Treatment and outcome of 432 patients with extensive-stage small cell lung cancer in first, second and third line - Results from the prospective German TLK cohort study.

OBJECTIVES: Despite intensive research, the therapeutic options in extensive-stage small cell lung cancer (SCLC) are still limited. Data from routine clinical practice, so-called "real-world data", are centrally important to assess and improve the standard of care. We present prospectively documented data on systemic first-, second- and third-line treatment, number of treatment lines and outcome parameters of patients treated by medical oncologists in Germany. MATERIALS AND METHODS: This is a descriptive analysis on 432 patients with extensive-stage SCLC enrolled at start of first-line therapy into the prospective German clinical cohort study TLK (Tumour Registry Lung Cancer). Patients were recruited by 87 sites between February 2010 and December 2013 and followed-up individually for 3 years. RESULTS: The majority of patients (93%) received a first-line platinum-based combination therapy. Carboplatin plus etoposide was documented more frequently than cisplatin plus etoposide (46 vs. 35%); patients receiving carboplatin were older (68 vs. 63 years) and more often presented with poorer performance status (17 vs. 11% ECOG ≥ 2). Both regimens yielded similar response and survival rates. Median first-line overall survival (OS) was 10.2 months (95% confidence interval [CI] 8.6-12.3) for carboplatin plus etoposide and 12.2 months (95% CI 10.1-14.7) for cisplatin plus etoposide. Most patients (77%) would have been eligible for participation in a clinical trial. 50% of the patients received a second and 22% a third line of treatment. Median second-line OS was 5.8 months (95% CI 4.8-7.5), median third-line OS 5.7 months (95% CI 3.8-7.0). CONCLUSION: To our knowledge, this is the first study of prospectively documented patients with extensive-stage SCLC in routine clinical practice. We present treatment algorithms as well as outcome parameters for a large cohort in first-, second- and third-line treatment. The survival times and response rates reported in this routine setting correspond to the respective measures from large prospective trials.

Adjuvant chemotherapeutic treatment of 1650 patients with early breast cancer in routine care in Germany: data from the prospective TMK cohort study.

BACKGROUND: Several regimens for which efficacy was established in randomized controlled trials are recommended in current treatment guidelines for early breast cancer. However, knowledge on use and effectiveness of commonly administered chemotherapeutic agents in real-life care and across all breast cancer subtypes is limited. METHODS: The prospective, multicentre German TMK cohort study (Tumour Registry Breast Cancer) recruited patients in 148 oncology outpatient-centres. Data from 1650 patients who completed adjuvant chemotherapy were analysed regarding treatment regimens and taxane use from 2007 to 2014. The association of patient characteristics with application of taxane-free regimens was examined with a multivariate regression model. RESULTS: The preferred adjuvant treatment shifted from fluorouracil, anthracycline and cyclophosphamide containing regimens to anthracycline/taxane combinations. Taxane use increased for all subtypes, and the greatest rise was among node-negative patients. Older age, node-negativity, lower grading, HR-positive/HER2-negative subtype and earlier start year of therapy were significantly associated with taxane-free therapy. CONCLUSIONS: Treatment with anthracycline/taxane-based chemotherapy in Germany has been rising for every subtype. The increased taxane use reflects updated guideline recommendations over the past decade. Cohort studies like the TMK provide insight into real-life treatment of patients outside of clinical trials.

Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial.

BACKGROUND: The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. METHODS: In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00973609. FINDINGS: Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5-25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1-8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3-7·4) for the bevacizumab alone group, and 6·4 months (4·8-7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 1·08 [95% CI 0·85-1·37]; p=0·53; upper limit of the one-sided 99·8% CI 1·42), whereas no treatment was not (HR 1·26 [0·99-1·60]; p=0·056; upper limit of the one-sided 99·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 [19%] patients in the fluoropyrimidine plus bevacizumab group, 67 [43%] in the bevacizumab monotherapy group, and 73 [46%] in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 [13%] of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 [14%] of 156 patients in the bevacizumab alone group, and 12 [8%] of 158 patients in the no treatment group). INTERPRETATION: Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies.

Upfront FOLFOXIRI+bevacizumab followed by fluoropyrimidin and bevacizumab maintenance in patients with molecularly unselected metastatic colorectal cancer.

BACKGROUND: The addition of bevacizumab (BEV) to standard doublet chemotherapy improves outcomes compared with chemotherapy alone in patients with metastatic colorectal cancer (mCRC). The OPAL study examined the effect of BEV+FOLFOXIRI followed by 5FU/LV and BEV maintenance on progression-free survival (PFS) in patients with previously untreated unresectable mCRC. METHODS: Eligible patients had histologically confirmed mCRC, ECOG performance status ⩽1 and were 18-70 years old. Patients received up to 12 cycles of FOLFOXIRI+BEV q2w (induction phase) followed by up to ⩽40 cycles of 5FU/LV+BEV q2w (maintenance phase). Median PFS was the primary end point; secondary end points included response, OS, secondary resection rate, safety and prognostic value of pharmacogenetic profiling. RESULTS: Ninety-seven patients were enrolled. Of these, 90 received study medication and formed the safety population: 64 males; median age 58 (range 28-71) years; ECOG performance status 0/1 in 54%/46% patients; and liver only disease in 35 patients. Relative dose intensities were 79-85% for all four drugs. The incidence of adverse events (AEs) was as previously reported and there were no new safety signals. In total, 87 serious AEs occurred in 39 patients (43%). Median PFS was 11.1 months (95% CI 9.4-12.0) and did thus not meet the primary objective of 12 months. Median OS was 32.2 months (95% CI 22.6-36.9). Fifty-two patients were pharmacogenetically profiled. CONCLUSIONS: FOLFOXIRI+BEV was feasible in this molecularly unselected mCRC patient population, showing a high efficacy in terms of survival, overall response and secondary resection rate. Pharmacogenomic profiling revealed no clinically relevant marker.

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.

Observational study of adjuvant therapy with capecitabine in colon cancer.

OBJECTIVE: This observational study was conducted to document the safety of capecitabine-based adjuvant therapy in patients with resected colon cancer under routine clinical conditions. RESEARCH AND DESIGN METHODS: ML20431 was a prospective, multicenter, non-interventional, observational study. It was designed to answer five research questions relating to safety, dosage and administration, and discontinuation from capecitabine-based adjuvant therapy. Patients were required to have R0 resected stage III colon cancer and have started treatment with capecitabine-based adjuvant therapy based on a decision by the investigator. Patients were followed over an observation period of ≤6 months after initiation of therapy. Investigators were required to complete the study case report form at study entry, each treatment cycle, and at the final examination. MAIN OUTCOME MEASURES: A total of 1485 patients were included in the study, and 1481 patients were treated with capecitabine and formed the analysis population. Most patients had colon cancer (78.3%), followed by rectal cancer (16.4%). Most patients had stage III disease (69.3%); the remaining patients had stage II disease (30.7%). The most common all-grade adverse reactions were hand-foot syndrome (46.9%), diarrhea (34.4%), and hemoglobin decreases (31.5%). Grade 3/4 adverse reactions were infrequent (<4%). Serious adverse events were reported in 96 patients (6.5%). Six or more cycles of treatment were completed by 77.9% of patients. Approximately two-thirds of patients (67.3%) received capecitabine monotherapy and the remainder (32.7%) received capecitabine in combination with ≥1 drugs, most commonly oxaliplatin (460 cases). Discontinuation of capecitabine was documented in 344 patients (23.2%). STUDY LIMITATIONS: no efficacy data were collected; the questionnaires for patients' expectations and satisfaction were not formally validated; and a few patients (<1.5%) had some retrospective data. CONCLUSIONS: The safety profile of capecitabine-based adjuvant therapy in a broad patient population with colon cancer is similar to that previously documented in phase III clinical trials.

Quality of life under capecitabine (Xeloda®) in patients with metastatic breast cancer: data from a german non-interventional surveillance study.

AIM: This non-interventional surveillance study (NIS) collected data on the quality of life (QoL) of patients treated with capecitabine as mono- or combination chemotherapy in an outpatient setting. METHODS: Capecitabine was administered orally for 14 days of each 21-day cycle. The main parameters of interest were QoL, compliance, patient and physician satisfaction, handling of hand-foot syndrome (HFS), and efficacy. The statistics were descriptive; some differences were compared using confidence intervals (CIs). RESULTS: 735 patients from 161 centers received at least 1 dose of capecitabine. The median duration of observation was 5.5 months overall. The QoL global score was 53% (mean from the entire study population at all times), without any correlation to HFS. The overall response rate (ORR) was 35.1%, and the disease control rate (DCR) 64.4%. The median progression-free survival (PFS) was overall 6.81 months (95% CI 6.32-7.63 months) and it was significantly higher in patients with HFS (8.4 months, 95% CI 7.5-9.2 months, hazard ratio (HR) 0.60; p < 0.0001). The safety and tolerability of capecitabine were considered acceptable. The HFS incidence (all grades) was 27.1%. CONCLUSIONS: Capecitabine had a favorable risk-benefit relation in outpatient therapy. The QoL remained stable over the course of the investigation, indicating good compliance. HFS was a strong predictor of longer PFS and had no negative impact on the global QoL.

Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.

BACKGROUND: Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment. METHODS: In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ≥18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2·5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7·5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00700102. FINDINGS: Between Feb 1, 2006, and June 9, 2010, 409 (50%) patients were assigned to bevacizumab plus chemotherapy and 411 (50%) to chemotherapy alone. Median follow-up was 11·1 months (IQR 6·4-15·6) in the bevacizumab plus chemotherapy group and 9·6 months (5·4-13·9) in the chemotherapy alone group. Median overall survival was 11·2 months (95% CI 10·4-12·2) for bevacizumab plus chemotherapy and 9·8 months (8·9-10·7) for chemotherapy alone (hazard ratio 0·81, 95% CI 0·69-0·94; unstratified log-rank test p=0·0062). Grade 3-5 bleeding or haemorrhage (eight [2%] vs one [<1%]), gastrointestinal perforation (seven [2%] vs three [<1%]), and venous thromboembolisms (19 [5%] vs 12 [3%]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3-5 adverse events were neutropenia (65 [16%] in the bevacizumab and chemotherapy group vs 52 [13%] in the chemotherapy alone group), diarrhoea (40 [10%] vs 34 [8%], respectively), and asthenia (23 [6%] vs 17 [4%], respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group. INTERPRETATION: Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers. FUNDING: F Hoffmann-La Roche.