WHO Performance Status Score Research Articles

Practice and Predictors of Do-Not-Resuscitate Orders in a Tertiary-Care Intensive Care Unit in Saudi Arabia.

The objective of this study was to describe Do-Not-Resuscitate (DNR) practices in a tertiary-care intensive care unit (ICU) in Saudi Arabia, and determine the predictors and outcomes of patients who had DNR orders. This retrospective cohort study was based on a prospectively collected database for a medical-surgicalIntensive CareDepartment in a tertiary-care center in Riyadh, Saudi Arabia (1999-2017). We compared patients who had DNR orders during the ICU stay with those with "full code." The primary outcome was hospital mortality. The secondary outcomes included ICU mortality, tracheostomy, duration of mechanical ventilation, and length of stay in the ICU and hospital. Among 24790 patients admitted to the ICU over the 19-year study period, 3217 (13%) had DNR orders during the ICU stay. Compared to patients with "full code," patients with DNR orders were older (median 67 years [Q1, Q3: 55, 76] versus 57 years [Q1, Q3: 33, 71], p < 0.0001), were more likely to be females (43% versus 38%, p < 0.0001), had worse premorbid functional status (WHO performance status scores 4-5: 606[18.9%] versus 1894[8.8%], p < 0.0001), higher prevalence of comorbid conditions, and higher APACHE II score (median 28 [Q1, Q3: 23, 34] versus 19 [Q1, Q3: 13, 25], p < 0.0001) and were more likely to be mechanically ventilated (83% versus 55%, p < 0.0001). Patients had DNR orders were more likely to die in the ICU (67.8% versus 8.5%, p < 0.0001) and hospital (82.4% versus 18.1%, p < 0.0001). On multivariable logistic regression analysis, the following were associated with an increased likelihood of DNR status: increasing age (odds ratio (OR) 1.01, 95% confidence interval (CI) 1.01-1.02), higher APACHE II score (OR 1.09, 95% CI 1.08-1.10), and worse WHO performance status score. Patients admitted in recent years (2012-2017 versus 2002-2005) were less likely to have DNR orders (OR 0.35, 95% CI 0.32-0.39, p < 0.0001). Patients with DNR orders had higher ICU mortality, more tracheostomies, longer duration of mechanical ventilation and length of ICU stay compared to patients with with "full code" but they had shorter length of hospital stay. In a tertiary-care hospital in Saudi Arabia, 13% of critically ill patients had DNR orders during ICU stay. This study identified several predictors of DNR orders, including the severity of illness and poor premorbid functional status.

MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial

Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. The Dutch Cancer Society and Bayer AG - Pharmaceuticals.

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial

The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up. In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18-76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0-2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed. Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4-12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5-13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months [95% CI 9·6-12·0]) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months [12·0-18·5]; hazard ratio [HR] 0·63 [95% CI 0·48-0·83], stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months [95% CI 29·0-39·1]) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months [95% CI 38·6-55·1]; HR 0·70 [95% CI 0·53-0·92], stratified log-rank p=0·011). These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery. Dutch Cancer Foundation (KWF Kankerbestrijding).

Real-world evidence of osimertinib in Chinese patients with EGFR T790M-positive non-small cell lung cancer: a subgroup analysis from ASTRIS study

PurposeASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non–small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study.MethodsAdults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0–2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety.ResultsA total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53–0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1–12.5) and 13.9 months (95% CI 13.1–15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively.ConclusionOsimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified.Clinical trial numberNCT02474355.

Study of dosimetry and clinical factors for assessment of xerostomia in head and neck squamous cell carcinoma treated by intensity-modulated radiotherapy: A prospective study.

AIM:Clinical and dosimetric factors related to toxicity in terms of xerostomia in patients with head and neck squamous cell cancer (HNSCC) treated with intensity-modulated radiotherapy (IMRT).MATERIALS AND METHODS:Patients older than 18 years, with the WHO Performance Status Score <2 with primary diagnosis of HNSCC Stage II, III, and IV who had undergone primary or postoperative radiotherapy (RT) treated by IMRT at the center, from November 2015 to November 2016 were included in the study. Patients were assessed by physical examination and questioned to score their quality of life for dryness (HNDR) and stickiness (HNSS) by EORTC-HN-35 (Hindi or English version) at baseline (before treatment), at 3, 6, and 12 months following treatment. The validation of EORTC-HN-35 for HNDR and HNSS in patients was handed.RESULTS:Thirty patients were included in the study. The mean symptom score values for HNSS at baseline, 3, 6, and 12 months' post-RT treatment were 17.8, 62.2, 64.4, and 20.8, respectively. Dryness and stickiness also increased over 3–6 months in follow-up but slightly relieved at 12 months, but it could not reach to baseline. In subgroup analysis, at baseline mean score of dryness of mouth in elderly patients (≥60 years) (P = 0.248), poor performance status (Eastern Cooperative Oncology Group 2) (P = 0.80) and patients with advanced stage (Stage III and IVA) (P = 0.185) was higher. Correlation of normal tissue complication probability for xerostomia with contralateral mean parotid gland showed insignificant linearity with shallow curve.CONCLUSION:Patients remained symptomatic for xerostomia chiefly till 6 months' postirradiation, but it was slightly relieved in 12 months but could not reach the baseline. Dosimetric sparing ofcontralateral parotid resulted in decreased probability of developing xerostomia.

Palliative external beam radiotherapy for advanced breast cancer patients with brain metastasis in the university college hospital Ibadan.

Background:Brain metastasis is a dreaded complication that significantly reduces the quality of life in breast cancer patients. The treatment options are limited by the inability of many chemotherapeutic agents to cross the blood–brain barrier. Surgery also has a limited role, except in few selected patients with oligometastasis. Therefore, whole-brain radiotherapy (WBRT) remains the available option that gives a gratifying result. However, the benefit of this treatment modality in our resource-poor environment needs to be investigated.Materials and Methods:The data of breast cancer patients with brain metastasis who were treated with WBRT using cobalt-60 equipment between 2005 and 2009 were retrospectively collected from the departmental medical record unit. The information extracted included biodata, presenting symptoms, imaging modality for confirmation of brain metastasis, treatment records, performance status pre-WBRT and 4 weeks post-WBRT, and other supportive treatments.Results:A total of 52 female patients were reviewed between 2005 and 2009. The mean age of patients was 44.7 years. The common clinical features on presentation were headache, nausea, and visual impairment in 30.8% of patients with the WHO performance status score ranging between 2 and 4. Patients with more than three brain deposits accounted for 71.2% of all the brain metastases. The mean radiation dose used for WBRT was 30 Gy in 10 fractions, and total responses recorded were 86.5% with 53.8% complete improvement in patients' performance status 4 weeks after WBRT treatment.Conclusion:WBRT is an effective treatment modality for patients with brain metastasis in our resource-poor environment. However, improvement of patients' performance status declined with advancing age.

Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study

Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR-/ALK- NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7-21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8-23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2-43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines. In patients with advanced and heavily pretreated NSCLC, the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts; the proportion of patients with EGFR-/ALK- NSCLC (cohorts 2 and 3) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted. AstraZeneca.

PC 02.01 Thoracic Radiation - YES

Small cell lung cancer (SCLC) accounts for 15%–20% of all lung cancers, and the overwhelming majority (>95%) are associated with tobacco exposure. The incidence of all types of lung cancer, including SCLC, has been declining in the United States with the onset of tobacco smoking cessation programs, although this trend took nearly 20 years to become evident among men. Overall survival (OS) rates for patients with lung cancer have also increased by about 5% since the advent of low-dose spiral computed tomography (CT) scanning to detect early lung cancer. The prognosis for patients with SCLC continues to be poor but has improved with the advent of smoking cessation campaigns, more effective chemotherapy agents and radiation planning and delivery techniques, and the use of prophylactic cranial irradiation (PCI) for those who experience a complete response to therapy. Consolidation with chest radiotherapy has improved OS among patients with extensive-stage SCLC who achieved a complete response to chemotherapy. SCLC often presents as bulky symptomatic masses, and mediastinal involvement is common with or without pleural effusion and extrathoracic disease. Extrathoracic spread (i.e., extensive-stage disease) is also quite common, being present in 80%-85% of cases at diagnosis. Brain metastases are present in approximately 20% of patients at diagnosis; roughly half of these metastases are symptomatic and the other half are detected by imaging. Predictors of poor prognosis include poor performance status, older age, and being male. The pathologic subtypes of the disease (small cell carcinoma and combined small cell carcinoma) all carry a similarly poor prognosis. Current guidelines of the U.S. National Comprehensive Cancer Network recommend the use of positron emission tomography (PET), CT scanning, or fused PET/CT scanning of the chest, liver, adrenals, bone, and other areas of concern in the diagnosis and staging of SCLC (NCCN guideline-SCLC 2017). Thoracic radiotherapy has also become important for improving OS among patients with SCLC who achieved a complete response to chemotherapy. In one prospectively randomized study of 498 patients with extensive-stage SCLC (WHO performance status score 0-2) who achieved complete response to chemotherapy, patients who received consolidation thoracic radiotherapy (30 Gy in 10 fractions) had significantly better 2-year OS rates than did those who did not receive thoracic radiotherapy (13% vs. 3%, P=0.004). Thoracic radiotherapy further improved thoracic-only failure rates (19.8% vs. 46% without, P=0.001) (Slotman B et al, Lancet Oncol 2015;385:36-42). However, many patients with extensive-stage SCLC do not respond to the standard etoposide/cisplatin chemotherapy (Fig 1). Those patients may need to receive molecular-targeted therapies or immunotherapy with the consolidating thoracic radiotherapy. Several histologic and immunohistochemical markers have been evaluated for diagnosing or monitoring treatment response in SCLC, including transcription thyroid factor-1 (positive in >85% of SCLC cases); cytokeratin 7; deletions in chromosome 3; Leu-7; chromogranin A; synaptophysin; myc amplification; and p53 mutations (present in ∼75% of cases). Deletions in tumor-suppressor genes are also relatively common and include fragile histidine triad (FHIT) (80%); RAS effector homologue (RASSF1) (>90%); TP53 (>75%); retinoblastoma-1 (RB1) (>90%); and retinoic acid receptor-beta (72%). However, to date no biomarkers have been validated for use in diagnosing SCLC. Moreover, mutations that are often present in non-small cell lung cancer (such as epidermal growth factor receptor [EGFR] mutations and anaplastic lymphoma kinase [ALK]) are rare in SCLC. Several clinicopathologic features have been linked with worse prognosis, including poor performance status, significant weight loss, high lactate dehydrogenase levels, large numbers of metastatic sites, and the presence of paraneoplastic syndromes. Because SCLC has the among the highest rates of somatic driver mutations, and because more than 95% of patients with SCLC are former or current smokers, immunotherapy seems a reasonable approach, as high mutation burdens correlate with good response to chemoradiotherapy and sensitivity to immunomodulators (Peifer M et al., Nat Genet 2012;44(10):1104-10). At MD Anderson Cancer Center, an ongoing phase I/II study of patients with extensive-stage SCLC has been proposed to the NRG as a prospective randomized study (PI J Welsh) (Fig 2). Use of thoracic radiotherapy to consolidate a site at which SCLC is quite likely to recur is reasonable, given that recurrence considerably reduces quality of their life as well as OS. In summary, in most cases SCLC presents as extensive-stage disease, for which outcomes are very poor. Consolidation with thoracic radiotherapy for patients who achieve a complete response to chemotherapy can improve 2-year OS rates. However, less toxic and more effective systemic treatment is also required to derive the greatest benefit from consolidation thoracic radiotherapy. thoracic radiotherapy extensive small-cell lung cancer, immunotherapyFig 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Increased expression of the histone H3 lysine 4 methyltransferase MLL4 and the histone H3 lysine 27 demethylase UTX prolonging the overall survival of patients with glioblastoma and a methylated MGMT promoter.

OBJECTIVE The purpose of the present study was to investigate the epigenetic and prognostic roles of an H3K4 methyltransferase (mixed lineage leukemia 4 [MLL4]) and H3K27 demethylase (ubiquitously transcribed tetratricopeptide repeat gene on X chromosome [UTX]) in progression-free survival (PFS) and overall survival (OS) of patients with glioblastoma (GBM) who were treated with radiotherapy, chemotherapy, or both after resection. In addition, the authors examined methylation at the promoter of the O-6-methylguanine-DNA methyltransferase ( MGMT) gene and other prognostic factors predicting length of PFS and OS in these patients. METHODS The medical records of 76 patients having a new diagnosis of histologically ascertained GBM in the period of January 2002 to December 2013 at the authors' institution were retrospectively reviewed. Immunohistochemical staining for MLL4 and UTX was performed on archived paraffin-embedded tissues obtained by biopsy or resection. The methylation status of the MGMT promoter in these tissues was determined by methylation-specific PCR analysis. RESULTS During the follow-up period (mean length 18.1 months, range 4.1-43.5 months), 68 (89.5%) of the patients died. The MGMT promoter was methylated in 49 patients (64.5%) and unmethylated in 27 (35.5%). The immunoreactivity pattern of UTX was identical to that of MLL4; increased expression of these 2 proteins was observed in samples from 34 patients (44.7%) and decreased expression in 42 patients (55.3%). The mean length of PFS was 9.2 months (95% CI 6.8-11.6 months). Extent of surgery, recursive partitioning analysis (RPA) class, and methylation status of the MGMT promoter were all associated with increased PFS in the multivariate analysis of factors predicting PFS. The mean length of OS was 18.6 months (95% CI 14.3-22.9 months). Patient age (p = 0.004), WHO performance status score (p = 0.019), extent of surgery (p = 0.007), RPA class (p = 0.036), methylation status of the MGMT promoter (p = 0.010), and increased expression of UTX-MLL4 (p = 0.001) were significantly associated with increased OS in multivariate analysis. Interestingly, in patients with an unmethylated MGMT promoter, immunoreactivity of UTX-MLL4 was not associated with changes in OS (p = 0.350). However, in the patients with a methylated MGMT promoter, increased UTX-MLL4 expression was strongly associated with increased OS (p < 0.001). CONCLUSIONS The results of this study suggest that increased expression of UTX-MLL4 positively influences the outcome of patients with GBM having a methylated MGMT promoter. Therefore, UTX-MLL4 immunoreactivity could be a useful predictor of the response to conventional treatment with radiotherapy or chemotherapy among GBM patients whose tumors have a methylated MGMT promoter.

2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial

Docetaxel administered every 3 weeks is a standard treatment for castration-resistant advanced prostate cancer. We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer, and did a prospective, multicentre, randomised, phase 3 study to compare efficacy and safety. Eligible patients had advanced prostate cancer (metastasis, a prostate-specific-antigen test result of more than 10·0 ng/mL, and WHO performance status score of 0-2), had received no chemotherapy (except with estramustine), had undergone surgical or chemical castration, and had been referred to a treatment centre in Finland, Ireland, or Sweden. Enrolment and treatment were done between March 1, 2004, and May 31, 2009. Randomisation was done centrally and stratified by centre and WHO performance status score of 0-1 vs 2. Patients were assigned 75 mg/m(2) docetaxel intravenously on day 1 of a 3-week cycle, or 50 mg/m(2) docetaxel intravenously on days 1 and 15 of a 4-week cycle. 10 mg oral prednisolone was administered daily to all patients. The primary endpoint was time to treatment failure (TTTF). We assessed data in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00255606. 177 patients were randomly assigned to the 2-weekly docetaxel group and 184 to the 3-weekly group. 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis. The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration (5·6 months, 95% CI 5·0-6·2 vs 4·9 months, 4·5-5·4; hazard ratio 1·3, 95% CI 1·1-1·6, p=0·014). Grade 3-4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group, including neutropenia (93 [53%] vs 61 [36%]), leucopenia (51 [29%] vs 22 [13%]), and febrile neutropenia (25 [14%] vs six [4%]). Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks (43 [24%] vs 11 [6%], p=0·002). Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated. Sanofi.

Do Results From Clinical Trials in Acute Myeloid Leukemia Reflect Clinical Reality? A Danish National Cohort Study of 813 Patients

AbstractAbstract 1477▪▪This icon denotes a clinically relevant abstractPrevious studies have documented the underrepresentation of women and elderly patients in American clinical trials of leukemia. If, characteristics of patients included in clinical protocols differ markedly from the characteristics of the majority of patients treated outside protocols the external validity of clinical trials may be threatened. Methods:The Danish National Acute Leukaemia Database (ALDB) includes detailed data on a large well-defined non-selected population of 2729 AML patients (covering >95% of AML patients diagnosed since Jan 2000). Since 2000 Danish AML patients have been included in 3 different British protocols (AML15, 16 and 17).We analysed a cohort of 2624 patients diagnosed with AML in Denmark since Jan. 2000 (105 APL-patients were excluded). We compared patients treated with curative intent according to the British protocols with patients treated with curative intent off-protocol with regard to characteristics, possible prognostic factors, CR-rate, and survival. For comparable groups we divided patients into 2 age groups (<60 and ≥60 years) and further excluded patients diagnosed before protocol inclusion was possible for the given age group. Results:813 patients were treated with curative intent (517 pts < 60 years (96% of all patients <60y) vs. 296 pts ≥60 year, (35 % of all patients >60y). Of these, 391 pts (232 pts <60 years, 44.9 % vs. 159 pts ≥60 years, 53.7 %) were treated according to protocols. For both age groups WHO performance status score (WHO PS) was found to be significantly lower in the on-protocol group. Presence of secondary AML (sAML) was found more frequent in the off-protocol groups, but was only statistically significant in the group under 60 years. In patients 60 years or older, a significantly higher LDH-level and WBC was found in the on-protocol groups. We did not find any difference in distribution of sex, age, cytogenetic changes, presence of extra medullary leukemia (EML) or blast counts. Allogeneic transplantation (alloHCT) was significantly more often performed in the protocol groups (table 1). For patients under 60 years of age overall survival (OS) was superior in the on-protocol group (fig. 1). For the older age group OS was similar in the on- and off-protocol group (fig. 2). After controlling for possible prognostic factors protocol participation seemed to be associated with longer OS in patients under 60 years (HR 0.66, 95%CI 0.48–0.99, p=0.02), but not in patients 60 years or older (HR 1.17, 95%CI 0.87–1.57). The unevenly distributed characteristics; LDH-level, sAML, WHO PS, performance of alloHCT were all found to be of significant importance to OS. Conclusions:AML patients included in the British AML trials in Denmark had a more favorable profile than patients treated with standard regimens. We found a superior survival in on-protocol patients under 60 years. This could not be fully explained by an uneven distribution of prognostic factors. A beneficial effect of the protocol treatments and confounding by co-morbidity are suggested. Population-based studies may thus have an important role in examining some aspects of prognosis in AML. In this context the Danish ALDB has proven to be a valuable data source.Table 1Clinical and demographic characteristics of 813 AML patientsAge < 60 years n =517Age ≥60 years n = 296Protocol n=232Off-protocol n = 285p-value*Protocol n = 159Off-protocol n= 137p-value*Age, median (range)47 (18–59)49 (15–59)NS67 (60–78)66 (60–83)NSSex, male %51.749.5NS59.860.6NSsAML (%)18 (7.7)71 (24.9)<.000142 (26.4)49 (35.8)0.08Cytogenetics, (%)0.0960.14Favorable18 (8.3)14 (5.5)2 (1.3)0 (0)Intermediate164 (75.9)185 (73.1)113 (74.3)102 (81.0)Adverse34 (15.7)54 (21.3)37 (24.3)24 (19.1)WHO PS (%)<0.0010.040118 (51.3)98 (34.8)68 (42.8)48 (35.0)191(39.6)124 (44.0)73 (45.9)59 (43.1)216 (7.0)43 (15.3)9 (5.7)20 (14.6)33 (1.3)11 (3.9)5 (3.1)6 (4.4)42 (0.9)6 (2.1)4 (2.5)4 (3.0)EML (%)33 (14.2)44 (15.4)NS18 (11.3)12 (8.8)NSMedian WBC (%)11 (0.6–269)12.2 (0.1–359)NS7.38 (0.2–355)19.1 (0.40–507)<0.002Median blast Count, bone marrow (range)60 (0-100)62 (0-100)NS51 (2-98)51(1-100)NSMedian LDH (range)399 (63-12742)410 (105-10596)NS299 (93-2500)496 (116-15900)<0.001CR-rate (%)78.975.4NS57.960.6NSAlloHCT (%)32.322.10.00914.54.40.003 [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Renal safety of intravenous ibandronate 6mg infused over 15 or 60 minutes in patients with breast cancer and bone metastases: A randomized, open-label study

1114 Background: Clinical data show that a single 15-minute intravenous infusion of ibandronate (IA) 6mg is associated with no significant changes in renal functioning. The aim of this study was evaluation of renal safety of repeated 15-minute intravenous infusions of IA 6mg in women with breast cancer and bone metastases. Methods: Patients (n=127) were randomized to receive treatment with intravenous ibandronate as a 15-minute infusion (n=101) or as a 60-minute infusion (n=26) every 3–4 weeks. Patients were stratified according to previous treatment and the presence or absence of visceral metastases. All patients had serum creatinine within normal limits and calculated creatinine clearance =50mL/min as assessed prior to each infusion throughout the trial. The primary endpoint was the percentage of patients with an increase in serum creatinine from baseline of =44.2μmol/L (0.5mg/dL) at any point in the study. Results: Three percent of patients in the 15 minute infusion (3/101) met the primary endpoint with either hydronephrosis due to tumor, severe diarrhea or pre-existing diabetes with urinary tract infection. No patients in the 60-minute infusion arm (0/26) had an increase in serum creatinine that met the primary endpoint. No clinically relevant changes were seen in serum creatinine, calculated or measured creatinine clearance, or levels of N-acetyl-β-D- glucosaminidase, a1-microglobulin or microalbumin in either arm. There were no marked changes in mean bone pain or analgesic requirement scores. A slight increase in mean WHO performance status score was seen in both arms. Most adverse events were mild or moderate. No clinically-relevant mean changes were observed in vital signs, hematology, blood chemistry including renal function or urinalysis parameters. Renal impairment was related to IA in the 3 patients with increased serum creatinine. Conclusions: IA 6mg administered as a 15- minute intravenous infusion every 3–4 weeks had a renal safety profile consistent with that of the 60-minute infusion, suggesting that a 15-minute infusion of ibandronate 6mg is well-tolerated in patients with breast cancer and bone metastases. No significant financial relationships to disclose.