).
Authors: T. S. Bekaii-Saab, J. C. Bendell, A. L. Cohn, H. Hurwitz, M. Kozloff, N. Roach, H. Tezcan, S. Feng, A. Sing, A. Grothey
Journal: Journal of Clinical Oncology (2010)

3595 Background: BV (Avastin) prolongs progression-free (PFS) and overall survival (OS) when added to CT in first- or second-line treatment (Tx) of mCRC. BRiTE, an OCS analyzing outcomes in mCRC patients (pts) receiving first-line BV, provided valuable information on continued use of BV beyond progression (BBP) (Grothey et al, JCO 2008). ARIES, a second OCS, includes mCRC pts on first- or second-line BV. Clinical outcomes of the second-line cohort based on whether pts received first-line BV (BV exposed or naive) are presented. Methods: Pts with locally advanced and unresectable mCRC receiving first- or second-line BV were eligible. No Tx regimens or assessments were protocol specified. Data were collected prospectively at baseline (BL) and quarterly. Demographics, disease history, CT, and BV use are described based on first-line BV exposure. Median (med) PFS and OS are Kaplan-Meier estimates. On-study BV-targeted adverse events (AE) were collected and are described for each group. Results: 489 second-line pts enrolled from 11/2006 to 10/2008. Med follow-up is 14.9 mo. BL characteristics of 463 second-line pts starting first-line Tx after BV approval are shown in the Table. BV-exposed pts had a trend towards improved second-line med OS vs. BV-naive pts (21.7 mo, 95% CI 17.8-27.0 vs. 17.5 mo, 95% CI 15.9-21.5 mo) with similar med second-line PFS (7.6 vs. 8.0 mo). BV-associated AE rates for second-line BV-naïve pts were low: GI perforation (0.4%); arteriothromboembolic events (1.8%); bleeding (1.1%). Conclusions: This is the first analysis of a second-line BV Tx cohort including mCRC pts who did or did not receive first-line BV. Despite comparable Tx (67% vs. 74% received all 3 active agents in BV-naive or - exposed pts respectively, p=0.10), BV-exposed pts had a numerically longer second-line med OS. These results along with the published BRiTE BBP analysis suggest a benefit from early and maintained VEGF suppression in pts with mCRC. Second-line, BV naive (n=255) Second-line, BV exposed (n=208) Median age (range) 64 (27-96) 64 (24-84) ECOG PS (%) 0/1/≥2 47/42/8 40/45/9 M/F (%) 53/47 62/38 First-line CT (%) FOLFOX 48 63 FOLFIRI 6 14 Capeox 10 9 First-line TTP (mo) 8.2 12.6 Second-line CT (%) FOLFOX 25 20 FOLFIRI 38 54 Capeox 5 4 Abbreviations: PS, performance status; TTP, time to progression. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Amgen, AstraZeneca, Bayer, Genentech, Genomic Health, Roche, sanofi-aventis Roche Genentech, Roche, sanofi-aventis Amgen, Bayer, Bristol-Myers Squibb, Genentech, Pfizer, Roche, sanofi-aventis, Standard Research Genentech
Mathematization of risk and benefit for first-line treatment of metastatic colorectal cancer: A graphical decision aid for patients and physicians
Authors: M. S. Sanatani, M. Vincent
Journal: Journal of Clinical Oncology (2006)

3627 Background: Advances in the treatment of metastatic colorectal cancer (mCRC) have improved median overall survival (mOS) from 1yr with 5-fluorouracil (FU) therapy to &gt;21 mos. This may come at cost of more toxicity. As the number of tested regimens increases, the question arises how to best present palliative treatment options. We present a simple way to compare treatment options in terms of risks &amp; benefits. Methods: The literature was surveyed for reports of 1 st -line systemic therapies for mCRC. The largest recent reports with detailed toxicity data were selected as representative for a regimen; if several comparable reports existed then all were selected. Toxicity sum (TS) of a regimen was calculated as % occurences in the study cohort of severe (≥ gr. 3) adverse effects: diarrhea+mucositis+neurocutaneous (excl. alopecia)+vomiting (or vomiting/nausea if not reported separately or nausea if no vomiting rep.)+febrile neutropenia (FN)(or infection if FN not rep. or leukopenia if infection not rep.)+toxic deathrate. Benefits (OS &amp; progression-free survival PFS in months) were divided by TS to give a benefit/toxicity (B/T) ratio &amp; plotted as benefit vs TS. Results: 30 regimens were found.OS, PFS &amp; TS for the various regimens ranged from 8.9–24.7 and 4.9–9.2 mos, &amp; 12–63 respectively. B/T ratios ranged from 0.1–0.53 (PFS) &amp; 0.22–1.19 (OS); higher values more favorable. Regimens with similar B/T ratios may still differ - longer OS &amp; PFS but at cost of more toxicity. Graphical presentation makes this clear. Intriguing &amp; open to interpretation was a narrow range of PFS while OS varied greatly between regimens. Weaknesses of our study incl omission of some regimen-specific toxicities, &amp; of symptom control benefit. Conclusions: Our comparative tool helps physicians discuss the large number of available options &amp; their clinical differences easily with patients, improving informed consent &amp; disclosure, in order to arrive at the treatment plan most appropriate to the individual. [Table: see text] [Table: see text]
Concurrent platinum-based chemotherapy with intensity modulated radiation therapy (IMRT) for locally advanced squamous cell carcinoma of the head and neck (SCCHN): A retrospective single institution analysis
Authors: N. F. Saba, J. Gaultney, S. Edelman, M. Tighiouart, L. W. Davis, F. R. Khuri, A. Chen, W. Grist, D. M. Shin
Journal: Journal of Clinical Oncology (2007)

16511 Background: Randomized clinical and meta-analysis data support the use of concurrent chemoradiation for treatment of locally advanced (SCCHN). IMRT is increasingly being used in treating SCCHN. We present outcome data from Emory University Winship Cancer Institute (WCI) with concurrent platinum based chemotherapy and IMRT, and analyze results according to primary site and nodal status. Methods: Between February 2003, and November 2005, 87 patients with locally advanced SCCHN underwent concurrent IMRT and platinum based chemotherapy. A total of 62 patients were treated with Cisplatin 100 mg/m2 d1,21,43, while 19 were treated with paclitaxel and carboplatin weekly for 7 weeks. Five patients were treated with other platinum based regimens. Follow up was documented in all cases with a median of 520 days (range 107 - 1269 days). Results: Patients were distributed among primary sites as follows: Hypopharynx (HP) 7 (8.0%), Larynx (L) 11(12.4%), Nasopharynx (NP) 13 (14.6%), and Oropharynx (OP) 56 (63.0%). T stage distribution was: T1: 16 patients (18.0%); lesions more advanced than T1 (&gt;T1): 68 (76.4%). N stage distribution was, N0 :16 patients (18.0%), N1: 8 (9.0 %),nodal stage N2a or higher: 61 (68.5%). Median age was 57 years (range 32–75), and 63 patients (71.0%) were male. The median overall survival (OS) and disease-free survival (DFS) post-therapy was not reached. The 3 year OS rate for the entire cohort was 86% (L 82%, NP 89 %, OP 86 % HP 80%). The 3 year DFS rate for the entire cohort was 74%, (L 85%, NP 60%, and OP 75%, HP 76%). There was no correlation between OS and T or N stage (p=0.143 and 0.44 respectively), or between DFS and T-stage (p=0.4). A significant correlation was found between DFS and N stage (p=0.008). Conclusion: With moderate follow up, this retrospective analysis reveals an excellent outcome for patients with locally advanced SCCHN treated with chemotherapy and IMRT concurrently, supporting concurrent therapy as the current standard of care. The significant correlation of DFS and nodal status suggests a possible greater impact future approaches such as induction therapy may have on patients with advanced nodal disease. No significant financial relationships to disclose.
Association between <i>XRCC1</i> gene haplotype tagging single nucleotide polymorphisms and non-small cell lung cancer in Korean patients.
Authors: G. Lee, I. Kim, D. Kim, S. Kim, H. Kim, J. Kang, S. Oh
Journal: Journal of Clinical Oncology (2010)

1541 Background: Single nucleotide polymorphisms (SNPs) in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. This study aimed to investigate the relationship between SNPs and haplotypes of the XRCC1 gene on the risk of NSCLC in Korean patients. Methods: Genotyping for SNPs in XRCC1 was performed using Sequenom's (San Diego, CA, USA) high-throughput matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in 140 NSCLC patients and 217 controls. Haplotype frequency estimation and association analysis were performed via permutation testing using the Haploview version 4.0 software (Broad Institute of MIT and Harvard, Cambridge, MA, USA). Results: Only an individual SNP of XRCC1, rs1001581, was associated with increased risk of NSCLC in Korean patients (adjusted odds ratio (OR), 2.121; 95% confidence interval (CI), 1.06-2.32; Ptrend = 0.004). Seven possible haplotypes were demonstrated in this study (if haplotype frequency was > 1%). Of seven haplotypes, the frequency of wild haplotype was 0.109 and wild haplotype showed protective effect of NSCLC risk in Korean patients (OR, 0.433; 95% CI, 0.299-0.489; p = 0.002). The association between wild haplotype and decreased risk of NSCLC and the relationship between rs1001581 and increased risk of NSCLC were stable on permutation testing, respectively (p = 0.02 and p = 0.04). Presence of rs1001581 and increased risk of NSCLC was stable on permutation testing among never- and ever-smokers (p = 0.007 and p = 0.039, respectively). The association between wild haplotype and decreased risk of NSCLC was stable on permutation testing only ever-smokers (p = 0.021). Conclusions: These findings suggest that wild haplotype consisted of wild 9 SNPs showed protective role against development of NSCLC in ever-smokers and rs1001581 non-coding SNP showed increased risk of NSCLC among never- and ever-smokers in Korean patients. Thus, this study presents several novel aspects on genetic susceptibility to NSCLC and larger studies of the role of rs1001581 for NSCLC risk would be needed regardless of smoking history. No significant financial relationships to disclose.
A phase I study of ixabepilone combined with dasatinib in patients with solid tumors.
Authors: C. C. Kaiser, D. J. Perry, A. S. Zimmer, J. W. Patterson, S. M. Swain
Journal: Journal of Clinical Oncology (2010)

e13514 Background: Dasatinib is a small molecule inhibitor of multiple oncogenic tyrosine kinase families, including SRC. Ixabepilone is a novel microtubule-stabilizing epothilone that has shown clinical activity in multiple solid tumors. Preclinical data shows synergy between SRC inhibitors and microtubule-stabilizing agents. This phase I study evaluated the safety and tolerability of ixabepilone and dasatinib in patients with advanced solid tumors. Methods: Standard eligibility criteria and cycle 1 dose-limiting toxicity (DLT) definitions were used. Ixabepilone (Ixa) was administered IV every 3 weeks over 3 hours and dasatinib (Das) orally once daily. Dose escalation is described in the Table. Results: Eleven pts (dose level 1, 3 pts; dose level 2, 6 pts; dose level 3, 2 pts) have been enrolled; 8 female; tumor types: breast (4), colon (3), gastric (1), head and neck (1), pancreas (1), renal cell (1); median age 56; median 4 cycles of ixabepilone and dasatinib (range: 1-6). One pt developed a dose-limiting toxicity at dose level 2 (Gr 4 neutropenia, Gr 3 febrile neutropenia, Gr 3 diarrhea, and Gr 3 nausea). One pt developed a dose-limiting toxicity at dose level 3 (Gr 3 diarrhea). A second pt at dose level 3 required dose reductions after cycle 1 (Gr 1 QTc prolongation) and cycle 2 (Gr 3 diarrhea, Gr 3 creatinine). Accrual to dose level 3 was halted though maximum tolerated dose was not reached. Two pts (head and neck, pancreatic cancer) had unconfirmed partial response (stable disease), 6 stable disease, and 3 progressive disease. Median duration of stable disease for 8 pts was 95 days (range 49-126). Conclusions: The recommended phase II dose of ixabepilone is 40 mg/m2 IV every 3 weeks and dasatinib 100 mg orally once daily. Dose level 2 is being expanded by an additional 6 to 9 pts to obtain further clinical and pharmacokinetic data. (Clinicaltrials.gov Identifier: NCT00717704) Dose level Ixa (mg/m2/d) Das (mg QD) Total no. of cycles No. of pts with DLT/total no. of pts Nature of DLT 1 30 100 11 0/3 2 40 100 23 1/6 Gr 4 neutropenia, Gr 3 febrile neutropenia, Gr 3 diarrhea, Gr 3 nausea 3 40 150 6 1/2 Gr 3 diarrhea Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb