Isobologram analysis of triple therapies

New concepts in radiation oncology are based on the concept that combinations of irradiation and molecular targeted drugs can yield synergistic or at least additive effects. Up to now the combination of two treatment modalities has been tested in almost all cases. Similar to conventional anti-cancer agents, the efficacy of targeted approaches is also subject to predefined resistance mechanisms. Therefore, it seems reasonable to speculate that a combination of more than two agents will ultimately increase the therapeutic gain. No tools for a bio-mathematical evaluation of a given degree of interaction for more than two anti-neoplastic agents are currently available. The present work introduces a new method for an evaluation of triple therapies and provides some graphical examples in order to visualize the results

Counting colonies of clonogenic assays by using densitometric software

Clonogenic assays are a useful tool to test whether a given cancer therapy can reduce the clonogenic survival of tumour cells. A colony is defined as a cluster of at least 50 cells which can often only be determined microscopically. The process of counting colonies is very extensive work and so we developed software that is able to count the colonies automatically from scanned flasks. This software is made freely available by us with a detailed description how to use and install the necessary features

Why "Radiation Oncology"

Radiotherapy continues to be a major treatment for solid tumours and is a cornerstone of modern oncology. The term 'radiation oncology' describes the integration of radiation therapy into the complexity of multi-modal therapy. Over the last ten years the crucial role of radiation therapy as part of multi-modality protocols in cancer care has been documented in numerous Phase III trials. Advances in treatment technology as well as the underlying biology of tumour resistance mechanisms will further strengthen the role of radiation oncology. The scientific role of radiation oncology is reflected by the increase in the number of papers related to radiation oncology in resources like Medline. In order to reflect the growing scientific importance of radiation oncology, radiation physics and radiation biology, we have initiated Radiation Oncology as the first open access journal in the field. Open access allows for a rapid and transparent publication process together with an unequalled opportunity to reach the widest reader spectrum possible

Surgery vs. radiotherapy in localized prostate cancer. Which is best?

Surgery and radiotherapy are currently accepted alternatives for the treatment of localized prostate cancer. In the absence of relevant randomized trials no decision regarding the superiority of any of the given approaches can be made. Up to now several cohort-based approaches indicate similar outcomes for both treatments. Based on a new population based approach, Merglen and co-workers recently concluded that surgery would offer the best chance of long-term control in terms of 10-year survival for T1–T3 prostate cancer patients. Unfortunately the strength of this trial is limited by several shortcomings. Most importantly, issues of radiation dosage have not been taken into account. In addition, several relevant parameters including Gleason score and PSA are not well balanced between the arms and the assignment to arbitrary risk groups does not reflect the real biological behaviour. Thus, the data provided do not support the strong conclusion issued by the authors. Based on the data available, surgery and radiotherapy still have to be considered as equally effective

Choline PET based dose-painting in prostate cancer - Modelling of dose effects

Background: Several randomized trials have documented the value of radiation dose escalation in patients with prostate cancer, especially in patients with intermediate risk profile. Up to now dose escalation is usually applied to the whole prostate. IMRT and related techniques currently allow for dose escalation in sub-volumes of the organ. However, the sensitivity of the imaging modality and the fact that small islands of cancer are often dispersed within the whole organ may limit these approaches with regard to a clear clinical benefit. In order to assess potential effects of a dose escalation in certain sub-volumes based on choline PET imaging a mathematical dose-response model was developed. Methods: Based on different assumptions for alpha/beta, gamma 50, sensitivity and specificity of choline PET, the influence of the whole prostate and simultaneous integrated boost (SIB) dose on tumor control probability (TCP) was calculated. Based on the given heterogeneity of all potential variables certain representative permutations of the parameters were chosen and, subsequently, the influence on TCP was assessed. Results: Using schedules with 74 Gy within the whole prostate and a SIB dose of 90 Gy the TCP increase ranged from 23.1% (high detection rate of choline PET, low whole prostate dose, high gamma 50/ASTRO definition for tumor control) to 1.4% TCP gain (low sensitivity of PET, high whole prostate dose, CN + 2 definition for tumor control) or even 0% in selected cases. The corresponding initial TCP values without integrated boost ranged from 67.3% to 100%. According to a large data set of intermediate-risk prostate cancer patients the resulting TCP gains ranged from 22.2% to 10.1% (ASTRO definition) or from 13.2% to 6.0% (CN + 2 definition). Discussion: Although a simplified mathematical model was employed, the presented model allows for an estimation in how far given schedules are relevant for clinical practice. However, the benefit of a SIB based on choline PET seems less than intuitively expected. Only under the assumption of high detection rates and low initial TCP values the TCP gain has been shown to be relevant. Conclusions: Based on the employed assumptions, specific dose escalation to choline PET positive areas within the prostate may increase the local control rates. Due to the lack of exact PET sensitivity and prostate alpha/beta parameter, no firm conclusions can be made. Small variations may completely abrogate the clinical benefit of a SIB based on choline PET imaging

Intra-fraction motion of the prostate is not increased by patient couch shifts

Background: During a fraction of external beam radiotherapy for prostate cancer, a mismatch between target volume and dose coverage may accumulate over time due to intra-fraction motion. One way to remove the residual error is to perform a couch shift in opposite direction. In principle, such couch shifts could cause secondary displacements of the patient and prostate. Hence it is interesting to investigate if couch shifts might amplify intra-fraction motion. Findings: Intra-fraction motion of the prostate and patient couch position were simultaneously recorded during 359 fractions in 15 patients. During this time, a total of 22 couch shifts of up to 31.5 mm along different axes were recorded. Prostate position and couch position were plotted before, during and after each couch shift. There was no visible impact of couch shifts on prostate motion. The standard deviation of prostate position was calculated before, during and after each couch shift. The standard deviation did not significantly increase during couch shifts (by 3 % on average, p = 0.88) and even slightly decreased after a couch shift (by 37 % on average;p = 0.02). Conclusions: Shifts of the patient couch did not adversely affect the motion of the prostate relative to the patient couch. Hence, shifts of the patient couch may be a viable way to correct the position of the prostate relative to the dose distribution

Radiotherapy and "new" drugs-new side effects?

Background and Purpose: Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments. Material and methods: Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab / trastuzumab / panitumumab / nimotuzumab, bevacizumab, sunitinib / sorafenib / lapatinib / gefitinib / erlotinib / sirolimus, thalidomide / lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms. Results: Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported. Conclusions: The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard to efficacy, early and late toxicity

Endometrial cancer - reduce to the minimum. A new paradigm for adjuvant treatments?

<p>Abstract</p> <p>Background</p> <p>Up to now, the role of adjuvant radiation therapy and the extent of lymph node dissection for early stage endometrial cancer are controversial. In order to clarify the current position of the given adjuvant treatment options, a systematic review was performed.</p> <p>Materials and methods</p> <p>Both, Pubmed and ISI Web of Knowledge database were searched using the following keywords and MESH headings: "Endometrial cancer", "Endometrial Neoplasms", "Endometrial Neoplasms/radiotherapy", "External beam radiation therapy", "Brachytherapy" and adequate combinations.</p> <p>Conclusion</p> <p>Recent data from randomized trials indicate that external beam radiation therapy - particularly in combination with extended lymph node dissection - or radical lymph node dissection increases toxicity without any improvement of overall survival rates. Thus, reduced surgical aggressiveness and limitation of radiotherapy to vaginal-vault-brachytherapy only is sufficient for most cases of early stage endometrial cancer.</p

Differential protection by wildtype vs. organelle-specific Bcl-2 suggests a combined requirement of both the ER and mitochondria in ceramide-mediated caspase-independent programmed cell death

<p>Abstract</p> <p>Background</p> <p>Programmed cell death (PCD) is essential for development and homeostasis of multicellular organisms and can occur by caspase-dependent apoptosis or alternatively, by caspase-independent PCD (ciPCD). Bcl-2, a central regulator of apoptosis, localizes to both mitochondria and the endoplasmic reticulum (ER). Whereas a function of mitochondrial and ER-specific Bcl-2 in apoptosis has been established in multiple studies, corresponding data for ciPCD do not exist.</p> <p>Methods</p> <p>We utilized Bcl-2 constructs specifically localizing to mitochondria (Bcl-2 ActA), the ER (Bcl-2 cb5), both (Bcl-2 WT) or the cytosol/nucleus (Bcl-2 ΔTM) and determined their protective effect on ceramide-mediated ciPCD in transiently and stably transfected Jurkat cells. Expression of the constructs was verified by immunoblots. Ceramide-mediated ciPCD was induced by treatment with human recombinant tumor necrosis factor and determined by flow cytometric measurement of propidium iodide uptake as well as by optical analysis of cell morphology.</p> <p>Results</p> <p>Only wildtype Bcl-2 had the ability to efficiently protect from ceramide-mediated ciPCD, whereas expression of Bcl-2 solely at mitochondria, the ER, or the cytosol/nucleus did not prevent ceramide-mediated ciPCD.</p> <p>Conclusion</p> <p>Our data suggest a combined requirement for both mitochondria and the ER in the induction and the signaling pathways of ciPCD mediated by ceramide.</p