Role and responsibility of oncologists in assisted suicide. Practice and views among members of the German Society of Haematology and Medical Oncology.

BACKGROUND: Physician-assisted suicide (PAS) is a controversial practice and regulatory frameworks differ regarding assigned physicians' roles. This study explores clinical experience and views of German oncologists concerning ethically and legally relevant aspects of PAS after change of the law. MATERIALS AND METHODS: An online survey was conducted among members of the German Society of Haematology and Medical Oncology (DGHO) in March 2021. Descriptive analysis, bivariate and multivariable logistic regression of quantitative data on determinants related to (un)willingness to assist with suicide as well qualitative analysis of free-text comments were carried out. RESULTS: Seven hundred and forty-five of 3588 DGHO members responded (20.8%). Of these, 29.9% reported requests for a lethal drug and 3.0% (n = 22) reported to have assisted with suicide. Almost half of them (47.0%, n = 350) objected to providing PAS, whereas 45.9% indicated a willingness at least under certain conditions. Of those respondents who did not object to PAS, 25.4% would also consider assistance if those willing to die had a psychiatric disease and 10.2% if requestors had no disease at all. A majority viewed a role for physicians regarding different tasks associated with assisted suicide. Respondents with <10 years of professional experience, working in hospital with religious affiliation and with subspecialisation in palliative care were significantly less frequently willing to assist suicide. CONCLUSIONS: Respondents are divided in their personal attitudes towards PAS but a majority supports involvement of physicians regarding different tasks related to assisted suicide. Data about the practice and envisaged professional role may inform development of an acceptable ethico-legal framework for a controversial practice.

A four-gene LincRNA expression signature predicts risk in multiple cohorts of acute myeloid leukemia patients.

Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in acute myeloid leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic non-coding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyze transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA genes are located in close proximity to hematopoietic coding genes and show strong expression correlations in AML, (iii) lincRNA gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomize survival in European Leukemia Net (ELN) risk groups and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML.

Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia.

We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.

[Future requirements for oncological care: Challenges due to demographic change]. / Herausforderung demographischer Wandel : Künftige Anforderungen an die onkologische Versorgung.

BACKGROUND: One of the major challenges of demographic change in Germany is the increase in the number of cancer patients. Urology is one of the most affected medical disciplines due to bladder and prostate cancer. This quantitative challenge coincides with a qualitative challenge through targeted oncology and a number of innovative drugs. OBJECTIVES: The task becomes even more complicated when considering the parallel increase of other diseases in the same patients. Severe comorbidity may limit oncological options. The future demands for oncology can be summarized as the following: higher incidence of cancer patients, more complex diagnostic workup and treatment, longer overall survival with cancer, increase in comorbidity, and higher need for oncologically trained physicians. High-quality and comprehensive cancer care in all geographic regions needs intensification of basic and healthcare research in close cooperation with networks of treating physicians. CONCLUSION: Oncologists have to be prepared for life-long learning, cooperative patient care, and for integration of other medical professions.

A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS: The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.

Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse.

In acute myeloid leukemia (AML), assessment of minimal residual disease (MRD) by flow cytometry (flow MRD) after induction and consolidation therapy has been shown to provide independent prognostic information. However, data on the value of earlier flow MRD assessment are lacking. Therefore, the value of flow MRD detection was determined during aplasia in 178 patients achieving complete remission after treatment according to AMLCG (AML Cooperative Group) induction protocols. Flow MRD positivity during aplasia predicted poor outcome (5-year relapse-free survival (RFS) 16% vs 43%, P<0.001) independently from age and cytogenetic risk group (hazard ratio for MRD positivity 1.71; P=0.009). Importantly, the prognosis of patients without detectable MRD was neither impacted by morphological blast count during aplasia nor by MRD status postinduction. Early flow MRD was also evaluated in the context of existing risk factors. Flow MRD was prognostic within the intermediate cytogenetic risk group (5-year RFS 15% vs 37%, P=0.016) as well as for patients with normal karyotype and NPM1 mutations (5-year RFS 13% vs 49%, P=0.02) or FLT3-ITD (3-year RFS rates 9% vs 44%, P=0.016). Early flow MRD assessment can improve current risk stratification approaches by prediction of RFS in AML and might facilitate adaptation of postremission therapy for patients at high risk of relapse.

The current and future role of the medical oncologist in the professional care for cancer patients: a position paper by the European Society for Medical Oncology (ESMO).

The number of cancer patients in Europe is rising and significant advances in basic and applied cancer research are making the provision of optimal care more challenging. The concept of cancer as a systemic, highly heterogeneous and complex disease has increased the awareness that quality cancer care should be provided by a multidisciplinary team (MDT) of highly qualified healthcare professionals. Cancer patients also have the right to benefit from medical progress by receiving optimal treatment from adequately trained and highly skilled medical professionals. Built on the highest standards of professional training and continuing medical education, medical oncology is recognised as an independent medical specialty in many European countries. Medical oncology is a core member of the MDT and offers cancer patients a comprehensive and systemic approach to treatment and care, while ensuring evidence-based, safe and cost-effective use of cancer drugs and preserving the quality of life of cancer patients through the entire 'cancer journey'. Medical oncologists are also engaged in clinical and translational research to promote innovation and new therapies and they contribute to cancer diagnosis, prevention and research, making a difference for patients in a dynamic, stimulating professional environment. Medical oncologists play an important role in shaping the future of healthcare through innovation and are also actively involved at the political level to ensure a maximum contribution of the profession to Society and to tackle future challenges. This position paper summarises the multifarious and vital contributions of medical oncology and medical oncologists to today's and tomorrow's professional cancer care.

Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG.

Chemomodulation of cytarabine by fludarabine has been attributed with a higher antileukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-induction chemotherapy in relapsed or refractory acute myeloid leukemia (AML). Patients (n=326, of which 281 were evaluable) were randomly assigned to SHAI (cytarabine, 1 g/m(2) bid, days 1-2 and 8-9 (3 g/m(2) for patients ≤ 60 years with refractory AML or ≥ 2nd relapse); idarubicin 10 mg/m(2) daily, days 3-4 and 10-11) or F-SHAI (SHAI with fludarabine, 15 mg/m(2), 4 h before cytarabine). Although complete remission (CR) rates (35% SHAI and 44% F-SHAI) and overall survival did not differ between both regimens, fludarabine prolonged time to treatment failure from 2.04 to 3.38 months (median, P<0.05). Twenty-seven percent of patients proceeded to allogeneic stem cell transplantation, with a significantly higher number of patients in CR or incomplete remission in the F-SHAI group (22 vs 10%, P<0.01). In conclusion, fludarabine has a beneficial, although moderate, impact on the antileukemic efficacy of high-dose cytarabine-based salvage therapy for relapsed and refractory AML.

[Venous thrombembolism in tumour patients]. / Venöse Thrombembolien bei Tumorpatienten.

Venous thrombembolism (VTE) is one of the most frequent complication in cancer patients. The current options in prophylaxis and therapy have to be balanced against the risks of major bleeding and the burden for the patients. The Gesellschaft für Thrombose- und Hämostaseforschung, the Deutsche Gesellschaft für Palliativmedizin and the German speaking Societies of Hematology and Oncology have recently published guidelines on VTE in cancer patients. Recommendations include diagnostics, individual prophylaxis and treatment.

[Systemic treatment of metastatic prostate cancer]. / Die systemische Therapie des metastasierten Prostatakarzinoms.

Systemic treatment of advanced prostate cancer is multifaceted. First-line therapy is antihormonal treatment with androgen deprivation or antiandrogens. Chemotherapy is effective in hormone refractory (castration resistant) prostate cancer. Alternative and supplementary options include radionuclides, steroids, and symptomatic measures. Use of bisphosphonates is standard in metastatic bone disease. Treatment of patients with metastatic prostate cancer is palliative. The aims are prolongation of overall survival, prolongation of progression-free survival, control and relief of symptoms, and restoration and maintenance of quality of life. Current options allow personalized patient care. New approaches and new drugs will increase the therapeutic possibilities considerably.

High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG.

The objective of this study for newly diagnosed acute promyelocytic leukemia (APL) was to evaluate the efficacy of an intensified double induction chemotherapy including high dose ara-C (HD) and all-trans retinoic acid (ATRA) followed by consolidation and 3 years maintenance therapy. In contrast to APL studies stratifying therapy according to pretreatment white blood cell (WBC) count < and > or =10 x 10(9)/l (low/intermediate and high risk according to the Sanz score), our patients received uniform therapy. From 1994 to 2005, 142 patients (age, 16-60 years) were enrolled. In the low/intermediate (n=105) vs high (n=37) WBC group, the rates of complete remission were 95.2 vs 83.8%, of induction death were 4.8 vs 16.2% (P=0.05) and of molecular remission were 87.5 vs 91.3% (P=1). Long-term overall survival was 84.4 vs 73.0% (P=0.12), event free survival was 78.3 vs 67.3% (P=0.11), relapse free survival was 82.1 vs 80.0% (P=0.83) and the cumulative incidence of relapse was 7.4 vs 11.4% (P=0.46). No relapse or death occurred after 4.7 years. ATRA and intensified chemotherapy including HD ara-C followed by prolonged maintenance therapy reduced the relapse risk in high risk patients. Pretreatment WBC count > or =10 x 10(9)/l count was no relevant prognostic factor for relapse.

Towards a pathogenesis-oriented therapy of acute myeloid leukemia.

Genetic and molecular techniques have provided increasing insights into the biology of acute myeloid leukemia (AML). These investigations showed that AML is not a homogeneous disease but a heterogeneous group of biologically different subentities. These subentities are currently primarily defined by cytogenetics by which three main subgroups can be discriminated: AML with balanced translocations, AML with unbalanced aberrations and AML without cytogenetically detectable aberrations. Within the latter group molecular alterations are identified in more than half of cases such as NPM mutations, FLT3 mutations, MLL duplications and mutations of CEBP-alpha. The clinical meaning of these findings is illustrated by substantial differences in response to therapy and long-term outcome. As demonstrated by the recent multicenter trial of the German AML Cooperative Group (AMLCG) and other studies intensification of induction therapy may improve the results in distinct subtypes but fails to do so in others. Therefore, new strategies need to be explored which incorporate the knowledge about the biology of AML to develop biology adapted treatment strategies. This process has just begun and is predominantly determined by the availability of new agents and their evaluation in clinical phase I and II studies. A variety of targets are currently explored and some trials have yielded promising results already. The step towards a biology adapted treatment of AML is long and requires the combined efforts of researchers, clinicians and the pharmaceutical industry. The first steps towards this goal have been taken and give rise to the hope for more effective and more specific therapies of AML.

Risk-adapted therapy of AML: the AMLCG experience.

Acute myeloid leukemia (AML) is a heterogeneous composition of biologically defined subgroups. Modern trials aim at developing subgroup-specific therapies. The German AML Cooperative Group 1999 trial asks three questions in a randomized factorial design: high-dose vs. standard-dose AraC during induction therapy; G-CSF priming vs. no G-CSF priming; and autologous stem cell transplantation vs. maintenance therapy. An interim analysis with 938 patients reveals subgroup-specific differences in treatment efficacies. Thus, the application of high-dose AraC during induction results in a superior outcome as compared to standard-dose AraC in patients with unfavorable prognosis but not in other patients. These results underline the need for large comprehensive trials to allow the detection of therapy effects in biologically defined subgroups of AML.

Transplantation strategies in AML: AMLCG data.

Allogeneic stem cell transplantation (allo-SCT) is considered the most potent postremission therapy for acute myeloid leukemia (AML). Its superior antileukemic activity is largely ascribed to the powerful graft-versus-leukemia (GvL) effects exerted by donor lymphocytes. However, due to considerable treatment-related lethality the gains in relapse prevention do not necessarily translate into survival advantages in the overall patient population. Therefore, allo-SCT for adult patients with AML in first complete remission (CR1) is currently recommended only for younger and medically fit patients who are at intermediate to high risk of relapse and have an HLA-identical sibling donor. Stem cell allografting from alternative donors in CR1 is considered an option for high risk patients as defined by cytogenetic abnormalities or incomplete response after one course of induction chemotherapy and should usually be performed in the context of a clinical protocol.

A new conditioning regimen involving total marrow irradiation, busulfan and cyclophosphamide followed by autologous PBSCT in patients with advanced multiple myeloma.

The overall survival of patients with advanced multiple myeloma (MM) undergoing high-dose chemotherapy and autologous stem cell transplantation (SCT) depends mainly on the quality of response. Thus, to improve the response rate, a new intensified high-dose chemoradiotherapy was evaluated in a phase I/II study. After induction chemotherapy, 89 patients (median age 51 years, range 32-60 years) with MM stage II/III received a conditioning regimen with total marrow irradiation (9 Gy), busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) followed by SCT. Regimen-related toxicity according to WHO criteria and response rates defined by EBMT/IBMTR were analyzed. The main toxicity was mucositis grade III/IV in 76%, and fever grade >I in 75% of patients. Three patients developed reversible veno-occlusive disease. Transplant-related mortality was 2%. Among patients with de novo and pretreated MM, a CR rate of 48 and 41%, respectively, was documented. With a median follow-up of 45 months, the actuarial median durations of event-free survival (EFS) and overall survival (OS) after transplant were 29 and 61 months for the whole group, 36 and 85 months for patients with de novo MM, respectively. Thus, administration of this intensified conditioning regimen was associated with tolerable toxicity, a high response rate and long EFS and OS.

In vitro response of myelodysplastic megakaryocytopoiesis to megakaryocyte growth and development factor (MGDF).

To evaluate a potential therapeutic role for megakaryocyte growth and development factor (MGDF) in myelodysplastic syndromes (MDS) we compared the in vitro response of normal and myelodysplastic megakaryopoiesis to MGDF on bone marrow mononuclear cells from nine MDS patients and four healthy donors in a short term liquid culture system. The cells were incubated with MGDF alone (1 ng/ml, 10 ng/ml and 100 ng/ml) and in combination with 20 ng/ml stem cell factor, 2 U/ml erythropoietin (EPO) and 100 ng/ml interleukin-3 (IL-3). Cytospins were prepared after 4 days and 10 days for CD61 APAAP staining. In addition, the ploidy of propidium iodide stained CD61 positive cells were detected by flow cytometry. The CD61+ cell number significantly increased (13-fold after 4 days, 56-fold after 10 days of culture) when MGDF (100 ng/ml) was added to the normal bone marrow (NBM) cultures (P=0.0003; P=0.0001). In the MDS cultures the absolute number of endomitotic cells as well as the percentage of polyploid cells remained significantly lower than in NBM after 10 days (P=0.0001). The effect of MGDF on polyploidization of MDS cells was significantly dose dependent (P=0.0051). We found no correlation between peripheral platelet count, cellularity of the bone marrow, number of bone marrow megakaryocytes or FAB-subtype and response to MGDF. Additional administration of IL-3 resulted in a left-shift of megakaryopoiesis in both groups. Even though the response of myelodysplastic megakaryocytic progenitors to MGDF shows inter-individual variations, it is significantly impaired overall. Our data suggest that higher doses of MGDF may be able to ameliorate thrombocytopenia in a subgroup of MDS patients.

Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.