Demographic Factors Associated With Non-Guideline-Based Treatment of Kidney Cancer in the United States.

Importance: Significant demographic disparities have been found to exist in the delivery of health care. Demographic factors associated with clinical decision-making in kidney cancer have not been thoroughly studied. Objective: To determine whether demographic factors, including sex and race/ethnicity, are associated with receipt of non-guideline-based treatment for kidney cancer. Design, Setting, and Participants: This retrospective cohort study was conducted using data from the National Cancer Database for the years 2010 through 2017. Included patients were individuals aged 30 to 70 years with localized (ie, cT1-2, N0, M0) kidney cancer and no major medical comorbidities (ie, Charlson-Deyo Comorbidity Index score of 0 or 1) treated at Commission on Cancer-accredited health care institutions in the United States. Data were analyzed from November 2020 through March 2021. Exposures: Demographic factors, including sex, race/ethnicity, and insurance status. Main Outcomes and Measures: Receipt of non-guideline-based treatment (undertreatment or overtreatment) for kidney cancer, as defined by accepted clinical guidelines, was determined. Results: Among 158 445 patients treated for localized kidney cancer, 99 563 (62.8%) were men, 120 001 individuals (75.7%) were White, and 91 218 individuals (57.6%) had private insurance. The median (interquartile range) age was 58 (50-64) years. Of the study population, 48 544 individuals (30.6%) received non-guideline-based treatment. Female sex was associated with lower adjusted odds of undertreatment (odds ratio [OR], 0.82; 95% CI, 0.77-0.88; P < .001) and higher adjusted odds of overtreatment (OR, 1.27; 95% CI, 1.24-1.30; P < .001) compared with male sex. Compared with White patients, Black and Hispanic patients had higher adjusted odds of undertreatment (Black patients: OR, 1.42; 95% CI, 1.29-1.55; P < .001; Hispanic patients: OR, 1.20; 95% CI, 1.06-1.36; P = .004) and overtreatment (Black patients: OR, 1.09; 95% CI, 1.05-1.13; P < .001; Hispanic patients: OR, 1.06; 95% CI, 1.01-1.11, P = .01). Individuals who were uninsured, compared with those who had insurance, had statistically significantly higher adjusted odds of undertreatment (OR, 2.63; 95% CI, 2.29-3.01; P < .001) and lower adjusted odds of overtreatment (OR, 0.72; 95% CI, 0.67-0.77; P < .001). Conclusions and Relevance: This study found that there were significant disparities in treatment decision-making for patients with kidney cancer, with increased rates of non-guideline-based treatment for women and Black and Hispanic patients. These findings suggest that further research into the mechanisms underlying these disparities is warranted and that clinical and policy decision-making should take these disparities into account.

Sample sizes of prediction model studies in prostate cancer were rarely justified and often insufficient.

OBJECTIVE: Developing clinical prediction models (CPMs) on data of sufficient sample size is critical to help minimize overfitting. Using prostate cancer as a clinical exemplar, we aimed to investigate to what extent existing CPMs adhere to recent formal sample size criteria, or historic rules of thumb of events per predictor parameter (EPP)≥10. STUDY DESIGN AND SETTING: A systematic review to identify CPMs related to prostate cancer, which provided enough information to calculate minimum sample size. We compared the reported sample size of each CPM against the traditional 10 EPP rule of thumb and formal sample size criteria. RESULTS: About 211 CPMs were included. Three of the studies justified the sample size used, mostly using EPP rules of thumb. Overall, 69% of the CPMs were derived on sample sizes that surpassed the traditional EPP≥10 rule of thumb, but only 48% surpassed recent formal sample size criteria. For most CPMs, the required sample size based on formal criteria was higher than the sample sizes to surpass 10 EPP. CONCLUSION: Few of the CPMs included in this study justified their sample size, with most justifications being based on EPP. This study shows that, in real-world data sets, adhering to the classic EPP rules of thumb is insufficient to adhere to recent formal sample size criteria.

[Revised guideline 'Brain metastases': More treatment options]. / Herziene richtlijn 'Hersenmetastasen'.

The guideline on brain metastasis from the Netherlands Society of Neurology has been updated. Important changes have been made, particularly with regard to treatment of brain metastases. Treatment of patients with brain metastases is complex and requires a multidisciplinary approach to formulate an optimal, individualized treatment plan. Neurosurgical resection may also be considered in patients with multiple brain metastases and one dominant, symptomatic lesion, if the patient is in good clinical condition. Stereotactic radiosurgery is a treatment option for patients with a maximum of 10 brain metastases, depending on the size and number of metastases. The indication for whole brain radiotherapy is relatively limited. Doctors should be cautious with whole brain radiotherapy in patients with a Karnofsky Performance Status <70. In patients with small, asymptomatic brain metastases, targeted therapy or immune therapy may be considered without locoregional therapy.

Influence of adherence with guideline-driven recommendations on survival in women operated for breast cancer: Real-life evidence from Italy.

BACKGROUND: A set of indicators to assess the quality of care for women operated for breast cancer was developed by an expert working group of the Italian Health Ministry in order to compare the Italian regions. A study to validate these indicators through their relationship with survival was carried out. METHODS: The 16,753 women who were residents in three Italian regions (Lombardy, Emilia-Romagna and Lazio) and hospitalized for breast cancer surgery during 2011 entered the cohort and were followed until 2016. Adherence to selected recommendations (i.e., surgery timeliness, medical therapy timeliness, appropriateness of complementary radiotherapy and mammographic follow-up) was assessed. Multivariable proportional hazards models were fitted to estimate hazard ratios for the association between adherence with recommendations and the risk of all-cause mortality. RESULTS: Adherence to recommendations was 53% for medical therapy timeliness, 73% for appropriateness of mammographic follow-up, 74% for surgery timeliness and 82% for appropriateness of complementary radiotherapy. Risk reductions of 26%, 62% and 56% were observed for adherence to recommendations on medical therapy timeliness, appropriateness of complementary radiotherapy and mammographic follow-up, respectively. There was no evidence that mortality was affected by surgery timeliness. CONCLUSIONS: Clinical benefits are expected from improvements in adherence to the considered recommendations. Close control of women operated for breast cancer through medical care timeliness and appropriateness of radiotherapy and mammographic monitoring must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes.

Anti-doping research and the Helsinki Declaration: (mis)match?

The fight against doping in sport is internationally coordinated by the World Anti-Doping Agency (WADA). Through its World Anti-Doping Code, WADA aims to harmonize anti-doping policies, rules and regulations. One key reference document bound to the Code is the International Standard for Laboratories (ISL), which mainly specifies the criteria that must be met for laboratory accreditation, as well as standards to adopt for the production of valid test results and evidentiary data. Within the ISL, the Code of Ethics refers to the Helsinki Declaration as a guiding framework for anti-doping research. However, inasmuch as anti-doping research structurally differs from human subject research as considered by the Helsinki Declaration, the applicability of the latter to anti-doping research can be called into question. In this work, we discuss how key principles of the Helsinki Declaration apply to anti-doping research and highlight frictions, incompatibilities and misalignments. Furthermore, we indicate possible solutions for operationalizing the Helsinki principles within the context of anti-doping research.

Practice variation on hospital level in the systemic treatment of metastatic colorectal cancer in The Netherlands: a population-based study.

Introduction: Population-based data on the implementation of guidelines for cancer patients in daily practice are scarce, while practice variation may influence patient outcomes. Therefore, we evaluated treatment patterns and associated variables in the systemic treatment of metastatic colorectal cancer (mCRC) in the Netherlands.Material and methods: We selected a random sample of adult mCRC patients diagnosed from 2008 to 2015 from the National Cancer Registry in 20 (4 academic, 8 teaching and 8 regional) Dutch hospitals. We examined the influence of patient, demographic and tumour characteristics on the odds of being treated with systemic therapy according to the current guideline and assessed its association with survival.Results: Our study population consisted of 2222 mCRC patients of whom 1307 patients received systemic therapy for mCRC. Practice variation was most obvious in the use of bevacizumab and anti-EGFR therapy in patients with (K)RAS wild-type tumours. Administration rates did not differ between hospital types but fluctuated between individual hospitals for bevacizumab (8-92%; p < .0001) and anti-EGFR therapy (10-75%; p = .05). Bevacizumab administration was inversely correlated to higher age (OR:0.2; 95%CI: 0.1-0.3) comorbidity (OR:0.6; 95%CI: 0.5-0.8) and the presence of metachronous metastases (OR:0.5; 95%CI: 0.3-0.7), but patient characteristics did not differ between hospitals with low or high bevacizumab administration rates. The hazard ratios for exposure to bevacizumab and anti-EGFR therapy were 0.8 (95%CI: 0.7-0.9) and 0.6 (95%CI: 0.5-0.8), respectively.Discussion: We identified significant inter-hospital variation in targeted therapy administration for mCRC patients, which may affect outcome. Age and comorbidity were inversely correlated with non-administration of bevacizumab but did not explain inter-hospital practice variation. Our data suggest that practice variation is based on individual strategy of hospitals rather than guideline recommendations or patient-driven decisions. Individual hospital strategies are an additional factor that may explain the observed differences between real-life data and results obtained from clinical trials.

N - 3 fatty acids during chemotherapy: toward a higher level of evidence for clinical application.

PURPOSE OF REVIEW: Recommendations for intakes of n - 3 fatty acids (FAs) in patients who are receiving chemotherapy for cancer are based on weak evidence. This review highlights themes within the emergent literature to suggest improvements in the design of studies that provide n - 3 FA supplements concurrent with cytotoxic agents. RECENT FINDINGS: Following earlier research in animal models and human pilot studies, recent human studies have evaluated the effect of providing n - 3 FAs during delivery of single agent and multiagent chemotherapy regimens for breast and gastro-intestinal cancers. Regimens were based on platinum compounds, fluoropyrimidines or both, and a variety of additional agents. Tumor location and stage, supplement dose and duration, and endpoints were dissimilar across studies. Overall, the recent research continues to support the safety and tolerability of n - 3 FA supplementation with chemotherapy and provides additional evidence, albeit weak, for enhanced tumor response, maintenance of weight and muscle, and reduction in inflammation and toxicities in the host across multiple cancer sites and chemotherapy regimens. SUMMARY: The barriers to implementation in practice remain small study sizes, variations in supplement dosage and methodology, and differences in primary endpoints. Randomized, blinded trials with a justifiable sample size, adequate doses, monitored compliance and measures of clinically important endpoints are required to move these findings to a higher level of evidence for implementation into clinical practice.

An updated European Organisation for Research and Treatment of Cancer (EORTC) protocol for pathological evaluation of sentinel lymph nodes for melanoma.

The sentinel lymph node (SLN) biopsy is a highly accurate staging procedure and the most important prognostic factor in melanoma patients. The European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group aimed to design an updated evolved SLN protocol for the histopathological workup and reporting. We herein recommend extending the distance between steps according to the short axis dimension of the lymph node and optimise both conventional sectioning and staining procedures including immunohistochemistry. We also provide guidance on the description of the spatial localisation of melanoma deposits in a SLN. The histopathological features to be reported include the following: presence or absence of the metastasis, the intranodal location of the metastasis (subcapsular, parenchymal, combined, extensive confluent and extensive multifocal), the number of the metastatic deposits (1, 2-5, 6-10, 11-20 and >20), the maximum dimension of the largest metastasis (indicating its site) and the presence of extracapsular extension and of naevus cells. This updated EORTC protocol is expected to clarify and simplify the existing procedures, ensuring a reasonable workload for the laboratory and for the pathologists resulting in cost saving with no loss, and possible increase, in accuracy.

Comparison of 4th ESO-ESMO international consensus guidelines for advance breast cancer and Chinese anti-cancer association committee of Breast Cancer Society guideline.

The primary aim of the international advance breast cancer (ABC) guidelines are to guide treatment decisions in many different healthcare settings, but need adaptations due to different access to care. These guidelines are based on the most up-to-date evidence. However, Chinese experts have a different national condition and policies to face. The Chinese Anti-Cancer Association Committee of Breast Cancer Society guideline (CBCS guideline) is to guide treatments and to reflect unmet needs of Chinese breast cancer patients. Although, most of the recommendations in the two guidelines are the same, some of them are different. In this article, with regard to country-specific peculiarities, a working group of Chinese breast cancer experts compare the similarities and differences between the ABC guideline and CBCS guideline and commented on the voting results of the ABC panelists. We also discuss why these differences exist, such as lack of access, different tumor biology and epidemiology, and even different culture. The money which patients have to pay out of pocket for their medical cost and the availability of drugs lie at the heart of the issues of guideline differences.

Treatment Patterns and Survival Outcomes in Patients With Follicular Lymphoma: A 2007 to 2015 Humedica Database Study.

BACKGROUND: Few studies have evaluated real-world treatment patterns and survival in follicular lymphoma (FL). This study evaluated these outcomes among newly diagnosed patients with FL in routine clinical care. PATIENTS AND METHODS: A retrospective study was conducted in newly diagnosed patients with FL from Humedica, a large United States electronic medical record database, from January 1, 2008 to July 31, 2015. Patients were followed from treatment initiation until death, loss to follow-up, or end of study (September 30, 2015). Treatment patterns were assessed in the follow-up period. Progression-free survival (PFS) and overall survival (OS) at 2 years were evaluated in the overall population using Kaplan-Meier analyses. OS was also compared between patients with and without evidence of disease progression within 2 years following first-line therapy (ie, early progressors vs. non-early progressors). RESULTS: A total of 1346 patients were included in the study, with most patients receiving rituximab-based regimens. Fewer early progressors received rituximab-based regimens. Across all lines, combination therapies predominated, particularly bendamustine + rituximab. Following first-line therapy, OS was 86.9% at 2 years, and median OS was not reached. Two-year PFS after first-line therapy was 64.6%, and median PFS was 48.1 months (95% confidence interval, 39.4-58.4 months). OS at 2 years was 76.8% among early progressors versus 90.4% among non-early progressors (P < .001); the median OS was not reached in both groups. CONCLUSION: In routine clinical practice, rituximab-based regimens predominated; however, utilization of these regimens differed among early and non-early progressors. The assessment of survival outcomes also highlights the negative impact of early progression on OS in the rituximab-era.

Arrabidaea chica for oral mucositis in patients with head and neck cancer: a protocol of a randomised clinical trial.

INTRODUCTION: Oral mucositis is an iatrogenic condition of erythematous inflammatory changes which tends to occur on buccal and labial surfaces, the ventral surface of the tongue, the floor of the mouth and the soft palate of patients receiving chemotherapy. This protocol of ongoing randomised parallel group clinical trial aims to access the therapeutic effect of an herbal gel containing 2.5% Arrabidaea chica Verlot standardised extract on oral mucositis in patients with head and neck cancer compared with low-level laser therapy. METHODS AND ANALYSIS: Patients with head and neck cancer held at Clinics Hospital of University of Campinas, Sao Paulo, who develop early signs/symptoms of oral mucositis are eligible. Baseline characteristics of participants include oral mucositis grade and quality of life assessments. Enrolment started in November 2017 with allocation of patients to one of the study groups by means of randomisation. Patients will be treated either with Arrabidaea chica or laser until wound healing. Monitoring includes daily assessment of mucositis grade and diameter measurement by photographs and millimetre periodontal probe. Treatments will be concluded once mucositis is healed. A blinded assessor will evaluate mucositis cure after referred by the study team. At this point, the gel tube will be weighed to indirectly assess patient's compliance. At close-out, data will be analysed by a blinded researcher following the procedures described in the statistical analyses. ETHICS AND DISSEMINATION: This clinical trial was approved by the ethics committee of research in humans at the Faculty of Medical Sciences of University of Campinas (report no. 1,613,563/2016). Results from this trial will be communicated in peer-reviewed publications and scientific presentations. TRIAL REGISTRATION NUMBER: RBR-5×4397.

Highly significant improvement in guideline adherence, relapse-free and overall survival in breast cancer patients when treated at certified breast cancer centres: An evaluation of 8323 patients.

OBJECTIVES: Certified multi-disciplinary breast cancer centres (CBCs) have been established worldwide. Development of CBCs, guideline-adherent systemic therapy and surgical management should now show an impact on outcomes. This analysis aimed to investigate whether guideline adherence (GA) rates, relapse-free survival (RFS) and overall survival (OS) have significantly improved at CBCs compared to the pre-certification period. MATERIALS AND METHODS: 8323 patients with primary breast cancer were treated in 17 German CBCs, which had been certified between 2003 and 2007 [2003 (n = 1), 2004 (n = 6), 2005 (n = 3), 2006 (n = 6) and 2007 (n = 1)]. 3544 patients (42.6%) were treated before certification and 4779 patients (57.4%) after certification. RESULTS AND CONCLUSION: A highly significant (p < 0.001) difference in 100%-GA was found between the various hospitals before certification (min 25.0%; max 54.6%). In 2008, when all participating hospitals were certified, the GA rate was 61.8% (min 39.5%, max 74.4%) and 69.2% (min 45.9%, max 86.4%) for patients <75 y (n = 6675). The difference between pre-certification 100%-GA (46.9%) and post-certification (57.2%) was highly significant (p < 0.001). RFS and OS were both significantly better after certification compared to the pre-certification period (RFS: HR = 0.79; 95% CI: 0.68-0.92; p = 0.003; OS: HR = 0.75; 95% CI: 0.65-0.85; p < 0.001). 5-year RFS (OS) of patients <75 y was 89.6% (85.4%) pre-certification and 91.4% (89.5%) post-certification. Since improvement in GA and outcomes correlated as well, GA remains a highly significant prognostic factor for RFS and OS regardless of NPI, intrinsic subtype and adjuvant systemic therapy. This suggests that the certification process is strongly associated with improvements in outcome.

Proton range verification in inhomogeneous tissue: Treatment planning system vs. measurement vs. Monte Carlo simulation.

In particle radiotherapy, range uncertainty is an important issue that needs to be overcome. Because high-dose conformality can be achieved using a particle beam, a small uncertainty can affect tumor control or cause normal-tissue complications. From this perspective, the treatment planning system (TPS) must be accurate. However, there is a well-known inaccuracy regarding dose computation in heterogeneous media. This means that verifying the uncertainty level is one of the prerequisites for TPS commissioning. We evaluated the range accuracy of the dose computation algorithm implemented in a commercial TPS, and Monte Carlo (MC) simulation against measurement using a CT calibration phantom. A treatment plan was produced for eight different materials plugged into a phantom, and two-dimensional doses were measured using a chamber array. The measurement setup and beam delivery were simulated by MC code. For an infinite solid water phantom, the gamma passing rate between the measurement and TPS was 97.7%, and that between the measurement and MC was 96.5%. However, gamma passing rates between the measurement and TPS were 49.4% for the lung and 67.8% for bone, and between the measurement and MC were 85.6% for the lung and 100.0% for bone tissue. For adipose, breast, brain, liver, and bone mineral, the gamma passing rates computed by TPS were 91.7%, 90.6%, 81.7%, 85.6%, and 85.6%, respectively. The gamma passing rates for MC for adipose, breast, brain, liver, and bone mineral were 100.0%, 97.2%, 95.0%, 98.9%, and 97.8%, respectively. In conclusion, the described procedure successfully evaluated the allowable range uncertainty for TPS commissioning. The TPS dose calculation is inefficient in heterogeneous media with large differences in density, such as lung or bone tissue. Therefore, the limitations of TPS in heterogeneous media should be understood and applied in clinical practice.

Development of the Pediatric Neuro-Oncology Rating of Treatment Intensity (PNORTI).

Measures of treatment intensity for childhood cancer are needed in research in order to control for variability in treatments. Existing measures of treatment intensity for childhood cancers do not reflect the complexities of treatment protocols for central nervous system (CNS) tumors. This paper describes the development of the Pediatric Neuro-Oncology Rating of Treatment Intensity (PNORTI). PNORTI development occurred in three phases. Phase 1: five experts in pediatric neuro-oncology created a 5-point scale of treatment intensity and 42 pediatric neuro-oncology providers completed a three-part online questionnaire to evaluate the classification system and apply the rating system to 16 sample patients. Validity was determined by respondents classifying therapy modalities into intensity levels. Inter-rater reliability was calculated from ratings of the 16 sample patients. Phase 2: three experts revised the PNORTI based on survey results and 18 pediatric neuro-oncology providers evaluated the classification system. Phase 3: ten experts in pediatric neuro-oncology refined and finalized the PNORTI and rated 10 sample patients using the PNORTI. Agreement between median ratings of the survey respondents and criterion raters for chemotherapy intensity (r's = .82 and 1.0) and overall treatment intensity level (r's = .91 and .94) were high in Phases 1 and 2. Inter-rater reliability also was very high when using the PNORTI to classify the 16 sample patients in Phase 1 (median agreement of r = .93 and rICC = .99) and the 10 sample patients in Phase 3 (median agreement of r = .92 and rICC = .98). The PNORTI is a valid and reliable method for classifying the intensity of different treatment modalities used in pediatric neuro-oncology.

The Dana Farber consortium protocol (DFCP) vs. classic Hyper-CVAD for treatment of acute lymphoblastic leukemia in patients <50 Y. Single institution experience.

BACKGROUND: The use of intensive pediatric protocols for the treatment of ALL is being extended to older adults. AIM OF THE STUDY: Analysis of the efficacy and toxicity results of pediatric DFCP vs. classic Hyper-CVAD protocol for the treatment of patients with ALL < 50 Y. PATIENTS AND METHODS: A retrospective single center comparative analysis of DFCP & classic Hyper-CVAD for first line treatment of patients with ALL < 50 Y. RESULTS: 73 patients were included, 43 received DFCP and 30 received Hyper-CVAD protocol. CR rate was 90.7% for DFCP vs. 83.7 for Hyper-CVAD (p 0.7). 3 Y Leukemia free survival was 57.4% (70.9% for DFCP vs. 41.6% Hyper-CVAD P 0.1) while 3Y OS was 62.6%% for the whole group, 72.6% DFCP vs. 48.5% Hyper-CVAD, P 0.04. Those with age <21 Y, had significantly longer 3 Y LFS and OS (P 0.04, 0.02, respectively). TOXICITY: pancreatitis occurred in 5 patients with DFCP and it was related to Asparginase and in 1 patient on Hyper-CVAD related to gall stones. Osteonecrosis affected 5 patients on DFCP. IN CONCLUSION: pediatric protocols are feasible in patients younger than 50 Y and they are more active than classic adult protocols. Although modifications of adult protocols may improve their results, this had to be investigated in randomized controlled trials.

Current Standard and Future Perspectives in the Treatment of Gastrointestinal Stromal Tumors.

The origin of gastrointestinal stromal tumors (GIST) from interstitial cells of Cajal or their precursor cells has been understood since the early 1990s. The first mutations within the KIT-gene have been described in the late 1990s. Even though these mutations were the breakthrough of small molecular therapy, we still do not know the factors responsible for their malignant transformation. Until then, we can only speak of recurrence risk. This review gives an introduction on the current understanding of GIST and highlights the remaining questions for diagnosis, tumor progression, and treatment in progressive disease.

The 2015 National Cancer Program in Sweden: Introducing standardized care pathways in a decentralized system.

Starting in 2015, the Swedish government has initiated a national reform to standardize cancer patient pathways and thereby eventually speed up treatment of cancer. Cancer care in Sweden is characterized by high survival rates and a generally high quality albeit long waiting times. The objective with the new national program to standardize cancer care pathways is to reduce these waiting times, increase patient satisfaction with cancer care and reduce regional inequalities. A new time-point for measuring the start of a care process is introduced called well-founded suspicion, which is individually designed for each cancer diagnosis. While medical guidelines are well established earlier, the standardisation is achieved by defining time boundaries for each step in the process. The cancer reform program is a collaborative effort initiated and incentivized by the central government while multi-professional groups develop the time-bound standardized care pathways, which the regional authorities are responsible for implementing. The broad stakeholder engagement and time-bound guidelines are interesting approaches to study for other countries that need to streamline care processes.

Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial.

BACKGROUND: Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib. METHODS: We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0-2. Before enrolment, all patients had received 3-18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841). FINDINGS: Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40-61) and 40 of 95 in the imatinib group (42%, 32-53%; difference 7·9% in favour of nilotinib; 95% CI -6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3-4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related. INTERPRETATION: While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included. FUNDING: Novartis Pharmaceuticals.

Concordance rates of biomarkers uPA and PAI-1 results in primary breast cancer vs. consecutive tumor board decision and therapy performed in clinical hospital routine: Results of a prospective multi-center study at certified breast centers.

OBJECTIVE: Biomarkers uPA and PAI-1 are guideline recommended by ASCO (USA) and AGO (Germany) in primary breast cancer to avoid unnecessary CTX in patients at medium risk for recurrence. For clinical quality assurance of uPA/PAI-1 testing, analysis of test-therapy concordance was performed. METHODS: Prospective non-interventional multi-center study over 2 years among six Certified Breast Centers in Germany to investigate uPA/PAI-1 results in consecutive decision making for tumor board recommendation and actual therapy in uninfluenced clinical setting. Concordance and discordance rates of uPA/PAI-1 testing were calculated and individual reasons for decision making analyzed. RESULTS: Among n = 93 uPA/PAI-1 tests evaluated n = 42/93 (45.2%) were uPA + PAI-1 negative and n = 51/93 (54.8%) uPA and/or PAI-1 positive. In uPA + PAI-1 negative test results in n = 35/42 (83.3%) CTX was avoided as recommended. But in n = 7/42 (16.7%) CTX was performed despite, resulting in over treatment. In uPA and/or PAI-1 positive test results in n = 26/51 (51.0%) CTX was performed but in n = 25/51 (49.0%) not despite recommendation for CTX which is under treatment. The conformity of uPA/PAI-1 test result vs. tumor board decision was n = 73/93 (78.5%). The overall concordance of uPA/PAI-1 test result vs. consecutive therapy was n = 61/93 (65.6%). A variety of reasons for individual result-deviating decisions were identified. CONCLUSIONS: Clinical quality assurance of uPA/PAI-1 biomarker testing showed inconsistency of test results with consecutive tumor board decision and/or final therapy performed in up to 1/3 of patients. To close this clinical quality gap in application of uPA/PAI-1 biomarkers, individual analysis of deviations is suggested with process optimization accordingly.