memo - Magazine of European Medical Oncology

Papakonstantinou, Georgios

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0116-6

The promise of all targeted therapies is the specific induction of cytotoxicity in malignant cells without adversely affecting normal tissues. Antibody–drug conjugates (ADCs) consist of a monoclonal antibody chemically linked to an anticancer agent, and are a niche class of drugs that raise great expectations, particularly as oncology drugs. Brentuximab vedotin and trastuzumab emtansine, both recently US Food and Drug Administration approved, open a promising new area in the therapy of hematologic malignancies and solid tumors. Further improvement of bioengineering and development of preclinical and clinical data are the challenges for the next generation of ADCs.

Hofer, Silvia

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0091-y

Steger, Günther G.; Bartsch, Rupert

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0119-3

Recent advances in the field of systemic treatment resulted in a significant decline of overall breast cancer mortality. Numerous important issues, however, remain unresolved. Among others, the optimal duration and sequence of endocrine therapy in the adjuvant setting are much debated. Furthermore, the advance of novel targeted treatment options in human epidermal growth factor receptor 2-positive and hormone-receptor-positive breast cancers resulted in an urgent need for establishing reliable predictive markers. Finally, in triple-negative breast cancer, there are currently no specific biologically targeted therapies available.

Petru, Edgar; Idris, Tina; Kolovetsiou, Vassilliki; Schest, Eva

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0115-7

Pircher, Andreas; Fiegl, Michael; Kocher, Florian; Hilbe, Wolfgang

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0120-x

At American Society of Clinical Oncology meeting 2013, some new data were presented, which might have a practice-changing potential. Epidermal growth factor receptor mutational testing was successfully performed in plasma samples, giving hope that tumor biopsies might be replaced by a more comfortable blood analysis. Some studies focused on new second-generation anaplastic lymphoma kinase inhibitors, which showed an impressive efficacy even in crizotinib refractory patients in phase I/II studies and support a sequence of tyrosine kinase inhibitors (TKIs) in this sub-entity of non-small-cell lung cancer (NSCLC). Immunological strategies are worth being tested also in lung cancer, as different strategies have proven first signs of efficacy (MUC1 antigen-specific cancer immunotherapy, programmed cell death ligand 1). Finally, a large phase III trial found that a new oral vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor TKI (nintedanib) combined with docetaxel improved outcome in second-line NSCLC patients when compared with docetaxel monotherapy.

Pall, Georg

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0107-7

Within the Head and Neck Cancer-Track at the American Society of Clinical Oncology (ASCO) Annual Meeting 2013 a large number of abstracts have been presented. The aim of this short review is to highlight those abstracts with the highest immediate clinical impact and to draw attention to some of the latest basic research findings, which might open new pathways toward more efficacious treatments.

Weinlich, Georg

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0114-8

‘There is a light at the end of the tunnel in the treatment of metastatic melanoma’ was the slogan of enthusiastic dermatologists around the world in 2010, when two new substances were approved by the Food and Drug Association in the United States and later on, the European Medicines Agency in Europe. Ipilimumab (Yervoy®) is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4, which switches off the mechanism of immune suppression and enables continuous, unrestrained stimulation of T-cells by dendritic cells. The objective response rates are only 10–15 %, but most of them are long lasting. The second approved substance is vemurafenib (Zelboraf®), a selective BRAF inhibitor. BRAF is a member of the Raf family, which is part of the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway. Approximately 40–60 % of cutaneous melanomas carry mutations in BRAF that lead to constitutive activation of downstream signalling through the MAPK pathway. However, the duration of response has been limited, as resistance to BRAF inhibitors develops within months after initiation of treatment. So in 2013 the question arises, whether the story of success in the treatment of metastatic melanoma is prolonged and whether there are some new promising substances in the treatment pipeline. At American Society of Clinical Oncology 2013, actual data of studies with other immune checkpoint molecules, such as programmed death-1 antibodies or antibodies against its ligand programmed death ligand 1, were presented, as well as data from downstream molecules of the MAPK pathway (e.g. MEK inhibitors). The most promising response rates, however, can be observed by combining these new substances.

Hofer, Silvia; Marosi, Christine

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0103-y

At this yearʼs American society of clinical oncology (ASCO) meeting (2013) a number of recently completed randomized Phase II and III trials regarding the treatment of high- and low-grade glioma were reported. The RTOG 0825 trial and the AVAglio trial, both double-blinded, placebo-controlled Phase III trials, addressed the benefits of bevacizumab in newly diagnosed glioblastoma (GBM) alongside to the standard of care (SOC). In the randomized Phase II GLARIUS trial, bevacizumab and irinotecan was compared to the SOC in GBM with a nonmethylated O6-Methylguanine-DNA Methyltransferase (MGMT) promoter. In the recurrent setting results from the Dutch BELOB randomized three arm phase II trial were presented: Bevacizumab alone vs. lomustine alone vs. the combination in recurrent GBM. The CENTRIC trial tested the integrin inhibitor cilengitide in newly diagnosed and MGMT promoter methylated GBM. Two trials on low-grade glioma (LGG) were presented: the single arm RTOG 0424 phase II trial for LGG with at least three risk factors and first results from the randomized phase III EORTC 22033-26033 trial, including LGG patients with one or more risk factors treated either with irradiation alone or temozolomide alone. Translational research results of these trials will be expected at a later point of time.

Zwierzina, Heinz

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0123-7

At American Society of Clinical Oncology’s 2013 meeting, the clinical development of innovative drugs targeting the immune system and progress in biomarker research represented some of the highlights. During recent years, immunomodulatory agents have become a very active field in clinical cancer research. After the successful development of the anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody ipilimumab in melanoma, the “programmed cell death protein 1” pathway is expected to become a cornerstone in several tumor types. One key challenge for anticancer treatment, in general, is the definition of biomarkers and the further individualization of therapy. Progress in molecular phenotyping and in serum proteomics as predictive markers was reported.

Dal-Pont, Christian; Schennach, Harald

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0113-9

Graft-versus-host disease not associated with stem cell transplantation is a rare event, but might be underdiagnosed. It occurs mainly as transfusion-associated graft-versus-host disease in a susceptible recipient between day 2 and 30 after transfusion of cellular blood components, which also contain lymphocytes. These transfused lymphocytes are the causative agents. Their major target is the bone marrow, resulting in bone marrow failure leading to pancytopenia and consecutive death. The fatality rate is high (approximately 90 %). Patients at risks are those with congenital or acquired immunodeficiencies. However, immunocompetent patients may also be affected. This is the case when human leukocyte antigen (HLA)-homozygous donors share one haplotype with the recipient or when HLA-matched components are selected. The diagnosis is mainly a clinical one, supported by laboratory findings in biopsies from the skin and bowel. The detection of chimerism by HLA typing or short tandem repeat polymorphism can confirm the diagnosis. So far, no reasonable treatment exists, so prevention is still the only effective measure. Gamma irradiation has been used for years with great success. However, also pathogen inactivation, although developed to minimize the infectious risk of blood components, has shown, as a beneficial by-product, to reduce the number of lymphocytes. Other graft-versus-host diseases not associated with stem cell transplantation are those occurring after solid organ transplantation, e.g., after liver or small bowel transplantation, which have a similar pathophysiology and bad prognosis.

Apostolou, Panagiotis; Papasotiriou, Ioannis

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0117-5

The fight against cancer is the focus of many research groups, as it is classified as one of the leading causes of death. The treatment of cancer is mainly composed of surgery, chemotherapy, radiation therapy, immunotherapy, and nowadays through targeted therapy as well. Targeted therapy targets the molecules whose expression correlates to carcinogenesis. It can be performed either with small molecule drugs or with monoclonal antibodies. Based on the capacity of the monoclonal antibodies to recognize a certain epitope of an antigen, and the fact that cancer cells express many antigens compared with normal (noncancer) cells abnormally in their surface, cytotoxicity may be induced directly in these cells. The cytotoxicity can be caused either via antibody-dependent cellular interaction or via the complement system. The possibility to create monoclonal antibodies against any antigen led to production of new medicines, many of which are already in clinical use. The ability to conjugate several molecules to antibodies also made the delivery of drugs/substances directly to cancer cells possible, thereby reducing the side effects of cancer treatment. This review presents the implementation of antibodies to targeted therapy, emphasizing the antibody-dependent cytotoxicity, as well as the monoclonal antibodies that are used in cancer treatment.

Toloudi, Maria; Papasotiriou, Ioannis

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0118-4

An important step in cancer drug research and development is to generate molecules and agents with better outcomes for inhibition of cancer progression. To date, classic cytotoxic chemotherapy is one of the most frequent methods of treatment. Cytotoxic agents currently used frequently have severe side effects. Thus, clinicians are forced to reduce the recommended dosage, or even avoid the extreme usage of these agents because they are nonselective and are distributed to healthy cells as well as cancer cells. Antibody drug conjugates (ADCs) are a new generation of drugs that consist of three parts: a monoclonal antibody (monoclonal antibodies), a small molecule, and a linker between the two. The use of this structure in research pipelines and recently in clinical practice is likely to achieve more precise and selective distribution and delivery of the cytotoxic agents to cancer cells. This review analyzes the structure of ADCs and the advantages of targeted chemotherapeutics. Possible methods of improvement are also discussed.

Karamouzis, Michalis V

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0111-y

Breast cancer accounts for about 20 % of female carcinomas. Expression of EGFR protein family receptors in breast carcinomas is quite common. ERBB-2 overexpression at protein level or gene amplification is present in approximately in one third of breast carcinomas and is associated with dismal prognosis. Pharmaceutical agents against ERBB-2 are currently used in breast cancer patients. The need for additional therapeutic strategies led to the development of a new class of agents called antibody-drug conjugates that were first evaluated in hematological malignancies. Trastuzumab emtansine (T-DM1) is the first immuno-conjugate that was tested and approved for the treatment of a solid tumor. In the present review, we will briefly update the rationale and clinical data of this agent and consider its perspectives in the treatment algorithm of breast cancer patients.

Chondropoulos, Spyridon Dimitrios; Delastic, Annaliza; Spyridonidis, Alexandros

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0121-9

In the past years, new emerging targeted therapies against specific markers have revolutionized the field of treating malignancies. In this article, we discuss the first available agent that targets a specific molecule in acute myeloid leukemia, as well as the future possibilities that genetic research unveil.

Stamatopoulou, Sofia

2013 memo - Magazine of European Medical Oncology

doi: 10.1007/s12254-013-0122-8

Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL) are lymphoproliferative types of cancer. The chemotherapy regimens of HL such as ABVD (doxorubicin, bleomycin, vinblastine, decarbazine) and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophospamide, vincristine, procarbazine, prednisone) have made the most curable malignancies. Unfortunately, 15–30 % of these patients will relapse again and treatment options become limited, so we need to develop new therapeutic approaches. ALCL has unique molecular and immunohistochemical features that make it an ideal model for developing targeted therapies. Antibody-drug conjugates (ADCs), consist of an antibody, a cytotoxic agent, a stable linker and allow delivery of high doses of cytotoxic drugs to cancer cells while sparing normal tissues exposure to high systemic concentration of the cytotoxic agent. Brentuximab vedotin is an anti-CD30 monoclonal antibody conjugate with a potent microtubule inhibitor monomethyl auristatin E. In August 2011, the United States Food and Drug Administration (FDA) approved brentuximab vedotin to treat HL after failure of autologous stem cell transplantation or at least two combination chemotheraphy regimens and for sALCL after failure of at least one prior multidrug chemotherapy regimen. With this approval, brentuximab vedotin is a promising ADC directed against the CD30 antigen.