Influence of Height on Risk and Outcome of Patients with Early Breast Cancer: A Pooled Analysis of 4,925 Patients from 5 Randomized Trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).

Background: Associations between height, cancer risk and worse outcome have been reported for several cancers including breast cancer. We hypothesized that in breast cancer clinical trials, tall women should be overrepresented and might have worse prognosis. Methods: Data of 4,935 women, included from 1990 to 2010 in 5 trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG), were analyzed retrospectively. The primary objective was to determine differences in height distribution between the ABCSG cohort and the Austrian female population according to a cross-sectional health survey conducted by the Austrian Statistic Center in 2006 and 2007. Secondary endpoints were disease-free survival (DFS) and overall survival (OS) in different height classes and differences of body mass index (BMI) distribution. Results: Breast cancer patients in the ABCSG cohort were only slightly but statistically significantly smaller compared to unselected Austrian adult females (mean 164.3 vs. 164.8 cm; p < 0.0001) and significantly more patients were seen in the lower body height class (50 vs. 46%; p < 0.0001) when using the median as a cutoff. However, after adjustment for age, the difference in body height between the two cohorts was no longer significant (p = 0.089). DFS and OS in the two upper height groups (≥170 cm) compared to the two lowest height groups (<160 cm) was not significantly different (5-year DFS: 84.7 vs. 83.0%; HR 0.91, 95% CI 0.73-1.13, p = 0.379; 5-year OS: 94.8 vs. 91.7%; HR 0.74, 95% CI 0.55-1.00, p = 0.051). The BMI of ABCSG patients was significantly higher than in the reference population (mean BMI 24.64 vs. 23.96; p < 0.0001). Conclusions: Our results do not confirm previous findings that greater body height is associated with a higher breast cancer risk and worse outcome.

Assessing the impact of antiemetic guideline compliance on prevention of chemotherapy-induced nausea and vomiting: Results of the nausea/emesis registry in oncology (NERO).

BACKGROUND: Evidence-based antiemetic guidelines offer predominantly consistent recommendations for chemotherapy-induced nausea and vomiting (CINV) prophylaxis. However, studies suggest that adherence to these recommendations is suboptimal. We explored inconsistencies between clinical practice and guideline-recommended treatment with a registry evaluating the effect of guideline-consistent CINV prophylaxis (GCCP) on patient outcomes. PATIENTS AND METHODS: This was a prospective, non-interventional, multicentre study. The primary objective was to assess the overall (Days 1-5) complete response (CR: no emesis/no rescue use) rates in patients who received GCCP or guideline-inconsistent CINV prophylaxis (GICP) using diaries for 5 days following chemotherapy. Cycle 1 results are presented in patients who received either (1) anthracycline/cyclophosphamide (AC) highly emetogenic chemotherapy (HEC), non-AC HEC or carboplatin, with GCCP for all these groups consisting of prophylaxis with an NK1 receptor antagonist (RA), 5-HT3RA and dexamethasone prior to chemotherapy or (2) moderately emetogenic chemotherapy (MEC), with GCCP consisting of a 5-HT3RA and dexamethasone prior to chemotherapy as per MASCC/ESMO 2016 guidelines, in place at the time of the study. RESULTS: 1,089 patients were part of the cycle 1 efficacy evaluation. Overall GCCP was 23%. CR rates were significantly higher (P < 0.05) in patients receiving GCCP (62.2%) versus GICP (52.6%) in the overall population, as well as in the subsets of patients receiving AC/non-AC HEC (60.2% versus 47.8%), MEC (73.8% versus 57.8%) and in those non-naïve to the chemotherapy received (65.9% versus 53.8%). No impact on daily living due to CINV (FLIE assessment) was observed in 43.4% patients receiving GCCP versus 28.5% GICP (P < 0.001). CONCLUSION: Consistent with prior studies, GCCP was very low; a significant benefit of almost 10% improved prevention of CINV was observed with GCCP. As per MASCC/ESMO guidelines, such an absolute difference should be practice changing. Comprehensive multifaceted strategies are needed to achieve better adherence to antiemetic guidelines.

The cancer survival index-A prognostic score integrating psychosocial and biological factors in patients diagnosed with cancer or haematologic malignancies.

OBJECTIVE: We aimed to investigate whether (1) psychological and social indicators influence survival in patients diagnosed with cancer or haematologic malignancies when important biological aspects are controlled for, (2) psychological, social and biological indicators can be utilised to design one collated index for survival, usable in clinical practice to identify patients at risk of shorter survival and to improve personalised healthcare provision. METHODS: In this cross-sectional study, 2263 patients with cancer or haematologic malignancies participated. We analysed 15 biological, psychological and social indicators as risk factors for survival with a Cox proportional hazards model. Indicators significantly associated with survival were combined to compute models for the identification of patient groups with different risks of death. The training sample contained 1122 patients. Validation samples included the remaining 1141 patients, the total sample, as well as groups with different cancer entities. RESULTS: Five indicators were found to significantly impact survival: Cancer site (HR: 3.56), metastatic disease (HR: 1.88), symptoms of depression (HR: 1.34), female sex (HR: 0.73) and anaemia (HR: 0.48). Combining these indicators to a model, we developed the Cancer Survival Index, identifying three distinct groups of patients with estimated survival times of 47.2 months, 141 months and 198.2 months (p < 0.001). Post hoc analysis of the influence of depression on survival showed a mediating effect of the following four factors, related to both depression and survival: previous psychiatric conditions, employment status, metastatic disease and haemoglobin levels. CONCLUSIONS: Psychosocial and biological factors impact survival in various malignancies and can be utilised jointly to compute an index for estimating the survival of each patient individually-the Cancer Survival Index.

Tissue distribution of epirubicin after severe extravasation in humans.

PURPOSE: As critical parameter after extravasation of cytotoxic vesicants, anthracyclines were determined in removed tissue from patients requiring surgical intervention due to tissue necrosis. We monitored their distribution within the affected lesion to establish a possible dose-toxicity relation. METHODS: From six patients scheduled for surgery, removed tissue flaps were systematically analysed by HPLC (epirubicin: 5 subjects; doxorubicin: 1 subject). RESULTS: After extravasation, tissue concentrations were highly variable with an individual anthracycline distribution pattern ranging from a few nanograms up to 17 µg per 100 mg tissue, which indicated a substantial difference in tissue sensitivity among patients. The resection borders coincided with the extension of the erythema and guided the surgical intervention after demarcation of the lesion, which occurred usually 2 or 3 weeks after extravasation. At that time, drug was hardly detected at the resection borders. Wound drains were negative for the extravasated drugs while showing a time profile of vascular growth factors and inflammatory cytokines, which was highly similar to routine surgery. In all six patients, surgical debridement with immediate wound closure led to healing within approximately 2 weeks, when therapy was resumed in all patients with reasonable time delay. CONCLUSION: Surgical intervention after demarcation of the extravasation lesion allows for almost uninterrupted continuation of treatment independent of the amount of extravasated anthracycline. As even minor amounts of the vesicants may trigger tissue necrosis, preventive measures merit the highest priority.

Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported. METHODS: Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005-005275-15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58-95), 240 (14·0%) patients in the denosumab and 287 (16·8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0·82, 95% CI 0·69-0·98, Cox p=0·0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89·2% (95% CI 87·6-90·8) at 5 years and 80·6% (78·1-83·1) at 8 years of follow-up, compared with 87·3% (85·7-89·0) at 5 years and 77·5% (74·8-80·2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3·6%] of 1709 in the denosumab group vs 58 [3·4%] of 1690 in the placebo group), meniscus injury (23 [1·3%] vs 24 [1·4%]), and cataract (16 [0·9%] vs 28 [1·7%]). One (<0·1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group. INTERPRETATION: Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy. FUNDING: Amgen.

Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer.

BACKGROUND: Patients with prostate cancer are at risk of impaired bone health. Prostate cancer has a propensity to metastasize to bone, after which patients are at risk of skeletal-related events (SREs). These complications are associated with increased mortality, substantial pain, and reduced quality of life. Patients are also at risk of bone loss due to androgen deprivation therapy (ADT), which can be compounded in elderly patients with reduced bone density. It is essential, therefore, that aspects of bone health and therapies able to prevent the occurrence of SREs are considered throughout the clinical course of prostate cancer. METHODS: We reviewed the literature regarding the molecular mechanisms underpinning bone lesion formation, the modes of action of therapies that prevent SREs, and the efficacy and safety of these therapies in patients with hormone-sensitive or castration-resistant prostate cancer (CRPC). RESULTS: Therapies such as denosumab (a RANKL inhibitor) and zoledronic acid (a bisphosphonate) were indicated for prevention of SREs. Radium-223 dichloride also has proven efficacy in delaying symptomatic SREs, as well as in improving overall survival through effects on bone metastases. Before development of bone metastases, low-dose denosumab may also be used for treatment of ADT-associated bone loss. Denosumab may also have the potential to delay bone metastases development in patients with CRPC, although this is not currently an approved indication. The safety profile of therapies to prevent SREs should be considered. This review consolidates the available evidence on use of denosumab and bisphosphonates in prostate cancer, differentiated by hormone-sensitive and castration-resistant disease. CONCLUSIONS: There is convincing evidence to support the use of denosumab and bisphosphonates to maintain bone health in patients with prostate cancer. Clinicians should be mindful of the adverse event risk profile of these therapies.

Subclinical involvement of the liver is associated with prognosis in treatment naïve cancer patients.

BACKGROUND: Routinely tested liver biomarkers as alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), butyryl-cholinesterase (BChE), albumin and bilirubin are altered in distinct malignancies and hepatic metastases. This study aimed to investigate whether all liver parameters have the ability to predict long-term mortality in treatment naïve cancer patients but without a malignant hepatic involvement. METHODS: We prospectively enrolled 555 consecutive patients with primary diagnosis of cancer without prior anticancer therapy. BChE, albumin, AST, ALT, GGT and bilirubin as well as the inflammatory makers C-reactive protein (CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) were determined. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR16-31) months 186 (34%) patients died. All liver parameters were significantly associated with all-cause mortality (p < 0.001 for all). However, for patients without a malignant primary or secondary hepatic involvement (82%) only the functional parameters BChE and albumin remained significantly associated with the primary endpoint (crude HR per 1-IQR increase 0.61, 95%CI:0.49-0.77; p < 0.001 for BChE and 0.58, 95%CI:0.47-0.70; p < 0.001 for albumin). This e ect was persistent after multivariate adjustment (adj.HR per 1-IQR increase 0.65, 95%CI:0.50-0.86; p = 0.002 for BChE and 0.63, 95%CI:0.50-0.79; p < 0.001 for albumin). BChE and albumin correlated inversely with CRP (r = -0.21, p < 0.001 and r = -0.36, p < 0.001), SAA (r = -0.19, p < 0.001 and r = -0.33, p < 0.001) and IL-6 (r = -0.13, p = 0.009 and r = -0.17, p = 0.001). CONCLUSIONS: Decreased serum BChE and albumin levels are associated with increased all-cause mortality in treatment-naïve cancer patients without a manifest malignant hepatic involvement irrespective of tumor entity or stage. This association may reflect progressing systemic inflammation and metabolic derangement with subclinical involvement of the liver.

The European Society for Medical Oncology Magnitude of Clinical Benefit Scale in daily practice: a single institution, real-life experience at the Medical University of Vienna.

BACKGROUND: The European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) has been designed to stratify the therapeutic benefit of a certain drug registered for the treatment of cancer. However, though internally validated, this tool has not yet been evaluated for its feasibility in the daily practice of a major center of medical oncology. METHODS: The practicability of the MCBS for advanced oncological diseases at the Clinical Division of Oncology, Medical University of Vienna, which constitutes one of the largest oncological centres in Europe, was analysed in a three-step approach. First, retrospectively collected data were analysed to gain an overview of treatments in regular use. Second, data were scored by using the MCBS. Third, the ensuing results were evaluated within corresponding programme directorships to assess feasibility in a real-life clinical context. RESULTS: In the majority of tumour entities, the MCBS results reported earlier are consistent with daily clinical practice. Thus, in metastatic breast cancer or advanced lung cancer, there was a high level of clinical benefit for first-line treatment standards, and these results reflected well real-life experience. However, analyses based on the first version of the MCBS are limited if it comes to salvage treatment in tumour entities in which optimal sequencing of potential treatment options is of major importance, as in metastatic colorectal or renal cell cancer. In contrast to this, it is remarkable that certain novel therapies such as nivolumab assessed for heavily pretreated advanced renal cancer reached the highest level of clinical benefit due to prolongation in survival and a favourable toxicity profile. The MCBS clearly underlines the potential benefit of these compounds. CONCLUSIONS: The MCBS is an excellent tool for daily clinical practice of a tertiary referral centre. It supports treatment decisions based on the clinical benefit to be expected from a novel approach such as immunotherapy in as yet untested indications.

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. METHODS: In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. INTERPRETATION: Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. FUNDING: Roche.

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

OBJECTIVE: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. METHODS: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. CONCLUSIONS: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. METHODS: In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. INTERPRETATION: Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. FUNDING: Amgen.

Outcome of chemotherapy extravasation in a large patient series using a standardised management protocol.

PURPOSE: In a longitudinal observation, extravasation of antitumoural compounds and the efficacy of its structured interdisciplinary management were assessed in a routine setting. METHODS: One hundred sixty-nine patients with extravasation of cytotoxics were managed according to a prospective approach documenting the extravasated compound, localisation, duration until full symptom resolution and sequelae. Surgery was implemented in the case of failure of conservative measures. RESULTS: In 155 (91.7 %) out of 169 patients, conservative management was successful (surgical intervention, 14 patients). Extravasations of anthracyclines (N = 44), platinum compounds (N = 41), vinca alkaloids (N = 20) and taxanes (N = 19) were often associated with erythema, oedema and pain. The median period until full resolution of symptoms differed among the administered cytotoxics (anthracyclines, 55 days; taxanes and vinca alkaloids, 27 days; platinum compounds, 14 days) with statistical significance between the vesicants. Histologically, surgically resected specimens showed extensive necrotic areas with inflammatory infiltrates at the periphery of the removed lesions. CONCLUSIONS: In a routine setting, the standardised management of cytotoxic extravasations by an interdisciplinary task force resulted in a satisfactory outcome. When surgical intervention was indicated, complete remission of the lesions within a median of 14 days reduced the delay in the administration of further chemotherapy to a minimum. The proposed approach is therefore considered as suitable to manage extravasations in cancer chemotherapy in a large number of subjects and to ensure patient adherence to cytotoxic treatment.

Indocyanine green video angiography predicts outcome of extravasation injuries.

BACKGROUND: Extravasation of cytotoxic drugs is a serious complication of systemic cancer treatment. Still, a reliable method for early assessment of tissue damage and outcome prediction is missing. Here, we demonstrate that the evaluation of blood flow by indocyanine green (ICG) angiography in the extravasation area predicts for the need of surgical intervention. METHODS: Twenty-nine patients were evaluated by ICG angiography after extravasation of vesicant or highly irritant cytotoxic drugs administered by peripheral i.v. infusion. Tissue perfusion as assessed by this standardized method was correlated with clinical outcome. RESULTS: The perfusion index at the site of extravasation differed significantly between patients with reversible tissue damage and thus healing under conservative management (N = 22) versus those who needed surgical intervention due to the development of necrosis (N = 7; P = 0.0001). Furthermore, in patients benefiting from conservative management, the perfusion index was significantly higher in the central extravasation area denoting hyperemia, when compared with the peripheral area (P = 0.0001). CONCLUSIONS: In this patient cohort, ICG angiography as indicator of local perfusion within the extravasation area was of prognostic value for tissue damage. ICG angiography could thus be used for the early identification of patients at risk for irreversible tissue damage after extravasation of cytotoxic drugs.

Pegfilgrastim prophylaxis in patients at different levels of risk for chemotherapy-associated febrile neutropenia: an observational study.

BACKGROUND: Guidelines for using granulocyte colony-stimulating factor (G-CSF) in patients receiving chemotherapies with 10-20% (intermediate) risk for febrile neutropenia (FN) recommend additional assessment of patient-related FN risk factors. OBJECTIVE: The current study evaluated adherence to guideline recommendations and analysed modalities of pegfilgrastim use. METHODS: Adult cancer patients scheduled to receive a chemotherapy regimen assessed by the investigators as intermediate FN risk and who received pegfilgrastim were prospectively enrolled in this observational study from 2007-2010. Risk factors at study entry, treatment modalities and FN assessment were documented by investigators, whereas guideline adherence was centrally checked in a post-hoc analysis, according to guideline categorizations. RESULTS: Thirty-seven centres enrolled 335 evaluable patients with solid and hematologic neoplasias. Although physicians initially rated the FN risk of all chemotherapies as intermediate, after central re-assessment this applied only to 63.9% of regimens; 21.2% were reassessed as low risk and 14.9% as high risk. Pegfilgrastim was used as primary prophylaxis in 80.3% of all patients. The most frequent FN risk factors considered by physicians when deciding to use pegfilgrastim were female gender, advanced disease, age ≥ 65 years, and anaemia. FN incidence was higher in patients with ≥ 4 FN risk factors than those with <4 risk factors (10% vs. 4.3%; p = 0.055) and in patients with severe comorbidity than those without (13.6% vs. 4.5%; p = 0.014). Overall FN rate was 5.7%. LIMITATIONS: Due to the observational design of the study, findings are descriptive in nature. Post-hoc assessment of chemotherapy FN risk was determined by author's opinion in some cases. CONCLUSIONS: Overall, there was good adherence of Austrian physicians to guideline recommendations; however, there are chemotherapy regimens and clinical settings in which FN risk assignment is unclear in the literature. FN incidence with pegfilgrastim prophylaxis was similar to that reported in other observational and randomized studies.

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial.

BACKGROUND: Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or capecitabine significantly improves progression-free survival and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine has not been investigated. We compared the efficacy of the two regimens. METHODS: In this open-label, non-inferiority, phase 3 trial, patients with HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease were randomised (by computer-generated sequence; 1:1 ratio; block size six; stratified by hormone receptor status, country, and menopausal status) to receive either intravenous bevacizumab (10 mg/kg on days 1 and 15) plus intravenous paclitaxel (90 mg/m(2) on days 1, 8, and 15) repeated every 4 weeks (paclitaxel group) or intravenous bevacizumab (15 mg/kg on day 1) plus oral capecitabine (1000 mg/m(2) twice daily on days 1-14) repeated every 3 weeks (capecitabine group) until disease progression or unacceptable toxic effects. Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel. We report results of an interim overall survival analysis, which was planned for after 175 deaths in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, we randomised 564 patients (paclitaxel group n=285; capecitabine group n=279) from 51 centres in 12 countries. The per-protocol population consisted of 533 patients (paclitaxel group n=268; capecitabine group n=265). After median follow-up of 18·6 months (IQR 14·9-24·7), 181 patients in the per-protocol population had died (89 [33%] in the paclitaxel group; 92 [35%] in the capecitabine group). The hazard ratio [HR] for overall survival was 1·04 (97·5% repeated CI -∞ to 1·69; p=0·059); the non-inferiority criterion of the interim analysis (interim α=0·00105) was not met. More patients who received bevacizumab plus paclitaxel had an objective response than did those who received bevacizumab plus capecitabine (125 [44%] of 285 patients vs 76 [27%] of 279; p<0·0001). Similarly, progression-free survival was significantly longer in the paclitaxel group than in the capecitabine group (median progression-free survival 11·0 months [95% CI 10·4-12·9] vs 8·1 months [7·1-9·2]; HR 1·36 [95% CI 1·09-1·68], p=0·0052). The most common adverse events of grade 3 or higher were neutropenia (51 [18%]), peripheral neuropathy (39 [14%]), and leucopenia (20 [7%]) in the paclitaxel group and hand-foot syndrome (44 [16%]), hypertension (16 [6%]), and diarrhoea (15 [5%]) in the capecitabine group. One treatment-related death occurred in the paclitaxel group; no deaths in the capecitabine group were deemed to be treatment-related. INTERPRETATION: In this planned interim analysis, the non-inferiority criterion was not met and overall survival results are inconclusive. Final results are expected in 2014. Progression-free survival was better, and more patients achieved an objective response, with bevacizumab plus paclitaxel than with bevacizumab plus capecitabine. Efficacy results in both groups were consistent with previous reports. FUNDING: Central European Cooperative Oncology Group; Roche.

Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid.

PURPOSE: Denosumab was shown to be superior to zoledronic acid in preventing skeletal related events (SRE) in patients with breast cancer and bone metastases in a randomized, double-blind phase III study. We evaluated further results from this study related to skeletal complications and health-related quality of life (HRQoL). EXPERIMENTAL DESIGN: Patients were randomized 1:1 to receive subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. Analyses reported here include the proportion of patients with one or multiple on-study SREs, time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in HRQoL (functional assessment of cancer therapy-general). RESULTS: Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%, P = 0.006). The incidence of first radiation to bone was 12% (n = 123) with denosumab versus 16% (n = 162) with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid (HR, 0.74; 95% confidence interval [CI], 0.59-0.94, P = 0.012) and prolonged the time to first SRE or hypercalcemia of malignancy by 18% (HR, 0.82; 95% CI, 0.70-0.95; P = 0.007). Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels. CONCLUSIONS: Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained HRQoL, providing an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer.

Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group.

PURPOSE: Anastrozole (ANA) alone delivers significant disease-free survival benefits over tamoxifen (TAM) monotherapy in postmenopausal women with early estrogen receptor-positive breast cancer. The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study is a large phase III clinical trial addressing the sequence strategy containing ANA in comparison with 5 years of TAM in a low- to intermediate-risk group of postmenopausal patients. PATIENTS AND METHODS: Endocrine receptor-positive patients with G1 or G2 tumors were eligible. After surgery, patients were randomly assigned to 5 years of TAM or 2 years of TAM followed by 3 years of ANA. Adjuvant chemotherapy and G3 and T4 tumors were exclusion criteria. Intention-to-treat and censored analyses of on-treatment recurrence-free survival (RFS) were performed, and exploratory survival end points and toxicity were investigated. RESULTS: Information from 3,714 patients, including 17,563 woman-years, with a median of 60 months of follow-up was available for this analysis. Median age was 63.8 years, 75% were node negative, and 75% had T1 tumors. Sequencing of ANA after identical 2-year treatment with TAM in both arms did not result in a statistically significant improvement of RFS (hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.01; P = .06). Exploratory analyses of distant relapse-free survival indicated a 22% improvement (HR, 0.78; 95% CI, 0.60 to 1.00). On-treatment adverse events and serious adverse events were consistent with known toxicity profiles of ANA and TAM treatment. CONCLUSION: Despite a low overall rate of recurrence in a population with breast cancer at limited risk of relapse, the a priori sequence strategy of 2 years of TAM followed by 3 years of ANA led to small outcome and toxicity benefits.