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Solid tumours make up 90% of all proliferative diseases and the main action for cure remains surgery, removing the visible tumour as well as the surrounding tissue. Radiotherapy is an added value for eliminating local microscopic as well as regional disease. Systemic treatment has a small impact on the outcome but has a cost, which is as much as all the other actions such as diagnostic tools and treatments. [ABSTRACT FROM AUTHOR]

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis and a high likelihood of acquired chemo-resistance. Although tyrosine kinase inhibitor (TKI) therapy has improved clinical outcome, most ALL patients relapse following treatment with TKI due to the development of resistance. We developed an in vitro model of Nilotinib-resistant Ph+ leukemia cells to investigate whether low dose radiation (LDR) in combination with TKI therapy overcome chemo-resistance. Additionally, we developed a mathematical model, parameterized by cell viability experiments under Nilotinib treatment and LDR, to explain the cellular response to combination therapy. The addition of LDR significantly reduced drug resistance both in vitro and in computational model. Decreased expression level of phosphorylated AKT suggests that the combination treatment plays an important role in overcoming resistance through the AKT pathway. Model-predicted cellular responses to the combined therapy provide good agreement with experimental results. Augmentation of LDR and Nilotinib therapy seems to be beneficial to control Ph+ leukemia resistance and the quantitative model can determine optimal dosing schedule to enhance the effectiveness of the combination therapy. [ABSTRACT FROM AUTHOR]

Background and purpose For tumor tracking, a correlation model is used to estimate internal tumor position based on external surrogate motion. When patients experience an internal/external surrogate drift, an update of the correlation model is required to continue tumor tracking. In this study, the accuracy of the internal tumor position estimation for both the clinical available update at discrete points in time (rebuild) and an in-house developed non-clinical online update approach was investigated. Methods A dynamic phantom with superimposed baseline drifts and 14 SBRT patients, treated with real-time tumor tracking (RTTT) on the Vero system, were retrospectively simulated for three update scenarios, respectively no update, clinical rebuild and 0.5 Hz automated online update of the correlation model. By comparing the target positions based on 0.5 Hz verification X-ray images with the estimated internal tumor positions regarding all three update scenarios, 95th percentile modeling errors (ME 95 ), incidences of full geometrical coverage of the CTV by a 5 mm extended PTV ( P 5mm ) and population-based PTV margins were calculated. Further, the treatment time reduction was estimated when switching from the clinical rebuild approach to the online correlation model update. Results For dynamic phantom motion with baseline drifts up to 0.4 mm/min, a 0.5 Hz intra-fraction update showed a similar accuracy in terms of ME 95 and P 5mm compared to clinical rebuild. For SBRT patients treated on Vero with RTTT, accuracy was improved by 0.5 Hz online update compared to the clinical rebuild protocol, yielding smaller PTV margins (from 3.2 mm to 2.7 mm), reduced ME 95,3D (from 4.1 mm to 3.4 mm) and an increased 5th percentile P 5mm (from 90.7% to 96.1%) for the entire patient group. Further, 80% of treatment sessions were reduced in time with on average 5.5 ± 4.1 (1 SD) min. Conclusion With a fast (0.5 Hz) automated online update of the correlation model, an efficient RTTT workflow with improved geometrical accuracy was obtained. [ABSTRACT FROM AUTHOR]

Purpose To report on the first clinical application of a real-time tumor tracking (RTTT) solution based on the Vero SBRT gimbaled linac system for treatment of moving tumors. Methods and materials A first group of 10 SBRT patients diagnosed with NSCLC or oligometastatic disease in lung or liver was treated with the RTTT technique. The PTV volumes and OAR exposure were benchmarked against the widely used ITV approach. Based on data acquired during execution of RTTT treatments, a first review was performed of the process. Results The 35% PTV volume reduction with RTTT of the studied single lesions SBRT irradiations of small target volumes is expected to result in a small (<1%) reduction of lung or liver NTCP. A GTV–PTV margin of 5.0 mm was applied for treatment planning of RTTT. From patient data on residual geometric uncertainties, a CTV–PTV margin of 3.2 mm was calculated. Reduction of the GTV–PTV margin below 5.0 mm without better understanding of biological definition of tumor boundaries was discouraged. Total treatment times were reduced to 34.4 min on average. Conclusion A considerable PTV volume reduction was achieved applying RTTT and time efficiency for respiratory correlated SBRT was reestablished with Vero RTTT. [ABSTRACT FROM AUTHOR]

Background Today it is unclear which technique for delivery of an additional boost after whole breast radiotherapy for breast conserved patients should be state of the art. We present a dosimetric comparison of different non-invasive treatment techniques for additional boost delivery. Methods For 10 different tumor bed localizations, 7 different non-invasive treatment plans were made. Dosimetric comparison of PTV-coverage and dose to organs at risk was performed. Results The Vero system achieved an excellent PTV-coverage and at the same time could minimize the dose to the organs at risk with an average near-maximum-dose (D2) to the heart of 0.9 Gy and the average volume of ipsilateral lung receiving 5 Gy (V5) of 1.5%. The TomoTherapy modalities delivered an average D2 to the heart of 0.9 Gy for the rotational and of 2.3 Gy for the static modality and an average V5 to the ipsilateral lung of 7.3% and 2.9% respectively. A rotational technique offers an adequate conformity at the cost of more low dose spread and a larger build-up area. In most cases a 2-field technique showed acceptable PTV-coverage, but a bad conformity. Electrons often delivered a worse PTV-coverage than photons, with the planning requirements achieved only in 2 patients and with an average D2 to the heart of 2.8 Gy and an average V5 to the ipsilateral lung of 5.8%. Conclusions We present advices which can be used as guidelines for the selection of the best individualized treatment. [ABSTRACT FROM AUTHOR]

Background: TomoBreast is a unicenter, non-blinded randomized trial comparing conventional radiotherapy (CR) vs. hypofractionated Tomotherapy (TT) for post-operative treatment of breast cancer. The purpose of the trial is to compare whether TT can reduce heart and pulmonary toxicity. We evaluate early toxicities. Methods: The trial started inclusion in May 2007 and reached its recruitment in August 2011. Women with stage T1-3N0M0 or T1-2N1M0 breast cancer completely resected by tumorectomy (BCS) or by mastectomy (MA) who consented to participate were randomized, according to a prescribed computer-generated randomization schedule, between control arm of CR 25x2 Gy/5 weeks by tangential fields on breast/chest wall, plus supraclavicular-axillary field if node-positive, and sequential boost 8x2 Gy/2 weeks if BCS (cumulative dose 66 Gy/7 weeks), versus experimental TT arm of 15x2.8 Gy/3 weeks, including nodal areas if node-positive and simultaneous integrated boost of 0.6 Gy if BCS (cumulative dose 51 Gy/3 weeks). Outcomes evaluated were the pulmonary and heart function. Comparison of proportions used one-sided Fisher's exact test. Results: By May 2010, 70 patients were randomized and had more than 1 year of follow-up. Out of 69 evaluable cases, 32 were assigned to CR (21 BCS, 11 MA), 37 to TT (20 BCS, 17 MA). Skin toxicity of grade ≥1 at 2 years was 60% in CR, vs. 30% in TT arm. Heart function showed no significant difference for left ventricular ejection fraction at 2 years, CR 4.8% vs. TT 4.6%. Pulmonary function tests at 2 years showed grade ≥1 decline of FEV1 in 21% of CR, vs. 15% of TT and decline of DLco in 29% of CR, vs. 7% of TT (P = 0.05). Conclusions: There were no unexpected severe toxicities. Short course radiotherapy of the breast with simultaneous integrated boost over 3 weeks proved feasible without excess toxicities. Pulmonary tests showed a slight trend in favor of Tomotherapy, which will need confirmation with longer follow-up of patients. [ABSTRACT FROM AUTHOR]

Background: Health-related quality of life (HRQOL) assessment is a key component of clinical oncology trials.However, few breast cancer trials comparing adjuvant conventional radiotherapy (CR) and hypofractionatedtomotherapy (TT) have investigated HRQOL. We compared HRQOL in stage I-II breast cancer patients who were randomized to receive either CR or TT. Tomotherapy uses an integrated computed tomography scanner to improve treatment accuracy, aiming to reduce the adverse effects of radiotherapy.Methods: A total of 121 stage I–II breast cancer patients who had undergone breast conserving surgery (BCS) or mastectomy (MA) were randomly assigned to receive either CR or TT. CR patients received 25 × 2 Gy over 5 weeks,and BCS patients also received a sequential boost of 8 × 2 Gy over 2 weeks. TT patients received 15 × 2.8 Gy over 3weeks, and BCS patients also received a simultaneous integrated boost of 15 × 0.6 Gy over 3 weeks. Patients completed the EORTC QLQ-C30 and BR23 questionnaires. The mean score (± standard error) was calculated at baseline, the end of radiotherapy, and at 3 months and 1, 2, and 3 years post-radiotherapy. Data were analyzed by the 'intention-to-treat' principle.Results: On the last day of radiotherapy, patients in both treatment arms had decreased global health status and functioning scores; increased fatigue (clinically meaningful in both treatment arms), nausea and vomiting, and constipation; decreased arm symptoms; clinically meaningful increased breast symptoms in CR patients and systemic side effects in TT patients; and slightly decreased body image and future perspective.At 3 months post-radiotherapy, TT patients had a clinically significant increase in role- and social-functioning scores and a clinically significant decrease in fatigue. The post-radiotherapy physical-, cognitive- and emotional-functioning scores improved faster in TT patients than CR patients. TT patients also had a better long-term recovery from fatigue than CR patients. ANOVA with the Bonferroni correction did not show any significant differences between groups in HRQOL scores.Conclusions: TT patients had a better improvement in global health status and role- and cognitive-functioning,and a faster recovery from fatigue, than CR patients. These results suggest that a shorter fractionation schedule may reduce the adverse effects of treatment. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to provide estimates of setup and internal margins of patients treated for rectal carcinoma using helical tomotherapy and to assess possible margin adaptations. Using helical tomotherapy, highly conformal dose distributions can be created, and the integrated megavoltage computed tomography (MVCT) modality allows very precise daily patient positioning. In clinical protocols, however, margins originating from traditional setup procedures are still being applied. This work investigates whether this modality can aid in redefining treatment margins. Methods and Materials: Ten patients who were treated with tomotherapy underwent MVCT scanning before and after 10 treatments. Using automatic registration the necessary setup margin was investigated by means of bony landmarks. Internal margins were assessed by delineating and describing the mesorectal movement. Results: Based on bony landmarks, movement of patients during treatments was limited to 2.45 mm, 1.99 mm, and 1.09 mm in the lateral, longitudinal, and vertical direction, respectively. Systematic errors were limited to <1 mm. Measured movement of the mesorectal space was −1.6 mm (± 4.2 mm) and 0.1 mm (± 4.0 mm) for left and right lateral direction. In the antero-posterior direction, mean shifts were −2 mm (± 6.8 mm) and −0.4 mm (± 3.8 mm). Mean shifts in the cranio-caudal direction were respectively −3.2 mm (± 5.6 mm) and −3.2 mm (± 6.8 mm). Conclusions: The use of the integrated MVCT on the tomotherapy system can minimize the setup margin for rectal cancer, and can also be used to adequately describe the internal margin allowing for direct treatment margin adaptation. [Copyright &y& Elsevier]

Abstract: Background and purpose: The purpose of this study is to assess retrospectively secondary patient motion induced by 6D patient setup correction. Materials and methods: For 104 patients, treated with Novalis®, 6D setup correction prior to treatment was performed by ExacTrac5.0/NovalisBody® in combination with the Robotic Tilt Module™ mounted underneath the Exact Couch® top. This 6D correction might induce additional setup errors due to patient reaction against the rotations. To evaluate induced secondary motion, the 6D setup correction is verified and evaluated with respect to the tolerance limits. Results: The majority of measured secondary motions are found within the tolerance limits. Detected secondary motions are mostly found in longitudinal shifts and lateral rotations, and mainly found in only 1 dimension during the same verification. The verifications indicate that the patient population can be divided into a group that hardly moves and a group that moves throughout all 6D setup corrections. The patient’s behavior can be predicted by the evaluation of the first five fractions as none of the patients demonstrate a learning curve during the treatment. Conclusions: 6D setup correction does not induce secondary motion for the majority of the patients and can therefore be applied for all treatment indications. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate the early side effects of a short course hypofractionated radiotherapy regimen in prostate cancer. Materials and methods: Three institutions (IRE, AZ VUB, GUH) included 36 patients with T1-T3N0M0 prostate cancer in a phase II study. Patients were treated with 56Gy in 16 fractions over 4 weeks. Early side effects were scored using the RTOG/EORTC criteria and the international prostate symptom index (IPSI) weekly during treatment and 1 and 2 months afterwards. The results were compared with two control groups of patients previously treated with conventional fractionation at AZ VUB (238 patients) and GUH (114 patients). Results: None of the patients experienced grade 3–4 toxicity. Grade 1–2 Gastro-intestinal (GI), grade 2 GI, grade 1–2 Genito-urinary (GU) and grade 2 GU toxicity occurred in 75%, 36%, 75% and 44% for the hypofractionation schedule. The corresponding figures were 25–44%, 6–29%, 47–53% and 16–44% for the control groups (p <0.01 for grade 1–2 GI and GU toxicity). Two months after treatment all GU and the majority of GI symptoms had resolved. The IPSI increased from (average ±1 SD) 5.6±4 pre-treatment to 10.0±6 during week 2–4 and had normalized (5.2±4) two months after treatment. Conclusions: Though no grade 3–4 side effects were observed, the investigated schedule results in a marked increase of grade 1–2 early side effects as compared to a conventional regimen. Side effects resolved within two months post-treatment. [Copyright &y& Elsevier]

Abstract: Background and purpose: Recalculating dose distributions using measured IMRT fluence fields imported into the treatment planning system (TPS) to evaluate the technical feasibility of a prototype developed for breathing synchronized irradiation. Patients and methods: DMLC–IMRT fluence patterns acquired on radiographic film, generated by the linac in non-gated and gated mode, have been imported into the TPS. The effect of dose blurring and possible interplay between organ motion and leaf motion, and the efficacy of a breathing synchronized irradiation technique (an adapted version of a commercially available image-guidance system: NOVALIS BODY/ExacTrac4.0, BrainLAB AG) have been evaluated using radiographic film mounted to a simple phantom simulating a breathing pattern of 16 cycles per minute and covering a distance of 4cm to obtain the resulting fluence maps. Two situations have been investigated to illustrate this principle: (a) a tumor located close to the diaphragm to assess the influence of organ motion on the dose to the target volume as well as to the gastro-intestinal tract that presents a high risk at intersecting with the beam during the breathing cycle. (b) A mediastinal lesion requiring complicated fluence patterns. Results: Importing measured fluence maps yielded highly disturbed reconstructed dose distributions in case of the non-gated delivery with the phantom in motion (both orthogonal and parallel to the leaf direction), whereas the measurements from the static (film fixed in space) and the gated delivery showed good agreement with the original theoretical dose distribution. These findings have been confirmed by the dose–volume histograms, corresponding tumor control probabilities, conformity index and dose heterogeneity values. The normal tissue complication probabilities investigated in this study seem to be affected to a lesser degree, which concurs with the observation that the motion effects result in a dose spread in the direction of motion. The applied breathing synchronization technique introduced an increased treatment time with a factor 3–4. Conclusions: The use of measured fluence fields, delivered by the linac in non-gated and gated mode, as imported fluence maps for the treatment planning system is an interesting quality assurance tool and revealed the dramatic impact of dose blurring and interplay between DMLC–IMRT dose delivery and organ motion, as well as the potential of breathing synchronization to resolve this issue. The possible advantage of breathing synchronized irradiation is compromised with an increased treatment time. [Copyright &y& Elsevier]

Background and purpose: Recent and large trials of adjuvant radiotherapy for breast cancer have shown an overall survival benefit in favour of radiotherapy. However, with longer follow-up the late lethal toxicity of radiotherapy might reduce the overall survival benefits. In this paper we investigate more deeply this hypothesis.Patients and methods: Overviews of the Early Breast Cancer Trialists’ Collaborative Group provide uniform data on more than 50 unconfounded trials on adjuvant radiotherapy for early breast cancer. These data were published at regular intervals: 1987, 1990, 1995, and 2000. The odds ratios (death of any cause) were borrowed to compare the benefits of adjuvant radiotherapy between the early publications and the more mature data of the same trials. Statistical significance is calculated following logrank statistics.The comparison of odds ratios (radiotherapy versus surgery only) was done for the whole group of trials, for the older (patients accrual started in 1970 or earlier) and the more recent trials (patient accrual started after 1970), and for the large (≥600 patients) and the small trials (<600 patients).Results: Comparison of early with more mature data reveals that the odds ratios for overall survival remain stable as data become more mature. The analyses of trials’ age and trials’ size, as predictors of overall survival benefit, indicate that these factors become statistically more significant with increasing maturity of the trials.In the large recent trials an overall survival benefit due to radiotherapy (odds reduction) of 10, 10, 12 and 13%, respectively P<0.3, 0.2, 0.005 and 0.00005 is found in the successive publications. The difference in survival benefit of radiotherapy between the group of large recent trials and group of old or small trials becomes more significant at the successive updates: 10 via 9% and 12 to 13% (odds reductions), with respectively P=0.2, 0.2, 0.004 and 0.00005.Conclusions: These results support the hypothesis that the survival benefit in the recent trials is an inherent characteristic of the recent and large trials, not influenced by follow-up duration. The effect of radiotherapy as performed in the large recent trials is clinically and statistically significantly different from the effect of radiotherapy in the old or small trials. As a consequence, predictions based on pooled data including old radiotherapy trials should not be extrapolated to modern radiotherapy. [Copyright &y& Elsevier]

Purpose: To evaluate early side effects in prostate cancer patients treated with image-guided conformation arc therapy (IGCAT) using a minimultileaf collimator and daily X-ray–assisted patient positioning. Methods and Materials: Between May 2000 and November 2004, 238 cT1-T3N0M0 tumors were treated with doses of 70 or 78 Gy. Seventy patients also received neoadjuvant or concurrent hormonal treatment. Median follow-up is 18 months (range, 4–55 months). The Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer toxicity scoring system was used to evaluate early side effects. Results: Grade 1, 2, and >2 acute side effects occurred in 19, 6, and 0% (gastrointestinal) and 37, 16, and 0% (genitourinary) of the patients. No relation between radiation dose and early side effects was observed. Conclusion: Patients treated with image-guided conformation arc therapy experience a low rate of Grade 2 (i.e., requiring medication) early side effects. The definitive evaluation of late side effects and biochemical control requires further follow-up. [Copyright &y& Elsevier]

Background: We conducted a randomized, prospective trial comparing external irradiation with external irradiation plus goserelin (an agonist analogue of gonadotropin-releasing hormone that reduces testosterone secretion) in patients with locally advanced prostate cancer. Methods: From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. The patients had a median age of 71 years (range, 51 to 80). Patients in both groups received 50 Gy of radiation to the pelvis over a period of five weeks and an additional 20 Gy over an additional two weeks as a prostatic boost. Patients in the combined-treatment group received 3.6 mg of goserelin (Zoladex) subcutaneously every four weeks starting on the first day of irradiation and continuing for three years; those patients also received cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone associated with the administration of goserelin. Results: Data were available for analysis on 401 patients. The median follow-up was 45 months. Kaplan–Meier estimates of overall survival at five years were 79 percent (95 percent confidence interval, 72 to 86 percent) in the combined-treatment group and 62 percent (95 percent confidence interval, 52 to 72 percent) in the radiotherapy group (P = 0.001). The proportion of surviving patients who were free of disease at five years was 85 percent (95 percent confidence interval, 78 to 92 percent) in the combined-treatment group and 48 percent (95 percent confidence interval, 38 to 58 percent) in the radiotherapy group (P<0.001). Conclusions: Adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer. (N Engl J Med 1997;337:295-300.) [ABSTRACT FROM AUTHOR]