bluuebunny/crossref_metadata_2025 huggingface dataset:
A retrospective analysis of data from two trials of sunitinib in patients with advanced renal cell carcinoma (RCC): Pitfalls of efficacy subgroup analyses based on dose-reduction status.
Authors: Khosravan Reza , Huang Xin , Wiltshire Robin , Lechuga Mariajose , Motzer Robert John
Published: February 2017

363

Background: Patients requiring sunitinib dose reduction who received a novel dose/schedule modification scheme had longer progression-free survival (PFS) than patients who did not require dose reduction and remained on 50 mg Schedule 4/2 (4 weeks on, 2 weeks off) (Bjarnason 2011). Our analysis compared sunitinib efficacy in advanced RCC patients with/without dose reduction using the label-approved, dose-reduction scheme (ie, 50 mg/37.5 mg/25 mg) and schedule (Schedule 4/2) and explored potential causes of any differences.

Methods: Data from a Phase 3 and a Phase 2 trial, sunitinib Schedule 4/2 arms only (N=375 and 146, respectively), were retrospectively analyzed, and pharmacokinetics and baseline characteristics of patients with/without dose reduction compared.

Results: In the Phase 3 trial, median (95% CI) PFS was 14.0 (13.1–16.2) months (mos) and 8.1 (6.3–10.6) mos with (n=194) and without (n=181) dose reduction, respectively. In the Phase 2 trial, corresponding PFS values were 13.4 (9.8–19.8) mos and 5.8 (3.9–8.5) mos (n=51 and 95, respectively). In the Phase 2 trial, steady-state mean (SD) total drug trough concentrations were 96.0 (42.2) ng/mL and 85.8 (43.4) ng/mL on Day 29 of Cycle 1 in patients with/without dose reduction, respectively. In both studies, the percent of patients with baseline Memorial Sloan-Kettering Cancer Center risk factors of 0 (favorable), 1–2 (intermediate), and 3 (poor) were 37–47%, 53–57% and 0–6% with dose reduction vs. 25–28%, 65–72%, and 0–10% without dose reduction. The mean (range) time to dose reduction was 7.2 (0.03–40.4) mos in the Phase 3 trial and 4.5 (0.4–22.6) mos in the Phase 2 trial.

Conclusions: Patients with dose reduction remaining on Schedule 4/2 appeared to have longer PFS than patients with no dose reduction. The differences were not caused by differences in plasma drug exposures; they appeared to be due, at least in part, to 1) differences in patients’ baseline prognostic factors and 2) patients’ PFS or longevity affecting their dose-reduction status. Thus, efficacy subgroup analysis based on patients’ dose-reduction status appears to be confounded, leading to biased results.
Correlation of germline MET mutation with response to the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Results from a multicenter phase II study (MET111644).
Authors: Srinivasan Ramaprasad , Bottaro Donald P. , Choueiri Toni K. , Vaishampayan Ulka N. , Rosenberg Jonathan E. , Logan Theodore , Harzstark Andrea Lynne , Rini Brian I. , Srinivas Sandy , Adams Laurel M. , Laubscher Kevin , Ottesen Lone Harild , McDermott David F. , Linehan W. Marston
Published: February 2017

372

Background: Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). Foretinib, an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors, was evaluated in a phase 2 study in pts with PRC. An important objective of this study was to evaluate whether activation of the MET receptor pathway by mutation, amplification, or gain of chromosome 7 was predictive for or correlated with clinical outcomes.

Methods: Pts were stratified based on status of MET pathway activation. Blood samples were collected at screening for determination of germline MET mutational status. Archival tumor tissue samples were obtained for the analysis of somatic MET mutation, amplification of the MET locus (7q31), and gain of chromosome 7 using standardized assays.

Results: A total of 74 pts were enrolled on the trial (37 each in intermittent and daily dosing arms); overall efficacy and safety data are reported separately at this meeting. Sixty-seven pts were evaluable for both mutation status and response. 5/10 pts (50%) with a germline MET mutation experienced a PR, while 5 pts (50%) had SD as their best response, including 4 pts who demonstrated tumor SLD reductions of > 10%, but did not achieve PR by RECIST 1.0. Responses were also seen in pts without germline MET mutation. However, the presence of a germline MET mutation was highly predictive of a response as only 5/57 pts (9%) without a mutation experienced a PR. Other measures of MET pathway activation did not appear to correlate with activity with only 1/5 pts (20%) with somatic MET mutation having a PR; furthermore, in the absence of a concomitant MET mutation, no responses were seen in patients with MET amplification (n=2) and only 1/18 (5%) pts with a gain of chromosome 7 experienced a PR.

Conclusions: The presence of germline MET mutations correlated strongly with activity of the MET inhibitor foretinib in pts with PRC. These data provide early proof of principle that MET may be a valid therapeutic target in a subset of patients with PRC.
Plasma cytokines and angiogenic factors (CAFs) associated with risk of recurrence and tumor dependence in patients (pts) with nonmetastatic renal cell carcinoma (RCC).
Authors: Zurita Amado J. , Khajavi Mehrdad , Wang Xuemei , Wood Christopher G. , Matin Surena F. , Fiorentino Stefania , McKee Kathryn S. , Tran Hai T. , Heymach John , Jonasch Eric
Published: February 2017

383

Background: Although recent years have brought great progress into understanding the pathogenesis of RCC and multiple promising biomarkers, no tumor tissue or blood-based test has yet been validated for clinical use. The main objectives of this exploratory analysis were to identify CAFs predictive of recurrence in RCC pts, and to gain insight into tumor dependency of individual factors by comparing CAFs pre- and post-nephrectomy (Nx).

Methods: Plasma samples were obtained before and up to 1 year after Nx from pts with sporadic, non-metastatic renal masses suspicious for RCC (n=73). Upon Nx, 52 pts showed dominant clear cell histology and 11 non-clear cell; 10 pts had non-cancerous lesions. RCC pts were categorized by risk of relapse based on pathologic staging (pT1/pT2 as low-risk [LR], n=38; pT3/pT4 as high-risk [HR], n=25). Multiplex bead suspension arrays and ELISA were used to measure concentrations of 58 CAFs including angiogenesis and invasion mediators (VEGF, VEGF-C, soluble CAIX [sCA9], hepatocyte growth factor and transforming growth factor-b1, among others), and multiple inflammatory and/or immunomodulatory chemokines and interleukins (IL). t-test and Wilcoxon signed rank or rank-sum tests were respectively used to assess changes in CAFs between pre- and post-Nx or to compare CAFs between subgroups of pts.

Results: Of 58 pre-Nx CAFs available in RCC pts, the concentrations of IL-8, granulocyte-colony stimulating factor, stromal cell-derived factor-1, and osteopontin, among others, were significantly higher in HR vs. LR-RCC (all P<0.01). In pts with clear cell RCC, sCA9 was also higher (P=0.004). A number of CAFs significantly decreased post-Nx, including sCA9, endoglin, and e-selectin, while others increased, such as stem cell factor, IL-12, and vascular cell adhesion molecule-1. The pre-Nx concentrations of e-selectin were lower in pts with eventual disease recurrence (P=0.008).

Conclusions: We identified pre-Nx CAFs associated with risk for recurrence, and post-Nx changes related to the presence of the tumor in pts with non-metastatic RCC. If validated in a larger study, these CAFs could be used for risk stratification of RCC pts.
Radium-223 chloride impact on skeletal-related events in patients with castration-resistant prostate cancer (CRPC) with bone metastases: A phase III randomized trial (ALSYMPCA).
Authors: Sartor A. Oliver , Heinrich Daniel , Helle Svein Inge , O'Sullivan Joe M. , Fossa Sophie D. , Chodacki Ales , Demkow Tomasz , Logue John P. , Seke Mihalj , Widmark Anders , Johannessen Dag Clement , Nilsson Sten , Hoskin Peter , Solberg Arne , James Nicholas David , Syndikus Isabel , Vogelzang Nicholas J. , O'Bryan-Tear C. Gillies , Shan Minghua , Parker Chris
Published: February 2017

9

Background: Radium-223 chloride (Ra-223) is a 1st-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included skeletal-related events (SREs).

Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‐223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use.

Results: 922 pts (Ra-223, n = 615; pbo, n = 307) were randomized from 6/2008-2/2011. Based on data from a planned interim analysis (n = 809), unblinded June 2011, Ra-223 significantly improved OS in pts with CRPC with bone mets vs pbo (median OS 14.0 vs 11.2 mo, respectively; two-sided P = 0.00185; HR = 0.695; 95% CI, 0.552-0.875). SREs were lower in the Ra-223 vs pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo vs 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807).

Conclusions: Ra-223 significantly delayed time to 1st SRE and SRE components, except surgical intervention. These reductions in SREs, particularly SCC, are noteworthy. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets.

[Table: see text]
Is docetaxel-prednisone (DP) feasible in frail elderly (age 75 or older) patients with castration-resistant metastatic prostate cancer (CRMPC)? GERICO10-GETUG P03 trial: A trial from elderly and genitourinary oncology UNICANCER groups.
Authors: Mourey Loic , Sevin Emmanuel , Latorzeff Igor , Houede Nadine , Meunier Jérome , Priou Frank , Gravis Gwenaelle , Carola Elisabeth , Orsini Christine , Filleron Thomas
Published: February 2017

93

Background: Standard treatment of CRMPC is DP 75 mg/m² every 3 weeks since a symptomatic and overall survival benefit was demonstrated. Little is known about feasibility of DP in unselected elderly patients (day to day practice).

Methods: Randomized phase II study evaluating prospectively the feasibility of DP administered every 3 weeks (60 mg / m² C1 then 70 mg / m² for subsequent cycles) or weekly (35mg/m² D1D8 with Day 1 = Day 21) in patients ≥75 years old, evaluated by comprehensive geriatric assessment, belonging to group 2 “vulnerable” or to group 3 “frail” of the classification proposed by the International Society of Geriatric Oncology (SIOG). Feasibility is defined as the possibility for a patient to receive 6 cycles of chemotherapy without fulfilling the criteria for withdrawal from study defined “a priori” by GERICO group: - stop or delay chemotherapy > 2 weeks - necessity to reduce chemotherapy dose > 25% - febrile neutropenia or NCI CTC grade III non-haematological toxicity (except alopecia) - loss of autonomy ( Activity of Daily Living (ADL) decrease≥2 points) →geriatric criterion It is a double randomized phase II based on a Simon’s optimum two stage design for each strata defined according to the SIOG criteria (α = 5%, 1-β = 90 %, p0 = 0.70 and p1 = 0.90). A pharmacokinetic / pharmacodynamic study (method of population pharmacokinetics) and pharmacogenetic study of PXR (pregnane X receptor) CYP3A4 and CYP3A5) are planed.

Results: 25 centers participate to the study (23 opened). 10 centers have included 22 patients (16 “vulnerable” and 6 “frail”) from December 2010 until now.

Conclusions: The results of this study will support the prescription of chemotherapy and its modalities, in patients aged 75 and over, classified as “vulnerable” or “frail” according to SIOG criteria, after comprehensive geriatric assessment.
Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy
Authors: Zardavas Dimitrios , Suter Thomas M. , Van Veldhuisen Dirk J. , Steinseifer Jutta , Noe Johannes , Lauer Sabine , Al-Sakaff Nedal , Piccart-Gebhart Martine J. , de Azambuja Evandro
Published: February 2017

Purpose

Women receiving trastuzumab with chemotherapy are at risk for trastuzumab-related cardiac dysfunction (TRCD). We explored the prognostic value of cardiac markers (troponins I and T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) to predict baseline susceptibility to develop TRCD. We examined whether development of cardiac end points or significant left ventricular ejection fraction (LVEF) drop was associated with markers’ increases.

Patients and Methods

Cardiac marker assessments were coupled with LVEF measurements at different time points for 533 patients from the Herceptin Adjuvant (HERA) study who agreed to participate in this study. Patients with missing marker assessments were excluded, resulting in 452 evaluable patients. A primary cardiac end point was defined as symptomatic congestive heart failure of New York Heart Association class III or IV, confirmed by a cardiologist, and a significant LVEF drop, or death of definite or probable cardiac causes. A secondary cardiac end point was defined as a confirmed significant asymptomatic or mildly symptomatic LVEF drop.

Results

Elevated baseline troponin I (> 40 ng/L) and T (> 14 ng/L), occurring in 56 of 412 (13.6%) and 101 of 407 (24.8%) patients, respectively, were associated with an increased significant LVEF drop risk (univariate analysis: hazard ratio, 4.52; P < .001 and hazard ratio, 3.57; P < .001, respectively). Few patients had their first elevated troponin value recorded during the study (six patients for troponin I and 25 patients for troponin T). Two patients developed a primary and 31 patients a secondary cardiac end point (recovery rate of 74%, 23 of 31). For NT-proBNP, higher increases from baseline were seen in patients with significant LVEF drop.

Conclusion

Elevated troponin I or T before trastuzumab is associated with increased risk for TRCD. A similar conclusion for NT-proBNP could not be drawn because of the lack of a well-established elevation threshold; however, higher increases from baseline were seen in patients with TRCD compared with patients without.
Management of Obesity
Authors: Alamuddin Naji , Bakizada Zayna , Wadden Thomas A.
Published: February 2017

This review examines weight loss and accompanying improvements in obesity-related comorbidities produced by intensive lifestyle intervention, pharmacotherapy, and bariatric surgery. Obese individuals lose approximately 6 to 8 kg (approximately 6% to 8% of initial weight) with 6 months of participation in a high-intensity lifestyle intervention (≥ 14 treatment visits) consisting of diet, physical activity, and behavior therapy. Such losses reduce progression to type 2 diabetes in at-risk people and decrease blood pressure and triglyceride levels. All diets, regardless of macronutrient composition, can produce clinically meaningful weight loss (> 5%) if they induce a deficit ≥ 500 kcal/d. Physical activity of 150 to 180 min/wk yields modest short-term weight loss compared with diet but contributes to improvements in obesity-related conditions. Gradual weight regain is common after lifestyle intervention but can be prevented by continued participation in monthly weight loss maintenance sessions, as well as by high levels of physical activity (ie, 200 to 300 min/wk). Patients unable to reduce satisfactorily with lifestyle intervention may be candidates for pharmacotherapy, recommended as an adjunct. Five medications have been approved by the US Food and Drug Administration for chronic weight management, and each has its own risk/benefit profile. The addition of these medications to lifestyle intervention increases mean weight loss by 2.5 to 8.9 kg compared with placebo. Patients with severe obesity who are unable to reduce successfully with lifestyle intervention and pharmacotherapy are eligible for bariatric surgery, including Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding. The first two procedures yield long-term (≥ 3 years) reductions of ≥ 20% of initial weight that are associated with decreases in morbidity and potentially mortality. Greater resources and dissemination efforts are needed to increase the availability of these three approaches for the millions of Americans who would benefit from them.
Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia WithNPM1Mutation: A Study by the Acute Leukemia French Association Group
Authors: Balsat Marie , Renneville Aline , Thomas Xavier , de Botton Stéphane , Caillot Denis , Marceau Alice , Lemasle Emilie , Marolleau Jean-Pierre , Nibourel Olivier , Berthon Céline , Raffoux Emmanuel , Pigneux Arnaud , Rodriguez Céline , Vey Norbert , Cayuela Jean-Michel , Hayette Sandrine , Braun Thorsten , Coudé Marie Magdeleine , Terre Christine , Celli-Lebras Karine , Dombret Hervé , Preudhomme Claude , Boissel Nicolas
Published: February 2017

Purpose

This study assessed the prognostic impact of postinduction NPM1-mutated ( NPM1m) minimal residual disease (MRD) in young adult patients (age, 18 to 60 years) with acute myeloid leukemia, and addressed the question of whether NPM1m MRD may be used as a predictive factor of allogeneic stem cell transplantation (ASCT) benefit.

Patients and Methods

Among 229 patients with NPM1m who were treated in the Acute Leukemia French Association 0702 (ALFA-0702) trial, MRD evaluation was available in 152 patients in first remission. Patients with nonfavorable AML according to the European LeukemiaNet (ELN) classification were eligible for ASCT in first remission.

Results

After induction therapy, patients who did not achieve a 4-log reduction in NPM1m peripheral blood-MRD (PB-MRD) had a higher cumulative incidence of relapse (subhazard ratio [SHR], 5.83; P < .001) and a shorter overall survival (OS; hazard ratio [HR], 10.99; P < .001). In multivariable analysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log reduction in PB-MRD were significantly associated with a higher relapse incidence and shorter OS. In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognostic value. In these patients with nonfavorable AML according to European LeukemiaNet, disease-free survival and OS were significantly improved by ASCT in those with a < 4-log reduction in PB-MRD. This benefit was not observed in those with a > 4-log reduction in PB-MRD, with a significant interaction between ASCT effect and PB-MRD response ( P = .024 and .027 for disease-free survival and OS, respectively).

Conclusion

Our study supports the strong prognostic significance of early NPM1m PB-MRD, independent of the cytogenetic and molecular context. Moreover, NPM1m PB-MRD may be used as a predictive factor for ASCT indication.
Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months
Authors: Leijen Suzanne , van Geel Robin M.J.M. , Sonke Gabe S. , de Jong Daphne , Rosenberg Efraim H. , Marchetti Serena , Pluim Dick , van Werkhoven Erik , Rose Shelonitda , Lee Mark A. , Freshwater Tomoko , Beijnen Jos H. , Schellens Jan H.M.
Published: February 2017

Purpose

AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)–mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies.

Patients and Methods

Patients were treated with carboplatin (area under the curve, 5 mg/mL⋅min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression.

Results

AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff.

Conclusion

To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development.
Association Between Out-Of-Pocket Costs, Race/Ethnicity, and Adjuvant Endocrine Therapy Adherence Among Medicare Patients With Breast Cancer
Authors: Farias Albert J. , Du Xianglin L.
Published: February 2017

Purpose

Previous studies suggest that adherence to adjuvant endocrine therapy (AET) for patients with breast cancer is suboptimal, especially among minorities, and is associated with out-of-pocket medication costs. This study aimed to determine whether there are racial/ethnic differences in 1-year adherence to AET and whether out-of-pocket costs explain the racial/ethnic disparities in adherence.

Methods

This retrospective cohort study used the SEER-Medicare linked database to identify patients ≥ 65 years of age with hormone receptor–positive breast cancer who were enrolled in Medicare Part D from 2007 to 2009. The cohort included non-Hispanic whites, blacks, Hispanics, and Asians. Out-of-pocket costs for AET medications were standardized for a 30-day supply. Adherence to tamoxifen, aromatase inhibitors (AIs), and overall AET (tamoxifen or AIs) was assessed using the medication possession ratio (≥ 80%) during the 12-month period.

Results

Of 8,688 patients, 3,197 (36.8%) were nonadherent to AET. Out-of-pocket costs for AET medication were associated with lower adjusted odds of adherence for all four cost categories compared with the lowest category of ≤ $2.65 ( P < .01). In the univariable analysis, Hispanics had higher odds of adherence to any AET at initiation (OR, 1.30; 95% CI, 1.07 to 1.57), and blacks had higher odds of adherence to AIs at initiation (OR, 1.27; 95% CI, 1.04 to 1.54) compared with non-Hispanic whites. After adjusting for copayments, poverty status, and comorbidities, the association was no longer significant for Hispanics (OR, 0.95; 95% CI, 0.78 to 1.17) or blacks (OR, 0.96; 95% CI, 0.77 to 1.19). Blacks had significantly lower adjusted odds of adherence than non-Hispanic whites when they initiated AET therapy with tamoxifen (OR, 0.54; 95% CI, 0.31 to 0.93) after adjusting for socioeconomic, clinic, and prognostic factors.

Conclusion

Racial/ethnic disparities in AET adherence were largely explained by women's differences in socioeconomic status and out-of-pocket medication costs.
Obesity and Other Cancers
Authors: Yang Lin , Drake Bettina F. , Colditz Graham A.
Published: February 2017

Purpose

Evidence on overweight, obesity, and an increased risk of cancer continues to accumulate and was updated in the 2016 handbook on weight control from the International Agency for Research on Cancer (IARC). The underlying primary data, together with dose-response meta-analysis and, finally, pooled analysis of individual participant data, add insight into the relation between obesity and cancer risk and prognosis. We summarize the evidence for mortality from prostate cancer, hematologic malignancies, and kidney cancer.

Methods

We reviewed pooled analysis of rare end points across cohorts, regardless of primary results reported from the individual studies, further reducing risk of publication bias. Of these cancer sites, only kidney cancer was included in the IARC 2002 report, although mortality from prostate cancer and hematologic malignancies was noted in the American Cancer Society prospective cohort study in 2003. The 2016 update from the IARC added details for prostate and hematologic malignancies, classifying the evidence as sufficient to conclude that avoiding excess body fatness lowers the risk of multiple myeloma but found that the evidence for it lowering the risk of prostate cancer mortality or diffuse large B-cell lymphoma was limited.

Results

A higher body mass index is associated with an increased risk of advanced prostate cancer and prostate cancer mortality and is associated with worse survival in most subtypes of hematologic malignancies, in a dose-response fashion. Evidence for kidney cancer is built mostly on retrospective data, which supports an obesity paradox in patients with the clear cell variant; however, population-based cohort data indicate that a higher cohort-entry body mass index is associated with worse kidney cancer–specific survival.

Conclusion

Together, these data add support to the evidence for a growing cancer burden caused by adiposity in both early adult and later adult life, yet leave open the question of the means of weight management after diagnosis as a strategy to improve survival.
Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems
Authors: Adam Mohamed Abdelgadir , Thomas Samantha , Hyslop Terry , Scheri Randall P. , Roman Sanziana A. , Sosa Julie A.
Published: February 2017

Purpose

Patient age is considered to play a unique prognostic role in papillary thyroid cancer (PTC), with a distinct staging dichotomization at 45 years of age. This is based on older, limited data demonstrating a marked rise in mortality around the ages of 40 to 50 years. We hypothesized that age is associated with compromised survival from cancer, with no cutoff denoting survival difference.

Patients and Methods

Patients with PTC who had surgery were identified from the SEER database (1998 to 2012). Multivariable proportional hazards modeling utilizing several flexible smoothing approaches were used to examine the association between age and cancer-specific survival (CSS) and to determine whether there is an age cut point that is associated with CSS decrement.

Results

A total of 31,802 patients with PTC were included. Median age was 45 years (range, 2 to 105 years). Ten-year CSS according to age was as follows: 2 to 19 years, 99.8%; 20 to 29 years, 99.9%; 30 to 39 years, 99.8%; 40 to 49 years, 99.5%; 50 to 59 years, 98.1%; 60 to 69 years, 94.8%; 70 to 79 years, 91.5%; 80 to 89 years, 79.2%; and ≥ 90 years, 73.9%. After adjustment for patient demographic and clinicopathologic characteristics, increasing age was associated with increasing mortality from the disease in a dose-dependent fashion, without an apparent cut point. Each of the smoothing approaches demonstrated a similar linearity of risk over all ages and provided close measures of goodness of fit to the data.

Conclusion

Patient age is significantly associated with death from PTC in a linear fashion, without an apparent age cut point demarcating survival difference. These results challenge the appropriateness of a patient age cut point in current staging systems for PTC and argue for considering a revision in how we anticipate prognosis for patients with PTC.
Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome
Authors: Kulke Matthew H. , Hörsch Dieter , Caplin Martyn E. , Anthony Lowell B. , Bergsland Emily , Öberg Kjell , Welin Staffan , Warner Richard R.P. , Lombard-Bohas Catherine , Kunz Pamela L. , Grande Enrique , Valle Juan W. , Fleming Douglas , Lapuerta Pablo , Banks Phillip , Jackson Shanna , Zambrowicz Brian , Sands Arthur T. , Pavel Marianne
Published: February 2017

Purpose

Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting.

Patients and Methods

Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg.

Results

Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were –0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were –0.9, –1.7, and –2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment.

Conclusion

Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.
Italian, Multicenter, Phase III, Randomized Study of Cisplatin Plus Etoposide With or Without Bevacizumab as First-Line Treatment in Extensive-Disease Small-Cell Lung Cancer: The GOIRC-AIFA FARM6PMFJM Trial
Authors: Tiseo Marcello , Boni Luca , Ambrosio Francesca , Camerini Andrea , Baldini Editta , Cinieri Saverio , Brighenti Matteo , Zanelli Francesca , Defraia Efisio , Chiari Rita , Dazzi Claudio , Tibaldi Carmelo , Turolla Gianni Michele , D’Alessandro Vito , Zilembo Nicoletta , Trolese Anna Rita , Grossi Francesco , Riccardi Ferdinando , Ardizzoni Andrea
Published: February 2017

Purpose

Considering promising results in phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line cisplatin plus etoposide for treatment of extensive-disease (ED) small-cell lung cancer (SCLC).

Patients and Methods

Treatment-naive patients with ED-SCLC were randomly assigned to receive either cisplatin plus etoposide (arm A) or the same regimen with bevacizumab (arm B) for a maximum of six courses. In the absence of progression, patients in arm B continued bevacizumab alone until disease progression or for a maximum of 18 courses. The primary end point was overall survival (OS).

Results

Two hundred four patients were randomly assigned and considered in intent-to-treat analyses (103 patients in arm A and 101 patients in arm B). At a median follow-up of 34.9 months in arm A and arm B, median OS times were 8.9 and 9.8 months, and 1-year survival rates were 25% and 37% (hazard ratio, 0.78; 95% CI, 0.58 to 1.06; P = .113), respectively. A statistically significant effect of bevacizumab on OS in patients who received maintenance was seen (hazard ratio, 0.60; 95% CI, 0.40 to 0.91; P = .011). Median progression-free survival times were 5.7 and 6.7 months in arm A and arm B, respectively ( P = .030). Regarding hematologic toxicity, no statistically significant differences were observed; for nonhematologic toxicity, only hypertension was more frequent in arm B (grade 3 or 4, 1.0% v 6.3% in arms A v B, respectively; P = .057).

Conclusion

The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in progression-free survival, which, however, did not translate into a statistically significant increase in OS. Further research with novel antiangiogenic agents, particularly in the maintenance setting, is warranted.
Androgen Deprivation Therapy and the Risk of Dementia in Patients With Prostate Cancer
Authors: Khosrow-Khavar Farzin , Rej Soham , Yin Hui , Aprikian Armen , Azoulay Laurent
Published: February 2017

Purpose

Recent observational studies have associated the use of androgen deprivation therapy (ADT) with an increased risk of dementia and Alzheimer’s disease, but these studies had limitations. The objective of this study was to determine whether the use of ADT is associated with an increased risk of dementia, including Alzheimer’s disease, in patients with prostate cancer.

Patients and Methods

Using the United Kingdom’s Clinical Practice Research Datalink, we assembled a cohort of 30,903 men newly diagnosed with nonmetastatic prostate cancer between April 1, 1988 and April 30, 2015, and observed them until April 30, 2016. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% CIs of dementia associated with the use of ADT compared with nonuse. ADT exposure was lagged by 1 year to account for delays associated with the diagnosis of dementia and to minimize reverse causality. Secondary analyses assessed whether the risk varied with cumulative duration of use and by ADT type.

Results

During a mean (standard deviation) follow-up of 4.3 (3.6) years, 799 patients were newly diagnosed with dementia (incidence, 6.0; 95% CI, 5.6 to 6.4) per 1,000 person-years. Compared with nonuse, ADT use was not associated with an increased risk of dementia (incidence, 7.4 v 4.4 per 1,000 person-years, respectively; adjusted hazard ratio, 1.02; 95% CI, 0.87 to 1.19). In secondary analyses, cumulative duration of use ( P for heterogeneity = .78) and no single type of ADT were associated with an increased risk of dementia.

Conclusion

In this population-based study, the use of ADT was not associated with an increased risk of dementia. Additional studies in different settings are needed to confirm these findings.
Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials
Authors: Cuzick Jack , Brentnall Adam R. , Segal Corrinne , Byers Helen , Reuter Caroline , Detre Simone , Lopez-Knowles Elena , Sestak Ivana , Howell Anthony , Powles Trevor J. , Newman William G. , Dowsett Mitchell
Published: February 2017

Purpose

At least 94 common single nucleotide polymorphisms (SNPs) are associated with breast cancer. The extent to which an SNP panel can refine risk in women who receive preventive therapy has not been directly assessed previously.

Materials and Methods

A risk score on the basis of 88 SNPs (SNP88) was investigated in a nested case-control study of women enrolled in the International Breast Intervention Study (IBIS-I) or the Royal Marsden study. A total of 359 women who developed cancer were matched to 636 controls by age, trial, follow-up time, and treatment arm. Genotyping was done using the OncoArray. Conditional logistic regression and matched concordance indices (mC) were used to measure the performance of SNP88 alone and with other breast cancer risk factors assessed using the Tyrer-Cuzick (TC) model.

Results

SNP88 was predictive of breast cancer risk overall (interquartile range odds ratio [IQ-OR], 1.37; 95% CI, 1.14 to 1.66; mC, 0.55), but mainly for estrogen receptor–positive disease (IQ-OR, 1.44; 95% CI, 1.16 to 1.79; P for heterogeneity = .10) versus estrogen receptor–negative disease. However, the observed risk of SNP88 was only 46% (95% CI, 19% to 74%) of expected. No significant interaction was observed with treatment arm (placebo IQ-OR, 1.46; 95% CI, 1.13 to 1.87; tamoxifen IQ-OR, 1.25; 95% CI, 0.96 to 1.64; P for heterogeneity = .5). The predictive power was similar to the TC model (IQ-OR, 1.45; 95% CI, 1.21 to 1.73; mC, 0.55), but SNP88 was independent of TC (Spearman rank-order correlation, 0.012; P = .7), and when combined multiplicatively, a substantial improvement was seen (IQ-OR, 1.64; 95% CI, 1.36 to 1.97; mC, 0.60).

Conclusion

A polygenic risk score may be used to refine risk from the TC or similar models in women who are at an elevated risk of breast cancer and considering preventive therapy. Recalibration may be necessary for accurate risk assessment.
Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study
Authors: Borgquist Signe , Giobbie-Hurder Anita , Ahern Thomas P. , Garber Judy E. , Colleoni Marco , Láng István , Debled Marc , Ejlertsen Bent , von Moos Roger , Smith Ian , Coates Alan S. , Goldhirsch Aron , Rabaglio Manuela , Price Karen N. , Gelber Richard D. , Regan Meredith M. , Thürlimann Beat
Published: February 2017

Purpose

Cholesterol-lowering medication (CLM) has been reported to have a role in preventing breast cancer recurrence. CLM may attenuate signaling through the estrogen receptor by reducing levels of the estrogenic cholesterol metabolite 27-hydroxycholesterol. The impact of endocrine treatment on cholesterol levels and hypercholesterolemia per se may counteract the intended effect of aromatase inhibitors.

Patients and Methods

The Breast International Group (BIG) conducted a randomized, phase III, double-blind trial, BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor–positive invasive breast cancer from 1998 to 2003. Systemic levels of total cholesterol and use of CLM were measured at study entry and every 6 months up to 5.5 years. Cumulative incidence functions were used to describe the initiation of CLM in the presence of competing risks. Marginal structural Cox proportional hazards modeling investigated the relationships between initiation of CLM during endocrine therapy and outcome. Three time-to-event end points were considered: disease-free-survival, breast cancer–free interval, and distant recurrence–free interval.

Results

Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen-letrozole (n = 189), letrozole-tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer–free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence–free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03).

Conclusion

Cholesterol-lowering medication during adjuvant endocrine therapy may have a role in preventing breast cancer recurrence in hormone receptor–positive early-stage breast cancer. We recommend that these observational results be addressed in prospective randomized trials.
Genomics of Multiple Myeloma
Authors: Robiou du Pont Sebastien , Cleynen Alice , Fontan Charlotte , Attal Michel , Munshi Nikhil , Corre Jill , Avet-Loiseau Hervé
Published: February 2017

Multiple myeloma (MM) is characterized by wide variability in the chromosomal/genetic changes present in tumor plasma cells. Genetically, MM can be divided into two groups according to ploidy and hyperdiploidy versus nonhyperdiploidy. Several studies in gene expression profiling attempted to identify subentities in MM without convincing results. These studies mostly confirmed the cytogenetic data and subclassified patients according to 14q32 translocations and ploidy. More-recent data that are based on whole-exome sequencing have confirmed this heterogeneity and show many gene mutations but without a unifying mutation. These newer studies have shown the frequent alteration of the mitogen-activated protein kinase pathway. The most interesting data have demonstrated subclonality in all patients with MM, including subclonal mutations of supposed driver genes KRAS, NRAS, and BRAF.
Global Use of Traditional and Complementary Medicine in Childhood Cancer: A Systematic Review
Authors: Diorio Caroline , Lam Catherine G. , Ladas Elena J. , Njuguna Festus , Afungchwi Glenn M. , Taromina Katherine , Marjerrison Stacey
Published: February 2017

Purpose

Traditional and complementary medicine (T&CM) strategies are commonly used in pediatric oncology. Patterns may vary based on country income. We systematically reviewed published studies describing T&CM use among pediatric oncology patients in low-income countries (LIC/LMIC), middle-income countries (UMIC), and high-income countries (HIC). Objectives included describing estimated prevalence of use, reasons for use, perceived effectiveness, modalities used, rates of disclosure, and reporting of delayed or abandoned treatment.

Methods

MEDLINE, EMBASE, Global Health, CINAHL, PsycINFO, Allied and Complementary Medicine Database, Cochrane Database of Systematic Reviews, and ProceedingsFirst were searched. Inclusion criteria were primary studies involving children younger than the age of 18 years, undergoing active treatment of cancer, and any T&CM use. Exclusion criteria included no pediatric oncology–specific outcomes and studies involving only children off active treatment. Data were extracted by two reviewers using a systematic data extraction form determined a priori.

Results

Sixty-five studies published between 1977 and 2015 were included, representing 61 unique data sets and 7,219 children from 34 countries. The prevalence of T&CM use ranged from 6% to 100%. Median rates of use were significantly different in LIC/LMIC (66.7% ± 19%), UMIC (60% ± 26%), and HIC (47.2% ± 20%; P = .02). Rates of disclosure differed significantly by country income, with higher median rates in HIC. Seven studies reported on treatment abandonment or delays.

Conclusion

The use of T&CM in pediatric oncology is common worldwide, with higher median prevalence of use reported in LIC/LMIC. Further research is warranted to examine the impact on treatment abandonment and delay.
Potential Obstacles in the Acquisition of Oral Anticancer Medications
Authors: Niccolai Jennifer L. , Roman Danielle L. , Julius Justin M. , Nadour Rachelle W.
Published: February 2017

Purpose:

To determine the amount of time elapsed between prescriber order and patient receiving oral anticancer medication.

Patients and Methods:

Adult patients with a diagnosis of cancer were prospectively identified in three outpatient oncology clinics when oral anticancer agents were prescribed during a 4-month observation period. For each patient, time to obtain medication was analyzed by the following time points: date of prescription, date of submission to insurance, date prior authorization was obtained, date financial assistance was received, date prescription was processed by pharmacy, and date patient received medication. Out-of-pocket cost and time spent by clinic staff to facilitate the medication acquisition process were recorded.

Results:

Thirty-four patients were prescribed oral anticancer medication during the data collection period. For the 27 patients who were eligible for the primary end point, medication acquisition required a median of 10 days (range, 3 to 28 days). Overall, the rate-limiting step for medication acquisition was processing by the pharmacy, with a median of 6 days (range, 1 to 27 days). Most patients’ prescription insurance plan covered a portion of medication cost, and the majority of patients considered their out-of-pocket expense to be affordable. Clinic staff spent a median of 2 hours per prescription to facilitate medication acquisition.

Conclusion:

Patients may encounter process barriers in acquiring oral therapy, particularly because of pharmacy processing time, as well as high copays. Time to treatment initiation may have implications for patients’ clinical outcomes. Adequate staff with dedicated time to facilitate this process should be used in the ambulatory oncology practice setting.
Drug Interaction Database Sensitivity With Oral Antineoplastics: An Exploratory Analysis
Authors: Bossaer John B. , Thomas Christan M.
Published: February 2017

Purpose:

Drug interactions are a concern in oncology with the shift toward oral antineoplastics (OAs). Using electronic databases to screen for drug interactions with OAs is a common practice. There is little literature to guide clinicians on the reliability of these systems with OAs. The primary objective of this study was to explore the sensitivity of commonly available drug interaction databases in detecting drug interactions with OAs.

Methods:

A list of 20 drug interactions with OAs was developed by two Board-certified oncology pharmacists. The list included multiple types of drug interactions. The sensitivity in detecting these interactions by MicroMedex, Facts & Comparisons, Lexi-Interact, and Epocrates were evaluated. These databases were chosen based on their local availability and widespread use in practice. Drugs.com was evaluated as a surrogate for a patient-accessible drug interaction database. The Cochran Q test was used to assess the sensitivity distribution across the five groups.

Results:

Lexi-Interact and Drugs.com had a sensitivity of 95% for the 20 tested drug interaction pairs. Epocrates had a sensitivity of 90%, and both Micromedex and Facts & Comparisons had a sensitivity of 70%. There was a statistically significant difference ( P = .016) in the distribution across the databases in detecting clinically significant drug interactions.

Conclusion:

Commonly used databases for identifying drug interactions with oral antineoplastics vary significantly in their sensitivity. Clinicians should not rely on a single database and should consider using multiple resources as well as sound clinical judgment. Further work is needed in this area.