tbuckley/cabot-search huggingface dataset:
Alternating hepatic artery chronotherapy with CPT-11 and systemic chronotherapy with 5-FU/FA + carboplatin for metastatic colorectal cancer confined to the liver: A phase II study
Authors: M. Shimonov, H. Hayat
Journal: Journal of Clinical Oncology (2005)

3707 Background: We prospectively evaluated the efficiency and side effect of a new combined chronotherapy protocol using combined systemic and intra-hepatic chemotherapy for patients with colorectal metastases confined to the liver. Patients & Methods: 24 patients (pts) with unresectable liver metastases (LM)were treated.Eighteen pts with synchronous colorectal cancer (CRC) and LM and six pts with LM. Patients with synchronous tumor were treated with colectomy and insertion of hepatic artery catheter through the gastroduodenal artery (19 pts) and percutaneously (5 pts). Chronotherapy was composed of alternating Hepatic artery infusion (HAI) and systemic infusion (SI) at alternating weeks. Systemic treatment included chronomodulated 5FU 700 mg/m2, FA 300 mg/m2 (22:00- 10:00; peak delivery 04:00) and carboplatine 40mg/m2 (10: 00- 22:00; peak delivery 16:00) for 4 days followed by HAI of chronomodulated CPT-11 100 mg/m2 (02:00–08:00;peak delivery 05:00) for 1 day. One treatment cycle included SI followed by HAI. Results: 24 chemonaive pts were recruited.Morbidity consisted mostly of epigastric pain during HAI (13/24, 56%), and mild GIT complains (46%) treated conservatively. 24 pts reported weight gain, maintained appetite and a normal life schedule, 4 pts complained of weakness and weight loss. All patients received ≥ 4 combined treatment cycles (8 to 22, median 16). Objective response was achieved in 17/24 (71%) with 5 pts with CR and 12 pts with PR. In 9 patients LM were treated by radiofrequency ablation (RFA) of them in 2 pts curative hepatectomy at a later stage was performed. Four patients have had hepatectomy. All “responding” patients are alive, while 6 patients have died because of disease progressn. Conclusions: This trial of combined chronotherapy treatment- alternating HAI and systemic, is safe, with low toxicity profile and a 71% response rate. No significant financial relationships to disclose.
Report card for compliance with NCCN guidelines in the surgical management of cutaneous melanoma across the United States: Time for remedial classes?
Authors: N. Wasif, R. J. Gray, B. A. Pockaj
Journal: Journal of Clinical Oncology (2010)

8515 Background: The National Comprehensive Cancer Network (NCCN) has clear guidelines for the management of cutaneous malignant melanoma (MM) with regard to margins of resection (RM), sentinel lymph node biopsy (SLNB) and regional nodal dissection (RLND). Our goal was to assess compliance with these guidelines in the management of MM in the general population of the United States. Methods: The Surveillance, Epidemiology, and End Results Database was queried to identify 35,126 patients with MM diagnosed from 2004-2006. Codes for RM, SLNB, and RLND were extracted and compliance with NCCN guidelines assessed for each. Multivariate regression analysis was used to identify factors predictive of non-compliance. Patients with in situ and Stage IV disease were excluded. Results: Noncompliance with NCCN recommendations for RM occurred in 64% of patients. An excisional biopsy was the only surgical resection performed in 10.8%. A RM of < 1 cm was seen in 62.2% of T1, 43.7of T2, 40.9% of T3 and 42.4% of T4 MM. Of the 14,031 patients who were eligible for SLNB, only 7,442 (53%) actually underwent SLNB. No surgical nodal staging was performed in 34.2% and 12.7% underwent elective RLND. In the 1,102/7,442 (15%) of patients with a positive SLNB the rate of completion RLND was 73.1%. On multivariate analysis, variables predictive of non-compliance with RM guidelines included head and neck primary (HR 1.36, 95% CI 1.26-1.46), female sex (HR 1.09, 95% CI 1.03-1.15), age > 60 years (HR 1.15, 95% CI 1.09-1.21) and T1 stage (HR 1.39, 95% CI 1.22-1.57). Factors predictive of SLNB included site other than head and neck, T Stage other than T1, age < 60 (HR 1.91, 95% CI 1.77-2.06) and male sex (HR 1.10, 95% CI 1.02-1.19). Conclusions: There is significant and worrisome heterogeneity in the surgical management of MM in the United States. Although some of this may be attributed to disparities in the provision of healthcare, it seems that guidelines supported by randomized trials are not being adhered to by treating physicians. A combination of patient and physician education and perhaps regionalization of melanoma care is needed to improve compliance and outcomes. No significant financial relationships to disclose.
Performance of the Revised Bethesda guidelines for identification of hereditary nonpolyposis colorectal cancer (HNPCC) mutation carriers
Authors: J. Balmaña, E. M. Stoffel, D. H. Stockwell, E. W. Steyerberg, A. M. Deffenbauch, J. E. Reid, B. C. Hendrickson, T. Scholl, W. W. Noll, S. Syngal
Journal: Journal of Clinical Oncology (2005)

9506 Background: The Bethesda guidelines (BG), delineating which individuals with colorectal neoplasia should undergo microsatellite instability testing, are often used as diagnostic guidelines for HNPCC. Developed in 1997, the BG were modified in 2001 and revised in 2004. We compared the performance of the revised BG with the previous versions for identification of individuals with MLH1/ MSH2 mutations. Methods: Personal and family history were obtained from test order forms for 898 consecutive, unrelated probands submitting blood samples for full gene sequencing of MLH1/ MSH2 to Myriad Genetic Laboratories, Inc. We calculated the sensitivity, specificity, positive predictive value (PPV), and the Receiver Operating Characteristics (ROC) curves for each of the versions of the BG for the presence of a germline mutation. Results: Sixty percent of the probands fulfilled the original, 65% the modified, and 57% the revised BG. Mutations were identified in 130 (14.5%) probands. Sensitivity of the revised BG for a mutation in MLH1/MSH2 was 71% (95% CI 62–78), considerably lower than the original and modified BG, which were 85% (95% CI 77–90), and 86% (95% CI 81–92), respectively. Of the 38 mutation carriers missed by the revised BG, 17 had colorectal adenoma, 7 had endometrial cancer, 8 had other HNPCC tumors, and 7 were unaffected or had a non-HNPCC cancer. The revised, original and modified BG had similar specificities, 46% (95% CI 42–49), 44% (95% CI 40–47), and 39% (95% CI 36–42), and PPV, 18% (95% CI 15–22), 20% (95% CI 17–24), and 20% (95% CI 17–23), respectively. The revised BG had a significant lower area under the ROC curve (0.58) compared to the original and modified BG (0.63 and 0.64,respectively; p=0.006). Conclusions: The revised BG are less sensitive than the previous versions. HNPCC diagnostic criteria that do not include colonic adenomas and extracolonic cancers may miss a substantial percentage of individuals with mutations. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Myriad Genetic Laboratories Myriad Genetics Laboratories Myriad Genetics Laboratories
A poor prognosis ER and HER2-negative, nonbasal, breast cancer subtype identified through postneoadjuvant endocrine therapy tumor profiling
Authors: M. J. Ellis, Y. Tao, J. Luo, J. Hoog, M. Watson, D. C. Allred, P. S. Bernard, T. O. Nielsen, C. M. Perou, J. Olson
Journal: Journal of Clinical Oncology (2008)

502 Background: Tumor estrogen receptor (ER) loss after neoadjuvant endocrine therapy (NET) was recently identified as an independent prognostic marker relapse (relative risk relapse 2.8 CI 1.2–6.4 P=0.02 and death from breast cancer RR 7.0 CI 2.4–20.9 P=0.0005 - SABCS 2007 Abstract 62). To investigate the switch from ER+ to ER- after NET we examined microarray gene expression data accrued from a multicenter Phase 2 study of neoadjuvant letrozole. Methods: Agilent 44K whole genome array data was generated from tumor specimens with >50% tumor prior to therapy (BL), and on treatment (OT) samples one month and/or surgery. 65 BL and OT pairs or triplets were obtained and a simple clustering algorithm was used to examine relationships between the BL and OT samples and reference samples (14 Basal [BAS] 6 HER2+ [HER2] and 4 Normal Breast). 50 genes were applied that have been identified as a minimal set capable of giving an intrinsic breast cancer subtype classification. Results: The BL clustering and central ER analysis revealed three false hormone receptor positive tumors, two ER- HER2- tumors that clustered with BAS cluster and one ER- HER2- tumor that strongly expressed the proliferation cluster (PLN) but not BAS or LUM markers. The OT clustering experiment revealed an additional 8 tumors in the ER- cluster that had HER2- /BAS-/LUM-/PLN+ characteristics with markedly poor Ki67 response (P=0.015). In BL samples these tumors were originally ER IHC+ and appeared in the LUM branch. These observations support the initial observation that about 10% of ER+ tumors transition to an ER- state early after the initiation of endocrine treatment (ET). Of the eight relapses that have occurred in the phase II letrozole trial population to date, three were tumors in the post treatment HER2-/BAS-/LUM-/PLN+ cluster and two were in the BL false ER+ group. Conclusions: Tumors that lose ER with neoadjuvant endocrine treatment lack both BAS and LUM gene expression. These unclassified proliferative tumors can exhibit a fulminant clinical course. ER expression should be tested soon after initiating NET (one month) to identify early ER loss so that treatment approaches can be adjusted to reflect the highly aggressive and ET resistant nature of this newly defined tumor subtype. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration University Genomics
Phase II study of capecitabine combined with gemcitabine in the treatment of androgen-independent prostate cancer with prior taxane exposure
Authors: A. J. Rodney, P. Dieringer, P. Mathew, E. Jonasch, N. Tannir, L. C. Pagliaro
Journal: Journal of Clinical Oncology (2005)

4750 Background: Single-agent response rates of 12% and 7% have been reported for capecitabine and gemcitabine, respectively, in androgen-independent prostate cancer (AIPCa). The primary objective of this study was to evaluate the response rate of capecitabine and gemcitabine in combination for the treatment of AIPCa that is progressing after taxane therapy. The secondary objective was to evaluate the safety and tolerability of chemotherapy with capecitabine and gemcitabine in these patients (pts). Methods: Men with AIPCa, metastatic or unresectable disease and prior docetaxel or paclitaxel treatment were eligible. This prospective phase II study was conducted at M. D. Anderson Cancer Center, with Simon optimal 2-stage clinical trial design. In the first stage, 22 pts were intended for treatment. If 8 pts responded, an additional 24 pts would be assigned. Patients were treated with starting doses of capecitabine 800 mg/m2 p.o. b.i.d. (1,600 mg/m2/day), days 1–14, and gemcitabine 800 mg/m2 i.v. over 30 minutes, days 1 and 8, repeated every 21 days. Results: Sixteen men were registered from 6/2003 to1/2004 and received a total of 36 courses (median 2; range 0–4). Median age was 67 years (39–74). All pts enrolled had a performance status of 1–2. Median prostate specific antigen (PSA) concentration was 232 ng/ml (8.1–915.1). All pts were assessable for toxicity and 15 were assessable for response. There were no responses, as measured by 50% decline in PSA. Two pts remained stable for 3 courses (9 weeks) and progressed in the fourth course. The study was terminated early because the response rate was not projected to exceed 30% (rejection error = 10%). Toxicities were notable: 2 pts had grade 3 thrombocytopenia, 2 pts had grades 3–4 neutropenia, and 3 pts had grade 3 infections. Grade 1–2 nonhematologic toxicities included hand-and-foot syndrome (4 pts), nausea (2 pts) and diarrhea (2 pts). Eight pts (50%) required dose reduction or omission. Conclusions: We conclude that the combination of capecitabine and gemcitabine for salvage treatment of pts with AIPCa after failure of taxane therapy was associated with significant toxicities and was ineffective for induction of disease regression. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Merck, Pfizer Celgene, Eli Lilly, Novartis
Anastrazole treatment in breast cancer does not cause androgenic effect
Authors: M. Mundia, M. F. Ali
Journal: Journal of Clinical Oncology (2006)

10614 Background: Aromatse Inhibitors are a class of drugs that inhibit tumor growth in hormone receptor positive breast cancers in postmenopausal women. They exert their action by inhibiting the enzyme aromatse involved in the last step in conversion of Androgens to estrogens. They are currently used extensively in both advanced and adjuvant treatments. Methods: Clinical Charts of postmenopausal women, with estrogen receptor positive breast cancer, receiving the non-steroidal aromatse inhibitor, Anastrazole 1 mg daily at a community oncology practice were evaluated for androgenic effect of the drug. Review included presence of clinical Hirsutism and serum testosterone levels. Results: There were 33 women, receiving Anastrazole, 29 for adjuvant therapy, and 4 for metastatic disease. Age 51–77years (median: 63 years), Duration of Anastrazole therapy 6 months to 42 months (median: 18 months), There was no Clinical evidence of hirsutism noted. Serum testosterone levels varied from 9 ng/ml to 58 ng/ml. (Normal range: 14–76 ng/ml) in 32 women. 1 woman had a serum testosterone level of 86 ng/ml with no clinical hirsutism. The most common side effect of Anastrazole was arthralgias, seen in three women. Conclusions: Anastrozole 1 mg daily does not appear to cause any clinical androgenic effect, or elevation of serum testosterone levels. No significant financial relationships to disclose.
Pemetrexed plus cisplatin (P+Cis) or pemetrexed plus carboplatin (P+Cb) for chemonaive patients (pts) with malignant pleural mesothelioma (MPM): Results of the International Expanded Access Program (EAP)
Authors: A. Santoro, M. O'Brien, R. Stahel, K. Nackaerts, P. Baas, L. Paz-Ares, S. Sundstrom, C. Visseren-Grul, J. Blatter, C. Manegold
Journal: Journal of Clinical Oncology (2007)

7562 Background: In a phase III study of P+Cis versus Cis, MPM pts demonstrated a significant survival benefit (12.1 mo vs 9.3 mo median survival; 50.3% vs 38.0% 1-yr survival) and clinical benefit in favor of P+Cis (Vogelzang 2003). Other studies similarly demonstrated efficacy associated with P+Cb. Before and during review by regulatory agencies, EAP provided access to P alone or P plus a platinum (Cis or Cb) for 3311 MPM pts in 13 countries. Safety and efficacy data for chemonaïve pts receiving P+platinum are summarized in this abstract. Methods: Eligible pts had histologic or cytologic diagnosis of MPM not amenable to curative treatment with surgery. P 500 mg/m 2 was given in combination with either Cis 75 mg/m 2 or Cb AUC 5 once every 21 days with standard pre- medication consisting of vitamin B 12 , folic acid, and dexamethasone. Investigator-determined response (RR) and survival data (with censoring) were recorded at the end of study participation. Myelosuppression data were also collected. Results: 1,704 chemonaïve pts received =1 dose of P+Cis (843 pts) or P+Cb (861 pts) and were evaluable for safety. For the P+Cis group, the median age was 62 yrs (range, 24–78) and 85.3% of pts were male. For the P+Cb group, the median age was 66 yrs (range, 35–89) and 80.5% of pts were male. More than 90% of pts in both groups had performance status (PS) data; 86.8% of P+Cis pts and 85.8% of P+Cb pts had Karnofsky PS =80. Among the study participants, 745 P+Cis pts and 752 P+Cb pts were evaluated for efficacy. See the table for efficacy and safety data. Conclusions: This large study confirmed the activity of P+Cis and P+Cb, demonstrating clinically similar one-year survival for the treatment of chemonaive pts with MPM. No significant financial relationships to disclose. [Table: see text]
Prevalence of anemia in cancer patients not receiving antineoplastic treatment (ANT): Data from the European Cancer Anaemia Survey (ECAS)
Authors: P. Gascon, P. J. Barrett-Lee
Journal: Journal of Clinical Oncology (2006)

8565 Background: Cancer-associated anemia occurs frequently in patients receiving ANT. Patients not receiving ANT may also have low hemoglobin (Hb) levels that may compromise optimal disease management and patient outcomes. Methods: Patients enrolled in ECAS (Ludwig et al, Eur J Cancer 2004;40:2293–2306) and not receiving ANT (chemotherapy, radiotherapy, or hormonal treatment) at enrollment were evaluated for prevalence of anemia (Hb &lt;12.0 g/dL), effect of anemia on performance according to WHO score (0 to 4), and anemia treatment. Disease status at enrollment was catagorized as newly diagnosed (ND), persistent/recurrent (P/R), or in remission. Results: Of 15,367 enrolled patients, 7947 (53%) were not receiving ANT: 60% ND; 28% P/R disease; 12% in remission. Anemia was present in 32% of patients, with Hb levels 10.0–11.9 g/dL in 24%, and &lt;10.0 g/dL in 8%. Anemia rates were P/R, 38%; ND, 30%; in remission, 25%. Poor performance scores correlated positively with lower Hb levels; for patients with Hb &lt;8.0 g/dL, 8.0–9.9 g/dL, 10.0–11.9 g/dL, and ≥12.0 g/dL, worse WHO scores of 2–4 were recorded for 43%, 41%, 25%, and 15%, respectively. During ECAS 1168 patients with data after enrollment never received ANT, and 40% were anemic at some time (at enrollment and/or at follow-up). Hb nadirs were approximately evenly distributed: 11.0–11.9 g/dL, 37%; 10.0–10.9 g/dL, 29%, and &lt;9.0–9.9 g/dL, 34%. Anemia was infrequently treated with only 31.4% of patients receiving anemia treatment at any time. Anemia treatments administered and mean Hb at initiation were 14% epoetin alone ± transfusion ± iron (9.8 g/dL); 9% transfusion ± iron (8.4 g/dL); 8% iron (11.7 g/dL). Conclusions: Almost one-third of cancer patients who are not actively receiving ANT are anemic, including 25% of patients considered to be in remission. Anemia has a negative effect on performance, with worse WHO scores related to lower Hb levels. Anemia appears to be undertreated, with less than one-third of anemic patients receiving anemia treatment, and then only when Hb nadirs are &lt;10.0 g/dL. To insure optimal management of cancer patients, all should be screened for anemia and receive the most effective anemia treatment. [Table: see text]
Cisplatin and capecitabine as first-line therapy for advanced gastric or gastroesophageal junction adenocarcinoma
Authors: A. Viteri, R. Barcelo-Galindez, I. Rubio, R. Fernandez, A. Muñoz, N. Fuente, T. Perez-Hoyos, G. Lopez-Argumedo, J. M. Mañe, G. Lopez-Vivanco
Journal: Journal of Clinical Oncology (2004)

4187 Background: Combination chemotherapy improves overall survival and quality of life in metastatic gastric cancer. Capecitabine (CAP), a new oral fluoropyrimidine has shown equivalent activity, similar toxicity and better feasibility when compared with 5FU. A new schedule with cisplatin (cDDP) and CAP was tested to assess activity and toxicity in a population of non-selected chemonaive stage IV gastric or gastroesophageal junction adenocarcinoma. Methods: From March 03, seventeen patients were included. Median age 58 y-o (29–76). Males/females 9/8. ECOG<3. Previous gastrectomy in 5. Previous adjuvant chemotherapy in one. Gastroesophageal junction adenocarcinoma in one, gastric adenocarcinoma in 16. Hepatic metastasis in 2, non-resectable ganglionar metastasis in 7, non-resectable T4 in 3, peritoneal disease in 9, pleura-lung in 2. Schedule: cDDP 60 mg/m2 i.v. day 1, CAP 1,250 mg/m2 b.i.d. for 14 days every three weeks. Evaluation with CT every three cycles or if progressive disease suspected. Results: Seventy-nine cycles have been given, median 4.65, range 2–8. Dose intensity for cDDP was 17.28 mg/m2/week (86.4%) and for CAP 9,675 mg/m2/week (82.9%). All patients were evaluated for toxicity (NCI-CTC v2): Grade 3/4 per cycle: Neutropenia 5/1, diarrhea 6/0, mucositis 2/0, nausea vomiting 1/0, anemia 1/0. Asthenia grade 2/3: 7/1, hand-foot syndrome grade 2/3: 9/2. Grade 3 per patient: Neutropenia 2, mucositis 1, diarrhea 4, nausea vomiting 1, hand-foot syndrome 1, asthenia 1. Sixteen evaluated for response, CR in 1, PR in 5, SD in 3 and PD in 7, ORR 37.5%, 95%CI: 13.8%–61.2%. Median progression free survival and median overall survival (Kaplan-Meier method) had not been reached at a median follow up of 26 weeks, with 7 patients that have progressed and 6 patients that have died. Conclusions: This combination of cDDP and CAP is active and well tolerated in gastric adenocarcinoma with a good feasibility and toxicity profile. Phase III and QoL studies will be started to compare it with cDDP and infusion 5FU. No significant financial relationships to disclose.
Combination of fulvestrant and lapatinib in non-HER2-overexpressing and adriamycin-resistant breast cancer cell lines
Authors: A. M. Emde, K. Maslak, H. Liu, A. E. Reles, K. Possinger, J. Eucker
Journal: Journal of Clinical Oncology (2007)

14050 Background: We evaluated whether combination of lapatinib, a dual tyrosine kinase inhibitor against EGFR and HER2, and fulvestrant, a full estrogen receptor antagonist, is superior in EGFR and HER2 overexpressing and non-overexpressing breast cancer cell lines regarding cell growth inhibition and effects on the protein expression level on special proteins such as PDK1 and ERK1/2. Methods: MTT assay and western blot analysis were performed in the different breast cancer cell lines BT474, T47D, MCF-7 and Adriamycin resistant MCF7 cells. Incubation time was 72h. Concentration of both agents in western blot: 1x10exp-7M, in MTT assay 10exp-11M to 10exp-5M. Results: MTT assay showed a significant stronger proliferation inhibition by lapatinib and fulvestrant in BT474 cells and non- overexpressing T47D cells at a concentration of 10E-7M compared to single agent treatment. By western blot analysis, we found a synergistic downregulation of PDK1 in the combination treatment both in BT474 and AR MCF7 cells, whereas not in T47D cells. In MCF7 cells a downregulation of p-PDK1 was observed after treatment with fulvestrant alone as well as lapatinib plus fulvestrant. Regarding ERK1/2, a synergistic downregulation could be observed in AR MCF7 cells. A downregulation of a p-ERK was detected in MCF-7 cells after treatment with lapatinib, fulvestrant or both. Conclusion: A synergistic action of lapatinib and fulvestrant was observed in all 4 cell lines despite their different receptor status regarding EGFR, HER2 and ER alpha. Shadeo et al. (2005) showed different copy number profiles in these breast cancer cell lines regarding the examined pathways. We could show by western blot analysis that the combination treatment had inhibitory effect on these cell lines according to their individual up-regulated pathways. Altogether, this suggests that the combination is a promising treatment not only in EGFR and HER2 over-expressing breast cancer and that treatment effect is also dependent on up-regulated pathways more likely than receptor status. No significant financial relationships to disclose.