A Phase 4 Study of Everolimus to Evaluate Efficacy and Safety in Patients with Metastatic Renal-Cell Carcinoma after Failure of First-Line Sunitinib or Pazopanib (SUNPAZ).

INTRODUCTION: Sunitinib and pazopanib are both standard first-line therapies for clear-cell metastatic renal-cell carcinoma (mRCC). Everolimus is a well-established second-line treatment. OBJECTIVE: To estimate the efficacy and safety of second-line everolimus following pazopanib or sunitinib. METHODS: SUNPAZ was an open-label, phase 4 clinical trial of everolimus in patients with clear-cell mRCC progressing after first-line sunitinib or pazopanib. The primary end point was the number of patients without progression 6 months after starting everolimus. Secondary end points included progression-free survival (PFS), overall survival (OS), and overall response rate. Enrollment was terminated early due to slow recruitment; all analyses are descriptive. RESULTS: Patients who received prior sunitinib (n = 16) or pazopanib (n = 13) were enrolled. One of 12 patients in the sunitinib group and 6/13 patients in the pazopanib group were progression-free by month 6 in the full analysis set. Median PFS in the sunitinib and pazopanib groups was 2.8 and 8.0 months, and median OS was 14.8 months and 20.4 months, respectively. Fifteen patients in the sunitinib group and 13 in the pazopanib group experienced adverse events. CONCLUSIONS: Safety and efficacy results confirm the second-line everolimus profile. However, baseline differences in patient populations should be taken into consideration.

[Results of a Pilot Study to Assess Quality Indicators in Outpatient Cancer Care]. / Ergebnisse einer Pilotstudie zur Erfassung von Qualitätsindikatoren in der ambulanten onkologischen Versorgung.

AIMS: Indicators of process quality were developed for outpatient oncology care in Germany with the aim to advance quality monitoring and assurance. In this pilot study, data to assess these quality indicators (QI) were gathered and analyzed for the first time. METHODS: Data were retrieved from patient records in oncology practices using an online data tool. Data were collected by practice-internal and in 7 (wave 1), 9 (wave 2) and 7 (wave 3) practices, respectively, by an external documentalist. RESULTS: Altogether, 5,160 patient records from 37 oncology practices were analyzed. The adherence rates varied considerably between QI as well as between practices (0-100%). In summary, adherence rates were higher for QI of basis documentation (81%) than for therapy planning and implementation (72%), holistic care and psychosocial wellbeing (71%) or pain management (63%). CONCLUSION: The ranges and high standard deviations show a high spread of adherence rates of QI. However, except for pain management, 100% fulfilment of QI requirements in some practices suggests that adherence to QI is generally feasible. Data collection for QI is resource intensive (time and personnel). Yet, collecting and examining data for QI provides useful information about areas with potential for improvement. QI can help improve the quality of care in oncology.

[Reimbursement differences in the ambulatory specialized care (ASV) compared to the previous care system. An exemplary analysis in medical oncology treating gastrointestinal malignancies]. / Vergütungsunterschiede bei der ambulanten spezialfachärztlichen Versorgung (ASV) im Vergleich zur bisherigen Behandlungsform.Eine explorative Analyse an drei Einrichtungen der Fachgruppe internistische Onkologie im Indikationsbereich gastrointestinale Tumoren.

INTRODUCTION AND AIM: The ambulatory specialized care (ASV) act (Sect. 116b of the Social Code Fifth Book [SGB V]) is intended to enable patients with a rare disease or a special course of disease or patients needing a highly specialized treatment to get access to outpatient care by office-based as well as hospital doctors. Data concerning care, service performance and fees - in comparison to the usual contract with the statutory insurance or the former Sect. 116b SGB V - are lacking. We explored the question whether differences in reimbursement between ASV and the previous system exist and which factors are influencing them. METHODS: We analyzed ICD-10 diagnoses, performance parameters as well as budgets and service fees in the former care system of medical oncologists in the institutions of three ASV participants of two federal countries treating gastrointestinal malignancies. We compared the results (fees, remuneration) to those from the statutory contract system and the former ambulatory care of hospitals and calculated the differences. Data were analyzed descriptively and analytically using SPSS. RESULTS: The analyses showed significant differences in the reimbursement rates between both office-based teams due to different budgets in the statutory contract system of the different federal countries. This led to additional remuneration of 12.5 to 49 % in ASV. The increase in fees of the hospital-guided team was exclusively due to the ASV-only fees of chapter 51 of EBM since there were no limitations of budgets even in the former system. DISCUSSION AND CONCLUSION: Exemplified with the ASV subgroup GIT, our study shows for the analyzed medical specialty that the difference in reimbursement in ASV is mostly due to the federal country-specific budgets and that the increase in honoraria can be substantial. Due to differences in budgets and quota systems, there may be different results in other ASV indications and specialist groups as well as in other federal states. Irrespective of these arguments, further aspects need to be taken into account when participation in ASV is considered.

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study).

OBJECTIVE: Azacitidine (Vidaza® ) is the standard treatment for patients with higher-risk myelodysplastic syndromes (MDS) not eligible for allogeneic stem cell transplantation. In the noninterventional study PIAZA, we evaluated the effectiveness and safety of azacitidine treatment in 149 patients with higher-risk MDS, chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) in routine clinical practice. METHOD: Patients were treated according to physician's discretion. Besides evaluation of safety and effectiveness, impact of covariates on progression-free survival (PFS) was assessed. RESULTS: Median age of patients was 75 years. 61.1% of patients were diagnosed with MDS, 31.5% with AML and 7.4% with CMML. Patients were treated with azacitidine for a median of seven cycles. Median PFS was 10.9 months. Median OS was 14.1 months. Two-year survival rate was 28.9%. 45.9% of patients showed CR or PR. Stable and progressive disease were observed in 37.2% and 8% of patients, respectively. Transfusion independence was reported in 64 of 89 patients. Eastern cooperative oncology group (ECOG) performance status (PS) and red blood cell (RBC) transfusion before azacitidine therapy were identified as predictive factors for PFS. CONCLUSION: In conclusion, we estimated the duration of PFS in a real-world setting and identified ECOG PS and RBC transfusion as predictive factors for PFS. The safety of azacitidine showed a similar profile as demonstrated in the pivotal clinical trials.

Patients' Trust in Physician, Patient Enablement, and Health-Related Quality of Life During Colon Cancer Treatment.

In cancer care, where patients and their families experience significant emotional distress and patients have to deal with complex medical information, patient centeredness is an important aspect of quality of care. The aim of this study is to examine the impact of patients' trust in their oncologists and patients' enablement on changes in health-related quality of life of colon cancer patients during follow-up care. We conducted a prospective study in a representative sample of private practices of German oncologists (N = 44). Patients (N = 131) filled out a standardized questionnaire prior to their first consultation (T0), directly after the first consultation (T1) and after two months (T2). Data were analyzed by structural equation modeling. Significant associations were found between trust in physician and changes in physical functioning between T1 and T2, and between trust in physician and patient enablement. Patient enablement is significantly associated with changes in physical functioning between T1 and T2. The results underline the importance of building a close and trustful patient-physician relationship in the oncology encounter. A central mechanism of the association between the quality of the relationship and health outcomes seems to be patient enablement. To enable patients to cope with their situation by making them understand their diagnosis, treatments, and side effects can impact health-related quality of life in physical domains.

Systemic therapy in metastatic renal cell carcinoma.

PURPOSE: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC). METHODS: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing. RESULTS: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited. CONCLUSIONS: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.

Recovery opportunities, work-home conflict, and emotional exhaustion among hematologists and oncologists in private practice.

Hematologists and oncologists in private practice play a central role in the care provided for cancer patients. The present study analyzes stress and relaxation aspects in the work of hematologists and oncologists in private practice in Germany in relation to emotional exhaustion, as a core dimension of burnout syndrome. The study focuses on the opportunities for internal recovery using breaks and time out during the working day, the frequency of working on weekends and on vacation, and the physician's work-home and home-work conflict. Postulated associations between the constructs were analyzed using a structural equation model. If work leads to conflicts in private life (work-home conflict), it is associated with greater emotional exhaustion. Working frequently at the weekend is associated with greater work-home conflict and indirectly with greater emotional exhaustion. By contrast, the availability of opportunities to relax and recover during the working day is associated with less work-home conflict and indirectly with less emotional exhaustion. These results underline the importance of internal recovery opportunities during the working day and a successful interplay between working and private life for the health of outpatient hematologists and oncologists.

Complete Remission of Metastatic Neuroendocrine Paragastric Carcinoma After "Neoadjuvant" Peptide Receptor Radionuclide Therapy and Surgery.

A 48-year-old man presenting with upper abdominal pain was diagnosed with neuroendocrine tumor after biopsy of a paragastric mass with multiple liver metastases. (68)Ga-DOTATATE PET/CT showed intense uptake in the paragastric tumor and in multiple liver metastases not allowing primary surgery. Two cycles with cumulative 14.6 GBq (177)Lu-DOTATATE were given resulting in a considerable improvement. Subsequent surgery resulted in a complete remission as demonstrated by (68)Ga-DOTATATE PET/CT. Usually, peptide receptor radionuclide (PRRT) therapy is considered a palliative treatment. Few patients demonstrate a very favorable response allowing resection of the primary tumor after downstaging metastatic disease burden.

The initial clinical interview--can it reduce cancer patients' fear?

PURPOSE: A common phenomenon among cancer patients is a fear of cancer recurrence or cancer progression (FOP). The aim of the present study was to analyze whether the oncologist is able to reduce patients' FOP at the initial clinical interview. METHOD: A prospective, longitudinal study included patients who were consulting private-practice oncologists in Germany for the first time. Recruitment was carried out by 44 members of the Professional Organization of Office-Based Hematologists and Oncologists. In the patient surveys, data on colon cancer patients' perceptions of communications with their oncologist and on patient-reported outcomes were collected over a period of 6 months. The present study analyzed the patients' data before their first consultation (T 0) and within 3 days after the first consultation (T 1). RESULTS: A total of 169 patients agreed to participate in the study. Backwards multiple regression analysis was conducted to determine whether the change (T 0-T 1) in FOP is associated with demographic, medical, or psychosocial determinants, or with the physician-patient communication. A significant association was found between the change in FOP and interruptions to the conversation, the comprehensibility of the information provided, the extent of perceived empathy from the physician, and the patient's social support and family status. CONCLUSION: Private social support and the initial medical encounter can help reduce FOP. Particularly, oncologists should ensure that they facilitate the presentation of information in a comprehensible way while avoiding interruptions and that they take particular care of patients with poor social support.

[WINHO quality indicators for outpatient oncology care in Germany]. / WINHO-Qualitätsindikatoren für die ambulante onkologische Versorgung in Deutschland.

The aim of the WINHO indicators project is to describe and enhance the quality of outpatient oncology care in Germany with indicators. This paper deals with the development of a set of evidence- and consensus-based meaningful indicators to assess the quality of outpatient oncology care in Germany. These indicators are intended to be applied in assessments of quality of patient care in oncology practices, in quality reports and in peer-to-peer benchmarking. A set of 272 already existing indicators was identified through internet and literature searches. After redundancy reduction and addition of newly developed indicators for areas of ambulatory oncology care that were not yet covered, a preliminary set of 67 indicators was established. The further development of the indicator set was based on a modified version of the two-step RAND/UCLA expert evaluation method, which has been internationally established for developing quality indicator sets. The indicators were modified after the first round of ratings. After completing and assessing the second round of ratings, a set of 46 homogeneously positively rated quality indicators is now available for outpatient oncology care in Germany.

Re-evaluation of laboratory predictors of response to current anemia treatment regimens of erythropoiesis stimulating agents in cancer patients.

BACKGROUND: Anemia is a major cause of morbidity in cancer. Erythropoiesis stimulating agents (ESA) are a mainstay of treatment, although some patients lack response for unknown reasons. Recently, ESA dosing recommendations have changed and iron is increasingly used as an adjunct. Due to these changes, potential laboratory predictors of response were re-evaluated. METHODS: This was a multi-center, observational study in cancer outpatients developing anemia under standard chemotherapy without absolute iron deficiency. For up to 12 weeks, laboratory data was collected while patients were treated with darbepoetin α (DA) either alone or along with intravenous iron. Baseline erythropoietin (Epo), changes in soluble transferrin receptor (sTfR) and in hemoglobin (Hb) early after treatment initiation were re-evaluated as response predictors, based on logistic regression models. RESULTS: Overall, 279 patients (mean age 66.1 years, 59.5% female) entered the study; 171 (61%) received at least one iron dose along with DA. Response and its predictability hardly increased through adjunct iron, although baseline ferritin <100 mg/L resulted in a 10 times higher probability of response to the combination than to ESA alone. Baseline Epo had low predictive value, regardless of tumor type or use of adjunct iron, although it varied with sex and age. If criteria for all three - Epo, sTfR, and Hb - were met, probability of preventing transfusions was 97%, dropping to 44%, if all three failed. CONCLUSIONS: Changes in ESA treatment recommendations had no impact on the predictability of response. Best prediction is still based on the immediacy of Hb increase.

Treatment of cancer-associated anaemia: results from a two-day cross-sectional survey in Germany.

BACKGROUND: The aim was to re-evaluate the current prevalence and management of cancer-associated anaemia as defined by the World Health Organisation (WHO) and related risk factors. PATIENTS AND METHODS: This was a prospective, 2-day web-based cross-sectional survey in cancer patients with non-myeloid malignancies in German outpatient clinics. RESULTS: 89 centres collected data from 3,867 patients, of whom 74% received active cancer therapy. The median age was 65 years (range 19-99 years) and almost two-thirds were women; 68% of the patients had solid tumours (breast 34%, colorectal 17%, lung 8%), with 56% of them being metastatic; 73% had a WHO performance score of ≤ 1. The mean haemoglobin level was 12.0 ± 1.7 g/dl (± standard deviation; range 4.3-17.8 g/dl); the prevalence of levels below 12.0 g/dl was 49%. Two-thirds of these patients were not treated for anaemia; one-third received erythropoiesis-stimulating agents (12.6%), iron therapy (8.1%), transfusions (7.5%) or combinations thereof (8.0%) during the 4 weeks before evaluation. Chemotherapy, female sex, age and poor performance status were identified as significant anaemia-associated factors. CONCLUSIONS: The prevalence of untreated anaemia and the decreased performance status of cancer patients in Germany have hardly changed since the European Cancer Anaemia Survey (ECAS) in 2001. The treatment practice may not only be driven by guidelines and does not yet reflect new concepts of anaemia management.

Second-line therapy for non-small cell lung cancer in clinical practice: final results and treatment pathways from the SELECTTION observational study.

OBJECTIVES: SELECTTION was a multinational, prospective observational study to assess the choice of and the time from initiation of second-line treatment to treatment discontinuation for any reason in patients with non-small cell lung cancer. METHODS: Treatment cohorts were constructed based on prescribed second-line treatments that were at the discretion of the treating physicians, for 1013 patients enrolled in 11 countries. Propensity score analysis was conducted to assess whether the cohorts were comparable. Time from initiation of second-line treatment to treatment discontinuation was the primary endpoint. Reasons for treatment discontinuation, overall survival, progression-free survival and choice of second-line treatment were secondary endpoints. RESULTS: The treatment cohorts were pemetrexed (46.2%), docetaxel (22.9%), erlotinib (20.4%) and other treatments (10.5%). Analyses of baseline data and propensity scores showed that the erlotinib cohort comprised substantially different patients compared with the pemetrexed and docetaxel cohorts: patients in the erlotinib cohort were more likely to be women, never-smokers, have adenocarcinoma and worse performance status. Therefore, comparisons of outcomes between cohorts were not appropriate. Although disease progression was the most common reason for treatment discontinuation in all cohorts, erlotinib patients tended to continue treatment after disease progression, whereas in the docetaxel and pemetrexed cohorts, discontinuation occurred soon after disease progression. CONCLUSIONS: In real-world clinical practice the profiles of patients assigned to erlotinib were distinctly different from those assigned to pemetrexed or docetaxel. The most common reason for treatment discontinuation was progressive disease, reflecting adherence to clinical recommendations. It is difficult to extrapolate these findings to the present, as both clinical practice and the approved indications for NSCLC treatments have evolved substantially.

Bendamustine plus mitoxantrone for relapsed/refractory chronic lymphocytic leukaemia (CLL): results of a multicentre phase II study of the German CLL Study Group (GCLLSG).

The efficacy of bendamustine (50 mg/m², days 1-3) plus mitoxantrone (10 mg/m², day 1), every 28 days for up to four courses, was evaluated in a Phase II multicentre trial enrolling 59 patients with relapsed or refractory B-cell chronic lymphocytic leukaemia (CLL). Major toxicities were grade 3/4 leucopenia, thrombocytopenia and infections in 42%, 12% and 12% of patients, respectively. Complete and partial response was achieved in 5/59 and 25/29 patients, respectively (overall response rate, 51%). Median time to progression was 22 months (range 1-49 + ) and median survival 27 months (range 0-49 + ). The combination of bendamustine and mitoxantrone is an active regime in relapsed or refractory CLL.

Biosimilar agents in oncology/haematology: from approval to practice.

The regulation of biosimilars is a process that is still developing. In Europe, guidance regarding the approval and use of biosimilars has evolved with the products under consideration. It is now more than 3 years since the first biosimilar agents in oncology support, erythropoiesis-stimulating agents, were approved in the EU. More recently, biosimilar granulocyte colony-stimulating factors have received marketing approval in Europe. This review considers general issues surrounding the introduction of biosimilars and highlights current specific issues pertinent to their use in clinical practice in oncology. Information on marketing approval, extrapolation, labelling, substitution, immunogenicity and traceability of each biosimilar product is important, especially in oncology where patients are treated in repeated therapy courses, often with complicated protocols, and where biosimilars are not used as a unique therapy for replacement of e.g. growth hormone or insulin. While future developments in the regulation of biosimilars will need to address multiple issues, in the interim physicians should remain aware of the inherent differences between biosimilar and innovator products.

Second-line therapy for NSCLC in clinical practice: baseline results of the European SELECTTION observational study.

OBJECTIVE: Although the efficacy of a number of drugs for the second-line treatment of non-small cell lung cancer (NSCLC) has been demonstrated in Phase III trials, very limited evidence exists on optimal duration of second-line treatment or the reasons why this treatment is stopped in standard clinical practice. SELECTTION (Survey in European Lung Cancer Evaluating Choice of Treatment and Tolerability In Observed NSCLC) was designed to assess the time from initiation of second-line treatment for NSCLC to treatment discontinuation for any reason, the reasons for discontinuation, and the impact of discontinuation on outcomes. METHODS: From October 2006 to January 2008, 1012 patients with advanced/metastatic NSCLC who completed or discontinued first-line treatment were enrolled in a multi-national, prospective observational cohort study (SELECTTION). Treatment cohorts were constructed based on the patients' distribution across second-line treatments that were assigned by physician decision (pemetrexed, docetaxel, erlotinib, other treatments). This report presents a descriptive analysis of the baseline data collected, including patient/disease characteristics, treatment history and planned second-line treatments. Factors that may have affected treatment choice, selected by physicians from a range of options, were also identified. RESULTS: Overall, 468 patients (46.2%) were enrolled in the pemetrexed cohort, 232 (22.9%) in docetaxel cohort, 206 (20.4%) in erlotinib cohort and 106 (10.5%) received other treatments. The profile of patients enrolled in the erlotinib cohort differed from those of patients enrolled in the pemetrexed or docetaxel cohorts in that erlotinib was more frequently planned for women, never-smokers and patients with adenocarcinomas. The primary reasons physicians gave for selection of the second-line treatment were tolerance and efficacy for pemetrexed, and preferred regimen for the particular patient and efficacy for the other treatments. CONCLUSIONS: In this observational study, pemetrexed, then docetaxel and erlotinib were the most frequently prescribed second-line treatments, which is in line with international guidelines. Erlotinib was most commonly prescribed to that subset of patients expected to gain the greatest benefit (those with adenocarcinoma, never-smokers and females). Pemetrexed was more frequently prescribed than docetaxel, with physicians most commonly choosing to prescribe the former agent because of its tolerability profile.

Malaria parasite actin polymerization and filament structure.

A novel form of acto-myosin regulation has been proposed in which polymerization of new actin filaments regulates motility of parasites of the apicomplexan class of protozoa. In vivo and in vitro parasite F-actin is very short and unstable, but the structural basis and details of filament dynamics remain unknown. Here, we show that long actin filaments can be obtained by polymerizing unlabeled rabbit skeletal actin (RS-actin) onto both ends of the short rhodamine-phalloidin-stabilized Plasmodium falciparum actin I (Pf-actin) filaments. Following annealing, hybrid filaments of micron length and "zebra-striped" appearance are observed by fluorescence microscopy that are stable enough to move over myosin class II motors in a gliding filament assay. Using negative stain electron microscopy we find that pure Pf-actin stabilized by jasplakinolide (JAS) also forms long filaments, indistinguishable in length from RS-actin filaments, and long enough to be characterized structurally. To compare structures in near physiological conditions in aqueous solution we imaged Pf-actin and RS-actin filaments by atomic force microscopy (AFM). We found the monomer stacking to be distinctly different for Pf-actin compared with RS-actin, such that the pitch of the double helix of Pf-actin filaments was 10% larger. Our results can be explained by a rotational angle between subunits that is larger in the parasite compared with RS-actin. Modeling of the AFM data using high-resolution actin filament models supports our interpretation of the data. The structural differences reported here may be a consequence of weaker inter- and intra-strand contacts, and may be critical for differences in filament dynamics and for regulation of parasite motility.

A new concept for the differential diagnosis and therapy of anaemia in cancer patients.

PURPOSE: This study aimed to prove the usefulness of the diagnostic plot, using the haemoglobin content of reticulocytes as a measure of functional iron deficiency (FID) and the ferritin index as a measure of iron availability, to customise anaemia treatment in cancer patients. METHODS: Based on results of this plot, cancer patients fulfilling practice guideline criteria to receive erythropoiesis-stimulating agents (ESAs) were allocated to treatment with ESAs alone, iron alone or the combination of both. Primary endpoint was the percentage of patients identified to require iron in addition or as an alternative to ESA therapy. RESULTS: Out of 303 patients screened, 286 were allocated to treatment: 204 patients were normochromic and iron replete and treated with ESAs alone, 22 had both FID and anaemia of chronic disease and were treated with ESAs and parenteral iron, and 60 were iron-depleted and treated with iron only. After 8 weeks, a haemoglobin increase >1 g/dL from baseline was shown by 56% of patients treated with ESAs alone, by 100% of patients receiving the combination, by 50% of normochromic and by 73% of hypochromic iron-depleted patients receiving iron only. Acute phase reaction did not diminish the response rate to ESAs. CONCLUSIONS: The diagnostic plot was superior to transferrin saturation and ferritin in predicting iron availability in hypochromic patients treated with ESAs and proved useful to select treatment for anaemia in cancer patients.