Radiation Oncology - Most accessed articles

Commissioning and early experience with a new-generation low-energy linear accelerator with advanced delivery and imaging functionalities.

Alessandro Clivio — 2011-09-30T00:00:00Z

Background: A new-generation low-energy linear accelerator (UNIQUE) was introduced in the clinical arena during 2009 by Varian Medical Systems. The world's first UNIQUE was installed at Oncology Institute of Southern Switzerland and put into clinical operation in June 2010. The aim of the present contribution was to report experience about its commissioning and first year results from clinical operation. Methods: Commissioning data, beam characteristics and the modeling into the treatment planning system were summarized. Imaging system of UNIQUE included a 2D-2D matching capability and tests were performed to identify system repositioning capability. Finally, since the system is capable of delivering volumetric modulated arc therapy with RapidArc, a summary of the tests performed for such modality to assess its performance in preclinical settings and during clinical usage was included. Results: Isocenter virtual diameter was measured as less than 0.2 mm. Observed accuracy of isocenter determination and repositioning for 2D-2D matching procedures in image guidance was <1.2 mm. Concerning reproducibility and stability over a period of 1 year, deviations from reference were found <0.3 ± 0.2% for linac output, <0.1% for homogeneity, similarly to symmetry. Rotational accuracy of the entire gantry-portal imager system showed a maximum deviation from nominal 0.0 of <1.2 mm. Pre treatment quality assurance of RapidArc plans resulted with a Gamma Agreement Index (fraction of points passing the gamma criteria) of 97.0 ± 1.6% on the first 182 arcs verified. Conclusions: The results of the commissioning tests and of the first period of clinical operation, resulted meeting specifications and having good margins respect to tolerances. UNIQUE was put into operation for all delivery techniques; in particular, as shown by the pre-treatment quality assurance results, it enabled accurate and safe delivery of RapidArc plans.

Treatment strategies for oesophageal cancer - time-trends and long term outcome data from a large tertiary referral centre

Maria Wolf — 2012-04-15T00:00:00Z

Background and objectivesTreatment options for oesophageal cancer have changed considerably over the last decades with the introduction of multimodal treatment concepts dominating the progress in the field. However, it remains unclear in how far the documented scientific progress influenced and changed the daily routine practice. Since most patients with oesophageal cancer generally suffer from reduced overall health conditions it is uncertain how high the proportion of aggressive treatments is and whether outcomes are improved substantially. In order to gain insight into this we performed a retrospective analysis of patients treated at a larger tertiary referral centre over time course of 25 years.Patients and methodsData of all patients diagnosed with squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the oesophagus, treated between 1983 and 2007 in the department of radiation oncology of the LMU, were obtained. The primary endpoint of the data collection was overall survival (calculated from the date of diagnosis until death or last follow up). Changes in basic clinical characteristics, treatment approach and the effect on survival were analysed after dividing the cohort into five subsequent time periods (I-V) with 5 years each. In a second analysis any pattern of change regarding the use of radio(chemo)therapy (R(C)T) with and without surgery was determined. Results: In total, 503 patients with SCC (78.5%) and AC (18.9%) of the oesophagus were identified. The average age was 60 years (range 35-91 years). 56.5% of the patients were diagnose with advanced UICC stages III-IV. R(C)T was applied to 353 (70.2%) patients; R(C)T+ surgery was performed in 134 (26.6%) patients, 63.8% of all received chemotherapy (platinum-based 5.8%, 5-fluorouracil (5-FU)12.1%, 42.3% 5-FU and mitomycin C). The median follow-up period was 4.3 years. The median overall survival was 21.4 months. Over the time, patients were older, the formal tumour stage was more advanced, the incidence of AC was higher and the intensified treatment had a higher prevalence. However there was only a trend for an improved OS over the years with no difference between RCT with or without surgery (p=0.08). The use of radiation doses over 54 Gy and the addition of chemotherapy (p=0.002) were associated with improved OS. Conclusion: Although more complex treatment protocols were introduced into clinical routine, only a minor progress in OS rates was detectable. Main predictors of outcome in this cohort was the addition of chemotherapy. The addition of surgery to radio-chemotherapy may only be of value for very limited patient groups.

The combination of olaparib and camptothecin for effective radiosensitization

Katsutoshi Miura — 2012-04-23T00:00:00Z

Background: Poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme involved in the repair of radiation-induced single-strand DNA breaks. PARP inhibitors such as olaparib (KU-0059436, AZD-2281) enhance tumor sensitivity to radiation and to topoisomerase I inhibitors like camptothecin (CPT). Olaparib is an orally bioavailable inhibitor of PARP-1 and PARP-2 that has been tested in multiple clinical trials. The purpose of this study was to investigate the characteristics of the sensitizing effect of olaparib for radiation and CPT in order to support clinical application of this agent. Methods: DLD-1 cells (a human colorectal cancer cell line) and H1299 cells (a non-small cell lung cancer cell line) with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The gammaH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT. Results: A radiosensitizing effect of olaparib was seen even at 0.01 muM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 muM, and its sensitizing effect was the same at both 0.01 muM and 1 muM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the gammaH2AX focus assay corresponded with the clonogenic assay findings. Conclusion: Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib was not dependent on the p53 status of tumor cells. These characteristics could be advantageous for clinical radiotherapy since tumor cells may be exposed to low concentrations of olaparib and/or may have different levels of p53 mutation. The combination of olaparib and CPT had a stronger radiosensitizing effect, indicating that combining a PARP inihibitor with a topoiomerase I inhibitor could be promising for clinical radiosensitization.

Dosimetric consequences of translational and rotational errors in frame-less image-guided radiosurgery

Matthias Guckenberger — 2012-04-24T00:00:00Z

Background: To investigate geometric and dosimetric accuracy of frame-less image-guided radiosurgery(IG-RS) for brain metastases.Methods and materialsSingle fraction IG-RS was practiced in 72 patients with 98 brain metastases. Patientpositioning and immobilization used either double- (n = 71) or single-layer (n = 27)thermoplastic masks. Pre-treatment set-up errors (n = 98) were evaluated with cone-beam CT(CBCT) based image-guidance (IG) and were corrected in six degrees of freedom without anaction level. CBCT imaging after treatment measured intra-fractional errors (n = 64). Pre- andpost-treatment errors were simulated in the treatment planning system and target coverageand conformity were evaluated. Three scenarios of 0 mm, 1 mm and 2 mm GTV-to-PTV(gross tumor volume) safety margins (SM) were simulated. Results: Errors prior to IG were 3.9 mm +/- 1.7 mm (3D vector) and the maximum rotational error was1.7degrees +/- 0.8degrees on average. The post-treatment 3D error was 0.9 mm +/- 0.6 mm. No differencesbetween double- and single-layer masks were observed. Simulation of RS without imageguidancereduced target coverage and conformity to 75% +/- 19% and 60% +/- 25% of plannedvalues. Each 3D set-up error of 1 mm decreased target coverage and dose conformity by 6%and 10% on average, respectively, with a large inter-patient variability. Pre-treatmentcorrection of translations only but not rotations did not affect target coverage and conformity.Post-treatment errors reduced target coverage by >5% in 14% of the patients. A 1 mm safetymargin fully compensated intra-fractional patient motion. Conclusions: IG-RS with online correction of translational errors achieves high geometric and dosimetricaccuracy. Intra-fractional errors decrease target coverage and conformity unless compensatedwith appropriate safety margins.

Clinical outcomes and toxicity using Stereotactic Body Radiotherapy (SBRT) for advanced cholangiocarcinoma

Brandon Barney — 2012-05-03T00:00:00Z

Background: To report single-institutional clinical outcomes and toxicity with SBRT forcholangiocarcinoma. Methods: From March 2009 to July 2011, 10 patients with 12 unresectable primary (n = 6) or recurrent(n = 6) cholangiocarcinoma lesions underwent abdominal SBRT. Sites treated included liver(n = 10), abdominal lymph nodes (n = 1), and adrenal gland (n = 1). SBRT was delivered inthree (n = 2) or five (n = 10) consecutive daily fractions over one week. The medianprescription dose was 55 Gy (range, 45-60). Treatment response was graded by RECISTv.1.1, and toxicities were scored by CTCAE v.4.0. Data was analyzed using the Kaplan-Meier method to determine rates of local control (LC), freedom from distant progression(FFDM) and overall survival (OS). Results: The median follow-up was 14 months (range, 2-26 months). LC, defined as freedom fromprogression within the SBRT field, was 100%, but four patients treated to intrahepatic sitesexperienced progression elsewhere in the liver. Estimates for FFDM at 6 and 12 months were73% and 31%, respectively. Sites of disease relapse included liver (n = 3), liver and lymphnodes (n = 1), liver and lungs (n = 1), lymph nodes (n = 1), and mesentery (n = 1). OSestimates for the cohort at 6 and 12 months were 83% and 73%, respectively. The mostcommon Grade [greater than or equal to]2 early toxicities were Grade 2 nausea and vomiting (n = 5) andgastrointestinal pain (n = 2). Late [greater than or equal to]2 toxicities included Grade 2 gastrointestinal pain (n = 3),Grade 3 biliary stenosis (n = 1), and Grade 5 liver failure (n = 1). Conclusions: SBRT shows promise as an effective local therapy for properly-selected patients withcholangiocarcinoma. Further follow-up is needed to better quantify the risk of latecomplications associated with SBRT.

Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes

Debra Freeman — 2011-01-10T00:00:00Z

PurposeHypofractionated, stereotactic body radiotherapy (SBRT) is an emerging treatment approach for prostate cancer. We present the outcomes for low-risk prostate cancer patients with a median follow-up of 5 years after SBRT.Method and MaterialsBetween Dec. 2003 and Dec. 2005, a pooled cohort of 41 consecutive patients from Stanford, CA and Naples, FL received SBRT with CyberKnife for clinically localized, low-risk prostate cancer. Prescribed dose was 35-36.25 Gy in five fractions. No patient received hormone therapy. Kaplan-Meier biochemical progression-free survival (defined using the Phoenix method) and RTOG toxicity outcomes were assessed. Results: At a median follow-up of 5 years, the biochemical progression-free survival was 93% (95% CI = 84.7% to 100%). Acute side effects resolved within 1-3 months of treatment completion. There were no grade 4 toxicities. No late grade 3 rectal toxicity occurred, and only one late grade 3 genitourinary toxicity occurred following repeated urologic instrumentation. Conclusion: Five-year results of SBRT for localized prostate cancer demonstrate the efficacy and safety of shorter courses of high dose per fraction radiation delivered with SBRT technique. Ongoing clinical trials are underway to further explore this treatment approach.

Accelerated Partial Breast Irradiation (APBI): A review of available techniques

Christopher Njeh — 2010-10-04T00:00:00Z

Breast conservation therapy (BCT) is the procedure of choice for the management of the early stage breast cancer. However, its utilization has not been maximized because of logistics issues associated with the protracted treatment involved with the radiation treatment. Accelerated Partial Breast Irradiation (APBI) is an approach that treats only the lumpectomy bed plus a 1-2 cm margin, rather than the whole breast. Hence because of the small volume of irradiation a higher dose can be delivered in a shorter period of time. There has been growing interest for APBI and various approaches have been developed under phase I-III clinical studies; these include multicatheter interstitial brachytherapy, balloon catheter brachytherapy, conformal external beam radiation therapy and intra-operative radiation therapy (IORT). Balloon-based brachytherapy approaches include Mammosite, Axxent electronic brachytherapy and Contura, Hybrid brachytherapy devices include SAVI and ClearPath. This paper reviews the different techniques, identifying the weaknesses and strength of each approach and proposes a direction for future research and development. It is evident that APBI will play a role in the management of a selected group of early breast cancer. However, the relative role of the different techniques is yet to be clearly identified.

NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/Mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity

Emmanouil Fokas — 2012-03-27T00:00:00Z

Background: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in tumor cells and promotes tumor cell survival after radiation-induced DNA damage. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition.Materials and methodsWe investigated the effect of two dual PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on endothelial cells. Analysis of target protein phosphorylation, clonogenic survival, number of residual γH2AX foci, cell cycle and apoptosis after radiation was performed in both tumor and endothelial cells. In vitro angiogenesis assays were conducted as well. Results: Both compounds effectively inhibited phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by increased number of γH2AX foci, was detected after irradiation in the presence of PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing in human umbilical venous endothelial cells (HUVEC) and human dermal microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell migration and capillary tube formation in vitro and enhanced the antivascular effect of irradiation. Treatment with NVP-BEZ235 moderately increased apoptosis in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both tumor and endothelial all cells tumor. Conclusions: The results of this study demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in tumor and endothelial cells and may be of benefit when combined with radiotherapy.

Association of single nucleotide polymorphisms in the genes ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with risk of severe erythema after breast conserving radiotherapy

Annette Raabe — 2012-04-26T00:00:00Z

PurposeTo examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position 509), XPD (codon 751), and XRCC1 (codon 399) with the risk of severe erythema after breast conserving radiotherapy.Methods and materialsRetrospective analysis of 83 breast cancer patients treated with breast conserving radiotherapy. A total dose of 50.4 Gy was administered, applying 1.8 Gy/fraction within 42 days. Erythema was evaluated according to the Radiation Therapy Oncology Group (RTOG) score. DNA was extracted from blood samples and polymorphisms were determined using either the Polymerase Chain Reaction based Restriction-Fragment-Length-Polymorphism (PCR-RFL) technique or Matrix-Assisted-Laser-Desorption/Ionization -Time-Of-Flight-Mass-Spectrometry (MALDI-TOF). Relative excess heterozygosity (REH) was investigated to check compatibility of genotype frequencies with Hardy-Weinberg equilibrium (HWE). In addition, p-values from the standard exact HWE lack of fit test were calculated using 100,000 permutations. HWE analyses were performed using R. Results: Fifty-six percent (46/83) of all patients developed erythema of grade 2 or 3, with this risk being higher for patients with large breast volume (odds ratio, OR = 2.55, 95% confidence interval, CI: 1.03-6.31, p = 0.041). No significant association between SNPs and risk of erythema was found when all patients were considered. However, in patients with small breast volume the TGFB1 SNP was associated with erythema (p = 0.028), whereas the SNP in XPD showed an association in patients with large breast volume (p = 0.046). A risk score based on all risk alleles was neither significant in all patients nor in patients with small or large breast volume. Risk alleles of most SNPs were different compared to a previously identified risk profile for fibrosis. Conclusions: The genetic risk profile for erythema appears to be different for patients with small and larger breast volume. This risk profile seems to be specific for erythema as compared to a risk profile for fibrosis.

Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced

Turid Hellevik — 2012-04-13T00:00:00Z

Background: Cancer-Associated Fibroblasts (CAFs) are significant components of solid malignancies and play central roles in cancer sustainability, invasion and metastasis. In this study we have investigated the invasive capacity and matrix remodelling properties of human lung CAFs after exposure to ablative doses of ionizing radiation (AIR), equivalent to single fractions delivered by stereotactic ablative radiotherapy (SART) for medically inoperable stage-I/II non-small-cell lung cancers. Methods: CAFs were isolated from lung tumour specimens from 16 donors. Initially, intrinsic radiosensitivity was evaluated by checking viability and extent of DNA-damage response (DDR) at different radiation doses. The migrative and invasive capacities of CAFs were thereafter determined after a sub-lethal single radiation dose of 18 Gy. To ascertain the mechanisms behind the altered invasive capacity of cells, expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) were measured in the conditioned media several days post-irradiation, along with expression of cell surface integrins and dynamics of focal contacts by vinculin-staining. Results: Exposing CAFs to 1 x 18 Gy resulted in a potent induction of multiple nuclear DDR foci (>9/cell) with little resolution after 120 h, induced premature cellular senescence and inhibition of the proliferative, migrative and invasive capacity. AIR promoted MMP-3 and inhibited MMP-1 appearance to some extent, but did not affect expression of other major MMPs. Furthermore, surface expression of integrins alpha2, beta1 and alpha5 was consistently enhanced, and a dramatic augmentation and redistribution of focal contacts was observed. Conclusions: Our data indicate that ablative doses of radiation exert advantageous inhibitory effects on the proliferative, migratory and invasive capacity of lung CAFs. The reduced motility of irradiated CAFs might be a consequence of stabilized focal contacts via integrins.