Real-world chart review study of adverse events management in patients taking tyrosine kinase inhibitors to treat metastatic renal cell carcinoma.

PURPOSE: The purpose is to describe management of adverse events of special interest across tyrosine kinase inhibitors approved for metastatic renal cell carcinoma. METHODS: We conducted a retrospective chart review in metastatic renal cell carcinoma patients initiating tyrosine kinase inhibitor monotherapy between 15 November 2010 and 15 November 2013, and experiencing ≥ 1 adverse events of special interest (diarrhea, fatigue, hand-foot syndrome, hypertension, or stomatitis/mucositis) within 3 months of initiation. Demographics, medical history, treatment regimens, and adverse events of special interest management data for 3.5 months postonset were collected. RESULTS: In 220 charts from 27 centers, tyrosine kinase inhibitors prescribed included sunitinib (55%), pazopanib (27%), axitinib (9%), and sorafenib (8%). During the study period, patients experienced 376 adverse events of special interest (13% serious). Fatigue was most common (62% of patients), followed by hypertension (37%), diarrhea (30%), stomatitis/mucositis (29%), and hand-foot syndrome (12%). Over half (56%) the adverse events of special interest were resolved or resolving. Treatment discontinuation due to adverse events of special interest occurred in 15% of patients. Prophylaxis was rarely provided (8%), whereas 59% of patients received adverse events of special interest treatment (pharmacologic (55%) and/or nonpharmacologic (7%)), 27% received tyrosine kinase inhibitor dose management, 23% received both adverse events of special interest treatment and dose management, and 31% received neither. Hypertension was the most treated (72% of all events), and fatigue was the least treated (9%); only 4% of patients received pharmacologic treatment for fatigue. CONCLUSIONS: Most adverse events of special interest were nonserious and more than half of the patients received pharmacologic and/or nonpharmacologic treatment. Fatigue was the most common yet least frequently treated adverse event of special interest, and few patients received prophylaxis or nonpharmacologic treatment. More emphasis on treatment and prophylaxis options for bothersome adverse events is warranted.

Axitinib in metastatic renal cell carcinoma: patient characteristics and treatment patterns in US community oncology centers.

AIM: To study patient characteristics and treatment patterns in real-world axitinib use for metastatic renal cell carcinoma. PATIENTS & METHODS: We conducted a retrospective analysis of second- or third-line axitinib use between 1 January 2012 and 31 October 2014 in 135 metastatic renal cell carcinoma patients using the US Oncology Network database. RESULTS: Overall, 86.7% had clear cell histology, 57.8% had stage III/IV disease at diagnosis and 55.6% were poor risk by Heng criteria. Median treatment duration was 4.6 months (range: 0.03-35.49); 80.7% initiated axitinib at 5 mg/day twice daily, and 67.4% maintained this dose. Overall, 77.8% discontinued treatment, mainly due to disease progression (50.5%) and toxicity (21.9%). CONCLUSION: Axitinib usage patterns were consistent with the National Comprehensive Cancer Network Guidelines®. Ease of use among community oncologists and patient tolerance are key features of axitinib.

A phase II single-arm study of irinotecan in combination with temozolomide (TEMIRI) in children with newly diagnosed high grade glioma: a joint ITCC and SIOPE-brain tumour study.

A multicenter, two stage phase II study, investigated irinotecan plus temozolomide in children with newly diagnosed high grade glioma. The primary endpoint was tumor response during a two-cycle treatment window, confirmed by external review committee. Patients received oral temozolomide 100 mg/(m(2) day) (days 1-5) and intravenous irinotecan 10 mg/(m(2) day) (days 1-5 and 8-12) for two 21-day cycles (three cycles for patients exhibiting objective tumor response). Standard treatment was then administered according to local investigator choice. In total 17 patients were enrolled and treated by local investigators. However, central pathology review found three patients did not have a diagnosis of high grade glioma and another four patients did not have evaluable disease according to independent central radiological review. The primary endpoint was based on the first ten evaluable patients as determined by the external review committee. Recruitment was stopped for futility after there were no complete or partial responses during the two-cycle treatment window in the first ten evaluable patients. Five patients had stable disease, and five progressed. Data for secondary endpoints including; time to tumor progression, time to treatment failure, and overall survival is reported. The safety profile of the treatment showed the combination was tolerable with two patients (11.8 %) having grade three nausea, and one (5.9 %) experiencing a grade four neutropenia, leading to permanent discontinuation from adjuvant treatment. Irinotecan plus temozolomide, although well tolerated did not improve outcome over historical controls in this setting.

Phase 1 and pharmacokinetic study of intravenous irinotecan in refractory solid tumor patients with hepatic dysfunction.

PURPOSE: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule. EXPERIMENTAL DESIGN: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 x institutional upper limit of normal (IULN) and ALT/AST

Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma.

OBJECTIVE: We conducted a retrospective analysis of two clinical trials in treatment-naïve patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT >18 months (longer DT) versus ≤18 months (shorter DT). PATIENTS AND METHODS: DT, objective response rate (ORR), tumor shrinkage, and overall survival (OS) were summarized for patients with longer and shorter DT. RESULTS: Overall, 152 patients (37.8%) had longer DT and 250 (62.2%) had shorter DT (median, 34.7 vs. 6.5 months, respectively). ORR in all 402 patients with advanced RCC was 43.5%. ORR was 75% for longer DT versus 24.4% for shorter DT (p < 0.0001). More patients with longer DT versus shorter DT had ≥10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p < 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment-related adverse events (AEs) grade ≥3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT. CONCLUSIONS: Longer duration (>18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS.

Real-World Treatment Patterns and Costs for Patients with Renal Cell Carcinoma Initiating Treatment with Sunitinib and Pazopanib.

BACKGROUND: Sunitinib and pazopanib are among the most prescribed targeted therapies for the systemic management of advanced renal cell carcinoma (RCC), but published cost comparisons between the 2 agents are few and limited by methodological and population differences. Also, sunitinib is administered on a 4-week on/2-week off cycle, and pazopanib is taken continuously. Thus, appropriate use and cost comparisons between the 2 drugs require methodological approaches to account for these differences. One way to accomplish this is to substitute expected for observed days supply. Recognizing the effects of nonrepresentative days supply values is important for assessing real-world treatment patterns and costs. OBJECTIVES: To (a) characterize demographic and clinical characteristics among patients with RCC newly initiating sunitinib or pazopanib, using a large administrative claims dataset; (b) characterize treatment patterns, persistence, and costs for each treatment group; and (c) assess the effect on treatment patterns and costs for sunitinib by substituting 42 days for prescriptions with 28- or 30-day supplies to account for sunitinib's 4-week on/2-week off dosing schedule. METHODS: This was a retrospective cohort study using health care claims data from the Truven MarketScan Research Databases, which include enrollment information and medical and pharmacy claims. Baseline patient demographic and clinical characteristics and treatment patterns (continuation, discontinuation, switching, or interruption; days supply; and persistence) were compared. Health care costs were calculated as mean daily index medication costs and as total, medical, and medication (all-cause and RCC-related) costs over the 12 months post-index period. Inclusion criteria were continuous health plan enrollment between 6 months pre-index and 12 months post-index; no RCC medications 6 months pre-index; ≥ 2 RCC diagnoses within ±180 days of index; and age ≥ 20 years. For demographic and clinical characteristics, treatment patterns, and costs, means (± standard deviations) for continuous data and relative frequencies for categorical data were reported. Chi-square tests or Student t-tests were used to evaluate differences other than costs. A generalized linear model with gamma distribution and log link was used for evaluating costs, controlling for patient demographic and pre-index clinical characteristics, persistence days, and index medication. All statistical tests were 2-tailed with significance set at P < 0.05 for all comparisons except for interactions with significance set at P < 0.10. The effects of substituting 42 days supply for sunitinib prescription records with 28 or 30 days supply were determined. RESULTS: In total, 609 (15.1% of the sunitinib overall sample) sunitinib patients and 183 (8.3% of the pazopanib overall sample) pazopanib patients were included. Demographic and clinical characteristics were similar for each treatment cohort. The persistence periods and number of prescriptions filled were also similar. Without substitution, significant differences were observed between treatment groups in patterns of index medication use (overall P = 0.0409), with fewer patients taking sunitinib continuing treatment than patients taking pazopanib. However, with substitution, treatment patterns differed significantly (overall P = 0.0026), but with more sunitinib patients than pazopanib patients continuing treatment. Without substitution, unadjusted daily mean index medication costs were significantly different for sunitinib ($216) versus pazopanib ($177, P < 0.0001). Substitution of sunitinib days supply eliminated the significant differences in daily index medication costs between treatment groups. The 1-year RCC-related and all-cause medication, medical, and total unadjusted costs were not significantly different between treatment groups, and substitution had no effect on these costs. After adjustment for possible confounding factors, these cost results were similar to those found with unadjusted analyses. CONCLUSIONS: In this study, patients with RCC who were initiating sunitinib and pazopanib had similar demographic and clinical characteristics and drug persistence patterns. The effect of substituting days supply values was demonstrated as an approach to considering differences in dosing cycles. Substitution significantly reduced sunitinib mean daily index medication costs and eliminated or reversed the direction of significant differences in costs between drugs during the persistence period. No significant differences were observed in unadjusted or adjusted 1-year costs. DISCLOSURES: This study was funded and conducted fully by Pfizer. All authors are employees of Pfizer. This work was presented in part as posters at the 2015 Genitourinary Cancers Symposium, of the American Society of Clinical Oncology; Rosen Shingle Creek, Orlando, FL; February 26-28, 2015, and the 20th Annual International Meeting of the International Society for Pharmacoeconomics and Outcomes Research; Philadelphia, PA; May 16-20, 2015. All authors contributed to study concept and design and to data interpretation. Mardekian was primarily responsible for data collection, along with Harnett. MacLean and Harnett worked on the manuscript, which was revised by MacLean and Mardekian.

Real-World Axitinib Use in the United States: A Retrospective Study Using Linked Datasets.

BACKGROUND: Axitinib is approved by the FDA for the treatment of advanced renal cell carcinoma (RCC) after failure of 1 previous systemic therapy and is distributed primarily through specialty pharmacies. Although the efficacy and safety of axitinib have been established in clinical trials, information from real-world populations will help to elucidate patients' clinical profiles and utilization patterns. Prescription records alone provide limited information on patient characteristics and other treatment experiences. Expansion of these data with information from medical claims databases should yield observational real-world data that may help to optimize therapy for patients with advanced RCC. OBJECTIVE: To link information from a specialty pharmacy database with information from medical and pharmacy claims databases to characterize real-world treatment patterns of axitinib as subsequent systemic therapy in patients with RCC in the United States. METHODS: This retrospective, observational, cohort study linked de-identified patient-level data from 22 specialty pharmacies that dispense axitinib with databases of longitudinal medical and pharmacy claims. Eligible patients had a diagnosis of RCC (> 1 claim for RCC defined as ICD-9-CM code 189.0), previously received > 1 systemic therapy, had the first prescription for axitinib dispensed between May 2012 and April 2013 (index), and had consistent claims reporting by pharmacies and physicians. All treatment data were used to calculate cycle, line of therapy, and duration of therapy; prescription data were used to determine axitinib dose modifications. Multivariate and logistic regression analyses were conducted to assess the effect of patient/prescriber characteristics on duration of axitinib therapy and dose modifications, respectively. RESULTS: In all, 1,175 patients met the study inclusion criteria and had data present in specialty pharmacy and claims databases. Most patients (74%) were male, and 68% were aged 55-74 years. Mean (SD) Charlson Comorbidity Index score was 2.7 (± 1.1); the most common comorbidity was hypertension (in 199 patients, 17%). Based on Rx-Risk-V, the most frequent concomitant conditions were pain (40%) and ischemic heart disease/hypertension (30%); the most frequent concomitant medications were antihypertensive medications (46%) and opiates (40%). Most prescribers (63%) were affiliated with an academic center, and all U.S. geographic regions were represented. In all, 847 patients (72%) had commercial insurance. Axitinib was prescribed as second-line therapy in 659 patients (56%), as third-line therapy in 326 patients (28%), and as fourth-line or later therapy in 190 patients (16%). In the overall population, mean (SD) duration of axitinib therapy was 168.6 (± 148.4) days. Axitinib treatment duration was 21 days longer in males than females (P = 0.013); 28 days longer in patients in the Northeast than in the Midwest or West (P = 0.010 and P = 0.016, respectively); and 26 days longer in patients receiving baseline hypothyroidism treatment (P = 0.004). In patients receiving second-line axitinib, the most common first-line therapy was sunitinib (56%), followed by pazopanib (16%) and everolimus (12%). Mean (SD) duration of second-line axitinib treatment was 172.3 (± 150.6) days and ranged from 127 days in patients who previously received temsirolimus to 196 days in those who previously received sorafenib. Of 1,025 patients who initiated axitinib at the standard 5 mg twice daily starting dose, 70% remained at this dose throughout treatment, whereas 10% had a dose increase. Younger age and gender (male) were associated with dose increases (OR = 0.958, 95% CI = 0.941-0.975 and OR = 0.573, 95% CI = 0.364-0.903, respectively). Baseline hypothyroidism treatment was associated with dose decreases and increases (OR = 1.662, 95% CI = 1.088-2.539 and OR = 2.149, 95% CI = 1.353-3.413, respectively). CONCLUSIONS: This analysis demonstrates the feasibility and utility of linking specialty pharmacy data to other longitudinal databases to better understand patient, provider, and reimbursement characteristics. These data provide insight into routine clinical use of axitinib as subsequent RCC therapy in the United States in the period following FDA approval, as well as additional information on sequencing of targeted agents in patients with advanced RCC. DISCLOSURES: This study was sponsored by Pfizer. MacLean and Cisar are employees of and hold stock in Pfizer. At the time of this analysis, Mehle, Eremina, and Quigley were employees of IMS Health who were paid consultants to Pfizer during the conduct of this study and in connection with the development of this manuscript. MacLean and Cisar contributed to study design and manuscript development. Mehle, Eremina, and Quigley contributed to study design, analysis, and manuscript development.

Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate.

PURPOSE: This phase III, randomized, open-label, multicenter study compared the overall survival associated with irinotecan plus gemcitabine (IRINOGEM) versus gemcitabine monotherapy (GEM) in patients with chemotherapy-naive, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: IRINOGEM patients received starting doses of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given weekly for 2 weeks every 3-week cycle. GEM patients received gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks (induction) and then weekly for 3 of 4 weeks. The primary end point of the trial was survival. Secondary end points included tumor response, time to tumor progression (TTP), changes in CA 19-9, and safety. RESULTS: In each arm, 180 randomly assigned patients comprised the intent-to-treat population evaluated for efficacy; 173 IRINOGEM and 169 GEM patients were treated. Median survival times were 6.3 months for IRINOGEM (95% CI, 4.7 to 7.5 months) and 6.6 months for GEM (95% CI, 5.2 to 7.8 months; log-rank P =.789). Tumor response rates were 16.1% (95% CI, 11.1% to 22.3%) for IRINOGEM and 4.4% (95% CI, 1.9% to 8.6%) for GEM (chi2 P <.001). Median TTP was 3.5 months for IRINOGEM versus 3.0 months for GEM (log-rank P =.352). However, subset analyses in patients with locally advanced disease suggested a TTP advantage with IRINOGEM versus GEM (median, 7.7 v 3.9 months). CA 19-9 progression was positively correlated with tumor progression. The incidence of grade 3 diarrhea was higher in the IRINOGEM group but grade 3 to 4 hematologic toxicities and quality-of-life outcomes were similar. CONCLUSION: IRINOGEM safely improved the tumor response rate compared with GEM but did not alter overall survival.

Phase I clinical and pharmacologic trial of intravenous estramustine phosphate.

PURPOSE: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP). PATIENTS AND METHODS: A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m(2). Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment. RESULTS: The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m(2), and cumulative fatigue developed after multiple cycles at 2,500 mg/m(2). Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 micromol/L after IV EMP doses greater-than-or-equal 2,000 mg/m(2). CONCLUSION: High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.

Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial.

Inhibitors of the vascular endothelial growth factor (VEGF) pathway frequently induce hypertension when used to treat patients with advanced renal cell carcinoma (RCC). This analysis characterizes hypertension and hypertension-related events in patients treated with the VEGF pathway inhibitors axitinib or sorafenib in the AXIS trial. AXIS was a randomized phase III study of axitinib versus sorafenib in patients with metastatic RCC following failure of one prior systemic regimen. Patients with uncontrolled hypertension were excluded, but patients with hypertension controlled with antihypertensive medication were allowed to participate. Guidelines for hypertension management included adjustment or addition of antihypertensive medications and/or axitinib or sorafenib dose reductions, interruptions, or discontinuations. Treatment-emergent all-causality hypertension occurred in 145 (40.4 %) axitinib-treated patients (N = 359) and 103 (29.0 %) sorafenib-treated patients (N = 355), with grade 3 hypertension reported in 55 (15.3 %) and 38 (10.7 %) patients, respectively, and grade 4 hypertension reported in one (0.3 %) patient in each arm. Hypertension-related events led to axitinib dose interruptions (n = 46; 12.8 %), dose reductions (n = 16; 4.5 %), or discontinuations (n = 1; 0.3 %). Approximately 50 % of axitinib-treated patients with grade 3 or 4 hypertension continued treatment for ≥ 9 months. Hypertension-related sequelae occurred in <1 % of axitinib-treated patients. Hypertension was more frequently observed during treatment with axitinib than sorafenib in patients with RCC, but axitinib-induced hypertension rarely led to treatment discontinuation or cardiovascular sequelae. Recommendations for monitoring blood pressure and managing hypertension during axitinib therapy are presented.

Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study.

BACKGROUND: This multicenter phase II study investigated temozolomide + irinotecan (TEMIRI) treatment in children with relapsed or refractory medulloblastoma. METHODS: Patients received temozolomide 100-125 mg/m(2)/day (days 1-5) and irinotecan 10 mg/m(2)/day (days 1-5 and 8-12) every 3 weeks. The primary endpoint was tumor response within the first 4 cycles confirmed ≥4 weeks and assessed by an external response review committee (ERRC). In a 2-stage Optimum Simon design, ≥6 responses in the first 15 evaluable patients were required within the first 4 cycles for continued enrollment; a total of 19 responses from the first 46 evaluable patients was considered successful. RESULTS: Sixty-six patients were treated. Seven responses were recorded during stage 1 and 15 in the first 46 ERRC evaluated patients (2 complete responses and 13 partial responses). The objective response rate during the first 4 cycles was 32.6% (95% confidence interval [CI], 19.5%-48.0%). Median duration of response was 27.0 weeks (7.7-44.1 wk). In 63 patients evaluated by local investigators, the objective response rate was 33.3% (95% CI, 22.0%-46.3%), and 68.3% (95% CI, 55.3%-79.4%) experienced clinical benefit. Median survival was 16.7 months (95% CI, 13.3-19.8). The most common grade 3 treatment-related nonhematologic adverse event was diarrhea (7.6%). Grade 3/4 treatment-related hematologic adverse events included neutropenia (16.7%), thrombocytopenia (12.1%), anemia (9.1%), and lymphopenia (9%). CONCLUSIONS: The planned study primary endpoint was not met. However, its tolerability makes TEMIRI a suitable candidate chemotherapy backbone for molecularly targeted agents in future trials in this setting.

Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer.

BACKGROUND: The prognostic potential of individual clinical and molecular parameters in stage II/III colon cancer has been investigated, but a thorough multivariable assessment of their relative impact is missing. METHODS: Tumors from patients (N = 1404) in the PETACC3 adjuvant chemotherapy trial were examined for BRAF and KRAS mutations, microsatellite instability (MSI), chromosome 18q loss of heterozygosity (18qLOH), and SMAD4 expression. Their importance in predicting relapse-free survival (RFS) and overall survival (OS) was assessed by Kaplan-Meier analyses, Cox regression models, and recursive partitioning trees. All statistical tests were two-sided. RESULTS: MSI-high status and SMAD4 focal loss of expression were identified as independent prognostic factors with better RFS (hazard ratio [HR] of recurrence = 0.54, 95% CI = 0.37 to 0.81, P = .003) and OS (HR of death = 0.43, 95% CI = 0.27 to 0.70, P = .001) for MSI-high status and worse RFS (HR = 1.47, 95% CI = 1.19 to 1.81, P < .001) and OS (HR = 1.58, 95% CI = 1.23 to 2.01, P < .001) for SMAD4 loss. 18qLOH did not have any prognostic value in RFS or OS. Recursive partitioning identified refinements of TNM into new clinically interesting prognostic subgroups. Notably, T3N1 tumors with MSI-high status and retained SMAD4 expression had outcomes similar to stage II disease. CONCLUSIONS: Concomitant assessment of molecular and clinical markers in multivariable analysis is essential to confirm or refute their independent prognostic value. Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone.

Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study.

PURPOSE: Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane. Now, with longer follow-up, a large number of non-breast cancer-related events have been reported. Exploratory analyses describe breast cancer-free survival (BCFS) and explore incidence and patterns of the different competing events. PATIENTS AND METHODS: Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) -positive and 547 with ER-unknown tumors. RESULTS: In all, 930 BCFS events have been reported (exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of 0.81 (95% CI, 0.71 to 0.92; P = .001) in favor of exemestane in the ER-positive/ER unknown group. Analysis partitioned at 2.5 years after random assignment showed that the on-treatment benefit of switching to exemestane (HR, 0.60; 95% CI, 0.48 to 0.75; P < .001) was not lost post-treatment, but that there was no additional gain once treatment had ceased (HR, 0.94; 95% CI, 0.80 to 1.10; P = .60). Improvement in overall survival was demonstrated, with 352 deaths in the exemestane group versus 405 deaths in the tamoxifen group (HR, 0.86; 95% CI, 0.75 to 0.99; P = .04). Of these, 222 were reported as intercurrent deaths (exemestane, 107; tamoxifen, 115). CONCLUSION: The protective effect of switching to exemestane compared with continuing on tamoxifen on risk of relapse or death was maintained for at least 5 years post-treatment and was associated with a continuing beneficial impact on overall survival.

Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.

PURPOSE: Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. RESULTS: KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10(-4)). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). CONCLUSION: In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.

PURPOSE The primary objective of this randomized, multicenter, phase III trial was to investigate whether the addition of irinotecan to the de Gramont infusional fluorouracil (FU)/leucovorin (LV) adjuvant regimen (LV5FU2) would improve disease-free survival (DFS) in patients with stage III colon cancer. PATIENTS AND METHODS After curatively intentioned surgery, patients with stage II and III colon cancer were randomly allocated surgery to receive LV5FU2 (LV 200 mg/m(2) as a 2-hour infusion, followed by FU; as a 400 mg/m(2) bolus and then a 600 mg/m(2) continuous infusion over 22 hours, days 1 and 2, every 2 weeks for 12 cycles: de Gramont regimen) with or without irinotecan (180 mg/m(2) as a 30- to 90-minute infusion, day 1, every 2 weeks). In total, 260 (7.9%) of 3,278 patients received an alternative high-dose infusional FU/LV regimen (Arbeitsgemeinschaft Internische Onkologie regimen) with or without irinotecan. Results The principal efficacy analysis was based on 2,094 treated patients with stage III disease, randomly allocated in the LV5FU2 strata. After a median follow-up of 66.3 months, the 5-year DFS rate was 56.7% with irinotecan/LV5FU2 and 54.3% with LV5FU2 alone (primary end point: log-rank P = .106). Combining irinotecan with LV5FU2 did not significantly improve overall survival in this patient group compared with LV5FU2 alone (5-year rate 73.6% v 71.3%, respectively; log-rank P = .094). The addition of irinotecan to LV5FU2 was associated with an increased incidence of grade 3 to 4 GI events and neutropenia. CONCLUSION Irinotecan added to LV5FU2 as adjuvant therapy did not confer a statistically significant improvement in DFS or overall survival in patients with stage III colon cancer compared with LV5FU2 alone.

Utility of Pretreatment Bilirubin Level and UGT1A1 Polymorphisms in Multivariate Predictive Models of Neutropenia Associated with Irinotecan Treatment in Previously Untreated Patients with Colorectal Cancer.

PURPOSE: Statistical models for predicting hematologic toxicity were evaluated based on UGT1A1 polymorphisms and baseline serum bilirubin. METHODS: Blood DNA samples were collected from 113 patients with untreated metastatic colorectal cancer receiving irinotecan (FOLFIRI, n = 36; mIFL, n = 41; CapeIRI, n = 36). The primary endpoint was absolute neutrophil count nadir during first treatment cycle. Linear regression models, with increased R(2) implying important additional predictive power, sequentially added age, sex, baseline bilirubin level, and UGT1A1 genotype. RESULTS: All models demonstrated low R(2), suggesting unaccounted variables. UGT1A1 genotype added approximately 8-9% during cycle 1 and from approximately 7% [mIFL regimen] to 26% [CapeIRI regimen] after cycle 1. Correlation between genotype and overall ANC nadir without regard to treatment was low (R = -0.201, P = 0.035). Patients with genotype 7/7 may have increased risk for severe neutropenia, but data are insufficient to characterize this. Contribution of baseline bilirubin level was negligible. CONCLUSIONS: Ability of UGT1A1 or baseline bilirubin to predict neutropenia is low and depends on regimen.

A phase II study of irinotecan in children with relapsed or refractory neuroblastoma: a European cooperation of the Société Française d'Oncologie Pédiatrique (SFOP) and the United Kingdom Children Cancer Study Group (UKCCSG).

PURPOSE: To evaluate the efficacy and safety of irinotecan in paediatric recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Thirty seven patients aged between 6 months and < or = 20 years, with relapsed or refractory neuroblastoma, received irinotecan at 600 mg/m(2) administered as a 60-min infusion, every 3 weeks. Tumour response was evaluated by conventional radiological and mIBG scans every two cycles. RESULTS: No objective response was observed during the study. Stable disease was observed in 13% of evaluable patients. Median times to progression and survival were 1.4 months (range, 1.2-1.5 months) and 8.8 months (range, 6.7-11.3 months), respectively. One forty two cycles were administered, with a median of two cycles per patient (range, 1-17 cycles). The most common grade 3-4 toxicities were neutropenia (65% of patients), anaemia (43%), thrombocytopenia (38%), vomiting (14%), abdominal pain or cramping (8%), and nausea (5%). CONCLUSION: Irinotecan administered intravenously as a single agent every 3 weeks induced no objective response in relapsed or refractory neuroblastoma.

Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group.

PURPOSE: This phase II study was designed to evaluate the efficacy of irinotecan administered intravenously once every 3 weeks in pediatric patients with recurrent or refractory rhabdomyosarcoma. PATIENTS AND METHODS: A total of 35 patients younger than age 20 years, with refractory or relapsed rhabdomyosarcoma for which standard treatments have failed, received irinotecan at 600 mg/m2 administered as a 60-minute infusion every 3 weeks. Concomitant treatments included atropine for cholinergic symptoms, loperamide for diarrhea at the first liquid stool, and preventive antiemetic treatment. Tumor response was assessed every two cycles until progression according to WHO criteria. RESULTS: The best overall response rate to irinotecan was 11.4% (95% CI, 3.2 to 26.7%; 2.9% complete responses, 8.5% partial responses) from all patients recruited. The median times to progression and survival were 1.4 and 5.8 months, respectively. A total of 112 cycles were administered, with a median number of two cycles per patient (range, 1 to 16). The most common grade 3/4 toxicities were neutropenia (46%), abdominal pain or cramping (17%), cholinergic syndrome (14%), nausea/vomiting (11%), anemia (11%), thrombocytopenia (9%), and diarrhea (6%). CONCLUSION: In heavily pretreated children with a high tumor burden who have been treated with multiagent chemotherapy, irinotecan administered intravenously as a single agent, at 600 mg/m2 every 3 weeks, showed an interesting objective response rate and a good tolerance profile in rhabdomyosarcoma.