Medication adherence with denosumab in patients with bone metastases from solid tumors treated in routine clinical settings: a retrospective study.

PURPOSE: To describe (non)adherence with denosumab among patients with solid tumors and bone metastases. METHODS: This retrospective, observational study pooled data from two completed prospective, multicenter cohort studies (X-TREME; Study 240) in adult patients with bone metastases from primary breast, prostate, lung, kidney, or other solid cancer types and administered denosumab 120 mg in routine clinical practice in Germany and Central and Eastern Europe. The studies were conducted between May 2012 and May 2017; pooled analysis was completed in August 2021. Medication adherence was described according to a three-component consensus taxonomy: initiation (first-ever administration ≤ 90 days from bone metastasis diagnosis), implementation (actual vs prescribed dosing; optimal implementation = regular/consistent dosing), and persistence (≤ 60-day gap between administrations at 3, 6, 9, and 12 months). Descriptive analyses were conducted for each cancer type. RESULTS: The analysis included 1748 patients with solid tumors and bone metastases. Adherence with denosumab was generally high across the initiation, implementation, and persistence phases. Most patients experienced timely initiation (from 64.4% [kidney cancer] to 81.2% [breast cancer]) and optimal implementation (from 62.4% [lung cancer] to 72.5% [breast cancer]). The proportion of patients who were persistent with treatment at 6 months ranged from 41.4% (lung cancer) to 77.8% (prostate cancer). CONCLUSIONS: This study revealed variations by cancer type in the initiation, implementation, and persistence of denosumab in patients with solid tumors and bone metastases in routine clinical practice. Further cancer-specific studies are warranted to examine the determinants of (non)adherence with denosumab, and potential ways to improve medication adherence.

Diagnosis, Therapy and Follow-up of Cervical Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry No. 032/033OL, May 2021) - Part 2 with Recommendations on Psycho-oncology, Rehabilitation, Follow-up, Recurrence, Palliative Therapy and Healthcare Facilities.

Aim This is an update of the interdisciplinary S3-guideline on the Diagnosis, Therapy and Follow-up of Cervical Cancer (AWMF Registry No. 032/033OL), published in March 2021. The work on the updated guideline was funded by German Cancer Aid (Deutsche Krebshilfe) as part of the German Guideline Program in Oncology. The guideline was coordinated by the German Society of Gynecology and Obstetrics ( Deutsche Gesellschaft für Gynäkologie und Geburtshilfe , DGGG) and the Working Group on Gynecological Oncology ( Arbeitsgemeinschaft Gynäkologische Onkologie , AGO) of the German Cancer Society ( Deutsche Krebsgesellschaft , DKG). Method The process used to update the 2014 S3-guideline was based on an appraisal of the available evidence using the criteria of evidence-based medicine, adaptations of existing evidence-based national and international guidelines or - if evidence was lacking - on the consensus of the specialists involved in compiling the update. After an initial review of the current literature was carried out according to a prescribed algorithm, several areas were identified which, in contrast to the predecessor version from September 2014, required new recommendations or statements which would take account of more recently published literature and the recent appraisal of new evidence. Recommendations The short version of this guideline consists of recommendations and statements on palliative therapy and follow-up of patients with cervical cancer. The most important aspects included in this updated guideline are the new FIGO classification published in 2018, the radical open surgery approach used to treat cervical cancer up to FIGO stage IB1, and the use of the sentinel lymph node technique for tumors ≤ 2 cm. Other changes include the use of PET-CT, new options in radiotherapy (e.g., intensity-modulated radiotherapy, image-guided adaptive brachytherapy), and drug therapies to treat recurrence or metastasis.

Diagnosis, Therapy and Follow-up of Cervical Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry No. 032/033OL, May 2021) - Part 1 with Recommendations on Epidemiology, Screening, Diagnostics and Therapy.

Aim This update of the interdisciplinary S3 guideline on the Diagnosis, Therapy and Follow-up of Cervical Cancer (AWMF Registry No. 032/033OL) was published in March 2021. This updated guideline was funded by German Cancer Aid (Deutsche Krebshilfe) as part of the German Guideline Program in Oncology. The guideline was coordinated by the German Society of Gynecology and Obstetrics ( Deutsche Gesellschaft für Gynäkologie und Geburtshilfe , DGGG) and the Working Group on Gynecological Oncology ( Arbeitsgemeinschaft Gynäkologische Onkologie , AGO) of the German Cancer Society ( Deutsche Krebsgesellschaft , DKG). Method The process of updating the S3 guideline dating from 2014 was based on an appraisal of the available evidence using the criteria of evidence-based medicine, adaptations of existing evidence-based national and international guidelines or - if evidence was lacking - on a consensus of the specialists involved in compiling the update. After an initial review of the current literature was carried out according to a prescribed algorithm, several areas were identified which, in contrast to the predecessor version from September 2014, required new recommendations or statements which took account of more recently published literature and the appraisal of the new evidence. Recommendations The short version of this guideline consists of recommendations and statements on the epidemiology, screening, diagnostic workup and therapy of patients with cervical cancer. The most important new aspects included in this updated guideline include the newly published FIGO classification of 2018, the radical open surgery approach for cervical cancers up to FIGO stage IB1, and use of the sentinel lymph node technique for tumors ≤ 2 cm. Other changes include the use of PET-CT, new options in radiotherapy (e.g., intensity-modulated radiotherapy, image-guided adaptive brachytherapy), and drug therapies to treat recurrence or metastasis.

Chemotherapy-induced peripheral neuropathy (CIPN): current therapies and topical treatment option with high-concentration capsaicin.

Cancer diagnosis and treatment are drastic events for patients and their families. Besides psychological aspects of the disease, patients are often affected by severe side effects related to the cancer itself or as a result of therapeutic interventions. Particularly, chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of oral or intravenous chemotherapy. The disorder may require dose reduction of chemotherapy and is accompanied by multiple symptoms with long-term functional impairment affecting quality of life (QoL), e.g., sensory and functional deteriorations as well as severe pain. Although CIPN may reverse or improve after termination of the causative chemotherapy, approximately 30-40% of patients are faced with chronicity of the symptoms. Due to the advantages in cancer diagnosis and treatments, survival rates of cancer patients rise and CIPN may occur even more frequently in the future. In this review, we summarize current recommendations of leading national and international societies regarding prevention and treatment options in CIPN. A special focus will be placed on current evidence for topical treatment of CIPN with high-dose capsaicin. Finally, an algorithm for CIPN treatment in clinical practice is provided, including both pharmacologic and non-pharmacologic modalities based on the clinical presentation.

Real-world use of denosumab and bisphosphonates in patients with solid tumours and bone metastases in Germany.

PURPOSE: Bisphosphonates and denosumab prevent bone complications in patients with bone metastases from solid tumours. This retrospective, longitudinal, cohort study provides data on their real-world use in this setting in Germany. METHODS: Adults with bone metastases from breast, prostate or lung cancer who were newly initiated on a bisphosphonate or denosumab between 1 July 2011 and 31 December 2015 were identified from a German healthcare insurance claims database. Primary outcomes included persistence, compliance, discontinuation and switch rates at 12 months. RESULTS: This study included 1130 patients with bone metastases: 555 (49%) had breast cancer, 361 (32%) prostate cancer and 242 (21%) lung cancer. Mean age was 65 years for patients with breast or lung cancer and 74 years for those with prostate cancer. Across all tumour types, compared with any bisphosphonate, 12-month persistence was higher with denosumab (breast cancer 78% vs 54-58%, prostate cancer 58% vs 50%, lung cancer 68% vs 34-60%), median time to discontinuation was longer with denosumab and switch rates were lower for denosumab (breast cancer 5% vs 14-19%, prostate cancer 2% vs 11%, lung cancer 3% vs 7-12%). Compliance at 12 months was longer for denosumab than for any bisphosphonate in breast cancer (75% vs 42-48%) and in prostate cancer (47% vs 36%). CONCLUSIONS: Patients initiated on denosumab following a diagnosis of bone metastases from breast, prostate or lung cancer had greater medication persistence, longer time to discontinuation, improved compliance and lower switch rates than those initiated on a bisphosphonate.

Guideline adherence in bone-targeted treatment of cancer patients with bone metastases in Germany.

PURPOSE: To assess adherence to the current European Society for Medical Oncology (ESMO) clinical practice guideline on bone health in cancer patients and the German guidelines for lung, breast, and prostate cancer among German oncologists in hospitals and office-based physicians and to identify predictors of guideline compliance to assess the needs for dedicated training. METHODS: This was a retrospective sample analysis representing hospitals and office-based physicians in Germany in 2016. Records from lung, breast, and prostate cancer patients who had received a diagnosis of bone metastasis between April 1, 2015, and March 31, 2016, were included. Oncologists at participating centers answered a self-assessment survey on aspects related to their professional life, including guideline adherence and years of clinical experience in medical oncology. Guideline adherence rates were assessed from patient records. Treatment variables and survey data were used to identify predictors of guideline compliance in a Classification and Regression Tree (CART) analysis. RESULTS: Disregarding recommendations for supplementation of calcium and vitamin D, guideline adherence among physicians treating lung, breast, or prostate cancer patients was 62%, 92%, and 83%, respectively. Compliance was 15%, 42%, and 40% if recommendations for dietary supplements were taken into account. Identified predictors of guideline compliance included treatment setting, medical specialty, years of professional experience, and frequency of quality circle attendance. CONCLUSIONS: Compliance with the ESMO and the German guidelines in cancer patients varies between medical specialties. In particular, patients with lung cancer and bone metastases often do not receive the recommended osteoprotective treatment and required supplementation. Discrepancies between guideline recommendations and common practice should be addressed with dedicated training.

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2019.

Every year the Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO), a group of gynecological oncologists specialized in breast cancer and interdisciplinary members specialized in pathology, radiologic diagnostics, medical oncology, and radiation oncology, prepares and updates evidence-based recommendations for the diagnosis and treatment of patients with early and metastatic breast cancer. Every update is performed according to a documented rule-fixed algorithm, by thoroughly reviewing and scoring the recent publications for their scientific validity and clinical relevance. This current publication presents the 2019 update on the recommendations for metastatic breast cancer.

Real-world safety experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim, short-acting recombinant human granulocyte colony-stimulating factors.

PURPOSE: Recombinant granulocyte colony-stimulating factors (rG-CSFs), such as filgrastim, are administered to prevent complications in patients receiving chemotherapy. In Europe, a biosimilar to filgrastim, tevagrastim/ratiograstim/biograstim, was approved in 2008. In the USA, the same product was approved as tbo-filgrastim under a 351(a) biologic license application in 2012 with the brand name Granix®. Postmarket surveillance remains a priority for monitoring the safety of biologics and biosimilars to identify rare and immunogenicity-related events. We report the global and US pharmacovigilance data for tevagrastim/ratiograstim/biograstim and tbo-filgrastim, respectively. METHODS: Cumulative exposure and adverse event data from initial approval in Europe to December 31, 2016, were collected globally from spontaneous reports submitted by healthcare professionals and consumers, scientific literature, competent authorities, and solicited case reports from non-interventional studies. A separate search was conducted on the global data set to identify reports originating from the USA and Puerto Rico to describe the US experience. RESULTS: Overall, the global safety profile of tevagrastim/ratiograstim/biograstim in the postmarket, real-world setting was comparable to clinical trial experience. Postmarket safety experience of tbo-filgrastim in the USA was consistent with global data. The most common SAEs were febrile neutropenia and decreased white blood cell count. The most common non-serious event was bone pain. There was no evidence of immunogenicity. CONCLUSIONS: This pharmacovigilance analysis indicates that postmarket experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim is consistent with clinical trials. Adverse reactions associated with the originator rG-CSF (capillary leak syndrome and glomerulonephritis) have not been observed with tevagrastim/ratiograstim/biograstim or tbo-filgrastim during the postmarket period.

Early identification and intervention matters: A comprehensive review of current evidence and recommendations for the monitoring of bone health in patients with cancer.

Bone metastases are common in patients with advanced solid tumors, and many individuals experience debilitating skeletal-related events (SREs; e.g. pathologic fracture, hypercalcemia, radiotherapy or surgery to bone, and spinal cord compression). These events substantially affect disease outcomes, including survival and quality of life, and healthcare systems. Plain radiography is the most widely used imaging modality for the detection of bone metastases; skeletal scintigraphy, computed tomography, positron emission tomography and magnetic resonance imaging offer greater sensitivity but their use in routine practice is restricted by high costs and limited availability. Biomarkers of bone turnover may also have a role in the early detection of bone metastases and can provide valuable prognostic information on disease progression. SREs can be delayed or prevented using agents such as the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor, denosumab, and bisphosphonates. Painful bone metastases can be treated with radiofrequency ablation, radiotherapy, or radionuclides such as radium-223 dichloride, which has been shown to delay the onset of SREs in men with castration-resistant prostate cancer. Close monitoring of bone health in patients with advanced cancer may lead to early identification of individuals with bone metastases who could benefit from early intervention to prevent SREs. This review examines current guideline recommendations for assessing and monitoring bone health in patients with advanced cancer, use of biomarkers and treatment of patients with bone metastases. The emerging evidence for the potential survival benefit conferred by early intervention with denosumab and bisphosphonates is also discussed, together with best practice recommendations.

Intravenous pamidronate versus oral and intravenous clodronate in bone metastatic breast cancer: a randomized, open-label, non-inferiority Phase III trial.

PURPOSE: Patients with metastasized breast cancer often suffer from discomfort caused by metastatic bone disease. Thus, osteoprotection is an important part of therapy in breast cancer metastasized to bone, and bisphosphonates (BPs) are a major therapeutic option. In this study, our objectives were to compare the side effects of oral versus intravenous BP treatment and to assess their clinical effectiveness. PATIENTS AND METHODS: In this prospective randomized, open-label, non-inferiority trial, we enrolled breast cancer patients with at least one bone metastasis and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned to one of the three treatment groups: A, 60 mg pamidronate intravenously q3w; B-iv, 900 mg clodronate intravenously q3w; and B-o, 2,400 mg oral clodronate daily. Assessments were performed at baseline and every 3 months thereafter. RESULTS: Between 1995 and 1999, 321 patients with confirmed bone metastases from breast cancer were included in the study. At first follow-up, gastrointestinal (GI) tract side effects were most common, and adverse effects on the GI tract were more frequent in the oral treatment group (P=0.002 and P<0.001, respectively). There were no statistically significant differences among the treatment cohorts for other documented side effects (skin, serum electrolytes, urinary tract, immune system, and others). No significant differences in clinical effectiveness of BP treatment, as assessed by pain score, were detected among the groups; however, pathologic fractures were more effectively prevented by intravenous than oral BP administration (P=0.03). Noncompliance rates were similar among the study cohorts. CONCLUSION: We conclude that oral BP treatment is significantly associated with higher rates of adverse GI side effects. Additionally, our data indicate that intravenous BP administration is more effective than oral treatment in prevention of pathologic fractures; hence, oral administration should be considered with caution.

Management of Metastatic Bone Disease Algorithms for Diagnostics and Treatment.

BACKGROUND: Bone is a frequent site of metastases in advanced cancer and is associated with significant skeletal morbidity. Current treatment options are aimed at preserving and improving functional independence and quality of life. MATERIALS AND METHODS: A review of current literature focusing on diagnostic tools and treatment approaches of bone metastasis in advanced cancer was performed and conclusions were incorporated into diagnostic and treatment algorithms. RESULTS: Radiologic imaging has added valuable tools for screening and diagnostics of bone metastasis. Clinical management of skeletal metastasis includes improved pain management, introduction of bone modifying agents and advancements in surgical and radiation therapy. We propose three algorithms enhancing the sensitivity of diagnostics and improving multidisciplinary management of vertebral and non-vertebral bone metastasis. CONCLUSION: Bone metastases are an expression of a systemic disease. Treatment options include highly specialized modalities yet need to be tailored to individual needs. Algorithms help standardize treatment procedures and can improve treatment outcome in a multidisciplinary setting.

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer.

PURPOSE: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. METHODS: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. RESULTS: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9%) and 31 (1.2%) in the denosumab and ZA groups, respectively. In total, 32 (6.9%) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1%, in patients continuing and switching to denosumab, respectively. CONCLUSION: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports.

Disseminated Tumor Cells in the Bone Marrow of Patients with Operable Primary Breast Cancer: Prognostic Impact in Immunophenotypic Subgroups and Clinical Implication for Bisphosphonate Treatment.

BACKGROUND: Disseminated tumor cells (DTC) in the bone marrow (BM) of primary breast cancer (BC) patients are a promising surrogate marker of micrometastatic spread and an independent predictor of poor prognosis for disease-free survival (DFS) and overall survival (OS). The present study aims to analyze DTCs as an independent prognostic factor for DFS/OS in tumor biology and bisphosphonate treatment. METHODS: A total of 504 patients with operable primary BC and a median observation time of 72.3 months [lower quartile (LQ) 58.1; upper quartile (UQ) 82.8] have been included. DTCs were detected via immunohistochemistry as MUC-1 positive cells in the BM of 59.13 % (298 of 504) of the patients. The immunophenotyping of cancer cells was achieved immunohistochemically as well. RESULTS: For luminal A/B carcinoma patients, we observed a significant benefit of BM DTC negativity with respect to DFS (luminal A, P = 0.0498; luminal B, P = 0.0224). In triple-negative patients, DTC-negative BM was associated with a longer OS (P = 0.0326). In a multivariate Cox survival analysis relating to DFS and OS, the DTC status was identified as an independent prognostic factor for DFS in luminal A/B BC (P = 0.0071). A multivariate Cox survival analysis among DTC-positive patients with luminal immunophenotype showed bisphosphonate application (P = 0.0326) to be an independent prognostic factor for DFS. CONCLUSIONS: The findings of our multivariate analyses reveal BM DTC positivity as an independent risk factor for DFS particularly in luminal A/B BC patients. This might be a novel criterion for the identification of candidates most likely to benefit from additional adjuvant therapy possibly including bisphosphonates.

14th St. Gallen International Breast Cancer Conference 2015: Evidence, Controversies, Consensus - Primary Therapy of Early Breast Cancer: Opinions Expressed by German Experts.

The key topics of this year's 14th St. Gallen Consensus Conference on the diagnosis and therapy of primary breast cancer were again questions about breast surgery and axillary surgery, radio-oncology and systemic therapy options in consideration of tumor biology, and the clinical application of multigene assays. This year, the consensus conference took place in Vienna. From a German perspective, it makes sense to substantiate the results of the vote of the international panel representing 19 countries in light of the updated national therapy recommendations of the AGO (Arbeitsgemeinschaft Gynäkologische Onkologie). Therefore, 14 German breast cancer experts, 3 of whom are members of the International St. Gallen Panel, have commented on the voting results of the St. Gallen Consensus Conference 2015 in relation to clinical routine in Germany.

The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease.

BACKGROUND: We compared the activity of denosumab with zoledronic acid for delaying or preventing hypercalcaemia of malignancy (HCM) in patients with advanced cancer and bone metastases or with multiple myeloma. METHODS: Patient-level data were combined from two identically designed, randomised, double-blind, active-controlled, phase III trials of advanced cancer patients with breast cancer and other solid tumours (excluding breast or prostate cancer) or multiple myeloma. End-points included time to first on-study HCM, time to first and subsequent on-study HCM, proportion of patients experiencing HCM and proportion of patients experiencing recurrent HCM. RESULTS: Denosumab significantly delayed the time to first on-study HCM, representing a 37% reduction in the hazard ratio (HR) compared with zoledronic acid (HR, 0.63; 95% confidence interval (CI): 0.41-0.98; P = 0.042) and reduced the risk of developing recurrent HCM (time to first and subsequent on-study HCM) by 52% (rate ratio, 0.48; 95% CI: 0.29-0.81; P = 0.006). The median time on study was 12.9 months. Fewer patients receiving denosumab compared with zoledronic acid experienced an HCM event (1.7% versus 2.7%; P = 0.028). Of the 84 patients experiencing an HCM event, 40% of those receiving zoledronic acid experienced >1 event of HCM compared with 31% of those receiving denosumab. CONCLUSION: Denosumab treatment was more efficacious than treatment with zoledronic acid in delaying or preventing HCM in advanced cancer patients with breast cancer, other solid tumours or multiple myeloma.

NADIR: A Non-Interventional Study on the Prophylaxis of Chemotherapy-Induced Neutropenia Using Lipegfilgrastim - First Interim Analysis.

BACKGROUND: The non-interventional study (NIS) NADIR was designed to assess the effectiveness and safety of lipegfilgrastim, a novel glycopegylated granulocyte-colony stimulating factor, in reducing the risk of both febrile and severe neutropenia. METHODS: Here, the interim analysis of NIS Nadir performed under real-world conditions at 80 oncology practices across Germany is reported. For a patient to be included, lipegfilgrastim at a subcutaneous single dose of 6 mg had to be administered during at least 1 cycle of the chemotherapy under consideration. RESULTS: The interim analysis included 224 patients. Median patient age was 61.1 years (interquartile range 51.2-70.2 years). Main tumor type was breast cancer followed by lung cancer, and non-Hodgkin's lymphoma (46.0, 13.4, and 10.7%, respectively). When lipegfilgrastim was given as primary prophylaxis, no patient developed febrile neutropenia (FN). 1.3% of patients developed FN when primary prophylaxis was withheld. Only 68.6% of patients undergoing chemotherapy and at high risk (> 20%) of developing FN were treated with lipegfilgrastim during the first cycle, exposing disparity between real-world practices and current treatment guidelines. Lipegfilgrastim was well tolerated. The only grade 3/4 treatment-related adverse event was anemia in 1 patient. CONCLUSION: Lipegfilgrastim was effective and safe when administered for the prevention of chemotherapy-induced neutropenia under real-world conditions.

German adjuvant intergroup node-positive study: a phase III trial to compare oral ibandronate versus observation in patients with high-risk early breast cancer.

PURPOSE: Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. PATIENTS AND METHODS: The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-ß of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. RESULTS: Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). CONCLUSION: Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.