World Health Organization Performance Status Research Articles

The outcome of surgical treatment for peri-acetabular metastases

We reviewed the outcome of patients who had been treated operatively for symptomatic peri-acetabular metastases and present an algorithm to guide treatment. The records of 81 patients who had been treated operatively for symptomatic peri-acetabular metastases between 1987 and 2010 were identified. There were 27 men and 54 women with a mean age of 61 years (15 to 87). The diagnosis, size of lesion, degree of pelvic continuity, type of reconstruction, World Health Organization performance status, survival time, pain, mobility and complications including implant failure were recorded in each case. The overall patient survivorship at five years was 5%. The longest lived patient survived 16 years from the date of diagnosis. The mean survival was 23 months (< 1 to 16 years) and the median was 15 months. At follow-up 14 patients remained alive. Two cementoplasties failed because of local disease progression. Three Harrington rods broke: one patient needed a subsequent Girdlestone procedure. One 'ice-cream cone' prosthesis dislocated and was subsequently revised without further problems. We recommend the 'ice-cream cone' for pelvic discontinuity and Harrington rod reconstruction for severe bone loss. Smaller defects can be safely managed using standard revision hip techniques.

Combined Chemoradiation Therapy With Twice-Weekly Gemcitabine and Cisplatin for Organ Preservation in Muscle-Invasive Bladder Cancer: Long-Term Results of a Phase 1 Trial

Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.

Abstract OT3-2-09: FALCON: A randomised, double-blind, multicentre, phase III study comparing fulvestrant 500 mg with anastrozole 1 mg for postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer who have not previously been treated with any hormonal therapy

Abstract Background: The Phase III CONFIRM study demonstrated that a higher dose (500 mg) of fulvestrant, an estrogen receptor (ER) antagonist for treatment of advanced breast cancer, was associated with a significant increase in progression-free survival (PFS) without increased toxicity versus fulvestrant 250 mg.Moreover, a Phase II study (FIRST) showed that first-line treatment with fulvestrant 500 mg was at least as effective as anastrozole 1 mg with a similar safety profile. The aim of the FALCON study is to investigate whether fulvestrant 500 mg is superior to anastrozole 1 mg as first-line endocrine therapy. FALCON is the only Phase III study in recent years to compare two endocrine therapies as first-line treatment in metastatic breast cancer (MBC); hence, results may potentially affect standard clinical practice in the future. Trial design: This is a randomised, double-blind, double-dummy, international, multicentre study comparing efficacy and tolerability of fulvestrant with anastrozole (NCT01602380). Eligible patients are randomised 1:1 to receive fulvestrant 500 mg or anastrozole 1 mg, and stratified at randomisation based on whether (1) they have locally advanced or MBC (2) they have received prior chemotherapy for locally advanced or MBC or not and (3) they have measurable or non-measurable disease. Eligibility criteria: Eligible are postmenopausal women with histologically confirmed, ER-positive, locally advanced or MBC who have not previously received any endocrine therapy. Patients may have received one line of cytotoxic chemotherapy but must show progressive disease prior to enrolment, have a World Health Organisation performance status of 0, 1 or 2 and at least one lesion that can be accurately assessed at baseline and is suitable for repeated assessment according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1) guidelines. Specific aims: The primary objective is to demonstrate the superior PFS of patients treated with fulvestrant 500 mg versus patients treated with anastrozole 1 mg. Secondary objectives include comparison of the overall survival (OS), the objective response rate (ORR), the clinical benefit rate (CBR) and quality of life (QoL) between the treatment groups, as well as safety and tolerability assessments. Statistical methods: Comparison of PFS and OS for fulvestrant 500 mg versus anastrozole 1 mg will be performed using a stratified log-rank test. A multiple testing procedure will be used to control the overall type 1 error rate at 2.5% (1-sided). Results will be presented as an estimated hazard ratio, associated confidence interval and p-value. ORR and CBR will be analysed using a logistic regression model and examination of the odds ratio of the 2 treatment groups. A time to deterioration analysis will be performed for QoL endpoints. Present accrual and target accrual: Recruitment is currently ongoing; on June 6, 2013, 101 patients had been randomised. The recruitment target is 450 patients; 124 study sites worldwide are currently initiated. Contact information: Please contact the authors for specific information about this study. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-09.

Primary CNS lymphoma treated with radiotherapy in Japan: a survey of patients treated in 2005–2009 and a comparison with those treated in 1985–2004

The aim of our study was to analyze changes over time in the characteristics, treatment, and outcome of patients with primary central nervous system lymphoma (PCNSL). Data on 315 patients with histologically proven PCNSL undergoing radiotherapy between 2005 and 2009 were collected from 20 Japanese institutions using a questionnaire. These data were then compared with data on 273 patients treated during the period 1995-2004 and those on 466 patients treated during the period 1985-1994. In terms of patient and tumor characteristics, we found a significant increase in mean patient age in the 2005-2009 period compared to the 1985-2004 period (63 vs. 58-59 years, respectively) and in the percentage of patients with better performance status (PS) during the 2005-2009 period compared with the 1995-2004 period (World Health Organization PS 0-2: 73 vs. 65 %, respectively). Regarding treatment, relative to the 1995-2004 period, significant changes in the 2005-2009 period were (1) decreased rate of attempting tumor resection (23 vs. 44 %); (2) increased use of chemotherapy (78 vs. 68 %), and (3) increased use of methotrexate (MTX)-containing regimens (84 vs. 53 %). The 5-year overall survival rates were 15.3, 30.1, and 36.5 % for patients seen during the 1985-1994, 1995-2004, and 2005-2009 periods, respectively, but relapse-free survival did not improve between the 1995-2004 and 2005-2009 periods (26.7 vs. 25.7 % at 5 years, respectively). Patients receiving MTX-containing chemotherapy had 5-year survival rates of 19, 50, and 44 % during these three periods, respectively. Although patient backgrounds differed among the study periods, recent trends were a high patient age, better PS, avoidance of extensive tumor resection, more frequent use of chemotherapy, and improved survival. The recent improvement in survival may be due to improvements in second-line treatment and supportive care.

Treatment of newly diagnosed malignant glioma in the elderly people: new trials that impact therapy

Glioblastoma (GB), World Health Organization Grade 4 glioma, is the most common malignant primary brain tumour with an annual incidence of 12,943 cases in the United States . It is a tumour of the elderly people with a median age of onset of 64 years, although children and young adults are also affected. GB is associated with a poor prognosis; despite best treatment, most community-based patients will not survive 1 year . Cures are rare and overall survival rates at 2 and 5 years are 26-48% and 12%, respectively, in highly selected, contemporary, clinical trial eligible patients . For protocol eligible US patients, the median survival is 16-17 months, which is partly a reflection of improved supportive care, recognition of pseudoprogression, exclusion of patients undergoing biopsy only and availability of bevacizumab at recurrence . Initial treatment for patients with high performance [Karnofsky Performance Status (KPS) > 60 and age < 71 years) consists of maximal safe surgical resection followed by adjuvant focal, external beam radiotherapy (RT) with concurrent temozolomide (TMZ) chemotherapy and post-RT TMZ for 6 months . TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials . The current standard treatment is based upon a European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) randomised, phase 3 trial of 573 patients with newly diagnosed GB (age 19-71 years and World Health Organization Performance Status ≤ 2) that compared RT alone [total dose 60 Gray (Gy)] to TMZ chemotherapy in combination with RT (total 60 Gy), followed by 6 months of post-RT TMZ (4,6,8).

Clinical management patterns and treatment outcomes in patients with non-small cell lung cancer (NSCLC) across Europe: EPICLIN-Lung study

Background:Throughout Europe, physicians face similar challenges in non-small cell lung cancer (NSCLC) management, but comprehensive international information on usual clinical practice is lacking so the burden of NSCLC is not fully understood.Methods:This multinational, multicentre, non-interventional study (NCT00831909) was conducted in eight European countries. Patients with confirmed NSCLC were consecutively enrolled from January to March 2009 and followed for 12 months or until death. Information was collected on patient and disease characteristics, diagnosis and treatment patterns, and clinical outcomes. Spontaneously reported adverse events (AEs) were also recorded.Results:Data were available for 3508 patients. Most patients (77.5%) were male, median (range) age was 65.0 years (21.6–90.7), the majority of patients had a World Health Organization performance status of ≤1 (74.7%), and 10.8% were never smokers. The most prevalent histologies were adenocarcinoma (43.8%) and squamous-cell carcinoma (29.4%). Most patients presented with advanced disease (11.6% with stage IIIA, 18.7% with stage IIIB, 48.6% with stage IV). In stage IV disease, median progression-free survival and overall survival (months) by first-line treatment cluster were platinum regimens: 6.5, 10.8; non-platinum regimens: 4.3, 8.5; regimens with bevacizumab 8.7, 12.9; investigational regimens: 5.6, 10.8; best supportive care: 5.4, 6.6. The most frequently reported severe (Common Terminology Criteria for Adverse Events v3.0 >2) AEs were blood/bone marrow (16.0%) and pulmonary/upper respiratory (7.8%). Key limitations of this study related to its non-interventional nature and wide regional focus; for example, achieving a representative sample of the overall NSCLC population, variation in recruitment between countries, and data based on information from medical records derived from routine visits.Conclusions:The Epidemiological Study to Describe NSCLC Clinical Management Pattern in Europe–Lung (EPICLIN-Lung) study provides new insights into the descriptive patterns and clinical management strategies for NSCLC across Europe, and how they affect patient outcomes.

C-MYC Expression In Newly Diagnosed Multiple Myeloma

BackgroundOverexpression of the c-MYC proto-oncogene plays an important role in the malignant phenotype of Burkitt lymphoma and diffuse large B cell lymphoma, but its role in multiple myeloma (MM) is controversial. Dysregulation of c-MYC, which is highly prevalent in human MM cell lines, is classically described as a late progression event. Translocations involving the c-MYC locus are reported to be present in approximately 13 % of newly diagnosed MM patients. However, a recent study showed expression of a MYC activation signature in 67 % of MM, and found c-MYC expression in 60 % of patients by immunohistochemistry (IHC). It has been suggested, that c-MYC expression is associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to MM, as an early event of MM pathogenesis, and that such a MYC addiction might have a useful therapeutic potential. However, the prevalence and the clinical associations of c-MYC expression among newly diagnosed MM patients need further assessment. PurposeWe conducted a retrospective IHC study to evaluate the prevalence of c-MYC expression in newly diagnosed MM. Secondly, we wanted to assess, whether c-MYC expression was associated with factors known to influence prognosis, such as the patient's clinical and laboratory features, end organ damage, International staging system (ISS) stage, and response to primary treatment. Thirdly, we wanted to assess, whether c-MYC expression was associated with known immunophenotypic variables in MM, such as CD20, Pax-5, Cyclin D1, and CD56. Material and methodsBone marrow aspirates from 119 patients diagnosed with MM from 2005-2010 were examined retrospectively. Tissue microarrays (TMAs) were constructed from formalin fixed, paraffin embedded samples using four 1mm cores from each patient sample. IHC was carried out with commercially available antibodies. Plasma cells were identified with anti-CD138 IHC. For detection of c-MYC, we used an anti-c-MYC rabbit monoclonal antibody obtained from Epitomics (Clone EP121). Samples were evaluated as c-MYC-positive, if at least 30 % of tumour cell nuclei were stained. Clinical data were obtained from the Danish Multiple Myeloma Database. Patients who received primary treatment (n=96) were examined separately based on whether they were treated with high-dose therapy (HDT) (n=31) or other treatment regimens (n=65). Response rates to primary treatment were evaluated. Associations between variables were assessed by calculating Fisher's exact tests. ResultsThe TMAs yielded sufficient material for assessment of c-MYC expression in 87 % of the study population. c-MYC expression was found in 44 (43 %) patients. At the time of diagnosis, c-MYC expression was significantly associated with the presence of extra-medullary myeloma (p = 0.026) and higher than the mean (36.6 %) bone marrow infiltration (p = 0.005). There were trends for c-MYC-positive patients to have World Health Organization (WHO) performance status 2 (p = 0.071) and hypercalcemia (p = 0.086). c-MYC expression was not associated with ISS stage, anemia, renal insufficiency or the evidence of bone disease. Among the patients who were not eligible for HDT, c-MYC expression had a trend to preclude achievement of complete response (CR) after primary treatment (p = 0.061). Only 5 patients achieved CR in this group, and all were c-MYC-negative. Such a trend was not found among patients who were treated with HDT, where c-MYC expression was not associated with specific response rates. Expression of CD20, Pax-5, Cyclin D1, and CD56 were found in 16 %, 38 %, 43 %, and 73 % of patients, respectively. c-MYC expression was not associated with any of the assessed immunophenotypic variables. Discussion and Conclusionc-MYC expression was found in almost half of newly diagnosed MM patients, which supports the theory that c-MYC activation is an early event in MM pathogenesis. c-MYC expression was associated with extra-medullary myeloma and high bone marrow infiltration, both factors known to have a negative effect on prognosis. Patient survival could not be evaluated in this cohort due to limited observation periods, but the results suggest that c-MYC expression should be studied further in patient cohorts with longer observation periods. Also, the mechanisms behind c-MYC expression should be addressed in future studies. c-MYC expression was not associated with the expression of CD20, Pax-5, Cyclin D1, or CD56. Disclosures:No relevant conflicts of interest to declare.

An international phase 3 trial in head and neck cancer: Quality of life and symptom results

The European Organization for Research and Treatment of Cancer (EORTC) 24954 phase 3 randomized clinical trial compared 2 schemes of combined chemotherapy for patients with resectable cancers of the hypopharynx and larynx: sequential induction chemotherapy and radiotherapy versus alternating chemoradiotherapy. The current study reports detailed effects of both treatment arms on health-related quality of life (HRQOL) and symptoms. A total of 450 patients aged 35 years to 76 years (World Health Organization performance status (WHO PS) ≤ 2) with untreated, resectable advanced squamous cell carcinoma of the larynx (tumor classification of T3-T4) or hypopharynx (tumor classification of T2-T3-T4) with regional lymph nodes in the neck classified as N0 to N2 with no metastases were randomized in this prospective phase 3 trial into either the sequential arm (control) or the alternating arm (experimental). QOL assessment was performed at randomization; at baseline; at 42 days; and at 6, 12, 24, 36, and 48 months. There were no observed differences with regard to the primary endpoint of Fatigue and secondary endpoint of Dyspnea. Significant differences were found in the secondary endpoints of Swallowing and Speech problems at 42 days after randomization in favor of patients in the sequential arm. Explanatory and sensitivity analysis revealed that the primary analysis favored the sequential arm, but the majority of differences in HRQOL did not exist at the end of treatment, and returned to baseline levels. In the current study, a trend toward worse scores was noted in the patients treated on the alternating chemoradiotherapy arm but very few differences reached the level of statistical significance. The HRQOL scores of the majority of patients returned to baseline after therapy.

A global analysis of multitrial data investigating quality of life and symptoms as prognostic factors for survival in different tumor sites

The objective of this study was to examine the prognostic value of baseline health-related quality of life (HRQOL) for survival with regard to different cancer sites using 1 standardized and validated patient self-assessment tool. In total, 11 different cancer sites pooled from 30 European Organization for Research and Treatment of Cancer (EORTC) randomized controlled trials were selected for this study. For each cancer site, univariate and multivariate Cox proportional hazards modeling was used to assess the prognostic value (P< .05) of 15 HRQOL parameters using the EORTC Core Quality of Life Questionnaire (QLQ-C30). Models were adjusted for age, sex, and World Health Organization performance status and were stratified by distant metastasis. In total, 7417 patients completed the EORTC QLQ-C30 before randomization. In brain cancer, cognitive functioning was predictive for survival; in breast cancer, physical functioning, emotional functioning, global health status, and nausea and vomiting were predictive for survival; in colorectal cancer, physical functioning, nausea and vomiting, pain, and appetite loss were predictive for survival; in esophageal cancer, physical functioning and social functioning were predictive for survival; in head and neck cancer, emotional functioning, nausea and vomiting, and dyspnea were predictive for survival; in lung cancer, physical functioning and pain were predictive for survival; in melanoma, physical functioning was predictive for survival; in ovarian cancer, nausea and vomiting were predictive for survival; in pancreatic cancer, global health status was predictive for survival; in prostate cancer, role functioning and appetite loss were predictive for survival; and, in testis cancer, role functioning was predictive for survival. The current results demonstrated that, for each cancer site, at least 1 HRQOL domain provided prognostic information that was additive over and above clinical and sociodemographic variables.

Brain Metastases from Thyroid Carcinoma: A Retrospective Study of 21 Patients

Brain metastases (BM) from differentiated thyroid carcinoma (DTC) are uncommon, and many questions about their management remain unsolved. The objective of this retrospective study was to analyze the characteristics, treatments, and outcomes of patients with BM from DTC. Among the 1523 patients with a DTC prospectively recorded in institutional databases between 1989 and 2012, 21 patients (1.4%) with BM were retrospectively retrieved. Patient characteristics, histological findings on initial thyroidectomy specimen, treatments, and time to death were reviewed. Overall survival (OS) was calculated using the Kaplan-Meier method. Survival curves for various subgroups of patients according to baseline characteristics and treatment received were compared. The mean age at initial and BM diagnosis was, respectively, 52.7 and 63.2 years. World Health Organization performance status (PS) at BM diagnosis was good (<2) for 12 patients and poor (≥2) for 9. The initial carcinoma was papillary for 12 patients, follicular for 5, and poorly differentiated for 4. Eighteen patients had other previous and/or synchronous distant metastases: lung (11), bone (10), and others (2 peritoneum, 1 liver, 1 adrenal gland, and 1 uterine cervix). The average interval between the first metastasis and the BM was 3 years (range 0-35.6 years). The mean number and the mean size of BM were, respectively, 2.8 (range 1-10) and 22.5 mm (range 3-44 mm). Surgery was performed for 10 patients and radiotherapy (RT) for 18, with 2 stereotactic radiosurgery (SRS), 2 conformal RT limited to the metastasis, and 15 whole-brain RT. The median OS after BM was 7.1 months. OS at 1 and 2 years were 41.6% and 35.6%. PS and realization of surgery or SRS had an impact on survival, with OS of 27 months when PS <2 versus 3 months when PS ≥2 (p=0.0009), and OS of 11.9 months after surgery or SRS versus 3.6 months in their absence (p=0.04). BM from thyroid cancer may have an indolent evolution with survival of one to two years or longer for specific groups of patients. Therefore, aggressive treatment options such as neurosurgery and RT should be strongly considered in patients with good PS.

New clinical, pathological and molecular prognostic models and calculators in patients with locally diagnosed anaplastic oligodendroglioma or oligoastrocytoma. A prognostic factor analysis of European Organisation for Research and Treatment of Cancer Brain Tumour Group Study 26951

BackgroundThe prognosis of patients with anaplastic oligodendrogliomas (AOD) and oligoastrocytomas (AOA) is variable. Biomarkers might be helpful to identify more homogeneous disease subtypes and improve therapeutic index. The aim of this study is to develop new clinical, pathological and molecular prognostic models for locally diagnosed anaplastic gliomas with oligodendroglial features (AOD or AOA). MethodsData from 368 patients with AOD or AOA recruited in The European Organisation for Research and Treatment of Cancer (EORTC) trial 26951 on adjuvant PCV (Procarbazine, CCNU, Vincristine) chemotherapy in anaplastic oligodendroglial tumours were used to develop multifactor models to predict progression free survival (PFS) and overall survival (OS). Different models were compared by their percentage of explained variation (PEV). Prognostic calculators were derived from these new models. ResultsTreatment (for PFS only), younger age, confirmed absence of residual tumour on imaging, frontal location, good World Health Organisation (WHO) performance status, absence of endothelial abnormalities and/or necrosis, 1p/19q codeletion and Isocitrate dehydrogenase 1 (IDH1) mutation were independent factors that predicted better PFS and OS. ConclusionsWe identified important prognostic factors for AOD and AOA and showed that molecular markers added a major contribution to clinical and pathological factors in explaining PFS and OS. With a positive predictive value of 92% for PFS and 94% for OS, our models allow physicians to precisely identify high risk patients and aid in making therapeutic decisions.

Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel versus carboplatin/docetaxel in initial treatment of metastatic Her-2-negative breast cancer

In view of the previous reports demonstrating the positive outcome of bevacizumab in metastatic breast cancer, we aimed at comparing the role of bevacizumab-based metronomic combination with taxane (paclitaxel) versus a different taxane (docetaxel)-based regimen in addition to carboplatin as initial treatment for metastatic Her-2-negative breast cancer. This is a randomized Phase III study comparing the progression-free survival (PFS) and safety in Her-2-negative female patients with initial diagnosis of metastatic breast cancer with World Health Organization performance status of 0-II. Forty-one patients were randomized from September 2008 to July 2009 to receive either; (1) bevacizumab 5 mg/kg day 1 and day 15, carboplatin area under the curve (AUC)-2 day 1, day 8, and day 15, and paclitaxel 60 mg/m(2) day 1, day 8, and day 15 (arm-I); or (2) carboplatin AUC-5 day 1, docetaxel 75 mg/m(2) day 1 (arm-II). The Kaplan-Meier method was used for estimating survival; log-rank test for comparing survival curves. The primary end point was PFS, and secondary end points were overall survival (OS) and safety. PFS was 10 months in arm I versus 10.2 months in arm II (P = 0.9). The OS rate was similar in both arms: 37.6 months for arm I versus 37.4 months for arm II (P = 0.92). The toxicity revealed higher incidence of hypertension and proteinuria in arm I; however, with higher incidence of grade III-IV neutropenia and neutropenic fever in arm II. No treatment-related mortality was recorded. Bevacizumab/carboplatin/paclitaxel and carboplatin/docetaxel show comparable PFS and OS with different toxicity profiles.

Gemcitabine Plus Capecitabine in Unselected Patients With Advanced Pancreatic Cancer

Gemcitabine in combination with capecitabine (GEMCAP) is a treatment option for patients with advanced pancreatic cancer (APC), but data are lacking concerning outcomes in unselected patients not enrolled to a randomized trial. Baseline demographic, clinical, toxicity, tumor response, and survival data were collected for previously untreated patients with APC receiving off-protocol GEMCAP at a single institution between 2005 and 2009. Data from 113 patients were included in the study. The mean age was 65 years; 51% of patients had metastatic disease; and 80% were of World Health Organization performance status 0 or 1. Patients received a mean of 20 weeks of chemotherapy. The objective response rate was 9.7%; the median overall survival was 8.7 months (95% confidence interval, 6.7-10.7), and 34% of patients were alive 1 year after starting treatment. Performance status (0 or 1 vs 2) was a significant prognostic factor (P < 0.0001). Grade 3 or 4 adverse events, excluding nonfebrile neutropenia, were experienced by 37 patients (33%), the commonest being lethargy (8%), hand-foot syndrome (8%), diarrhea (7%), thrombocytopenia (4%), and febrile neutropenia (6%). Gemcitabine in combination with capecitabine is effective and tolerable in unselected patients with APC, and outcomes are comparable with those of patients receiving GEMCAP in clinical trials.

Can the prognosis of individual patients with glioblastoma be predicted using an online calculator?

In an exploratory subanalysis of the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada (EORTC/NCIC) trial data, Gorlia et al. identified a variety of factors that were predictive of overall survival, including therapy administered, age, extent of surgery, mini-mental score, administration of corticosteroids, World Health Organization (WHO) performance status, and O-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Gorlia et al. developed 3 nomograms, each intended to predict the survival times of patients with newly diagnosed glioblastoma on the basis of individual-specific combinations of prognostic factors. These are available online as a "GBM Calculator" and are intended for use in patient counseling. This study is an external validation of this calculator. One hundred eighty-seven patients from 2 UK neurosurgical units who had histologically confirmed glioblastoma (WHO grade IV) had their information at diagnosis entered into the GBM calculator. A record was made of the actual and predicted median survival time for each patient. Statistical analysis was performed to assess the accuracy, precision, correlation, and discrimination of the calculator. The calculator gives both inaccurate and imprecise predictions. Only 23% of predictions were within 25% of the actual survival, and the percentage bias is 140% in our series. The coefficient of variance is 76%, where a smaller percentage would indicate greater precision. There is only a weak positive correlation between the predicted and actual survival among patients (R(2) of 0.07). Discrimination is inadequate as measured by a C-index of 0.62. The authors would not recommend the use of this tool in patient counseling. If departments were considering its use, we would advise that a similar validating exercise be undertaken.

Prospective, multicenter, randomized, independent-group, open-label phase II study to investigate the efficacy and safety of three regimens with two doses of sagopilone as second-line therapy in patients with stage IIIB or IV non-small-cell lung cancer

IntroductionSagopilone is the first fully synthetic epothilone in clinical development and has proven preclinical activity in tumor models. This multicenter, randomized, open-label, phase II study examined the efficacy and safety of three regimens with two doses and two infusion durations of second-line sagopilone in pretreated patients with stage IIIB or IV non-small-cell lung cancer. MethodsEligibility criteria included: at least one measurable lesion by modified response evaluation criteria in solid tumors; World Health Organization performance status of 0 or 1; and failure of previous platinum-based chemotherapy. Patients were randomized to receive: 16mg/m2 sagopilone over 3h (treatment arm A); 22mg/m2 sagopilone over 0.5h (treatment arm B); or 22mg/m2 sagopilone over 3h (treatment arm C). Treatment duration was two to six courses every 3 weeks; more than six treatment courses were permitted if there was sustained clinical benefit. The primary efficacy endpoint was best overall response after six courses; at least five confirmed responders per arm indicated a successful outcome. ResultsIn total, 128 patients (44, arm A; 41, arm B; 43, arm C) were randomized; 127 received at least one infusion of sagopilone. Baseline demographic data were similar across all arms. Eight patients across all arms had a confirmed partial response; the primary endpoint was not achieved. The most frequently reported adverse event (AE) was peripheral sensory neuropathy (75%). Most hematologic AEs were grade 1 or 2. ConclusionAs fewer than five patients per arm responded after six treatment courses, the primary endpoint was not met. Sagopilone was only moderately tolerated. Most AEs, including peripheral neuropathy, were grade 1 or 2; hematologic toxicities were rare.

Evaluation of Patient Enrollment in Oncology Phase I Clinical Trials

For anticancer drug development, it is crucial that patients participate in early-phase clinical trials. The main aim of this study was to gain insight into the motivations and other variables influencing patients in their decision to participate in phase I oncology trials. Over a period of 25 months, all patients who were informed about (specific) phase I trials in our cancer center were retrospectively included in this study. Data on providing informed consent and final phase I enrollment were collected. In total, 365 patients, with a median age of 59 years and a median World Health Organization performance status score of 1, were evaluated. The majority of patients (71%) were pretreated with systemic therapy, with a median of two lines. After specific study information had been given, 145 patients (40%) declined informed consent, 54% of them mainly because of low expectations regarding treatment benefits and concerns about potential side effects. Patients who had received previous systemic therapy consented more frequently than others. After initial consent, 61 patients (17%) still did not receive study treatment, mostly because of secondary withdrawal of consent or rapid clinical deterioration prior to first dosing. After specific referral to our hospital for participation in early clinical trials, only 44% of all patients who were informed about a specific phase I trial eventually participated. Reasons for both participation and nonparticipation were diverse. Patient participation rates could be improved by forming an experienced and dedicated study team.

Pain characteristics and management of inpatients admitted to a comprehensive cancer centre: a cross‐sectional study

This prospective, cross-sectional study aimed to assess cancer pain and its management in an inpatient setting at a comprehensive cancer centre in Denmark. One hundred and eighty-eight inpatients with cancer were invited to participate (May/June 2011). Demographics, diagnoses, World Health Organization performance status, health-related quality of life, pain and data regarding analgesic treatment were registered. One hundred and thirty-four (71.3%) patients agreed to participate in the study. Most frequent diagnoses were leukaemia (27.6%) and lung cancer (14.2%). A high prevalence of pain was observed, 65.7%. Thirty-two per cent reported moderate to severe pain when it was at its worst, 96% reported no or mild pain when it was at its least. Nearly 22% reported moderate to severe pain when the pain was categorised as average. Breakthrough pain episodes were reported by 30.5%. Adjuvant medication was sparsely used and not always correctly indicated. Out of 88 patients with pain, 62.5% were left untreated according to the Electronic Medication System. Higher health-related quality of life was associated with lower pain intensity. The use of opioids with or without adjuvants was associated with higher pain intensity and higher number of breakthrough pain episodes. Approximately two thirds of inpatients reported pain and one third had breakthrough pain. A substantial number of patients with pain were left untreated. Opioid-treated patients reported highest pain intensity and number of breakthrough episodes; however, analgesic medication seemed to be underused. Measures to improve pain assessment and management are highly required.

Anemia and performance status as prognostic markers in acute hypercapnic respiratory failure due to chronic obstructive pulmonary disease.

BackgroundIn patients with acute hypercapnic respiratory failure (AHRF) during exacerbations of COPD, mortality can be high despite noninvasive ventilation (NIV). For some, AHRF is terminal and NIV is inappropriate. However there is no definitive method of identifying patients who are unlikely to survive. The aim of this study was to identify factors associated with inpatient mortality from AHRF with respiratory acidosis due to COPD.MethodsCOPD patients presenting with AHRF and who were treated with NIV were studied prospectively. The forced expiratory volume in 1 second (FEV1), World Health Organization performance status (WHO-PS), clinical observations, a composite physiological score (Early Warning Score), routine hematology and biochemistry, and arterial blood gases prior to commencing NIV, were recorded.ResultsIn total, 65 patients were included for study, 29 males and 36 females, with a mean age of 71 ± 10.5 years. Inpatient mortality in the group was 33.8%. Mortality at 30 days and 12 months after admission were 38.5% and 58.5%, respectively. On univariate analysis, the variables associated with inpatient death were: WHO-PS ≥ 3, long-term oxygen therapy, anemia, diastolic blood pressure < 70 mmHg, Early Warning Score ≥ 3, severe acidosis (pH < 7.20), and serum albumin < 35 g/L. On multivariate analysis, only anemia and WHO-PS ≥ 3 were significant. The presence of both predicted 68% of inpatient deaths, with a specificity of 98%.ConclusionWHO-PS ≥ 3 and anemia are prognostic factors in AHRF with respiratory acidosis due to COPD. A combination of the two provides a simple method of identifying patients unlikely to benefit from NIV.

Effects of Cardiovascular Drugs on Mortality in Severe Chronic Obstructive Pulmonary Disease

Cardiovascular drugs may improve survival in chronic obstructive pulmonary disease (COPD). However, previous studies did not account for major sources of bias, and drug effects have not been evaluated in severe COPD. To estimate the time-dependent effects of cardiovascular drugs on survival in oxygen-dependent COPD, accounting for immortal and immeasurable time bias. Prospective national study of patients starting long-term oxygen therapy for COPD in Sweden between 1 October 2005 and 30 June 2009. Effects on mortality were estimated using extended Cox regression adjusted for age, sex, PaO2, PaCO2, World Health Organization performance status, body mass index, comorbidity, and concomitant medications. Immortal and immeasurable time bias was addressed by analyzing all medications as time-dependent variables and accounting for hospitalized time, respectively. Time-dependent effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, antiplatelet drugs, β-blockers, and statins on all-cause mortality were measured. Of the 2,249 included patients, 1,129 (50%) died under observation. No patient was lost to follow-up. The adjusted time-dependent model was compatible with reduced mortality for antiplatelet drugs (hazard ratio [HR], 0.86; 95% CI, 0.75-0.99; P = 0.030) and trends for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (HR, 0.90; 95% CI, 0.79-1.04; P = 0.166) and statins (HR, 0.86; 95% CI, 0.72-1.03; P = 0.105), whereas β-blockers increased mortality (HR, 1.19; 95% CI, 1.04-1.37; P = 0.010). This study supports that antiplatelet drugs improve survival and β-blockers decrease survival in oxygen-dependent COPD.

Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus

To assess tumour regression grade (TRG) and lymph node downstaging to help define patients who benefit from neoadjuvant chemotherapy. Two hundred and eighteen consecutive patients with adenocarcinoma of the esophagus or gastro-esophageal junction treated with surgery alone or neoadjuvant chemotherapy and surgery between 2005 and 2011 at a single institution were reviewed. Triplet neoadjuvant chemotherapy consisting of platinum, fluoropyrimidine and anthracycline was considered for operable patients (World Health Organization performance status ≤ 2) with clinical stage T2-4 N0-1. Response to neoadjuvant chemotherapy (NAC) was assessed using TRG, as described by Mandard et al. In addition lymph node downstaging was also assessed. Lymph node downstaging was defined by cN1 at diagnosis: assessed radiologically (computed tomography, positron emission tomography, endoscopic ultrasonography), then pathologically recorded as N0 after surgery; ypN0 if NAC given prior to surgery, or pN0 if surgery alone. Patients were followed up for 5 years post surgery. Recurrence was defined radiologically, with or without pathological confirmation. An association was examined between t TRG and lymph node downstaging with disease free survival (DFS) and a comprehensive range of clinicopathological characteristics. Two hundred and eighteen patients underwent esophageal resection during the study interval with a mean follow up of 3 years (median follow up: 2.552, 95%CI: 2.022-3.081). There was a 1.8% (n = 4) inpatient mortality rate. One hundred and thirty-six (62.4%) patients received NAC, with 74.3% (n = 101) of patients demonstrating some signs of pathological tumour regression (TRG 1-4) and 5.9% (n = 8) having a complete pathological response. Forty four point one percent (n = 60) had downstaging of their nodal disease (cN1 to ypN0), compared to only 15.9% (n = 13) that underwent surgery alone (pre-operatively overstaged: cN1 to pN0), (P < 0.0001). Response to NAC was associated with significantly increased DFS (mean DFS; TRG 1-2: 5.1 years, 95%CI: 4.6-5.6 vs TRG 3-5: 2.8 years, 95%CI: 2.2-3.3, P < 0.0001). Nodal down-staging conferred a significant DFS advantage for those patients with a poor primary tumour response to NAC (median DFS; TRG 3-5 and nodal down-staging: 5.533 years, 95%CI: 3.558-7.531 vs TRG 3-5 and no nodal down-staging: 1.114 years, 95%CI: 0.961-1.267, P < 0.0001). Response to NAC in the primary tumour and in the lymph nodes are both independently associated with improved DFS.