First-line Treatment With Bendamustine and Rituximab for Old and Frail Patients With Aggressive Lymphoma: Results of the B-R-ENDA Trial.

The incidence of aggressive B-cell lymphomas increases with age, but for elderly or frail patients not eligible for doxorubicin-containing treatment standard therapy remains to be defined. In this prospective, multicenter, phase-2 B-R-ENDA trial, we investigated the feasibility, toxicity, and efficacy of 8 cycles rituximab combined with 6 cycles bendamustine (BR) in elderly or frail aggressive B-cell lymphoma patients: 39 patients aged >80 years and 29 patients aged 61-80 years with elevated Cumulative Illness Rating Scalescore >6 were included. Progression-free survival (PFS) and overall survival (OS) at 2 years were 45% (95% confidence interval [CI], 28%-61%) and 46% (28%-63%) for the patients age >80, as well 32% (13%-51%) and 37% (17%-57%) for frail patients age 64-80, respectively. In a preplanned retrospective analysis, we found no significant differences in PFS and OS comparing the outcome of the 39 patients age >80 years with 40 patients aged 76-80 years treated with 6xR-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and 2 x rituximab in the RICOVER-60 trial (DSHNHL 1999-1, NCT00052936, EU-20243), yet we detected lower rates of infections and treatment-related deaths in the BR-treated patients. We demonstrate that older and frail patients with aggressive B-cell lymphoma who are not able to receive standard CHOP-based therapy can benefit from anthracycline-free therapy as a feasible and effective therapeutic option.

Trabectedin for Patients with Advanced Soft Tissue Sarcoma: A Non-Interventional, Prospective, Multicenter, Phase IV Trial.

This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23-84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3-6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6-21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile.

Dual HER2 blockade with pertuzumab (P) and trastuzumab (T) in patients with HER2-positive metastatic breast cancer (mBC) relapsing after adjuvant treatment with T: results from a German non-interventional study (NIS) HELENA (NCT01777958).

PURPOSE: NIS HELENA documented outcomes in clinical routine practice of first-line therapy with P plus T and docetaxel (D) of patients with advanced HER2-positive BC and prior (neo)adjuvant T. METHODS: Between 06/2013 through 07/2016, 126 patients (in-label use of P at study start = full analysis set, FAS) in 81 German study sites were included. Intense documentation period was limited to 28 treatment cycles. Maximum follow-up (FU) was 24 months (mos). Safety was assessed in the safety set (SAF = eligible patients with at least one dose of P, n = 132). Median progression-free survival (PFS) was the main parameter of interest. RESULTS: Mean age of FAS patients was 55.1 [30.7-80.2] years, 81.7% (95.2%) were < 65 (75) years of age. 51.6% of the FAS patients were hormone receptor-positive (HR+), 91.3% had distant, 73.0% visceral, and 18.3% non-visceral metastases. Median disease-free interval was 40.2 [6.6-95.9] mos. Effectiveness (FAS): Median PFS was 18.8 [15.1; 24.2] mos. Overall response rate was 64.3% (55.6; 72.1). Median overall survival was 55.9 mos [41.2, not reached]. Safety (SAF): 93.9% of patients had an adverse event (AE), 32.6% a serious AE (SAE). AEs related to P occurred in 53.8% of SAF, SAEs related to P in 13.6%. Diarrhea was the most frequently reported related (S)AE. There were 8 (6.1%) patients with a fatal AE. CONCLUSION: Based on the outcomes from NIS HELENA, results of dual blockade with P+T in patients relapsing after (neo)adjuvant T as reported from the CLEOPATRA study (NCT01777958) can be transferred to routine clinical practice. No new safety signals were detected.

Treatment of Metastatic Colorectal Carcinoma with Bevacizumab in First-Line and beyond First Progression: The KORALLE Non-Interventional Cohort Study.

INTRODUCTION: The non-interventional study (NIS) KORALLE evaluated the effectiveness and safety of bevacizumab in patients with metastatic colorectal carcinoma (mCRC) treated with bevacizumab in combination with fluoropyrimidine-based chemotherapy in the first-line setting and beyond first progression in routine clinical practice. METHODS: This prospective, multicenter NIS observed adult patients with mCRC who started first-line bevacizumab therapy. The planned maximum duration of observation per patient was 21 months. The primary effectiveness variable was progression-free survival in the first-line therapy setting (PFS-1). Secondary effectiveness variables included PFS after first progression as well as overall survival and overall response rate. All analyses were carried out descriptively for the full analysis population set (FAS). Effectiveness analyses were also assessed for predefined subgroups based on therapy goals. RESULTS: Between December 2012 and July 2016, 2,429 eligible patients were observed at 314 sites in Germany. In the first-line setting in the FAS, the median PFS-1 was 10.3 months (95% CI: 9.9; 10.8), the median overall survival was 16.9 months (95% CI: 16.3; 17.5), and the overall response rate (ORR-1) was 44.2% (95% CI: 41.6%; 46.8%). Effectiveness results of all subgroups were similar to the FAS. Overall, 80.9% of patients experienced any adverse events, 36.6% of patients experienced serious adverse events, and 8.8% of patients experienced fatal adverse events. CONCLUSION: The NIS KORALLE provided broad real-world evidence on effectiveness and safety of bevacizumab. Despite different treatment intentions, the combination of bevacizumab plus fluoropyrimidine-based chemotherapy was similarly effective in all subgroups in routine clinical practice. The safety information reported in this study is consistent with the known safety profile of bevacizumab.

A Prospective Real-World Multi-Center Study to Evaluate Progression-Free and Overall Survival of Radiotherapy with Cetuximab and Platinum-Based Chemotherapy with Cetuximab in Locally Recurrent Head and Neck Cancer.

Treatment options of locoregional recurrent head and neck squamous cell cancer (HNSCC) include both local strategies as surgery or re-radiotherapy and systemic therapy. In this prospective, multi-center, non-interventional study, patients were treated either with platinum-based chemotherapy and cetuximab (CT + Cet) or re-radiotherapy and cetuximab (RT + Cet). In the current analysis, progression-free survival (PFS) and overall survival (OS) were compared in patients with locoregional recurrence. Four hundred seventy patients were registered in 97 German centers. After exclusion of patients with distant metastases, a cohort of 192 patients was analyzed (129 CT + Cet, 63 RT + Cet). Radiotherapy was delivered as re-irradiation to 70% of the patients. The mean radiation dose was 51.8 Gy, whereas a radiation dose of ≥60 Gy was delivered in 33% of the patients. Chemotherapy mainly consisted of cisplatin/5-flurouracil (40%) or carboplatin/5-flurouracil (29%). The median PFS was 9.2 months in the RT + Cet group versus 5.1 months in the CT + Cet group (hazard ratio for disease progression or death, 0.40, 95% CI, 0.27-0.57, p < 0.0001). Median OS was 12.8 months in the RT + Cet group versus 7.9 months in the CT + Cet group (hazard ratio for death, 0.50, 95% CI, 0.33-0.75, p = 0.0008). In conclusion, radiotherapy combined with cetuximab improved survival compared to chemotherapy combined with cetuximab in locally recurrent HNSCC.

A European, Observational, Prospective Trial of Trabectedin Plus Pegylated Liposomal Doxorubicin in Patients with Platinum-Sensitive Ovarian Cancer.

PURPOSE: The noninterventional, prospective NIMES-ROC phase IV study (NCT02825420) evaluated trabectedin plus pegylated liposomal doxorubicin (PLD) in real-life clinical practice. PATIENTS AND METHODS: Eligible participants included adults with platinum-sensitive recurrent ovarian cancer (PS-ROC) who had received one or more cycles of trabectedin/PLD before inclusion according to the marketing authorization. The primary endpoint was progression-free survival (PFS) according to investigator criteria. RESULTS: Two hundred eighteen patients from five European countries were evaluated, 72.5% of whom were pretreated with at least two prior chemotherapy lines and received a median of six cycles of trabectedin/PLD (range: 1-24). Median PFS was 9.46 months (95% confidence interval [CI], 7.9-10.9), and median overall survival (OS) was 23.56 months (95% CI, 18.1-34.1). Patients not pretreated with an antiangiogenic drug obtained larger median PFS (p < .007) and OS (p < .048), largely owning to differences between the two populations. Twenty-four patients (11.0%) had a complete response, and 57 patients (26.1%) achieved a partial response for an objective response rate (ORR) of 37.2%. Fifty-nine patients (27.1%) had disease stabilization for a disease control rate of 64.2%. No statistically significant difference in PFS, OS, or ORR was observed by BRCA1/2 status and platinum sensitivity. Most common grade 3/4 adverse events (AEs) were neutropenia (30.3%), anemia (6.4%), thrombocytopenia (5.5%), and asthenia (5.0%). No deaths attributed to treatment-related AEs or unexpected AEs occurred. CONCLUSION: The combination of trabectedin/PLD represents a clinically meaningful and safe option for patients with PS-ROC regardless of prior treatment with an antiangiogenic drug, being comparable with previously observed outcomes in selected and less pretreated patients from clinical trials. IMPLICATIONS FOR PRACTICE: This noninterventional, prospective study, conducted in 57 reference sites across Europe, consistently confirmed that trabectedin plus pegylated liposomal doxorubicin (PLD) in routine clinical practice represents a clinically meaningful and safe option for women with platinum-sensitive recurrent ovarian cancer. Although the study population represented a heterogeneous, older, and more pretreated population than those in prospective clinical trials, the combination of trabectedin plus PLD induced comparable clinical benefits, with a similar and manageable safety profile. Overall, these findings show that trabectedin in combination with PLD maintains antitumor activity when administered to heavily pretreated patients in real-life clinical practice.

Treatment response lowers tumor symptom burden in recurrent and/or metastatic head and neck cancer.

BACKGROUND: Head and neck squamous cell cancer (HNSCC) frequently causes severe symptoms that may be reduced, when the tumor is successfully treated. The SOCCER trial studied the association of treatment response with patient reported tumor symptom burden in first line treatment of recurrent and/or metastatic HNSCC. METHODS: In this prospective, multi-center, non-interventional trial patients were treated either with platinum-based chemotherapy and cetuximab or radiotherapy and cetuximab. Tumor symptom burden was assessed every four weeks with a questionnaire containing ten visual analogue scales (VAS, range 0-100), which were summarized to the overall VAS score. RESULTS: Fourhundred seventy patients were registered in 97 German centers. A total of 315 patients with at least the baseline and one subsequent questionnaire were available for analysis. Changes in the VAS score were rated as absolute differences from baseline. Negative values indicate improvement of symptoms. The overall VAS score improved significantly at the first post-baseline assessment in responders (- 2.13 vs. non-responders + 1.15, p = 0.048), and even more for the best post-baseline assessment (- 7.82 vs. non-responders - 1.97, p = 0.0005). The VAS for pain (- 16.37 vs. non-responders - 8.89, p = 0.001) and swallowing of solid food (- 16.67 vs. non-responders - 5.06, p = 0.002) improved significantly more in responders (best post-baseline assessment). In the multivariable Cox regression analysis, worse overall VAS scores were associated with worse overall survival (hazard ratio for death 1.12 per 10 points increment on the overall VAS scale, 95% CI 1.05-1.20, p = 0.0009). CONCLUSION: In unselected patients beyond randomized controlled trials, treatment response lowers tumor symptom burden in recurrent and/or metastatic HNSCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00122460 . Registered 22 Juli 2005.

Prophylaxis of chemotherapy-induced neutropenia and febrile neutropenia with lipegfilgrastim in patients with non-Hodgkin lymphoma (NADIR study).

OBJECTIVE: The prospective non-interventional study (NIS) NADIR was designed to evaluate both effectiveness and safety of prophylactic use of lipegfilgrastim (Lonquex® ), a glycopegylated granulocyte colony-stimulating factor, in cancer patients with different tumor entities undergoing chemotherapy in routine clinical practice. The primary objective was incidence of severe neutropenia, febrile neutropenia (FN), and neutropenia-associated complications. METHOD: NADIR was a national, multicenter, prospective NIS. RESULTS: Here, we present the data on patients with non-Hodgkin lymphoma (NHL). Final analysis comprised 337 NHL patients having received ≥1 administration of lipegfilgrastim. Primary prophylaxis with lipegfilgrastim was documented in 78.7% of patients with high risk to develop FN. In total, ≥1 severe neutropenia (grade 3/4) was reported in 115 (34.1%) patients and ≥1 event of FN documented in 15 (4.5%) patients. Grade 3/4 infections were reported in 22 (6.5%) patients overall. Most frequently reported adverse events (AEs) related to lipegfilgrastim in total were bone pain (5.4%), leukocytosis (2.1%), back pain (1.8%), platelet count decreased (1.2%), and myalgia (1.2%). Fatal serious AEs were documented in 9 (2.7%) patients; none were attributable to lipegfilgrastim. CONCLUSION: Prophylaxis or therapeutic intention with lipegfilgrastim in NHL patients in routine clinical practice showed similar effectiveness and safety as demonstrated in the pivotal trials.

Trabectedin plus pegylated liposomal doxorubicin (PLD) for patients with platinum-sensitive recurrent ovarian cancer: a prospective, observational, multicenter study.

PURPOSE: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany. METHODS: Eligible patients were adults with platinum-sensitive ROC, pretreated with ≥ 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination. RESULTS: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving ≥ 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression-free survival was 6.3 months and median overall survival was 16.4 months. CONCLUSION: Trabectedin plus PLD confer clinically meaningful benefit to pre-treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile.

Rituximab in combination with chemotherapy for the treatment of chronic lymphocytic leukaemia in clinical practice.

OBJECTIVES: This study was conducted to investigate the real-world effectiveness and tolerability of rituximab-containing chemoimmunotherapies, which have become the standard of care for chronic lymphocytic leukaemia (CLL), particularly for physically fit patients. Furthermore, current treatment patterns in clinical practice were documented, and an unselected real-life population was compared with older, comorbid patients. METHODS: Prospective, multicentre, observational study with rituximab-containing chemoimmunotherapy in CLL patients. RESULTS: Of 681 patients in total, 485 were enroled in cohort 1 (unselected) and 196 in cohort 2 (comorbid "slow-go" patients). The median patient age was higher than in most randomised controlled trials (cohort 1: 70 years and cohort 2: 75 years). The most common treatment regimen in both first-line and relapsed patients was rituximab-bendamustine. Two-year progression-free survival rate for first-line therapy was 84.1% for cohort 1 and 69.8% for cohort 2 (with best overall response rate 81.8% for cohort 1 and 76.6% for cohort 2). General and B-symptoms declined during treatment and remained at low level or decreased further until study end. The safety profile observed in randomised clinical trials was confirmed. CONCLUSION: Chemoimmunotherapy with rituximab is feasible and safe in a wide variety of clinical settings in CLL, including the treatment of older patients with comorbidities (ClinicalTrials.gov NCT01178086).

Rapid infusions of human normal immunoglobulin 50g/l are safe and well tolerated in immunodeficiencies and immune thrombocytopenia.

Intravenous immunoglobulin (IVIg) is accepted as an effective and well-tolerated treatment for primary and secondary immunodeficiencies (ID) and immune thrombocytopenia (ITP). Adverse reactions of IVIg are usually mild, comprising transient flu-like symptoms, change in blood pressure and tachycardia. However IVIg therapy can be burdensome for both patients and healthcare facilities, since the infusion may take up to 4h to administer. The objective of our multicentre, prospective, open-label phase III trial was to evaluate the tolerability and safety of human normal immunoglobulin 50g/l (Ig VENA) at high intravenous infusion rates in adult patients with ID and ITP who had previously tolerated IVIg treatment, by progressively increasing infusion rate up to 8ml/kg/hr. 39 ID patients received three infusions, 5 ITP patients received up to a maximum of 5 infusions for a maximum of 5days. Overall 55 adverse events were reported in 18 patients, and all were mild and self-limiting. Two serious adverse events occurred in ID patients and 1 in an ITP patient; none was fatal or treatment-related. No clinically significant changes or abnormalities were observed in vital signs, laboratory results and HRQoL. In summary, in this study, more rapid IVIg infusions were well tolerated by ID and ITP patients, while maintaining their quality of life, helping to minimise the time spent in outpatient hospital visiting to potentially optimise adherence to treatment.

Treosulfan in the Treatment of Advanced Ovarian Cancer - Results of a German Multicenter Non-interventional Study.

BACKGROUND: Data on routine systemic treatment of patients with ovarian cancer are currently available only to a limited degree. The alkylating agent treosulfan is approved in oral (p.o.) and intravenous (i.v.) form for the treatment of ovarian carcinoma. The present non-interventional study analyzed the clinical use of treosulfan in Germany, evaluating the mode of application, toxicity, and response and survival rate. PATIENTS AND METHODS: Two hundred and forty-eight ovarian cancer patients in 57 Centers, who received treosulfan mainly either i.v. (5,000-8,000 mg/m(2) d1, q21d or q28d) or p.o. (400-600 mg/m(2) d1-14 or 21, q28d) for at least one therapy cycle were evaluable and were included in the study. RESULTS: With a median age of 70 years (range=36-92 years), predominantly elderly patients received treosulfan treatment. Most participants presented serous histology (131, 52.8%) and advanced-stage FIGO III (122, 49%) or IV (55, 22%) disease. Median ECOG status was 1 (range=0-2), whereas cardiac co-morbidity was common (31%). Treosulfan was usually administered as second- (26%), third- (21%) or fourth-line (17%) therapy. Two hundred and one patients received i.v. and 47 p.o. TREATMENT: The most common reason for dose modifications was due to hematological toxicity (46%). The main reason for a therapy discontinuation was progressive disease (38.5%). Response was observed in 25.8% of participants, disease stabilization in 28.6 % and progress in 45.6%. The median progression-free and overall survival was 196 and 405 days, respectively. CONCLUSION: In predominantly elderly and heavily pre-treated patients with recurrent ovarian cancer, treosulfan featured a clinical relevant efficacy and well-manageable, mostly hematological, toxicity, which resulted in a positive therapeutic index.

Trastuzumab in advanced breast cancer--a decade of experience in Germany.

BACKGROUND: Trastuzumab was registered in 2000 for the treatment of metastatic breast cancer, both as monotherapy and combination therapy with paclitaxel. In this prospective, non-interventional observation study, the 10-year experience with trastuzumab in the routine management of HER2-positive breast cancer was reviewed. METHODS: Between 2000 and 2010, 1843 evaluable patients with advanced HER2-positive breast cancer were recruited in 223 institutions across Germany. Patients were prospectively monitored for about one year. Additional information on long-term outcomes, progression-free survival (PFS), and overall survival (OS) were retrieved at several follow-up points. There were no restrictions with respect to diagnostic or therapeutic procedures. Patients were stratified into three cohorts depending on the treatment regimen, i.e. trastuzumab monotherapy (n=228, 12%), trastuzumab combined with chemotherapy (n=1346, 73%), or trastuzumab combined with endocrine therapy (n=269, 15%). RESULTS: Median age was 59.5 years with a proportion of 28% being older than 65 years. Over a maximum follow-up period of more than 10 years, 1538 PFS events were documented in 83% of patients, resulting in an estimated median PFS of 11.8 months. Median OS, based on recorded death in 64% of patients, amounted to 34.4 months, with 48% (95% confidence intervals 45-50%) still alive after three years. The subgroup selected for a treatment combination with endocrine drugs only had distinctly longer PFS and OS than the other two groups, achieving medians of 23.3 months and 56.3 months, respectively. Median PFS and OS in elderly patients over 65 years of age was 11.4 months and 28.3 months, respectively. Adverse reactions, including cardiac toxicity, of severity grade 3 or 4 were rare. CONCLUSIONS: The superior outcome of treatment strategies including trastuzumab in HER2 overexpressing breast cancer, proven in pivotal studies, was confirmed in the management of advanced breast cancer in Germany in the routine setting. Our data suggest a comparable clinical benefit of treatment with trastuzumab in elderly patients (>65 years), who are typically under-represented in randomized clinical studies.

Caspofungin for treatment of invasive aspergillosis in Germany: results of a pre-planned subanalysis of an international registry.

BACKGROUND: This study is a pre-planned country-specific subanalysis of results in Germany from a multinational multicenter registry to prospectively assess real-world experience with caspofungin administered for treatment of proven or probable invasive aspergillosis (IA). METHODS: Data from patients treated with caspofungin for a single episode of IA were collected. Effectiveness was determined by the local investigator as favorable (complete or partial response) or unfavorable (stable disease, failure or death) at the end of caspofungin therapy. Descriptive statistics with binomial exact confidence intervals were employed. RESULTS: Forty-two consecutive patients were identified in three German centers. Three patients (7%) had proven IA and 39/42 (93%) had probable IA (modified European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria). Forty-one patients had pulmonary IA and one had tracheal IA. Caspofungin monotherapy was received by 36/42 patients (86%); of these, 26/36 (72%) received salvage therapy. A favorable response was observed in 29/42 patients (69%; 95% CI 53 to 82%); of these, 21/29 (72%) had a complete and 8/29 (28%) a partial response. Favorable response rate was 69% in patients with monotherapy (95% CI 52% to 84%; 25/36 patients), and 67% in patients receiving combination therapy (95% CI 22% to 96%; 4/6 patients). Favorable response rate in patients with first line therapy was 64% (95% CI 31% to 89%; 7/11 patients), and 73% in patients with second line therapy (95% CI 54% to 88%; 20/30 patients). No adverse events were reported. In total, 35/42 patients (83%; 95% CI 69 to 93%) survived seven days after completion of caspofungin therapy. CONCLUSIONS: These real-life findings in Germany are consistent with the international findings from this registry and with findings from randomized studies.

Caspofungin use in daily clinical practice for treatment of invasive aspergillosis: results of a prospective observational registry.

BACKGROUND: A prospective observational registry assessed real world experience with caspofungin monotherapy or combination therapy for the initial or salvage treatment of proven or probable invasive aspergillosis (IA). METHODS: Data were collected from April 2006 to September 2007 for patients treated with caspofungin for a single episode of IA. Clinical effectiveness was categorized as favorable (complete or partial) or unfavorable (stable disease or failure) at the end of caspofungin therapy (EOCT). RESULTS: Consecutive patients (n = 103) with proven or probable IA (per EORTC/MSG criteria) were identified from 11 countries. Malignancy (76.7%), neutropenia (64.1%), allogeneic hematopoietic stem cell transplantation (HSCT, 22.3%), solid organ transplantation (8.7%), autologous HSCT (4.9%), and HIV/AIDS (2.9%) were the most common underlying conditions. Most patients (84.5%) had pulmonary IA. Aspergillus fumigatus was the most frequently isolated species. The majority of patients received caspofungin monotherapy (82.5%) primarily as salvage therapy (82.4%). The main reason for switching to salvage therapy was clinical failure of the first-line therapy (69%). A favorable response at EOCT was seen in 56.4% (57/101) of patients overall, including 56.5% (48/85) and 56.3% (9/16) of patients receiving caspofungin monotherapy and combination therapy, respectively. Favorable response rates in clinically relevant subgroups were: malignancy, 51.9% (41/79); allogeneic HSCT, 56.5% (13/23); and neutropenia at time of hospitalization, 53.0% (35/66). There was a 72.3% (73/101) survival at 7 days after EOCT. Serious adverse events related to caspofungin were reported in 4 cases (3.9%); 3 patients (2.9%) discontinued treatment due to an adverse event related to caspofungin. CONCLUSIONS: Caspofungin was both effective and well tolerated among high-risk patient groups such as those with neutropenia and active malignancies.

Efficacy of caspofungin and itraconazole as secondary antifungal prophylaxis: analysis of data from a multinational case registry.

Patients surviving invasive fungal disease (IFD) and needing further antineoplastic chemotherapy are at high risk of recurrent fungal infection. In the absence of randomised controlled trials in this area, secondary prophylactic regimens are diverse. From 448 patients registered with the Multinational Case Registry of Secondary Antifungal Prophylaxis, we performed an analysis of patients receiving caspofungin (CAS) or itraconazole (ITC). All patients had an underlying haematological malignancy and had been diagnosed with an episode of IFD earlier in their course of treatment. Data collected comprised demographics, underlying disease, first episode of IFD, antifungal prophylaxis, incidence and outcome of breakthrough IFD and survival. A total of 75 patients were evaluated, comprising 28 receiving CAS and 47 receiving ITC. Patients in the CAS group were more likely to have had progression of underlying disease (32.1% vs. 8.5%; P=0.028) as well as incomplete response of initial IFD at baseline (85.7% vs. 57.4%; P=0.005). Allogeneic stem cell transplantation was more prevalent in patients receiving CAS (46.4% vs. 14.9%; P=0.010). There was no difference in the occurrence of breakthrough IFD between both groups (32.1% vs. 31.9%). Treatment outcomes for recurrent IFD and overall mortality did not differ between groups. Both ITC and CAS were equally effective in preventing second episodes of IFD. Patients with uncontrolled first IFD, uncontrolled underlying disease or those receiving stem cell transplantation were more likely to have received CAS prophylaxis. Despite antifungal prophylaxis, risk of breakthrough IFD was high in both groups.

Treatment of invasive fungal infections in cancer patients--recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. Early antifungal treatment is mandatory to improve survival. Today, a number of effective and better-tolerated but more expensive antifungal agents compared to the former gold standard amphotericin B deoxycholate are available. Clinical decision-making must consider results from numerous studies and published guidelines, as well as licensing status and cost pressure. New developments in antifungal prophylaxis improving survival rates result in a continuous need for actualization. The treatment options for invasive Candida infections include fluconazole, voriconazole, and amphotericin B and its lipid formulations, as well as echinocandins. Voriconazole, amphotericin B, amphotericin B lipid formulations, caspofungin, itraconazole, and posaconazole are available for the treatment of invasive aspergillosis. Additional procedures, such as surgical interventions, immunoregulatory therapy, and granulocyte transfusions, have to be considered. The Infectious Diseases Working Party of the German Society of Hematology and Oncology here presents its 2008 recommendations discussing the dos and do-nots, as well as the problems and possible solutions, of evidence criteria selection.

Effect of once-weekly epoetin beta on survival in patients with metastatic breast cancer receiving anthracycline- and/or taxane-based chemotherapy: results of the Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study.

PURPOSE: The Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study evaluated whether epoetin beta would improve survival in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: BRAVE was an open-label, randomized, multicenter study in patients with MBC treated with anthracycline- and/or taxane-based chemotherapy. Patients (hemoglobin [Hb] < 12.9 g/dL) were randomly assigned (1:1) to epoetin beta 30,000 U subcutaneously once weekly or control for 24 weeks. The primary efficacy variable was overall survival. Secondary efficacy outcomes included progression-free survival, transfusion- and severe anemia-free survival, Hb response, safety, and quality of life (QoL). RESULTS: After 18 months of follow-up, 62 (27%) of 231 patients survived with epoetin beta therapy and 63 (27%) of 232 with control. No difference was detected in overall survival (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) or progression-free survival (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448). There was a statistically significant benefit on transfusion- and severe anemia-free survival compared with control (HR = 0.59; P = .0097). Median Hb level increased with epoetin beta (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) but did not change with control (11.5 v 11.4 g/dL). Patients receiving epoetin beta experienced more thromboembolic events (TEEs) compared with controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%). Epoetin beta did not significantly improve QoL in this study where patients had a high baseline Hb value. CONCLUSION: In patients with MBC receiving chemotherapy and initial Hb less than 12.9 g/dL, epoetin beta increased Hb. No difference was detected in overall survival. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty.

Risk factors for breakthrough invasive fungal infection during secondary prophylaxis.

BACKGROUND: Intensive chemotherapy with severe neutropenia is associated with invasive fungal infections (IFIs) leading to high mortality rates. During leukaemia induction chemotherapy, IFI often prohibited further curative treatment, thus predisposing for leukaemia relapse. Continuing myelosuppressive chemotherapy after diagnosis of IFI has become feasible with the now expanding arsenal of safe and effective antifungals. Secondary prophylaxis of IFI is widely administered, but reliable data on outcome and risk factors for recurrent IFI during subsequent chemotherapy are not available. This study determines risk factors for recurrent IFI in leukaemia patients. METHODS: From 25 European cancer centres, 166 consecutive patients with acute myelogenous leukaemia (AML) and a recent history of proven or probable pulmonary IFI were included. Patients were followed for recurrence or breakthrough IFI during the subsequent chemotherapy cycle. RESULTS: Of the 166 patients included, 69 (41.6%) were female, the median age was 53 years (range 2-81) the and 3 (1.8%) were <16 years. Recurrent IFI occurred in 26 patients (15.7%). Multiple logistic regressions yielded predisposing factors: duration of neutropenia [per additional day; odds ratio (OR) 1.043, confidence interval (CI) 1.008-1.078], high-dose cytarabine (OR 3.920, CI 1.120-12.706), number of antibiotics (per antibiotic; OR 1.504, CI 1.089-2.086), partial response as outcome of prior IFI (OR 4.037, CI 1.301-12.524) and newly diagnosed AML (OR 3.823, CI 0.953-15.340). Usage of high efficiency particulate air filter appeared protective (OR 0.198, CI 0.036-1.089). CONCLUSIONS: Duration of neutropenia, high-dose cytarabine, prior antibiotic therapy and a partial response to the first IFI therapy were risk factors for recurrent IFI and should be considered in AML patients with prior pulmonary IFI undergoing further chemotherapy.