Recommendations for risk minimization when using Janus kinase inhibitors for the treatment of chronic inflammatory skin diseases.

In accordance with article 20 of Regulation (EC) No 726/2004, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has re-evaluated the safety of Janus kinase inhibitors for the treatment of inflammatory diseases and formulated safety information deviating from the previous indications in the respective summary of product characteristics of the products concerned. These refer to the consideration of a possibly increased risk of venous thromboembolic or severe cardiovascular events, an increased infection rate and an increase in the prevalence of skin cancer across drugs and indications. Therefore, in patients with independent risk factors (age 65 years and older, smokers or former smokers, patients with oral contraception or hormone replacement therapy and other risk factors), it is recommended to use Janus kinase inhibitors therapeutically only if there are no suitable treatment alternatives. To facilitate a pragmatic and thorough detection of high-risk patients in everyday clinical practice, an interdisciplinary checklist was developed that is suitable as a working tool from the perspective of the dermatologist.

Ramucirumab in combination with dacarbazine in patients with progressive well-differentiated metastatic pancreatic neuroendocrine tumors (RamuNET): study protocol for a multicenter single-arm trial.

BACKGROUND: Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients. METHODS: The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p < =p0 = 60% versus H1: p > =p1 = 80%, alpha = 0.05, beta = 0.1. DISCUSSION: This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET. TRIAL REGISTRATION: EudraCT: 2017-001207-68 . Date of registration: 2018.01.03.

Desmoplastic small round cell tumors: Multimodality treatment and new risk factors.

BACKGROUND: To evaluate optimal therapy and potential risk factors. METHODS: Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed. RESULTS: Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse. CONCLUSION: Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.

Trabectedin: Supportive care strategies and safety profile.

Trabectedin is an approved antineoplastic agent for the treatment of adult patients with advanced soft tissue sarcomas or in combination with pegylated liposomal doxorubicin (PLD) in patients with relapsed platinum sensitive ovarian cancer. The mechanism of action is still not fully understood but many typical side effects seen with other chemotherapy drugs are less common, mild or unreported. Although this apparent favorable safety profile suggests a well-tolerated and manageable therapeutic option in the palliative care setting, trabectedin does have specific adverse side effects which can be hazardous for individual patients. The most commonly observed toxicities with trabectedin include neutropenia, nausea, vomiting, and increases in liver transaminases, anemia, fatigue, thrombocytopenia, anorexia and diarrhea. However, for most patients the appropriate use of supportive care strategies can reduce or overcome these side effects. We present a concise review of the safety data of trabectedin with the corresponding overview of the supportive care strategies.

Changes in the diagnosis and treatment of patients with low grade lymphoma in Germany: years 2006-2009.

Today's treatment options for indolent lymphoma and chronic lymphocytic leukemia (CLL) range from watch & wait, immunochemotherapy up to allogeneic transplantation. We describe changes in the diagnosis and treatment of indolent lymphoma and CLL in Germany between 2006 and 2009. Two nation-wide surveys in the fourth quarter of 2006 and 2009 included patients with indolent lymphoma and CLL. Data from 576 patients from 46 centers in Q4/2006 were compared with data from 521 patients from 57 centers in Q4/2009. The subpopulation of patients ≥ 70 years of age and the number of patients with comorbidities increased from 39% to 55% and 47% to 55%, respectively. Both in indolent lymphoma and CLL, Rituximab and R-based immunochemotherapy (50.6% vs. 64.4%) as well as bendamustine (4.8 % vs. 24%) were much more frequently applied. In contrast, high dose chemotherapy consolidation was almost abandoned in first line treatment. Supportive care is given more frequently, with exception of erythropoietin and immunoglobulins. Our national survey confirmed that scientific results were rapidly transferred into clinical care of indolent lymphoma.

Neuroendocrine tumors of the bronchopulmonary system (typical and atypical carcinoid tumors): current strategies in diagnosis and treatment. Conclusions of an expert meeting February 2011 in Weimar, Germany.

Neuroendocrine tumors (NETs; syn. carcinoid tumors) are highly or moderately differentiated neoplasms. They comprise a large variety of rare and heterogeneous tumors with an estimated incidence of 3-5/100,000/year. They can arise in virtually every internal organ, but mainly occur in the gastroenteropancreatic and bronchopulmonary systems. Around 25% of the NETs are localized in the bronchopulmonary system. Approximately 2% of all lung tumors are NETs. According to the World Health Organization (WHO) classification of lung tumors, bronchopulmonary NETs are subdivided into typical carcinoids (TCs) and atypical carcinoids (ACs). The parameter with the highest impact on NET behavior and prognosis is the histological classification and staging according to the tumor/node/metastasis (TNM) system. The diagnosis of NETs is established by histological examination and the immunohistochemical detection of general neuroendocrine markers, such as chromogranin A (CgA) and synaptophysin. Serum markers and the use of functional imaging techniques are important additive tools to establish the diagnosis of a NET. The only curative option for lung NETs is complete surgical resection. Beyond that, the currently available interdisciplinary therapeutic options are local ablation, biotherapy (somatostatin analogues), or chemotherapy. New therapeutic options such as peptide receptor radionuclide therapy (PRRT) and molecularly targeted therapies achieve promising results and are under further evaluation. This report is a consensus summary of the interdisciplinary symposium 'Neuroendocrine Tumors of the Lung and of the Gastroenteropancreatic System (GEP NET) - Expert Dialogue' held on February 25-26, 2011 in Weimar, Germany. At this conference, a panel of 23 German experts shared their knowledge and exchanged their thoughts about research, diagnosis, and clinical management of NETs, whereby special attention was paid to NETs of the respiratory tract.

Metastatic esophagogastric adenocarcinoma: trends in first-line treatment and predictive factors for the implementation of HER2 testing in clinical practice during the first year after trastuzumab market approval.

PURPOSE: Little is known about the use of first-line chemotherapy in clinical practice in patients with advanced esophagogastric adenocarcinoma, and no data have been published regarding potential obstacles for the implementation of molecular testing for targeted agents in this patient group. Here, we sought to evaluate factors influencing treatment decisions with special focus on the implementation of HER2 testing during the first year after trastuzumab market approval in Germany. METHODS: A total of 754 patients undergoing treatment decisions for palliative first-line therapy in 2010 were documented using Therapiemonitor(®). Drug use and intensity of first-line treatment were analyzed. Data on HER2 testing and test algorithm are described, and variables influencing HER2 testing were selected using bivariate analysis. Significant factors were included in a multivariate logistic regression analysis. RESULTS: Compared with previous years, treatment intensity has further increased. The use of chemotherapy triplets rose from 10.1 % in 2006 to 60.3 % in 2010. In 2010, 49.1 % of patients were tested for HER2 and in 52.2 % of these patients the currently proposed test algorithm was used. Using multivariate logistic regression analysis age ≥67 years and "initiating institution: practice" were found to negatively impact the likelihood of HER2 testing, while treatment goal "prevention of progression", multiple metastases and a Karnofsky status >80 % showed positive correlation with HER2 testing. CONCLUSION: The tendency to use more intensive first-line chemotherapy regimens in patients with advanced esophagogastric adenocarcinoma continued in 2010. Only a minority of patients had an access to the appropriate molecular diagnostics and therefore to treatment with trastuzumab. The access was limited due to the preselection following individual, clinical and institutional factors.

Treatment of indolent lymphoma in Germany - results of a representative population-based survey.

BACKGROUND: In advanced-stage indolent lymphoma, therapeutic approaches may vary from watch and wait, antibody monotherapy, immunochemotherapy, or dose-intensified consolidation up to allogeneic strategies. In this nationwide survey, representative hematologic/oncologic centers monitored current treatment strategies in indolent lymphoma in general practice. METHODS: Four hundred ninety-five centers involved in the treatment of indolent lymphoma including university hospitals, community hospitals, and oncologists in practice were identified and contacted. Thirteen percent of centers provided information on 741 patients, which corresponds to 10% of the expected national prevalence. Detailed data on 576 unselected patients from 46 representative centers (2 university hospitals, 25 community hospitals, and 19 oncologists in practice) for whom a treatment decision took place in the fourth quarter of 2006 (start, change, or end of therapy) were included in this analysis. Data were verified by monitoring the pseudonymized patient documents. RESULTS: Median age was 67 years (range, 17 to 95 years) and 65% of patients were 60 years of age or older. Concomitant disease was frequent with cardiac disease (29%), hypertension (28%), diabetes (11%), and renal impairment (7%) being the most typical combinations. Histologies included 39% follicular lymphoma, 26% chronic lymphocytic leukemia (CLL), 10% marginal zone, 9% mantle cell lymphoma (MCL), and 16% other. Only 10% of the overall patient population were treated within these studies. The aim of initial therapy was curative in 35%, and physicians aimed at improved survival in 62% and palliation only in 54% of patients. Radiation (10%), antibody monotherapy (4%), chemotherapy (33%), and combined immunochemotherapy (31%) were the most frequent approaches. Applied chemotherapies included cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) (46%), fludarabine combinations (F/FC/FCM: 15%), chlorambucil (14%), CVP/COP (9%) and bendamustin (4%). Maintenance was used in 12% and autologous/allogeneic stem cell consolidation were rarely applied (both in 3% of patients). At first relapse, combined approaches including immunochemotherapy (49%), maintenance therapy (16%), and autologous/allogeneic transplantation (14%/4%) were more frequently administered. As expected, different treatment strategies and response rates were observed in follicular lymphoma (FL), MCL, and CLL. Interestingly, supportive measures including antibiotics (34%), erythrocyte transfusions (32%), granulocyte colony-stimulating factor (22%), immunoglobulines (19%), antifungal drugs (13%), and erythropoetin (10%) were frequently applied even in first-line therapy. Overall response was 83% (FL: 97%, MCL: 95%, CLL: 74%) with a 39% complete response (FL 63%, MCL 54%, CLL 15%) rate. DISCUSSION: In this population-based survey, patients characteristics differed significantly from published study cohorts as did clinical strategies and therapeutic approaches. Thus, clinically more relevant studies in medically compromised patients are urgently warranted.

Phase 2 trial of docetaxel, gemcitabine, and oxaliplatin combination chemotherapy in platinum- and paclitaxel-pretreated epithelial ovarian cancer.

BACKGROUND: This phase 2 trial was designed to evaluate the efficacy and toxicity of a combination of docetaxel, gemcitabine, and oxaliplatin for platinum- and paclitaxel-pretreated epithelial ovarian cancer. PATIENTS AND METHODS: Heavily pretreated patients (N = 30; median age, 61 years) received docetaxel, 55 mg/m2; gemcitabine, 500 mg/m2 (day 1); and oxaliplatin, 70 mg/m2 (day 2) biweekly. Twelve patients had platinum-sensitive disease, and 18 patients had platinum-resistant disease. RESULTS: Median follow-up was 18.6 months. No differences in patient characteristics were observed between patients with carboplatinum-sensitive and carboplatinum-resistant disease. In patients with carboplatin-sensitive disease, an overall response (OR) of 83.3%, a progression-free survival of 10.6 months, and an overall survival of 18.9 months were observed. In patients with carboplatinum-resistant disease, an OR was seen in 38.9% with a progression-free survival of 5.3 months and an overall survival of 16.3 months. Patients with platinum-refractory disease (progression under previous carboplatinum therapy, n = 13) had an OR of 23%, whereas patients with objective response but relapse less than 6 months after carboplatinum therapy had an OR of 80.0%. Grade 3 and 4 toxicities were only observed for anemia (6.7%), neutropenia (20.0%), thrombopenia, peripheral neuropathy, and diarrhea (16.7%). No neutropenic fever or treatment-related death occurred. CONCLUSIONS: In comparison with current standard protocols, a combination of docetaxel, gemcitabine, and oxaliplatin showed considerably higher efficacy without remarkable increased toxicity; particularly for patients with early relapse after a platinum-containing therapy.

Venous access ports: frequency and management of complications in oncology patients.

Totally implantable venous access ports have been in use now for over 20 years. They are valuable instruments for long-term intravenous treatment of patients with cancer. Apart from perioperative difficulties, the typical complications associated with venous access ports are venous thrombosis, port infection, extravasation, pinch off syndrome, dislocation, occlusion and catheter leakages. The vast majority of these complications are avoidable, or at least the complication rate can be reduced with health care personnel training and education of patients. This review will give a broad overview on the frequency and possible complications related to port devices. Furthermore, this review suggests strategies for management including proposals to avoid such complications.

Successful treatment of mediastinal lymphomatoid granulomatosis with rituximab monotherapy.

Lymphomatoid granulomatosis is a rare Epstein-Barr virus (EBV)-positive-B-cell lymphoproliferative disorder. Treatment options include corticosteroids, antiviral therapy, interferon-alpha and chemotherapy. However, long-term prognosis is poor and no therapeutic standard has been established yet. In a 21-year-old woman, a biopsy of mediastinal mass revealed lymphomatoid granulomatosis. Combined therapy with valganciclovir and interferon-alpha proved ineffective. In view of the CD20 expression of the tumor cells, monotherapy with rituximab was intiated. After 3 months a complete remission was achieved. Rituximab was continued for another 6 months with subsequent consolidation radiotherapy. This is the first report of an enduring complete remission (20 months) of a non-CNS lymphomatoid granulomatosis treated with rituximab.

Antiemetic efficacy of an oral suspension of granisetron plus dexamethasone and influence of quality of life on risk for nausea and vomiting.

OBJECTIVES: To assess the antiemetic efficacy of an oral suspension of granisetron/dexamethasone in patients receiving chemotherapy and to determine whether quality-of-life parameters influence the risk for postchemotherapy nausea and vomiting (PCNV). PATIENTS AND METHODS: In an open monocentric study, an oral suspension containing 2 mg granisetron and 16 mg (4 mg for moderately emetogenic chemotherapy) dexamethasone was administered to 43 chemotherapy-naive patients before highly (n = 16) or moderately (n = 27) emetogenic chemotherapy and on the 3 subsequent days (2 for moderately emetogenic chemotherapy). Emetic episodes were recorded and quality of life was assessed prior to each cycle with a questionnaire based on EORTC QLQ-30. RESULTS: In the group undergoing highly (moderately) emetogenic chemotherapy, complete control of acute vomiting was achieved in 60-72.7% (92.6-95.0%), and complete control of delayed vomiting in 37.5-40.0% (75.0-92.2%), of patients within the first 3 (5) cycles. The following quality-of-life parameters were significantly associated with PCNV: tiredness (RR = 1.3, p < 0.05), pain (RR = 1.5), impairment of daily life by pain (RR = 1.7), sensation of abdominal pressure and fullness (RR = 2.5), impairment of social activities (RR = 2.9). CONCLUSIONS: Once-daily oral administration of a suspension of granisetron/dexamethasone is an active prophylaxis of nausea and vomiting and compares favorably with data reported on intravenous administration. Quality-of-life parameters assessed pre-treatment could help to identify patients at high risk for nausea and vomiting so that antiemetic therapy can be tailored to individual patient risk.

Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers.

Combination protocols of 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan or oxaliplatin have demonstrated high activity in metastatic colorectal cancer. Capecitabine, an oral 5-FU prodrug, may replace infusional 5-FU/LV in combination protocols with irinotecan or oxaliplatin. We therefore initiated a phase II study with capecitabine plus either irinotecan or oxaliplatin to determine the efficacy and toxicity of specific combination protocols in patients with advanced gastrointestinal (GI) tumors. Capecitabine 1000 mg/m(2) taken orally twice a day on days 1-14, plus oxaliplatin 70 mg/m(2) on days 1 and 8, or irinotecan 100 mg/m(2) on days 1 and 8; repeated every 3 weeks in an outpatient setting. Patient and tumor characteristics were as follows: median age, 68 years (range, 34-77 years); sex: 10 women, 33 men; tumor types: 35 colorectal cancer; 8 other GI tumors including 5 gastric, 2 pancreatic, and 1 duodenal cancer. All 43 patients treated were evaluable for toxicity (capecitabine/oxaliplatin, 24 patients; capecitabine/irinotecan, 19 patients), and 39 were evaluable for efficacy (capecitabine/oxaliplatin, 22; capecitabine/irinotecan, 17). Grade 3/4 toxicities (National Cancer Institute Common Toxicity Criteria Version 2.0) were limited to diarrhea, 9 patients (capecitabine/irinotecan, n = 5; capecitabine/oxaliplatin, n = 4); hand-foot syndrome, 1 patient (capecitabine/irinotecan); nausea, 2 patients (capecitabine/oxaliplatin); vomiting, 1 patient (capecitabine/oxaliplatin); and peripheral neuropathy, 1 patient (capecitabine/oxaliplatin). No grade 3/4 myelosuppression was noted for either protocol. Capecitabine/irinotecan and capecitabine/oxaliplatin demonstrated significant clinical activity in colorectal cancer and other GI cancers as first-line and salvage therapy. Capecitabine/oxaliplatin and capecitabine/irinotecan show an excellent safety profile and clinical activity in colorectal cancer and other advanced GI tumors. The main toxicity in both arms was manageable diarrhea. This trial served as basis for a randomized multicenter phase II study comparing capecitabine/oxaliplatin and capecitabine/irinotecan as first-line therapy in patients with advanced colorectal cancer.