tbuckley/cabot-search huggingface dataset:
Pharmacokinetics (PK) of the highly lipophilic and blood stable camptothecin AR-67 (7-t-butyldimethylsilyl-10- hydroxycamptothecin) in adult patients with solid malignancies
Authors: M. Leggas, J. Horn, E. Tsakalozou, J. A. Moscow, S. Z. Fields, J. C. Houchins, J. R. Eckardt, P. DeSimone, B. K. Kee, J. J. Rinehart, S. M. Arnold
Journal: Journal of Clinical Oncology (2009)

2546 Background: Camptothecin analogs possess a labile lactone ring, which readily undergoes a pH dependent, albeit reversible, hydrolysis in plasma to yield a carboxylate moiety. The latter is considered inactive due to its electronegative charge that impedes transport into cells. Furthermore, the carboxylate is cleared rapidly and causes toxicity in eliminating organs due to lactonation. AR-67 is a highly lipophilic 3 rd generation analog with superior stability of its lactone form in preclinical models. This report describes the PK of AR-67 in patients with refractory solid tumors enrolled in a phase I study. Methods: AR-67 was infused over 1 hr for 5 days every 21-days. PK was performed on the 1 st and 4 th day of cycle 1. Blood, plasma, and urine were collected (0–24 hrs) from 26 patients (see 09-AB-30336-ASCOAM) treated at 9 dose levels: 1.2–12.4 (mg/m 2 /day). AR-67 carboxylate and lactone were assayed with a validated chromatography method. Results: AR-67 was detectable at all dose levels. Blood concentrations mirrored those in plasma and were superimposable when adjusted by the hematocrit. AR-67 concentration peaked at the end of the 1-hr infusion and declined biexponentially with a terminal t 1/2 of 1.4 hr (plasma lactone). A linear relationship was observed between dose and AUC. The lactone clearance on Day 1 was 16.6 (±5.5) vs. 19.6 (±6.3) L/hr/m 2 on Day 5. The carboxylate clearance was ∼ 6-fold higher. Lactone was the major form in all samples and its area under the time vs. concentration curve (AUC) was 85.5% (range 74.0%-94.1%) of the total AUC. Urine (0–24 hr) contained 2.5% (0.3%-6.7%) of the dose on Day 1 vs. 2.7% (0.9–11.1%) on Day 4. Extensive metabolite peaks were not observed in plasma, blood, or urine samples. Plasma protein binding of the carboxylate was 90% (range 80%-96%) vs. 95% (range 90%-98%) for the lactone. Conclusions: AR-67 is a lipophilic camptothecin with a unique PK profile. Unlike other clinically approved analogs with lower lactone stability (35%-65%), over 85% of the AR-67 AUC is in the active lactone form. This high lactone-low carboxylate exposure coupled with the apparently limited metabolism of AR-67 may result in increased activity and decreased toxicity. [Table: see text]
An open, randomized, multicentre, phase III trial comparing the efficacy of two tamoxifen (T) schedules in preventing gynecomastia (gy) induced by bicalutamide monotherapy (BM) in prostate cancer patients (pca pts)
Authors: D. Bedognetti, A. Rubagotti, G. Conti, F. Francesca, O. De Cobelli, L. Canclini, M. Gallucci, F. Aragona, P. Di Tonno, F. Boccardo
Journal: Journal of Clinical Oncology (2009)

e16080 Background: BM is a valuable option for pca pts who wish to avoid the consequences of androgen deprivation and to mantain sexually active.BM is commonly well tolerated:however gy and mastalgia virtually develop in all pts and represent a major cause of treatment discontinuation. We had previously demonstrated that T is safe and effective in preventing breast events induced by BM without affecting B tumor activity (Boccardo, J Clin Oncol. 2005;23:808). However possible interferences between B and T,especially after prolonged administration, remain a matter of concern.In order to reduce the exposure to T,we considered the putative advantages of a weekly administration based on T effects being dose -dependent and on drug long half-life. Methods: This was a non inferiority trial. 80 pts with localized, locally advanced or biochemically recurrent pca were randomly assigned to receive daily B (150 mg) plus T 20 (mg) continuously (d group: n = 41) or same but with T at 20 mg/weekly after the first 8 weeks (wk group: n = 39). Gy (primary endpoint), breast pain (bp), serum PSA levels and sexual functioning scores were evaluated. Results: At a median F.U. of 24.2 mos (95% CI: 23.7 -24.6) gy developed in 31.7% of pts in d group and in 74.4% of pts in wk group (p &lt; 0.000). Bp occurred in 12.2% and 46.1% of pts respectively (p = 0.008) and it was more severe in patients switched to weekly T. The incidence of Aes was comparable (d group:58.8%;wk goup: 56.4%). However most events were mild and easily manageable. There were no major differences among treat. schedules relative to sexual functioning scores, PSA behaviour and disease progression. Conclusions: This study failed to demonstrate that it might be possible to maintain comparable prophylactic effect of T by switching from a daily to a weekly schedule and confirms that T at the daily dose of 20mg is safe and effective in preventing the incidence and severity of BM induced breast events. No significant financial relationships to disclose.
Preliminary data from a phase II study of cetuximab with irinotecan in heavily pretreated patients with epidermal growth factor (EGFR)-expressing metastatic colorectal cancer (mCRC): LABEL
Authors: A. Buzaid, C. de Cerqueira Mathias, F. Perazzo, S. Simon, L. Fein, J. Hidalgo, A. M. Murad, R. Esser, A. Loos, G. Lerzo
Journal: Journal of Clinical Oncology (2007)

14521 Background: Cetuximab (Erbitux) is a monoclonal antibody directed against EGFR that is active in combination with irinotecan in patients (pts) with mCRC, who have progressed during or after a prior irinotecan therapy. Methods: This open, single-arm phase II Latin American study investigated this combination in pts with EGFR-expressing mCRC progressing on or within 3 months of chemotherapy containing at least 6 weeks (w) of irinotecan-based therapy. The primary objective was to assess the best overall confirmed response rate (RR). Sample size calculations were based on an expected rate of 20% (±8%). Planned enrollment was 100 pts. Secondary objectives were to explore the duration of response (DOR), progression-free survival (PFS) time, the 12-week PFS rate, and overall survival time. Pts were treated with cetuximab (initial dose 400 mg/m 2 then 250 mg/m 2 weekly), plus irinotecan at the same dose and schedule (including dose reductions) as pre-study. Preliminary Results: Of 151 pts from 14 centers screened and in the database, 106 (70%, 3 pts missing) were EGFR-expressing and, of these, 79/106 (75%) were treated on-study. Forty (51%) were male; median age was 59 years [27–82]; 70 (89%) pts had a Karnofsky performance status = 90 and 9 (11%) pts = 80. Nineteen (24%) pts had received = 3 prior treatment regimens, 42 (53%) were previously treated with an oxaliplatin-based regimen for metastatic disease. The confirmed overall RR was 26.6% [17.3–37.7]. Median DOR was 23.9 w [17.1–30], median PFS time was 17.7 w [11.7–18.9], and the 12-week PFS rate was 58% [47–69]. Thirty-three (42%) pts were alive at data cut-off. Median survival was 9.7 months [7.9–13.1]. Treatment was well tolerated with the most common grade 3/4 adverse events including: diarrhea, 20%; neutropenia,10%; acne-like rash, 9%. No grade 3/4 infusion-related reactions were reported. Conclusions: The overall confirmed RRs observed in this heavily pretreated population fully met the expectations for the primary endpoint of this study. LABEL confirmed in a Latin American setting the activity and safety of cetuximab plus irinotecan seen in previous studies. No significant financial relationships to disclose.
Sorafenib plus interferon-α2b (IFN) as first-line therapy for advanced renal cell carcinoma (RCC): SWOG 0412
Authors: C. W. Ryan, B. H. Goldman, P. N. Lara, T. M. Beer, H. A. Drabkin, E. Crawford
Journal: Journal of Clinical Oncology (2006)

4525 Background: Sorafenib is a RAF and multiple receptor tyrosine kinase inhibitor active in RCC. IFN has modest activity in RCC and has immunologic, anti-angiogenic, and anti-proliferative effects. Sorafenib and IFN may simultaneously target anti-angiogenic and MAP kinase pathways, providing the basis for this phase II combination study. Methods: Eligible patients (pts) had metastatic or unresectable RCC with a clear cell component, no prior systemic therapy, performance status 0–1, measurable disease. Treatment: IFN 10 x 10 6 IU s.c. 3x/week and sorafenib 400 mg p.o. BID. Response assessment was performed q8 weeks. This was a single-stage trial with a planned sample size of 55. Primary endpoint was RECIST response rate. Results: Of 67 registered pts, 58 are eligible &amp; evaluable. Pt characteristics: median age 61 years (42–84), male:female (40:18), prior nephrectomy 86%. MSKCC prognostic categories (42 pts) were good:intermediate:poor (28%:67%:5%). With a median follow-up of 6.5 months, 79% (46/58) of pts are alive, 41% (24/58) remain on treatment. Assessment of progression-free survival is premature. Overall response rate (53 pts) is 19% (95% CI: 9%, 32%) with CR 2% and PR 17% (9% confirmed, 8% unconfirmed). Toxicities affecting &gt;50% of subjects were: fatigue, anorexia, diarrhea, nausea, rigors/chills, fever, anemia, leukopenia. Most common Grade 3+ toxicities were fatigue (24%), leukopenia (10%), anorexia (6%), diarrhea (6%), hyponatremia (6%). All pts experienced some toxicity, with 36 (62%) experiencing at least one Grade 3+ toxicity. Hand-foot syndrome, a common side effect of sorafenib, was seen in only 10% of pts. Conclusions: The overall response rate of 19% for the combination of sorafenib and IFN in advanced RCC is greater than expected with either IFN or sorafenib alone. Toxicity is typical of IFN and notable for minimal hand-foot syndrome. Further studies with this combination are warranted. [Table: see text]
The clinical implications of JAK2<sup>V617F</sup> mutation in idiopathic myelofibrosis
Authors: W. Li, S. Zhang, J. Li
Journal: Journal of Clinical Oncology (2007)

17542 Background: JAK2 V617F is a novel molecular mechanisms of BCR/ABL-negative MPD especially polycythemia vera. However, its role may not be well clarified in idiopathic myelofibrosis (IMF). Methods: To investigate its prevalence and clinical significance in Chinese IMF patients, Allele-Specific PCR (AS-PCR) in combination with sequence analysis were introduced to screen JAK2 V617F mutation in our research. Genomic DNA of 12 IMF patients was extracted from peripheral blood mononuclear cells, and AS-PCR was firstly adopted to amplify the exon 12 of JAK2 gene which harbored V617F mutation. The positive samples with JAK2 V617F mutation were further confirmed by sequence analysis. In addition, the clinical features of JAK2 V617F positive and negative subgroup were compared. Results: The JAK2 V617F mutation was identified in 6 IMF patients (50%, 6/12) by AS-PCR and sequence analysis. Its presence is significantly associated with a higher platelet counts, megakaryocyte counts of bone marrow and incidence rate of thrombosis in IMF patients. Conclusions: AS-PCR is a sensitive and accurate technique in identification of JAK2 V617F mutation. JAK2 V617F mutation of our research is similar to other reports. Moreover, the clinical process of JAK2 V617F positive subgroup may be more invasive in comparison with JAK2 V617F negative subgroup. No significant financial relationships to disclose.
Concurrent urologic and palliative care after cystectomy for treatment of muscle-invasive bladder cancer.
Authors: Michael W. Rabow, Carly Benner, Nancy Shepard, Maxwell V. Meng
Journal: Journal of Clinical Oncology (2014)

11 Background: To characterize the impact of palliative care concurrent with usual urologic care for bladder cancer patients undergoing cystectomy. Methods: Prospective, 6 month, serial cohort study comparing 33 participants receiving usual care with cystectomy for muscle invasive bladder cancer with 30 participants also receiving concurrent palliative care. Patients and family caregivers completed validated symptom assessment and satisfaction surveys pre-operatively and two, four, and six months post-operatively. Results: The intervention group saw improvements in most symptom measures over the six months following cystectomy compared to the control group. Depression and anxiety decreased over the six-month period for intervention patients, but increased over this time among controls (p=0.01). Fatigue fell to a minimum for intervention group participants at four months, while it peaked at this time for control participants (0.002). Quality of life and post-traumatic growth scores followed a similar pattern, with scores peaking at four months for the intervention group while controls reported their lowest scores at this time (p=0.01 and p=0.03, respectively). Changes in pain scores did not reach statistical significance. Neither family caregiver burden nor patient satisfaction showed statistically significant changes over time. Conclusions: Patients who received concurrent palliative care in addition to usual urologic care following radical cystectomy for muscle-invasive bladder had better outcomes, including improved fatigue, depression, quality of life, and post-traumatic growth. While further research on this topic is needed, our results suggest that providing palliative care services in addition to usual urologic care for bladder cancer patients may significantly reduce post-operative symptoms.
Response of brain metastases to simulation whole brain and topotecan
Authors: M. Aun, T. N. Ansari
Journal: Journal of Clinical Oncology (2008)

11560 Background: To see the response of topotecan with whole brain radiation with brain metastases. Methods: Prognosis of patients with brain metastases is poor when conventionally treated with whole brain radiation alone. Early studies have suggested that topotecan crosses the blood brain barrier and has synergistic cytotoxic with radiation. So we conducted a study at Oncology Department Combined Military Hospital Rawalpindi to determine the efficacy and toxicity of topotecan and whole brain radiation in patients with brain metastases. Results: Thirty patients with brain metastases received 2 mg/m2 topotecan once weekly for 2 weeks with concurrent whole brain radiation, 3,000 cGy, for 2 weeks. A complete response was observed in 2 (6.67 %) of the 30 eligible patients at the end of one month after completing radiation therapy, 14 (46.67 %) patients had a partial response, 10 (33.33 %) patients had stable disease while 4 (13.33 %) patients showed progressive disease. Adverse events of grade 3 or higher included 2 (6.67 %) cases each of neutropenia and vomiting. Other minor complications (grade 1/2) were nausea and vomiting in 12 (40 %) cases, constipation in 5 (6.67 %) cases, anemia in 10 (33.33 %) cases, neutropenia in 8 (26.67 %) cases, and mucositis in 6 (20 %). Conclusions: We concluded that topotecan as radiation sensitizer is well tolerated and effective for the treatment of brain metastases. No significant financial relationships to disclose.
A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: A trial of the PMH Phase II Consortium
Authors: S. Welch, H. J. Mackay, H. Hirte, G. F. Fleming, R. Morgan, L. Wang, C. Blattler, S. P. Ivy, A. M. Oza
Journal: Journal of Clinical Oncology (2009)

5576 Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Vascular endothelial growth factor (VEGF) overexpression in EC correlates with poor outcome, thus targeting VEGF is a rational therapeutic approach. We have conducted a two-stage open-label phase II study in advanced EC with sunitinib, an oral tyrosine kinase inhibitor of multiple VEGF receptors. Methods: Eligible pts have recurrent or metastatic EC and have received up to 1 prior chemotherapy (CT) regimen for metastatic disease. Sunitinib is given at 50 mg daily (OD) for 4 consecutive weeks (wks) followed by 2 wks off. Dose could be reduced to 37.5 mg OD and then 25 mg OD in the setting of toxicity. Imaging is repeated every 12 wks. Primary objectives are objective response rate (ORR by RECIST) and rate of 6-month progression-free survival (PFS). If 1 or more responses occur in the first 15 evaluable pts, the study would continue to a second stage (total = 30 pts). Secondary objectives are time to progression (TTP), overall survival (OS), and safety. Results: We report the results of the first stage of this study. Sixteen pts have been treated (median age: 63; range 41–74) with 37 cycles of sunitinib (median 2; range: 1–7). Baseline ECOG PS was 0 (7 pts), 1 (8 pts), or 2 (1 pt). Histology was endometrioid (7 pts), serous (5 pts), clear cell (1 pt), or mixed/other (3 pts). Most pts had high-grade histology (G3: 8; G2: 4; G1: 2; GX: 2). Nine pts had prior adjuvant CT, 8 pts had 1 prior CT for advanced EC, 4 pts had prior hormones and 7 pts had prior radiotherapy. Partial response was achieved by 2 pts (ORR = 12.5%), and 2 other pts had a best response of stable disease; 3 of these pts remained progression-free &gt; 6 months. Median TTP = 2.5 months (95% CI: 2.47-NR), and median OS = 6.2 months (95% CI: 5.1-NR). Grade 3/4 adverse events (AE) in &gt;10% of pts were fatigue (7 pts, 44%) and hypertension (5 pts, 31%). Dose reduction was required for 11 of 16 pts (69%). Two pts were inevaluable after receiving &lt;2 cycles due to AE (grade 4 hyponatremia; grade 3 fatigue) and 1 other pt has yet to complete 2 cycles. Conclusions: Sunitinib shows preliminary activity in EC. This trial will proceed to a second stage of accrual to further explore the efficacy and safety of sunitinib in advanced EC. [Table: see text]
Phase II study of iproplatin in advanced ovarian carcinoma.
Authors: C Sessa, J Vermorken, J Renard, S Kaye, D Smith, W ten Bokkel Huinink, F Cavalli, H Pinedo
Journal: Journal of Clinical Oncology (1988)

Iproplatin (cis-dichloro-trans dihydroxy-bis-isopropyl-amine platinum [IV]; CHIP) was administered intravenously (IV) at monthly intervals at doses of 300 mg/m2 and 240 mg/m2 to ten previously untreated and 97 previously treated patients with advanced ovarian carcinoma. The overall response rate was 78% among patients with no prior chemotherapy, 42% among patients with prior chemotherapy not including cisplatin, and 22% among patients with prior chemotherapy including cisplatin. Overall response rates to iproplatin were 6.4% and 54% in patients with/without clinical evidence of tumor resistance to cisplatin. Thrombocytopenia was the dose-limiting toxicity, median time to nadir and to recovery being 2 and 4 weeks, respectively. Patients who had received prior chemotherapy regimens for greater than 1 year showed a 10% greater reduction in platelet count (mean platelet nadir +/- SD, 57.5 +/- 49.96 X 10(3)/microL) and a higher incidence of grade 3 to 4 thrombocytopenia after the first cycle than patients who had received prior chemotherapy regimens for less than 1 year (94.7 +/- 65.99 X 10(3)/microL) Moderate to severe vomiting and diarrhea occurred in 84% and 16% of patients pretreated with chemotherapy. Neuropathy (6%) was reported only in patients with prior cisplatin treatment. Mild and reversible renal toxicity was observed in 6% of cases. Iproplatin is an active drug in ovarian cancer; the results achieved in patients previously treated with cisplatin strongly suggest that the two drugs are cross-resistant.
Premorbidity personality traits and coping strategies in chemotherapy-treated cancer patients
Authors: F. Barbato, G. Marchioro, M. Bari, G. Azzarello, E. Vattemi, D. Sartori, M. Dandrea, C. Minotto, C. Anzolin, O. Vinante
Journal: Journal of Clinical Oncology (2004)

8202 Background: Cancer and treatment related factors are traumatic events for the patients. In fact, a large majority of patients experience disruption in their quality of life through loss of roles, functional abilities and problems with social relationship. It has been reported that depression strongly affects patients' coping strategies. Stage of disease, treatment modalities, symptom status and personality traits have been investigated, but there is still inadequate understanding of how these factors affect psychological adjustment. We conducted an observational, longitudinal study to investigate the correlation between patients' mood disorders and cancer diagnosis/treatment or personality traits. Methods: 199 consecutive cancer patients referred to Day Hospital section for front-line chemotherapy were investigated. On admission patients were submitted to Projective Test of Zulliger (ZT) and Beck Depression Inventory (BDI). BDI was repeated every 15 days (9 observations) along with the Rorschach Test (RT) at the third control and the Rorschach Parallele Test (RPT) at the eighth control. Results: Up till now 53 patients (20 male, 33 female; median age 59.3, range 36–59) are eligible for analysis. On the basis of the BDI no patient fulfilled the parameters configuration corresponding to depressive personality trait. In fact, 38.6% of patients showed an increased BDI score at the third evaluation, while 38.6% and 22.8% showed a decrease or stability, respectively. Only the BDI somatic factor (F3) related to depression trait was significantly present in all patients. According to both ZT and RT, majority of patients (79.2% and 98.1%, respectively) showed a decrease of personal resources to face environmental demands. Conclusions: No patient presents a premorbidity major mood disorder. The attention of the patient is mainly directed to the somatic disease. The projective test, showing an unconscious reduction of coping strategies might be predictive for subsequent major mood disorders. On the basis of these results, we suggest the importance of psychoeducational interventations in cancer patients during chemotherapy. No significant financial relationships to disclose.
Management of elderly breast cancer patients in Spain: A national observational, prospective, multicenter study
Authors: A. Clopes, N. Paladio, G. Cajaraville, M. J. Carreras
Journal: Journal of Clinical Oncology (2005)

8107 Background: The cancer incidence in individuals ≥65 years is >60%. The increasing life expectancy will increase the number of patients (pts) older than 65 with breast cancer (BC). However, elderly pts are underrepresented in clinical trials (CT) and age may be factor in the selection of chemotherapy treatments. Methods: National observational, prospective, multicenter study including pts with BC treated with IV chemotherapy in Spain between 10–15/May/04. The proportion of older (≥65 years) vs. younger (<65 years) pts according to number of pts enrolled in CT and type of treatment and the median cost of treatment (euros/patient/wk) of both groups were compared using a chi-square analysis and a Student t test, respectively. Crude data were adjusted to number of preparations/day/hospital and incidence of BC. Results: 2053 pts (111 hospitals) with BC were evaluated, including 477 older pts (23.23%, median age 71.4±4.6). Comparison of young and old pts showed significant differences in the median cost of treatments (548.41 euros/pt/wk vs. 423.46 euros/pt/wk, p<0.05) and the number of pts enrolled in CT (6.26% vs. 2.72%, p=0.003). Differences were also observed in the number of pts receiving adjuvant and palliative treatments (44% vs. 37.3%, p=0.009; 47.14% vs. 56.18%, p=0.001) although this was not seen in the group of pts receiving neoadjuvant regimens (8.6% vs. 6.49%, p=0.136). Pts of both groups treated with neoadjuvant and adjuvant chemotherapy presented late-stage and late-stage disease, respectively although this was not significant in the latter group (p=0.001, p=0.148). Older pts more often receive treatment with CMF compared to younger pts (p<0.0001) as opposed to anthracyclines. Conclusions: In BC pts, age seems to be a factor in the selection of cytotoxic drugs and in the enrolment of pts in CT. No significant financial relationships to disclose.