tbuckley/cabot-search huggingface dataset:
Imatinib with cisplatin in recurrent and/or metastatic salivary adenoidcystic carcinoma – response assessed by FDG-PET scanning
Authors: N. J. Slevin, K. L. Mais, I. Bruce, T. Ward, B. Carrington, P. Hulse, S. Banerjee, P. Julyan, A. Sykes, J. Homer
Journal: Journal of Clinical Oncology (2004)

5604 Background: Adenoidcystic carcinoma (ACC) of salivary glands is characterised by slow growth, systemic metastases and poor response to conventional chemotherapy. 80 – 90% of ACC demonstrate c-kit positivity such that treatment with imatinib is conceptually attractive. Patient experience reported on the ACC website suggests that imatinib may stabilise disease. 3-dimensional synergy analysis has been performed at this centre for both ACC primary cultures and squamous carcinoma cell lines. Mild synergy between cisplatin and imatinib was found in 2 of 3 cell lines as well as in ACC culture. Consequently we chose imatinib with cisplatin for phase II study in patients with recurrent and/or metastatic ACC. Methods: 14 patients (aged 29 - 77) with ACC have entered the study. Imatinib was used alone in an initial dose of 800mg daily for 2 months with response assessed using both FDG-PET and conventional imaging. Patients then received the combination of daily imatinib (in a reduced dose) with cisplatin 80mg/m2 at monthly intervals. Depending on responses and toxicity, patients then continued on maintenance imatinib. Results: Of 12 evaluable patients, 2 developed progressive disease on imatinib alone and left the study. 5 of 10 receiving the combination of imatinib and cisplatin have shown reductions in tumour size with 1 of these 5 constituting a partial response. The remaining 5 patients have stable disease, albeit with short follow-up. FDG-PET was useful in assessing response and discriminating between imatinib and cisplatin in terms of their relative contribution to clinical outcome. Toxicity from the imatinib-cisplatin combination (median 5 cycles) included one grade 4 thrombocytopenia, one grade 3 anaemia and three grade 3 neutropenia. Non-haematological toxicities included one grade 3 hyponatremia, two grade 3 fatigue and one grade 3 oedema. Conclusions: The combination of imatinib (400mg daily) and cisplatin (80mg/m2) shows useful activity in ACC, Because of slow growth and response characteristics as well as a tendency to cystic degeneration as a response within 'stable' disease, FDG-PET is helpful in assessing response. No significant financial relationships to disclose.
DNA-repair gene (DRG) single nucleotide polymorphisms (SNPs) influence on response and survival in stage IV SCCHN patients treated with CDDP-based therapy
Authors: M. Quintela-Fandino, R. Hitt, P. P. Medina, S. Gamarra, M. Amador, L. Manso, H. Cortes Funes, M. Sanchez-Cespedes
Journal: Journal of Clinical Oncology (2006)

5505 Background: CDDP kills tumor cells by DNA cross-linking. SNPS at DRG may influence the ability of patients to respond to CDDP. We studied the role of the SNPs XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A and XRCC1-Arg399Gln to influence the response to CDDP-based therapy and to predict survival in SCCHN patients Methods: SNPs were genotyped in DNA from peripheral lymphocytes using PCR-restriction fragment length polymorphism in 103 stage IV (0% M1) SCCHN patients followed prospectively. Treatment schedules were concurrent CDDP/RT (n = 28), CDDP + fluoropyrimidine (FP)→ CDDP/RT (33) or CDDP + FP + taxane→CDDP/RT (42). Endpoints: to assess the impact of the SNPs in OS (Kaplan Meier and Cox’s model) and in response to chemotherapy (multivariate multinomial regression). The covariables gender, age, treatment type, number of polymorphic (poly.) variants (0–8), smoking and alcohol consumption and amount (mg) of CDDP were included in the multivariate analysis Results: Median age 60 yrs (39–94); 97 (94%) male. After 78 months of follow-up, 24% had died, 22% had relapsed and 51% were free of disease. The allele frequencies for the homozygous common allele, heterozygous and homozygous poly. variant were: ERCC1: 53, 40 and 7%; XPD312: 50, 42 and 8%; XPD751: 35, 57 and 8%; XRCC1: 35, 51 and 13%. Overall, 9%, 16%, 22%, 20%, 24%, 6%, 1% and 1% of the patients harbored 0, 1, 2, 3, 4, 5, 6 and 7 poly. variants simultaneously. Table shows OS according to genotype. Patients with only common alleles had a median OS of 5.1 months (4.3–6.0) vs not reached for patients with ≥1 variant (p = 0.0000)(mean 6.2 (4–8.4) vs 61.3 (53–59.8). Each variant allele decreases the probability of dying 2.1 fold (p = 0.0000) on the Cox’s analysis (7 variants = 175 fold protection) and increases 2.94 fold (multinom. reg.)the probability of achieving a CR vs PD (p = 0.041) Conclusions: In our series the poly. variants at DRG are the strongest prognosis factors and accurately predict clinical response among SCCHN patients. [Table: see text] No significant financial relationships to disclose.
Final results of a Phase I study of Liposome Entrapped Paclitaxel (LEP-ETU) in patients with advanced cancer
Authors: N. Damjanov, M. N. Fishman, J. L. Steinberg, G. J. Fetterly, A. Haas, A. Grahn, C. Lauay, J. L. Dul, J. W. Sherman, E. H. Rubin
Journal: Journal of Clinical Oncology (2005)

2048 Background: LEP-ETU is an easy-to-use liposomal formulation of paclitaxel developed to reduce toxicities while maintaining or enhancing efficacy by eliminating the drug formulation component polyoxyethylated castor oil (CremophorEL). Methods: This Phase I, dose-escalation study was designed to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of LEP-ETU in adult patients with advanced cancer. Paclitaxel pharmacokinetics (PK) and antitumor effects of LEP-ETU were also assessed. LEP-ETU was infused intravenously over 90 minutes once every 21 days. Results: A total of 25 patients received LEP-ETU at doses of 135 (n=3), 175 (n=4), 225 (n=3), 275 (n=3), 325 (n=6), and 375 (n=6) mg/m2. Primary tumor sites included breast, ovary, and colon. Initial patients (n=9, 135–225 mg/m2) were premedicated on the day of infusion to prevent infusion-related reactions (IRRs); later patients (n=16, 225–375 mg/m2) were not premedicated and 75% completed multiple infusions without IRRs. The remaining 25% were able to continue treatment with premedication. The most frequent adverse events were fatigue, nausea, anemia, hypoesthesia, and neutropenia. One DLT of neutropenia occurred at 325 mg/m2. Two patients experienced DLTs (1 neutropenia, 1 neuropathy) at 375 mg/m2. A dose of 325 mg/m2 was determined to be the MTD. Mean paclitaxel AUC0-∞ was linear at doses of LEP-ETU up to 325 mg/m2. Modeling data suggested that LEP-ETU may have a PK profile comparable to paclitaxel/Cremophor EL (Taxol) when both are administered at 175 mg/m2 over 180 minutes. Partial tumor response was observed in 3 patients (12%), stable disease in 11 patients (44%), and progressive disease in 7 patients (28%), with 4 patients (16%) not assessed (1 withdrawal, 3 DLTs in Cycle 1). Conclusions: Infusion of LEP-ETU over 90 minutes at doses above the MTD of Taxol was well tolerated. With or without premedication, most patients completed multiple infusions without experiencing IRRs. With increasing LEP-ETU doses, systemic exposure to paclitaxel was linear. Evidence of anti-tumor activity was observed, with partial response occurring in 3 patients and stable disease occurring in 11 patients. Next step studies have been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NeoPharm
Should chemotherapy (Cx) for advanced non-small cell lung cancer (NSCLC) be platinum-based? A literature-based meta-analysis of randomized trials
Authors: F. Barlesi, J.-L. Pujol, J.-P. Daurès
Journal: Journal of Clinical Oncology (2005)

7213 Background: Platinum-based Cx are world-wide accepted regimens in the treatment of advanced NSCLC. Third generation anti-cancer agents share a better efficacy/toxicity profile when compared with the older ones. Therefore, several recent studies have tested the hypothesis that non-platinum containing regimens can be an alternative therapy to the classical platinum-based Cx in advanced NSCLC. Methods: We made a meta-analysis of published data reporting trials randomizing a platinum-containing Cx versus a doublet platinum-free Cx including at least one third generation anti-cancer agent namely, vinorelbine (V), docetaxel (D), gemcitabine (G), and paclitaxel (P) in order to determine possible differences in survival, response and toxicity. Fourteen trials have been identified in the medical literature (5943 randomized patients). The experimental arms were GV (four trials), GD or GP (seven trials), G - epidoxorubicin (one trial), VP (one trial), and G - ifosfamide (one trial). The comparator consisted of a doublet Cx of a platinum compound plus a third generation drug in all studies except two where the comparator was a triplet Cx. Updated data were available for all studies but one. The Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in the risk of death at one year for patients receiving a platinum-based Cx. Results: A statistical heterogeneity was detected when the whole trials was considered (chi2 test: 21.05; p = 0.049). This heterogeneity has been identified as belonging to the two studies that used triplets as the standard arms. When the analysis was restricted to the eleven studies that used a well-recognised platinum-based doublet as standard, there was no statistical heterogeneity (chi2 test: 16.6; p = 0.084). Patients treated with a cisplatin-containing regimen benefited from a significant reduction of risk of death at one year with OR=0.88, 95% CI [0.78 - 0.99]; p = 0.044. Conclusions: A platinum-containing regimen induced a significant reduction in the risk of death when compared with platinum-free regimen. A complete analysis of the risk of toxic-death, toxicity and response will be presented. No significant financial relationships to disclose.
Gestational trophoblastic disease: 25-year experience at the Instituto Nacional de Enfermedades Neoplasicas (INEN)
Authors: L. Mas Lopez, M. Olivera, L. Casanova, C. Santos, S. Neciosup, H. Gomez, J. Leon, C. Velarde, J. Mariategui, T. Vidaurre
Journal: Journal of Clinical Oncology (2007)

16031 Background: To evaluate the clinical behavior and results of treatment of gestational trophoblastic disease at INEN between 1980 to 2005. Methods: This is a retrospective analysis of patients with gestational trophoblastic disease, clinical characteristics, results of treatment, toxicity, objective response and survival from January 1980 to December 2005. Descriptive statistics and Kaplan-Meier for survival analysis were performed. Results: Since Jan 1980 to Dec 2005. 595 patients were admitted at INEN; Hydatidiform mole 254 (42.7%) choriocarcinoma 201 (33.8%) invasive mole 41(6.8%). FIGO scoring System, high risk (score &gt;6): 247 (41.5%), low risk (score 1–6): 348 (58.5%). Age ranged from 14 to 54 years, with 255 (44%) cases between 20 to 29 years. The sities of metastasis: lung 67.3%, vaginal 17.9%, brain 8.7%, liver 5.1%. The patients with low risks received treatment with Metotrexate 0.4mg/kg x day x 5 days po, reach disease control with a mean course of 6 (1 - 14), complete remission in 66.1% cases and 97% the overall survival rate to 20 years. Patients with high risk received treatment with: MAC 77 patients, MEC 19 patients, EMACO 48 patients and BEP 14 patients and achieved complete remission in 32.5%, 36.8%, 50% and 25% respectively. On the high risk group we detected two groups according to score &gt; 12 and &lt; 12, with diferent probability of survival at 20 years, for the group with score &lt;12, 80% and the group with score &gt;12, 48%. 98 patients were identified with score &gt;12, and the age of these patients ranged from 15 to 51 years, with a mean age of 36.5 years. The blood B- HCG titers of these patients ranged from 198 to 6710,500. Liver and brain metastasis in 26 cases, number metastasis mayor 8 in 78 cases. Conclusions: Gestational trofhoblastic disease is highly curable. Patients of low risk achieved a 97% overall survival rate to 20 years. There are differences in the overall survival rate between patients of high risk with a score &lt; 12 (80%) and score &gt;12 (48%). This group presented with brain and liver metastasis, and it is important to define the best treatment for this group of patients No significant financial relationships to disclose.
A phase I, open-label mass balance study of the hedgehog pathway inhibitor (HPI) GDC-0449 in healthy female subjects of non-childbearing potential.
Authors: B. L. Lum, G. E. Morrison, I. Chang, K. Jorga, C. Hop, Y. Shin, V. Malhi, M. Xie, J. A. Low, R. A. Graham
Journal: Journal of Clinical Oncology (2010)

2558 Background: In a phase I trial, GDC-0449, a small molecule HPI, was well tolerated in patients (pts) with solid tumors and showed promising efficacy in advanced basal cell carcinoma (Von Hoff et al., N Engl J Med. 361:1164-72, 2009). The pharmacokinetics of GDC-0449 have been assessed in cancer pts and healthy subjects, and are characterized by nonlinear properties and a very long half-life of ∼10-14 d. The purpose of this study was to determine routes of elimination and extent of GDC-0449 metabolism, to provide information about GDC-0449 dosing for special pt populations. Methods: Six healthy female subjects of non-childbearing potential were enrolled; each received a single 30 ml oral suspension of 150 mg GDC-0449 and 6.5 μ g 37 kBq (1000 nCi) 14C-GDC-0449 (PRA, Netherlands). Since the half-life of GDC-0449 is 10-14 d, blood, urine, and feces samples were collected over 56 d (cumulatively over the first 14 days, then weekly), to permit sample collection for up to 5 half-lives. Nonradioactive GDC-0449 plasma concentrations were assessed by liquid chromatography with tandem mass spectrometry (Tandem Labs, US); total radioactivity in plasma, urine, and feces was measured by accelerator mass spectrometry ( Xceleron, UK). Results: Following a single oral dose, a mean maximum GDC-0449 plasma concentration (Cmax) of 7.67 ± 1.12 μ M was achieved with an associated time to reach Cmax (Tmax) of 18.2 (range: 4-48) hrs. On average, 69.3% of the administered dose was recovered, with 67.3% and 1.96% cumulative excretion in feces and urine, respectively. Comparison of total radioactivity (GDC-0449 plus metabolites) with parent GDC-0449 concentrations in plasma over time suggests that parent GDC-0449 was the primary drug-related species in circulation. Conclusions: The results of this study suggest that GDC-0449 and any associated metabolic products are mainly eliminated in feces following oral administration. Minimal recovery of radioactivity in urine suggests that patients with renal dysfunction will not require alterations in GDC-0449 dosing, nor will studies in this pt population be required. Future evaluation of GDC-0449 in pts with hepatic dysfunction may be warranted.
Surgical management of the positive sentinel lymph node in elderly breast cancer patients
Authors: M. L. Gemignani, G. L. Giron, J. Fey, L. L. Montgomery, V. Sachini, L. Sclafani, A. Heerdt, P. I. Borgen, K. Van Zee, H. Cody
Journal: Journal of Clinical Oncology (2004)

872 Background: Standard practice is to perform a completion axillary lymph node dissection (ALND) in breast cancer patients with positive sentinel lymph nodes (SLNs). However, among patients with a negative intraoperative frozen section (FS) who prove SLN-positive on final pathologic examination, the risk of non-SLN metastases is small. Here we examine whether patient age (<70 vs. ≥70 years) and the presence of comorbidity affect the decision to perform completion ALND in this setting. Methods: From 7/97 to 7/03, 1510 patients with invasive cancer were SLN-positive by intraoperative FS, or on final pathologic exam by hematoxylin-eosin (H&E) and/or anticytokeratin immunohistochemistry (IHC). Among 219 women =70 and 1291 women <70 years old, we examined the effect of age and (for older patients) comorbidity on surgical decisions in those patients with a negative FS who proved SLN-positive on final pathologic exam. Results: Comparing the older and younger groups, lymphovascular invasion was less frequent (32% vs. 40%, respectively, P=0.036) and breast-conserving surgery was more frequent (66% vs. 57%, P=0.015) in the older group. Among those 70 or older, moderate or severe comorbidity was present in 61%, but (compared with those with minimal or no comorbidity) did not affect the type of breast operation or the performance of completion ALND. Completion ALND was done less often in the older patients (P <0.0001). Conclusions: Compared with women <70 years old, older women were less likely to have a completion ALND after a positive SLN biopsy, but comorbidity did not appear to affect treatment decisions. No significant financial relationships to disclose.
Plitidepsin cardiac safety analysis.
Authors: A. Soto-Matos, S. Szyldergemajn, S. Extremera, B. Miguel-Lillo, V. Alfaro, C. Coronado, P. Lardelli, E. Roy, C. S. Corrado, C. M. Kahatt
Journal: Journal of Clinical Oncology (2010)

e13599 Background: Plitidepsin (Aplidin, APL) is a cyclic depsipeptide of marine origin in phase II/III development in cancer patients (pts). It induces apoptosis through rapid and sustained JNK activation. Some depsipeptides have been linked to increased cardiac toxicity. Methods: Clinical databases were searched for cardiac adverse events (CAEs) in studies with single-agent APL as of Nov08. Demographic, clinical, and pharmacological variables were explored by univariate and multivariate regression logistic analysis. Results: Forty-six of the 578 pts (8.0%) treated had at least 1 CAE; of these 1.9% (11) were APL-related. No fatal cases occurred. CAEs were classified into 3 main groups. The most frequent were rhythm abnormalities (RA) (n=31; 5.4%), whereas atrial fibrillation (AF)/flutter accounted for most cases (n=15; 2.6%). Of note, no cases of life-threatening ventricular arrhythmias occurred. The myocardial injury events (MI) (n=17; 3.0%) included possible ischemic related events as well as non-ischemic events. Finally, miscellaneous (M) (n=6; 1.0%) included all other CAEs that did not fit in neither prior one. None of the M events was related to APL. Significant associations were found with prostate or pancreas cancer diagnosis (p=0.002), known baseline cardiac risk factors (p=0.002), myalgia at baseline (p=0.004), lower Hgb levels (p= 0.006) and grade > 2 hypokalemia (p=0.006). Treatment-related variables, such as APL dose, N of cycles or schedule did not result in any association. ECGs performed before and after APL administration (n=136) did not show any relevant effect on QTc interval. None of the PK parameters analyzed (Cmax and AUC from day 0 to day 28) had any significant impact on the probability of developing a CAE. Conclusions: The most frequent type of CAEs observed were AF/atrial flutter, although its incidence was not different to what is reported in age-matched healthy population. All other type of CAEs were rare. No dose- cumulative pattern was observed; moreover, no treatment-related variables were associated with CAEs. Relevant risk factors identified were related to pts condition and/or disease-related characteristics rather than to drug exposure. Data available on 578 adult pts with advanced cancer treated with singe-agent APL supports a safe cardiac profile. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PharmaMar PharmaMar
Glycodelin: A possible new biological marker in colorectal cancer
Authors: R. Govindarajan, S. Parthasarathy
Journal: Journal of Clinical Oncology (2006)

20081 Background: Glycodelin is a 28 kDa glycoprotein expressed in normal human reproductive tract. It is over expressed in various gynecological malignancies and vascular endothelium. Since angiogenesis has been associated with and antiangiogenic therapy is effective in colorectal cancer, it is possible that glycodelin could be a mediator in the pathogenesis and be a potential target in the treatment of this disorder. To assess whether the serum glycodelin was expressed in metastatic colorectal cancer, analysis of serum samples obtained from patients participating in a clinical trial were analyzed. Methods: Serum glycodelin levels from 19 controls (5 males, 9 premenopausal females and 5 postmenopausal females) and 24 patients with metastatic colorectal cancer (15 males and 9 females) enrolled into a phase II treatment protocol were measured. All patients had progressed on prior chemotherapy. Samples were obtained prior to the initiation of any further therapy. Glycodelin levels were measured by an Elisa based immuno assay using polyclonal antibodies raised against a peptide derived from the sequence of human glycodelin. Results: The median age of the patient populatin was 62.5 yrs. (range 29–78); of the males was 65 yrs. (range 57–78); of females was 58 yrs. (range 29–66). The median serum glycodelin level of whole control group was 41 nG/50μL (range 26–61); of 5 males 27 nG/50 μL (range 13–41); of 9 premenopausal females was 64 nG/50 μL (range 46–86); and of 5 postmenopausal women was 38 nG/ 50 μL (range 27–49). The median serum glycodelin level of patients with metastatic colorectal cancer was 128 nG/ 50 μL (range 51–523); of men was 128 nG/50 μL (range 51–523) and of women was 120 nG/50 μL(range 51–377). Serial glycodelin levels dropped by more than 50% in patients who had a clinical response or those who had stable disease. Conclusions: Serum glycodelin level was elevated in patients with metastatic colorectal cancer compared to controls. Whether glycodelin plays a role in the pathogenesis of colorectal cancer; can be a useful index to measure response and be useful as a potential target in the management of patients with colorectal cancers needs further evaluation. No significant financial relationships to disclose.
Outcome of favorable histology Wilms' tumor: Experience at KFSH&amp;RC, Saudi Arabia
Authors: I. M. Al Fawaz, M. Ayas, S. Rifai, Y. Khafaga, M. Al Shabanah, Z. Habib
Journal: Journal of Clinical Oncology (2004)

8557 Background: Reports of the outcome of Favorable Histology Wilms' Tumor from developed countries were excellent. However, there were limited reports from developing countries. This study from Saudi Arabia is to share with you our experience in this regard. Methods: Between 1980–2001 there were 144 evaluable cases of favorable histology Wilms' tumor seen at KFSH&RC excluding bilateral disease. The diagnosis was established by upfront nephrectomy in 88, FNA in 45, and open biopsy in 11. According to the National Wilms' Tumor Study (NWTS) group staging system, there were 44 cases(30.6%) in stage 1, 23(16%) stage 2, 47(32.6%) stage 3, 30(20.8%) stage 4. The therapy consisted of surgery, radiation and chemotherapy according to the NWTS protocols opened during that time. Results: The outcome for the 1st line therapy were, 119 cases complete remission(CR), 7 progressive disease(PD), 11 death on therapy, and 7 lost to follow-up. Among the CR cases, 24 relapsed off therapy. Second line chemotherapy +/- surgery, +/- radiation were given to the relapse and PD cases. At last contact there were 110 alive without disease, 9 alive with disease, 18 dead, and 7 lost to follow-up. With a median follow-up of 35 months(0.10–170 months), the 5 years overall survival(OS) and event-free survival(EFS) for the whole group were, 85% and 58% respectively. According to the stage of disease, the 5 years OS and the EFS were, 95% and 83% for stage 1, 86% and 61% for stage2, 85% and 57% for stage 3, 65% and 24% for stage 4. Conclusions: In comparison of our results to that of NWTS-3, we noticed higher percentage of our patients in stage 3 and 4. However, the rate of relapse/progressive disease in our patients (31/144) 22% is comparable to that of the NWTS-3 figure(27%). Therefore, in spite of late presentation of disease in our patients, the overall survival of our patients is still comparable to the Western experience. No significant financial relationships to disclose.