Trial supports targeted radiotherapy for early breast cancer but protocol still requires 3 weeks of daily therapy

Commentary on: Coles CE, Griffin CL, Kirby AM, et al. IMPORT Trialists. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 2017;390:1048–60. Context The evidence-based local treatment for early breast cancer is breast-conserving surgery and radiotherapy, requiring 3–6 weeks of daily whole breast external beam radiation therapy, which is inconvenient for patients and expensive. The suggestion that targeted radiation to the tumour bed with modern techniques may be adequate was proposed in 1995.1 This was heralded as a new standard2 with the publication of the TARGIT-A trial3 4 of single-dose targeted intraoperative radiotherapy (TARGIT-IORT), later confirmed by other European studies using brachytherapy5 that requires 5 days of inpatient stay or EBRT.6 Methods In this study,7 in 30 UK centres, from 2007 to 2010, women aged ≥50 years, who had undergone breast-conserving surgery for unifocal invasive ductal carcinoma ≤3 cm in size with a 2 mm non-cancerous excision margin, were randomly assigned (1:1:1) to receive daily over 3 weeks one of three regimens: (1) 40 Gy whole breast irradiation (WBI); (2) 36 Gy WBI with 40 Gy partial breast irradiation (PBI); or (3) 40 Gy PBI targeted to the tumour bed. The primary endpoint was ipsilateral local relapse with a non-inferiority margin of 2.5% at 5 years. For quality of life, 72 different patient-reported outcome measures (PROM) were analysed and radiotherapy toxicity was assessed by photographs and clinicians. Neither patients, clinicians nor data analysts were masked to treatment allocation. Findings Five-year estimated incidence of local relapse was 1.1% (95% CI 0.5 to 2.3) with WBI (n=674) and 0.5% (0.2–1.4) with PBI (n=669); non-inferiority was confirmed. Unlike in prior trials,3–6 radiotherapy toxicity was not reduced. Of the 72 PROMs assessed, only two (breast appearance and texture) were reported to have better cumulative scores with PBI. The incidence of only one PROM (‘breast appearance changed’) was reduced at 5 years (from 27% to 15%). Commentary IMPORT-LOW provides further mature randomised evidence supporting PBI. However, PBI with IMPORT-LOW protocol offers little advantage to patients or the healthcare system. The 2 mm clear margins this protocol requires render many patients ineligible; acceptable margins are currently much smaller, for example, >0 mm in USA.8 The authors emphasise the benefit in two quality of life domains, although 72 were tested, with 5-year benefit seen in only one. Clearly, IMPORT-LOW patients had considerably better prognosis cancers than in other trials that have proven non-inferiority of targeted radiation to whole breast radiation. Compared with TARGIT-A, for example, only 3% versus 16% were node positive, and 9% versus 15% were grade 3. Therefore, the low recurrence rate is not surprising. Who benefits from the IMPORT-LOW protocol? For patients and healthcare systems, the 3-week daily regimen has adverse physical, social, financial9 and environmental impacts10 and offers no advantage over conventional radiation. PBI using IMPORT-LOW is also resource consuming (and therefore expensive), and keeps radiotherapy departments very busy. Conversely, TARGIT-IORT delivered during the operation enables over 80% of patients to avoid visiting the radiotherapy centre at all. The relevance here is that although published twice in The Lancet, with an independent editorial concluding that it should be offered as an alternative to conventional EBRT, TARGIT-IORT is not even mentioned in the IMPORT-LOW paper. We find this surprising since the number of patients with a median follow-up of 5–6 years is similar (~1200 vs 1300), and both proved non-inferiority. Implications for practice Targeted radiation methods range from the 3-week daily course required for IMPORT-LOW with 16 hospital visits, to the single-dose TARGIT-IORT given during lumpectomy. Several other approaches are also available,5 6 and as all are effective, patients are entitled to choose what is right for them, based on convenience, personal cost, quality of life and side effects. Acknowledgments We thank Professor Michael Baum, Professor Michael Douek, Mr Nathan Coombs, Professor Max Bulsara, Dr Julian Singer, Dr David Morgan, Dr Shiroma D’Silva and Ms Marcelle Bernstein for valuable discussion about this manuscript

COMPARISON OF PROLIFERATING CELL NUCLEAR ANTIGEN (PCNA) STAINING AND BRDURD-LABELING INDEX UNDER DIFFERENT PROLIFERATIVE CONDITIONS IN-VITRO BY FLOW-CYTOMETRY

PC10 is a monoclonal antibody against proliferating cell nuclear antigen (PCNA). The staining pattern in immunochemistry depends on fixation and detergent extraction treatment. The aim of this study was to validate the flow cytometric PCNA assay against Bromodeoxyuridine-labelling index (BrdUrd-LI) under different proliferative conditions in vitro. Expression of PCNA in methanol fixed cells with, and without, prior detergent extraction with EDTA/Triton was compared to BrdUrd-labelling index in NIH-3T3 fibroblasts and human Caski tumour cells in exponential phase and under confluent conditions. Serum stimulation and serum starvation conditions were studied. The results for BrdUrd-LI and PCNA-index after extraction showed good correlation for 3T3 fibroblasts and for Caski cells, with some differences for serum withdrawn Caski cells. There was no correlation between the number of cells that were positive for PCNA without extraction and BrdUrd-LI. Spheroid cells with G(1)-DNA-content showed an almost synchronous recruitment and progression through the cell cycle after trypsination and replating. Tightly bound PCNA paralleled this synchronicity whereas total PCNA did not change significantly. The results demonstrate that immunochemical detection of non-extractable PCNA-index gives similar results as compared with BrdUrd-labelling index under different proliferative conditions in vitro for different monolayer cell lines, whereas without extraction PCNA does not correlate with BrdUrd-LI in these fast growing cell lines due to its long half-life. PCNA expression parallels the progression through the cell cycle in V79 spheroids, a primitive model of tumour growth

Robustness of sweeping-window arc therapy treatment sequences against intrafractional tumor motion

Purpose: Due to the potentially periodic collimator dynamic in volumetric modulated arc therapy (VMAT) dose deliveries with the sweeping-window arc therapy (SWAT) technique, additional manifestations of dosimetric deviations in the presence of intrafractional motion may occur. With a fast multileaf collimator (MLC), and a flattening filter free dose delivery, treatment times close to 60 s per fraction are clinical reality. For these treatment sequences, the human breathing period can be close to the collimator sweeping period. Compared to a random arrangement of the segments, this will cause a further degradation of the dose homogeneity. Methods: Fifty VMAT sequences of potentially moving target volumes were delivered on a two dimensional ionization chamber array. In order to detect interplay effects along all three coordinate axes, time resolved measurements were performed twice-with the detector aligned in vertical (V) or horizontal (H) orientation. All dose matrices were then moved within a simulation software by a time-dependent motion vector. The minimum relative equivalent uniform dose EUDr,m for all breathing starting phases was determined for each amplitude and period. Furthermore, an estimation of periods with minimum EUD was performed. Additionally, LINAC logfiles were recorded during plan delivery. The MLC, jaw, gantry angle, and monitor unit settings were continuously saved and used to calculate the correlation coefficient between the target motion and the dose weighed collimator motion component for each direction (CC, LR, AP) separately. Results: The resulting EUDr,m were EUDr,m(CCV) = (98.3 +/- 0.6)%, EUDr,m(CCH) = (98.6 +/- 0.5)%, EUDr,m(AP(V)) = (97.7 +/- 0.9)%, and EUDr,m(LRH) = (97.8 +/- 0.9)%. The overall minimum relative EUD observed for 360. arc midventilation treatments was 94.6%. The treatment plan with the shortest period and a minimum relative EUD of less than 97% was found at T = 6.1 s. For a partial 120 degrees arc, an EUDr,m = 92.0% was found. In all cases, a correlation coefficient above 0.5 corresponded to a minimum in EUD. Conclusions: With the advent of fast VMAT delivery techniques, nonrobust treatment sequences for human breathing patterns can be generated. These sequences are characterized by a large correlation coefficient between a target motion component and the corresponding collimator dynamic. By iteratively decreasing the maximum allowed dose rate, a low correlation coefficient and consequentially a robust treatment sequence are ensured. (C) 2015 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 Unported License

Coherent molecule formation in anharmonic potentials near confinement-induced resonances

We perform a theoretical and experimental study of a system of two ultracold atoms with tunable interaction in an elongated trapping potential. We show that the coupling of center-of-mass and relative motion due to an anharmonicity of the trapping potential leads to a coherent coupling of a state of an unbound atom pair and a molecule with a center of mass excitation. By performing the experiment with exactly two particles we exclude three-body losses and can therefore directly observe coherent molecule formation. We find quantitative agreement between our theory of inelastic confinement-induced resonances and the experimental results. This shows that the effects of center-of-mass to relative motion coupling can have a significant impact on the physics of quasi-1D quantum systems.Comment: 7 pages, 4 figure

Quick X-ray microtomography using a laser-driven betatron source

Laser-driven X-ray sources are an emerging alternative to conventional X-ray tubes and synchrotron sources. We present results on microtomographic X-ray imaging of a cancellous human bone sample using synchrotron-like betatron radiation. The source is driven by a 100-TW-class titanium-sapphire laser system and delivers over $10^8$ X-ray photons per second. Compared to earlier studies, the acquisition time for an entire tomographic dataset has been reduced by more than an order of magnitude. Additionally, the reconstruction quality benefits from the use of statistical iterative reconstruction techniques. Depending on the desired resolution, tomographies are thereby acquired within minutes, which is an important milestone towards real-life applications of laser-plasma X-ray sources

Fermionization of two distinguishable fermions

In this work we study a system of two distinguishable fermions in a 1D harmonic potential. This system has the exceptional property that there is an analytic solution for arbitrary values of the interparticle interaction. We tune the interaction strength via a magnetic offset field and compare the measured properties of the system to the theoretical prediction. At the point where the interaction strength diverges, the energy and square of the wave function for two distinguishable particles are the same as for a system of two identical fermions. This is referred to as fermionization. We have observed this phenomenon by directly comparing two distinguishable fermions with diverging interaction strength with two identical fermions in the same potential. We observe good agreement between experiment and theory. By adding one or more particles our system can be used as a quantum simulator for more complex few-body systems where no theoretical solution is available

Atom-Dimer Scattering in a Three-Component Fermi Gas

Ultracold gases of three distinguishable particles with large scattering lengths are expected to show rich few-body physics related to the Efimov effect. We have created three different mixtures of ultracold 6Li atoms and weakly bound 6Li2 dimers consisting of atoms in three different hyperfine states and studied their inelastic decay via atom-dimer collisions. We have found resonant enhancement of the decay due to the crossing of Efimov-like trimer states with the atom-dimer continuum in one mixture as well as minima of the decay in another mixture, which we interpret as a suppression of exchange reactions of the type |12>+|3> -> |23>+|1>. Such a suppression is caused by interference between different decay paths and demonstrates the possiblity to use Efimov physics to control the rate constants for molecular exchange reactions in the ultracold regime.Comment: 5 pages, 3 figure

Quantification and Assessment of Interfraction Setup Errors Based on Cone Beam CT and Determination of Safety Margins for Radiotherapy

Introduction To quantify interfraction patient setup-errors for radiotherapy based on cone-beam computed tomography and suggest safety margins accordingly. Material and Methods Positioning vectors of pre-treatment cone-beam computed tomography for different treatment sites were collected (n = 9504). For each patient group the total average and standard deviation were calculated and the overall mean, systematic and random errors as well as safety margins were determined Results The systematic (and random errors) in the superior-inferior, left-right and anterior-posterior directions were: for prostate, 2.5(3.0), 2.6(3.9) and 2.9(3.9) mm; for prostate bed, 1.7(2.0), 2.2(3.6) and 2.6(3.1) mm; for cervix, 2.8(3.4), 2.3(4.6) and 3.2(3.9) mm; for rectum, 1.6(3.1), 2.1(2.9) and 2.5(3.8) mm; for anal, 1.7(3.7), 2.1(5.1) and 2.5(4.8) mm; for head and neck, 1.9(2.3), 1.4(2.0) and 1.7(2.2) mm; for brain, 1.0(1.5), 1.1(1.4) and 1.0(1.1) mm; and for mediastinum, 3.3(4.6), 2.6(3.7) and 3.5(4.0) mm. The CTV-to-PTV margins had the smallest value for brain (3.6, 3.7 and 3.3mm) and the largest for mediastinum (11.5, 9.1 and 11.6mm). For pelvic treatments the means (and standard deviations) were 7.3 (1.6), 8.5 (0.8) and 9.6 (0.8) mm. Conclusions Systematic and random setup-errors were smaller than 5mm. The largest errors were found for organs with higher motion probability. The suggested safety margins were comparable to published values in previous but often smaller studies