Minglun Li

Current concepts in clinical radiation oncology

Based on its potent capacity to induce tumor cell death and to abrogate clonogenic survival, radiotherapy is a key part of multimodal cancer treatment approaches. Numerous clinical trials have documented the clear correlation between improved local control and increased overall survival. However, despite all progress, the efficacy of radiation-based treatment approaches is still limited by different technological, biological, and clinical constraints. In principle, the following major issues can be distinguished: (1) The intrinsic radiation resistance of several tumors is higher than that of the surrounding normal tissue, (2) the true patho-anatomical borders of tumors or areas at risk are not perfectly identifiable, (3) the treatment volume cannot be adjusted properly during a given treatment series, and (4) the individual heterogeneity in terms of tumor and normal tissue responses toward irradiation is immense. At present, research efforts in radiation oncology follow three major tracks, in order to address these limitations: (1) implementation of molecularly targeted agents and ‘omics’-based screening and stratification procedures, (2) improvement of treatment planning, imaging, and accuracy of dose application, and (3) clinical implementation of other types of radiation, including protons and heavy ions. Several of these strategies have already revealed promising improvements with regard to clinical outcome. Nevertheless, many open questions remain with individualization of treatment approaches being a key problem. In the present review, the current status of radiation-based cancer treatment with particular focus on novel aspects and developments that will influence the field of radiation oncology in the near future is summarized and discussed.

Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathways

ZM447439 (ZM) is a potent and selective inhibitor of aurora-A and -B kinase with putative anti-tumoral activity. Inhibitors of aurora kinases were shown to induce apoptosis in vitro and in vivo. To investigate the underlying mechanisms, cell death pathways triggered by ZM was analysed in HCT-116 colorectal cancer cells. Through correlation of polyploidization and apoptosis in different knockout cells, the interrelation of these cellular responses to ZM was investigated. ZM induced apoptosis in a concentration- and time-dependent manner. ZM-induced apoptosis was associated with an upregulation of p53, breakdown of the mitochondrial membrane potential (DeltaPsim) and activation of caspase-3. To precisely define key components for ZM-induced apoptosis, knockout cells lacking p53, Bak, Bax or both Bak and Bax were used. Lack of p53 reduced ZM-induced apoptosis and breakdown of DeltaPsim, while lack of Bak, Bax or both almost completely inhibited apoptosis and breakdown of DeltaPsim. Since no difference in apoptosis induction was detectable between HCT-116 cells lacking Bak, Bax or both, apoptosis induction depended non-redundantly on both Bak and Bax. Phenomenally, ZM induced notable polyploidization in all examined cells, especially in p53-/- cells. A correlation between polyploidization and apoptosis was observed in wild-type, and also in p53-/- cells, albeit with a modest extent of apoptosis. Moreover, in Bak-/-, Bax-/- and Bak/Bax-/- cells apoptosis was totally inhibited in spite of the strongest polyploidization, suggesting apoptosis may be a secondary event following polyploidization in HCT-116 cells. Thus ZM-induced apoptosis depends not only on polyploidization, but also on the intracellular apoptotic signaling.

The role of PDGF in radiation oncology.

Platelet-derived growth factor (PDGF) was originally identified as a constituent of blood serum and subsequently purified from human platelets. PDGF ligand is a dimeric molecule consisting of two disulfide-bonded chains from A-, B-, C- and D-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors. PDGF is a potent mitogen and chemoattractant for mesenchymal cells and also a chemoattractant for neutrophils and monocytes. In radiation oncology, PDGF are important for several pathologic processes, including oncogenesis, angiogenesis and fibrogenesis. Autocrine activation of PDGF was observed and interpreted as an important mechanism involved in brain and other tumors. PDGF has been shown to be fundamental for the stability of normal blood vessel formation, and may be essential for the angiogenesis in tumor tissue. PDGF also plays an important role in the proliferative disease, such as atherosclerosis and radiation-induced fibrosis, regarding its proliferative stimulation of fibroblast cells. Moreover, PDGF was also shown to stimulate production of extracellular matrix proteins, which are mainly responsible for the irreversibility of these diseases. This review introduces the structural and functional properties of PDGF and PDGF receptors and discusses the role and mechanism of PDGF signaling in normal and tumor tissues under different conditions in radiation oncology.

Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model

BackgroundWe have previously shown that small molecule PDGF receptor tyrosine kinase inhibitors (RTKI) can drastically attenuate radiation-induced pulmonary fibrosis if the drug administration starts at the time of radiation during acute inflammation with present but limited effects against acute inflammation. To rule out interactions of the drug with acute inflammation, we investigated here in an interventive trial if a later drug administration start at a time when the acute inflammation has subsided - has also beneficial antifibrotic effects.MethodsWhole thoraces of C57BL/6 mice were irradiated with 20 Gy and treated with the RTKI imatinib starting either 3 days after radiation (during acute inflammation) or two weeks after radiation (after the acute inflammation has subsided as demonstrated by leucocyte count). Lungs were monitored and analyzed by clinical, histological and in vivo non-invasive computed tomography as a quantitative measure for lung density and lung fibrosis.ResultsIrradiation induced severe lung fibrosis resulting in markedly reduced mouse survival vs. non-irradiated controls. Both early start of imatinib treatment during inflammation and late imatinib start markedly attenuated the development of pulmonary fibrosis as demonstrated by clinical, histological and qualitative and quantitative computed tomography results such as reduced lung density. Both administration schedules resulted in prolonged lifespans. The earlier drug treatment start resulted in slightly stronger beneficial antifibrotic effects along all measured endpoints than the later start.ConclusionsOur findings show that imatinib, even when administered after the acute inflammation has subsided, attenuates radiation-induced lung fibrosis in mice. Our data also indicate that the fibrotic fate is not only determined by the early inflammatory events but rather a complex process in which secondary events at later time points are important. Because of the clinical availability of imatinib or similar compounds, a meaningful attenuation of radiation-induced lung fibrosis in patients seems possible.

Hypofractionated radiotherapy for prostate cancer

In the last few years, hypofractionated external beam radiotherapy has gained increasing popularity for prostate cancer treatment, since sufficient evidence exists that prostate cancer has a low α/β ratio, lower than the one of the surrounding organs at risk and thus there is a potential therapeutic benefit of using larger fractionated single doses. Apart from the therapeutic rationale there are advantages such as saving treatment time and medical resources and thereby improving patient’s convenience. While older trials showed unsatisfactory results in both standard and hypofractionated arm due to insufficient radiation doses and non-standard contouring of target volumes, contemporary randomized studies have reported on encouraging results of tumor control mostly without an increase of relevant side effects, especially late toxicity. Aim of this review is to give a detailed analysis of relevant, recently published clinical trials with special focus on rationale for hypofractionation and different therapy settings.

Investigating deformable image registration and scatter correction for CBCT-based dose calculation in adaptive IMPT

PURPOSE This work aims at investigating intensity corrected cone-beam x-ray computed tomography (CBCT) images for accurate dose calculation in adaptive intensity modulated proton therapy (IMPT) for prostate and head and neck (H&N) cancer. A deformable image registration (DIR)-based method and a scatter correction approach using the image data obtained from DIR as prior are characterized and compared on the basis of the same clinical patient cohort for the first time. METHODS Planning CT (pCT) and daily CBCT data (reconstructed images and measured projections) of four H&N and four prostate cancer patients have been considered in this study. A previously validated Morphons algorithm was used for DIR of the planning CT to the current CBCT image, yielding a so-called virtual CT (vCT). For the first time, this approach was translated from H&N to prostate cancer cases in the scope of proton therapy. The warped pCT images were also used as prior for scatter correction of the CBCT projections for both tumor sites. Single field uniform dose and IMPT (only for H&N cases) treatment plans have been generated with a research version of a commercial planning system. Dose calculations on vCT and scatter corrected CBCT (CBCTcor) were compared by means of the proton range and a gamma-index analysis. For the H&N cases, an additional diagnostic replanning CT (rpCT) acquired within three days of the CBCT served as additional reference. For the prostate patients, a comprehensive contour comparison of CBCT and vCT, using a trained physicians delineation, was performed. RESULTS A high agreement of vCT and CBCTcor was found in terms of the proton range and gamma-index analysis. For all patients and indications between 95% and 100% of the proton dose profiles in beams eye view showed a range agreement of better than 3 mm. The pass rate in a (2%,2 mm) gamma-comparison was between 96% and 100%. For H&N patients, an equivalent agreement of vCT and CBCTcor to the reference rpCT was observed. However, for the prostate cases, an insufficient accuracy of the vCT contours retrieved from DIR was found, while the CBCTcor contours showed very high agreement to the contours delineated on the raw CBCT. CONCLUSIONS For H&N patients, no considerable differences of vCT and CBCTcor were found. For prostate cases, despite the high dosimetric agreement, the DIR yields incorrect contours, probably due to the more pronounced anatomical changes in the abdomen and the reduced soft-tissue contrast in the CBCT. Using the vCT as prior, these inaccuracies can be overcome and images suitable for accurate delineation and dose calculation in CBCT-based adaptive IMPT can be retrieved from scatter correction of the CBCT projections.

Adjuvant radiotherapy after breast conserving surgery – A comparative effectiveness research study

PURPOSE The purpose of this retrospective outcome study was to validate the effectiveness of postoperative radiotherapy in breast conserving therapy (BCT) and to evaluate possible causes for omission of radiotherapy after breast conserving surgery (BCS) in a non-trial population. METHODS Data were provided by the population-based Munich Cancer Registry. The study included epidemiological data of 30.811 patients diagnosed with breast cancer from 1998 to 2012. The effect of omitting radiotherapy was analysed using Kaplan-Meier-estimates and Cox proportional hazard regression. Variables predicting omission of radiotherapy were analysed using multivariate logistic regression. RESULTS Use of postoperative radiotherapy after BCS was associated with significant improvements in local control and survival. 10-year loco-regional recurrence-free-survival was 90.8% with postoperative radiotherapy vs. 77.6% with surgery alone (p<0.001). 10-year overall survival rates were 55.2% with surgery alone vs. 82.2% following postoperative radiotherapy (p<0.001). Variables predicting omission of postoperative radiotherapy included advanced age (women ⩾80 years; OR: 0.082; 95% CI: 0.071-0.094, p<0.001). CONCLUSIONS This study shows a decrease in local control and a survival disadvantage if postoperative radiotherapy after breast conserving surgery is omitted in an unselected cohort of primary breast cancer patients. Due to its epidemiological nature, it cannot answer the question in whom postoperative radiotherapy can be safely omitted.

Technical Note: Millimeter precision in ultrasound based patient positioning: experimental quantification of inherent technical limitations.

PURPOSE To identify the relevant technical sources of error of a system based on three-dimensional ultrasound (3D US) for patient positioning in external beam radiotherapy. To quantify these sources of error in a controlled laboratory setting. To estimate the resulting end-to-end geometric precision of the intramodality protocol. METHODS Two identical free-hand 3D US systems at both the planning-CT and the treatment room were calibrated to the laboratory frame of reference. Every step of the calibration chain was repeated multiple times to estimate its contribution to overall systematic and random error. Optimal margins were computed given the identified and quantified systematic and random errors. RESULTS In descending order of magnitude, the identified and quantified sources of error were: alignment of calibration phantom to laser marks 0.78 mm, alignment of lasers in treatment vs planning room 0.51 mm, calibration and tracking of 3D US probe 0.49 mm, alignment of stereoscopic infrared camera to calibration phantom 0.03 mm. Under ideal laboratory conditions, these errors are expected to limit ultrasound-based positioning to an accuracy of 1.05 mm radially. CONCLUSIONS The investigated 3D ultrasound system achieves an intramodal accuracy of about 1 mm radially in a controlled laboratory setting. The identified systematic and random errors require an optimal clinical tumor volume to planning target volume margin of about 3 mm. These inherent technical limitations do not prevent clinical use, including hypofractionation or stereotactic body radiation therapy.

A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

The chaperone heat shock protein 90 (HSP90) crucially supports the maturation, folding, and stability of a variety of client proteins which are of pivotal importance for the survival and proliferation of cancer cells. Consequently, targeting of HSP90 has emerged as an attractive strategy of anti-cancer therapy, and it appears to be particularly effective in the context of molecular sensitization towards radiotherapy as has been proven in preclinical models of different cancer entities. However, so far the clinical translation has largely been hampered by suboptimal pharmacological properties and serious hepatotoxicity of first- and second-generation HSP90 inhibitors. Here, we report on NW457, a novel radicicol-derived member of the pochoxime family with reduced hepatotoxicity, how it inhibits the DNA damage response and how it synergizes with ionizing irradiation to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer in vitro and in vivo.

Timing of thoracic irradiation in limited stage small-cell lung cancer: is it still a star on the rise?

Early cisplatin-based concurrent chemoradiotherapy (CRT) is a mainstay treatment in limited stage small-cell lung cancer (LS SCLC; the Union for International Cancer Control stage I-III). This is based on the several randomized trials and meta-analyses. Most considerable of them are the National Cancer Institute of Canada (NCIC), Intergroup-0096, and the Japan Clinical Oncology Group (JCOG)-9104 trials [1-3]. These studies included pre-chemotherapy extent of the tumor in radiation portals and demonstrated 5-year survival rates over 20%. Importantly, starting point and application of thoracic irradiation (TRT) in these trials was different. In NCIC study mild hypofractionated TRT was applied with the second cycle whereas in the INT-0096 and JCOG-9104 (concurrent arm) trials accelerated hyperfractionated radiotherapy was started with the first cycle of chemotherapy. In all these trials TRT began within 30 days after initiation of chemotherapy, treatment time of TRT was less than 30 days and dose delivery of chemotherapy and TRT was more than 80%. Another substantial aspect was that deferred application of TRT in the late arms of NCIC and JCOG-9104 trials resulted in the increase of CRT duration as a whole treatment. A retrospective study has reported that in LS SCLC duration of CRT, itself, can also affect overall survival. Recently published randomized phase III trial of Sun et al. [4] demonstrated that outcome achieved with TRT starting with the third cycle of chemotherapy is non-inferior to results when radiotherapy was administered from the first day of systemic treatment. Median survival, remission rates and estimated 5-year survival rates were equal in early and late arms and comparable with best historical results. Although total radiation dose was lower than actual standard, dose-delivery of chemotherapy and TRT was high. In the late TRT arm initially involved lymph nodes were considered in the target definition even a significant response occurred after the second chemotherapy cycle. How can we declare the results of this study? Most relevant finding of Sun et al. [4] is, probably, the fact that in both arms complete responders to CRT demonstrated significant better outcome compared to partial and non-responders. Complete response remains to be highly significant variable correlating with overall survival on the multivariate analysis. This strong correlation is very important and was not reported in the earlier randomized trials. Solely, study of Jeremic et al. [5] found higher complete remission rate in the early TRT arm accompanied with better long-term results, but remission grade of the tumor, itself, was not analysed as a prognostic factor. There is a growing body of evidence to keep response of the tumor in course of CRT under control. Small studies have already demonstrated that rapid achievement of complete remission in LS SCLC can be a significant prognostic factor.