"What's measured gets done": a call for a European semester for cancer to improve cancer outcomes in Central and Southeastern Europe.

Cancer mortality varies widely across Europe, and survival depends on where you live. In particular, the inequality between countries in Central and South-Eastern Europe (CEE) and Western Europe (WE) is striking. The COVID-19 pandemic has brought existing inequalities into sharp focus, and the economic disruption it has caused threatens to deepen them. The Central European Cooperative Oncology Group (CECOG) has created a platform with the aim to reduce health inequalities and to improve patient access to cancer care. The subject of discussion is the value of new treatments to create willingness to invest in improving cancer outcomes while managing the budget. The platform includes various stakeholders as scientific leaders, policy makers, payers, patients and industry.

Perspectives for Cancer Care and Research in Central and Eastern Europe.

BACKGROUND: Discrepancies between the outcomes of cancer patients between Western European and Central and Eastern European (CEE) countries have often been observed. Despite the enormous economic and civilizational progress made in these countries after the abolishment of the communist regime, structural problems persist. SUMMARY: The present article reviews the domains of medical oncology education, human resources in oncology, cancer care, and clinical research in CEE in order to comprehensively assess the current situation and needs, describe important initiatives, and also propose ways to improving cancer outcomes in the region. Activities are under way to address these issues in national action plans to divert funding into oncology-related education, research, the purchase of equipment, and the attainment of modern hospital organization and structures. KEY MESSAGE: Over the past more than 30 years, CEE countries have made enormous economic and societal progress. Nevertheless, challenges especially in the health care sector persist.

Determination of Extravasation Effects of Nal-Iri and Trabectedin and Evaluation of Treatment Options for Trabectedin Extravasation in a Preclinical Animal Model.

Background: Extravasation during chemotherapy administration can lead to dangerous adverse effects ranging from pain to tissue necrosis. Evidence-based data about prevention and treatment of extravasation injuries of some clinically used compounds still remains elusive. This work aimed to investigate, in a preclinical mouse model, the effects of extravasation of two chemotherapeutic agents, nanoliposomal irinotecan (nal-Iri) and trabectedin. In addition, we aimed to study treatment options for injuries induced by extravasation of these substances. Methods: Mice were subcutaneously injected with nal-Iri or trabectedin applied in clinically used concentration. Doxorubicin was used as a positive control. In subsequently performed experiments, hyaluronidase, DMSO and tacrolimus were tested as potential treatments against extravasation-induced injuries by trabectedin. Systemic effects were analyzed by observation and documentation of the health status of mice and local reactions were measured and graded. In addition, hematoxylin-eosin stained histological sections of the treated skin areas were analyzed. Results: Of the two tested substances, only trabectedin showed vesicant effects. Subcutaneous injection of trabectedin caused erythema formation in mice by day two that was progressing to skin ulcerations by day five. Furthermore, we found that topical treatment of mice with tacrolimus or DMSO reduced the vesicant effects of trabectedin. The results observed in vivo were supported microscopically by the analysis of histological sections. Conclusions: We recommend classifying trabectedin as a vesicant agent and nal-Iri as a non-vesicant agent. Furthermore, our results obtained in a preclinical model suggest that tacrolimus and DMSO might be suitable treatment options of trabectedin extravasations, a finding that might be further utilized in clinical studies.

Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study.

BACKGROUND: An earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis. METHODS: Postmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death). RESULTS: OS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81-1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81-1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed. CONCLUSIONS: Palbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors. TRIAL REGISTRATION: NCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT).

Establishment of a virtual transborder tumor board for cancer patients in Central and Southeastern Europe : An initiative of the Central European Cooperative Oncology Group (CECOG).

PURPOSE: To establish a transborder virtual tumor board (VTB) fostering state-of-the-art management of cancer patients by exchanging knowledge and expertise among oncologists in Central and Southeastern Europe (CEE). METHODS: We established and implemented a VTB based on the WebEx platform. This allowed for password-protected and secure upload of patient cases to be presented and discussed among colleagues from various oncology centers scattered throughout CEE in order to arrive at a recommendation for further diagnoses and/or treatment. RESULTS: A total of 73 cases from 16 oncology centers located in 11 CEE countries were uploaded by 22 physicians; 71 were discussed over the course of 17 virtual meetings between June 2018 and May 2019 and 12 different kinds of malignant diseases were discussed with lung cancer (46.6%), melanoma (19.2%) and bladder cancer (13.6%) being the most commonly presented tumor entities. Of the discussed patients, 93.3% had stage IV disease at the time of presentation, 62.6% received chemotherapy or targeted treatment and 67.1% were treated with immune checkpoint inhibitors (ICPIs). The most common causes for presentation and discussion of patient cases were related to the use of ICPIs (80%). CONCLUSION: When the need for expertise exceeds locally available resources, web-based VTBs provide a feasible way to discuss patient cases and arrive at conclusions regarding diagnoses and/or treatment across large geographic distances. Moreover, VTBs provide an innovative way for proper, state-of-the-art management of patients with malignant diseases in times of social distancing and the resulting need for restricted interaction during the current SARS-CoV­2 (severe acute respiratory syndrome coronavirus type 2) pandemic.

Thirteen-year analyses of medical oncology outpatient day clinic data: a changing field.

BACKGROUND: Novel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology. METHODS: Numbers of patients and patient contacts admitted to medical oncology day clinics of a large European academic cancer centre in the period from 2006 to 2018 were analysed using our patient administration system. RESULTS: A patient cohort of 9.870 consecutive individual patients with 125.679 patient contacts was descriptively and retrospectively characterised. Mean age was 59.9 years. A substantial increase in both individual patients treated per year (+45.4%; 2006: 1.100; 2018: 1.599) and annual patient contacts (+63.3%; 2006: 8.857; 2018: 14.467) between 2006 and 2018 was detected. Hence and most interestingly, the ratio of visits per patient increased by approximately one visit per patient per year over the last 12 years (+12.4%; 2006: 8.0; 2018: 9.0). Further, a decrease of patient contacts in more prevalent entities like breast cancer was found, while contacts for orphan diseases like myeloma and sarcoma increased substantially. Interestingly, female patients showed more per patient contacts as compared with men (13.5 vs 11.9). Lastly, short-term safety data of outpatient day clinic admissions are reported. CONCLUSIONS: We present a representative and large set of patient contacts over time that indicates an increasing load in routine clinical work of outpatient cancer care. Increases observed were highest for orphan diseases, likely attributed to centralisation effects and increased treatment complexity.

Access to Novel Drugs for Non-Small Cell Lung Cancer in Central and Southeastern Europe: A Central European Cooperative Oncology Group Analysis.

BACKGROUND: Treatment of non-small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune-oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries. MATERIAL AND METHODS: The Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries. RESULTS: Although first-generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies-even for ALK inhibitors and checkpoint inhibitors in first-line-there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries. CONCLUSION: The access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making.

Non-Small Cell Lung Cancer in Countries of Central and Southeastern Europe: Diagnostic Procedures and Treatment Reimbursement Surveyed by the Central European Cooperative Oncology Group.

This article analyzes the availability of different diagnostic procedures of non-small cell lung cancer (NSCLC) and the reimbursement landscape of drugs for NSCLC in countries of central and southeastern Europe (CEE). A survey was conducted by the Central European Cooperative Oncology Group. Results of the survey show that both availability and reimbursement of diagnoses of molecular alterations in NSCLC, the detection of which is essential for therapeutic decisions, varies widely between countries of CEE. Not only is "reflex" testing often substituted by analyses performed only "on demand," but reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. It was concluded that a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options. IMPLICATIONS FOR PRACTICE: This article provides an overview of the limitations in lung cancer treatment in countries of central and southeastern Europe, as well as the reimbursement status of various lung cancer treatment regimens in these countries, which directly impacts treatment options.

Review of cancer treatment with immune checkpoint inhibitors : Current concepts, expectations, limitations and pitfalls.

Immunotherapy by checkpoint inhibition is about to profoundly change cancer therapy. The number of indications are growing at an unprecedented speed. Clinical studies have demonstrated efficacy in a variety of solid tumors and in hematologic malignancies, although some clinical trials have produced negative results. Thus, it is fair to assume that there are obvious limitations and pitfalls in immunotherapy. Future concepts for combination treatment of immune checkpoint inhibitors have to be developed, but there is also urgent need for better and standardized biomarkers to identify those cancer patients who will benefit from treatment by checkpoint inhibition. The current overview summarizes current knowledge on immune checkpoint inhibitor treatment in malignancies, its outlook and limitations, diagnostic means and, finally, side effect management.

CECOG educational illustrations: the blood-brain barrier and its relevance for targeted cancer therapies and immuno-oncology.

The blood-brain barrier (BBB) protects the central nervous system (CNS) from potentially harmful substances and molecules by limiting their influx from the blood stream into the brain parenchyma. Understanding the structure and functioning of the BBB is of major importance for the development of effective medical treatments for primary and secondary brain tumours. Therefore, we provide here a concise and illustrated educational description of the anatomy and physiology of the BBB and current concepts on its role for targeted cancer therapies and immuno-oncology.

Cancer immune cycle: a video introduction to the interaction between cancer and the immune system.

This educational video discusses and visualises the key steps of the complex interaction between cancer and the immune system. Essential steps of the cancer immune cycle take place in the tumour itself and in regional lymph nodes, with immune cells travelling between these distinct sites. Antigen-presenting cells such as dendritic cells migrate into the tumour microenvironment and take up tumour antigens. Antigen-presenting cells travel to regional lymph nodes, where they present the tumour antigens to naïve T cells in order to initiate a tumour-specific T cell response. Activated tumour-specific T cells multiply by clonal expansion and enter the blood flow and travel from the regional lymph node to the tumour site. As soon as activated T cells arrive at the tumor site they start a tumour-specific immune response. Co-inhibitory receptors modulate the immune response and may be exploited by tumour cells to escape immunological destruction. In summary, the cancer immune cycle involves several pivotal steps that are essential for generation of a successful specific antitumour immune response. Importantly, dysfunction of a single step may interrupt the entire cycle, thus impairing the immune-mediated control of tumour growth. Immune modulatory therapies such as vaccines or immune checkpoint modulators target specific steps of the cancer immune cycle with the ultimate aim of facilitating an antitumour immune response.

Phase II study on the efficacy and safety of Lapatinib administered beyond disease progression and combined with vinorelbine in HER-2/neu- positive advanced breast cancer: results of the CECOG LaVie trial.

BACKGROUND: Vinorelbine constitutes effective chemotherapy for metastatic breast cancer (MBC) and acts synergistically with trastuzumab in HER-2/neu positive disease. The present study was set out to evaluate the efficacy and safety of vinorelbine when combined with lapatinib, an anti-HER2 tyrosine-kinase inhibitor, as late-line regimen administered beyond previous disease progression on prior lapatinib in patients with HER-2/neu- positive MBC. METHODS: The CECOG LaVie study was designed as open-labeled, single-arm, multicenter phase II trial. Patients had to be pretreated with lapatinib plus chemotherapy, and received lapatinib at a daily dose of 1250 mg in combination with vinorelbine 20 mg/m(2) i.v. on days 1 and 8 of a three-week cycle until disease progression, intolerable toxicity or withdrawal of consent. Progression-free survival (PFS) was defined as primary study endpoint; secondary endpoints included overall survival (OS), response rate according to RECIST 1.1, and safety. The study was terminated early due to poor accrual. RESULTS: A total number of nine patients were included; lapatinib administered beyond disease progression combined with vinorelbine resulted in a median PFS of 7.7 months (95% CI 0.56-14.91) and a median OS of 23.4 months (95% CI 16.61-30.13), respectively. Partial remission was seen in one of nine patients, three patients had stable disease of > six months, whereas the remaining five patients had primary disease progression. In two patients, modification of vinorelbine dose due to toxicity became necessary; no dose modification was needed for lapatinib. The majority of reported adverse events (AE) were grade 1 and 2 in severity with diarrhea being the most commonly observed AE CONCLUSION: In this heavily pretreated patient population, combination of vinorelbine plus lapatinib showed encouraging activity and was characterized by an acceptable safety profile. Despite the low patient number, lapatinib plus vinorelbine may constitute a potential treatment option in heavily pretreated patients with HER-2/neu-positive MBC previously exposed to lapatinib. TRIAL REGISTRATION: EudraCT number 2009-016826-15, (15. 10.2009).

Management of bite wounds in children and adults-an analysis of over 5000 cases at a level I trauma centre.

BACKGROUND: Bite wounds are among the commonest types of trauma to which man is the subject. They account for 5 % of the total traumatic wounds evaluated in the emergency department (ED) and approximately 1 % of all the ED visits. Early estimation of infection risk, adequate antibiotic therapy and if indicated surgical treatment are the cornerstones of successful cure of bite wounds. METHODS: A total of 5248 consecutive trauma patients were collected prospectively and analysed retrospectively over a period of 15 years in this study at a level I trauma centre, Department of Trauma Surgery, Medical University of Vienna, Austria. RESULTS: The mean age was 33.8 years (range 0-97), 2620 (49.9 %) were male and 2628 (50.1 %) were female individuals. In our study population, a total of 2530 dog bites (48.2 %), 930 cat bites (17.8 %), 357 other animal bites (6.8 %), 426 human bites (8.1 %) and 1005 human self-bites (19.2 %) have been observed. A total of 995 wounds (19.0 %) have been infected. Surgery was done in 132 wounds (2.5 %). CONCLUSION: We could show a six times higher infection rate of cat bites compared to dog bites. Human bites showed a total infection rate of 8.2 %. Observed infection rate of puncture wounds and wounds greater than 3 cm was 1.5 times higher than for all other wounds in the present study. Total infection rates within 24 h to antibiotic administration was 29.3 %, compared to 65.0 % < 48 h and 81.1 % < 72 h. Time interval also influenced the overall outcome showing a 2.6 increase in acceptable and 1.3 increase in poor outcome after 72 h.

Educational video: the role of PD-L1 in the local tumour microenvironment.

Watch the video here. Building on our previous educational video on the interaction between cancer and the immune system, we highlight in this video the role of programmed death ligand 1 (PD-L1) in the tumour microenvironment. We explain the function of important immune cell types found in the tumour microenvironment and how they interact with each other and with cancer cells. Dendritic cells take up tumour antigen and transport it to the regional lymph node for T cell priming. T cells are the main mediators of the adaptive immune system and kill tumour cells via release of cytotoxins. Macrophages are the main effector cells of the innate immune system and have various functions such as phagocytosis and antigen presentation. Therapeutic monoclonal antibodies that bind to PD-1 or PD-L1, so called immune checkpoint inhibitors, prevent the interaction of these immune-suppressive molecules and thus facilitate an effective T cell-mediated antitumour immune response.

Influence of adjunctive classical homeopathy on global health status and subjective wellbeing in cancer patients - A pragmatic randomized controlled trial.

OBJECTIVES: The use of complementary and alternative medicine has increased over the past decade. The aim of this study was to evaluate whether homeopathy influenced global health status and subjective wellbeing when used as an adjunct to conventional cancer therapy. DESIGN: In this pragmatic randomized controlled trial, 410 patients, who were treated by standard anti-neoplastic therapy, were randomized to receive or not receive classical homeopathic adjunctive therapy in addition to standard therapy. The study took place at the Medical University Vienna, Department of Medicine I, Clinical Division of Oncology. MAIN OUTCOME MEASURES: The main outcome measures were global health status and subjective wellbeing as assessed by the patients. At each of three visits (one baseline, two follow-up visits), patients filled in two different questionnaires. RESULTS: 373 patients yielded at least one of three measurements. The improvement of global health status between visits 1 and 3 was significantly stronger in the homeopathy group by 7.7 (95% CI 2.3-13.0, p=0.005) when compared with the control group. A significant group difference was also observed with respect to subjective wellbeing by 14.7 (95% CI 8.5-21.0, p<0.001) in favor of the homeopathic as compared with the control group. Control patients showed a significant improvement only in subjective wellbeing between their first and third visits. CONCLUSION: Results suggest that the global health status and subjective wellbeing of cancer patients improve significantly when adjunct classical homeopathic treatment is administered in addition to conventional therapy.

Public perception of cancer care in Poland and Austria.

BACKGROUND: We compared the public perception of cancer care in Poland and Austria. Both countries are members of the European Union (EU) but reflect two extremes in health-related per capita spending. Recently, the EUROCARE-5 study reported on very discrepant cancer outcomes between the two countries. METHODS: A one-time survey was conducted to compare the public perception of cancer treatment in Poland and Austria. In total, 3,649 subjects, representing the general population, cancer patients, and cancer patients' family members, were surveyed. RESULTS: In both countries, cancer was considered the most challenging problem of the health care system, and health care was indicated as the most important issue influencing political election decisions. Polish compared with Austrian cancer patients gave a significantly lower positive assessment of overall cancer treatment efficacy and detection methods. Cancer cure rates estimated by Polish and Austrian citizens were 29% and 44%, respectively. The majority of all citizens interviewed thought that cancer patients should have access to all available registered cancer drugs. However, only 18% of Poles versus 62% of Austrians agreed with the notion that the available cancer treatment in their countries is of a standard comparable to that of other EU countries. Consequently, 24% of Poles and 7% of Austrians identified financial status, age, gender, and residence as factors influencing the availability of cancer treatments. CONCLUSION: In both countries, cancer is considered the most challenging problem of the health care system, and health care issues may strongly influence decisions for political elections. Vast differences in the two populations' perceptions of cancer care reflect actual cancer outcomes and the national per capita spending on health-related issues.

Lack of correlation between blood group and HER-2 status in adenocarcinomas of the upper gastrointestinal tract.

The assessment of the human epidermal growth factor receptor-2 (HER-2) status has become a routine diagnostic procedure for patients with advanced-stage gastroesophageal adenocarcinoma. The aim of this study was to evaluate the possible correlation between the HER-2 status and the ABO blood group. HER-2 status determination and routine ABO typing was performed according to current standards. We evaluated the correlation between the HER-2 status and the ABO and Rhesus (Rh) system in 100 consecutive patients with adenocarcinoma of the upper gastrointestinal tract. There were no significant differences between HER-2 status and ABO and Rh system. Furthermore, no correlation was observed between the HER-2 status and the ABO and Rh type in patients with adenocarcinoma of the upper gastrointestinal tract.

Pre- and postoperative treatment modalities for esophageal squamous cell carcinoma.

BACKGROUND: The objective of this article was to review randomized clinical trials (RCTs) utilizing pre- and postoperative treatment modalities for esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: A computerized (MEDLINE) and manual search was performed to identify articles published on this topic between 1984 and 2012. RESULTS: We identified a total of 49 published RCTs, which included a total of 8,785 patients with ESCC. Treatment modalities consisted of pre- (n=38) and postoperative (n=11) chemo-, radio- and chemoradiotherapy. While both preoperative chemotherapy and chemoradiotherapy apparently improve R0 resection, they often result in substantial postoperative morbidity and mortality. Only for preoperative chemoradiotherapy does there seem to be a significant benefit in overall survival. CONCLUSION: R0 resection remains the only curative therapy for patients with ESCC. While preoperative chemoradiotherapy may improve overall survival, there is still the need for well-designed RCTs, which should include a homogeneous patient collective, to clarify the question of definitive benefit.

PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.

Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-ß (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.