[Show abstract][Hide abstract] ABSTRACT: The Inhomogeneity Correction Factor (ICF) method provides heterogeneity correction for the fast calculation TG43 formalism in seeds brachytherapy. This study compared ICF corrected plans to their standard TG43 counterparts looking at their capacity to assess inadequate coverage and/or risk of any skin toxicities for patients who received Permanent Breast Seed Implant (PBSI).
No preview · Article · Dec 2015 · International journal of radiation oncology, biology, physics
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to estimate the influence of adjuvant radiotherapy for primary breast cancer (BC) on the risk of contralateral BC (CBC) in BRCA1 or BRCA2
(BRCA1/2) mutation carriers, with special attention to patients irradiated at age younger than 40 years. Additionally, tendencies in locoregional treatments and rates of contralateral risk-reducing mastectomy over time were explored. In this retrospective cohort study, 691 BRCA1/2-associated BC patients treated between 1980 and 2013 were followed from diagnosis until CBC or censoring event including ipsilateral BC recurrence, distant metastasis, contralateral risk-reducing mastectomy, other invasive cancer diagnosis, death, or loss to follow up. Hazard ratios (HR) for CBC associated with radiotherapy were estimated using Cox regression. Median follow-up time was 8.6 years [range 0.3–34.3 years]. No association between radiotherapy for primary BC and risk of CBC was found, neither in the total population (HR 0.82, 95 % CI 0.45–1.49) nor in the subgroup of patients younger than 40 years at primary diagnosis (HR 1.36, 95 % CI 0.60–3.09). During follow-up, the number of patients at risk decreased substantially since a large proportion of patients were censored after contralateral risk-reducing mastectomy or BC recurrence. Over the years, increasing preference for mastectomy without radiotherapy compared to breast-conserving surgery with radiotherapy was found ranging from less than 30 % in 1995 to almost 50 % after 2010. The rate of contralateral risk-reducing mastectomy increased over the years from less than 40 % in 1995 to more than 60 % after 2010. In this cohort of BRCA1/2-associated BC patients, no association between radiotherapy for primary BC and risk of CBC was observed in the total group, nor in the patients irradiated before the age of 40 years. The number of patients at risk after 10 and 15 years of follow-up, however, was too small to definitively exclude harmful effects of adjuvant radiotherapy.
Preview · Article · Oct 2015 · Breast Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: Our objective was to construct a novel radiation nanomedicine for treatment of breast cancer (BC) expressing epidermal growth factor receptors (EGFR), particularly triple-negative tumors (TNBC). Gold nanoparticles (AuNP; 30 nm) were modified with polyethyleneglycol (PEG) chains (4 kDa) derivatized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the β-emitter, 177Lu and with PEG chains (5 kDa) linked to panitumumab for targeting BC cells expressing EGFR. The AuNP were further coated with PEG chains (2 kDa) to stabilize the particles to aggregation. The binding and internalization of EGFR-targeted AuNP (177Lu-T-AuNP) into BC cells was studied and compared to non-targeted 177Lu-NT-AuNP. The cytotoxicity of 177Lu-T-AuNP and 177Lu-NT-AuNP was measured in clonogenic assays using BC cells with widely different EGFR densities: MDA-MB-468 (10e6 receptors/cell), MDA-MB-231 (10e5 receptors/cell) and MCF-7 cells (10e4 receptors/cell). Radiation absorbed doses to the cell nucleus of MDA-MB-468 cells were estimated based on subcellular distribution. Darkfield and fluorescence microscopy as well as radioligand binding assays revealed that 177Lu-T-AuNP were specifically bound by BC cells dependent on their EGFR density whereas the binding and internalization of 177Lu-NT-AuNP was significantly lower. The affinity of binding of 177Lu-T-AuNP to MDA-MB-468 cells was reduced by 2-fold compared to 123I-labeled panitumumab (KD= 1.3 ± 0.2 nM vs. 0.7 ± 0.4 nM, respectively). The cytotoxicity of 177Lu-T-AuNP was dependent on the amount of radioactivity incubated with BC cells, their EGFR density and the radiosensitivity of the cells. The clonogenic survival (CS) of MDA-MB-468 cells overexpressing EGFR was reduced to <0.001% at the highest amount of 177Lu-T-AuNP tested (4.5 MBq; 6 × 1011 AuNP per 2.5 × 10e4-1.2 × 10e5 cells). 177Lu-T-AuNP were less effective for killing MDA-MB-231 cells or MCF-7 cells with moderate or low EGFR density (CS = 33.8 ± 1.6% and 25.8 ± 1.2%, respectively). Since the β-particles emitted by 177Lu have a 2 mm range, 177Lu-NT-AuNP were also cytotoxic to BC cells due to a cross-fire effect but 177Lu-T-AuNP were significantly more potent for killing MDA-MB-468 cells overexpressing EGFR than 177Lu-NT-AuNP at all amounts tested. The cross-fire effect of the β-particles emitted by 177Lu may be valuable for eradicating BC cells in tumors that have low or moderate EGFR expression or cells that are not targeted by 177Lu-T-AuNP as a consequence of heterogeneous intratumoral distribution. The radiation dose to the nucleus of a single MDA-MB-468 cell was 73.2 ± 6.7 Gy, whereas 177Lu-NT-AuNP delivered 5.6 ± 0.6 Gy. We conclude that 177Lu-T-AuNP is a promising novel radiation nanomedicine with potential application for treatment of TNBC, in which EGFR is often overexpressed.
No preview · Article · Sep 2015 · Molecular Pharmaceutics
[Show abstract][Hide abstract] ABSTRACT: Purpose Permanent breast seed implant is an accelerated partial breast irradiation technique realizing the insertion of 103Pd seeds in the seroma after lumpectomy. We report the 5-year efficacy and tolerance for a cohort, pooling patients from 3 clinical trials. Methods and Materials The trials accrued postmenopausal patients with infiltrating ductal carcinoma or ductal carcinoma in situ 3 cm and clear surgical margins, who were node negative, and had a planning target volume <120 cm;bsupe. The outcomes included overall and disease-free survival and local and contralateral recurrence at 5 years. The true local recurrence rate was compared using 2-tailed paired t tests for estimates calculated using the Tufts University ipsilateral breast tumor recurrence and Memorial Sloan Kettering ductal carcinoma in situ nomograms. Results The cohort included 134 patients, and the observed local recurrence rate at a median follow-up period of 63 months was 1.2% 1.2%, similar to the estimate for whole breast irradiation (P=.23), significantly better than for surgery alone (relative risk 0.27; P<.001), and significantly lower than contralateral recurrence (relative risk 0.33; P<.001). The 5-year overall survival rate was 97.4% 1.9%, and the disease-free survival rate was 96.4% 2.1%. At 2 months, 42% of the patients had erythema, 20% induration, and 16% moist desquamation. The rate of mainly grade 1 telangiectasia was 22.4% at 2 years and 24% at 5 years. The rate of asymptomatic induration was 23% at 2 years and 40% at 5 years. Conclusions The 5-year data suggest that permanent breast seed implantation is a safe accelerated partial breast irradiation option after lumpectomy for early-stage breast cancer with a tolerance profile similar to that of whole breast irradiation.
Full-text · Article · Jul 2015 · International journal of radiation oncology, biology, physics
[Show abstract][Hide abstract] ABSTRACT: This is the final report of a prospective phase I study which evaluated the feasibility, toxicities, and biochemical control in prostate cancer patients treated with a hypofractionated boost utilizing a fiducial marker-based daily image guidance strategy and small patient-specific PTV margins.
Low- and intermediate-risk prostate cancer patients underwent transperineal ultrasound-guided implantation of three gold fiducial markers and were treated with three-dimensional conformal radiotherapy to 42 Gy (2 Gy/day). During the first nine fractions of treatment, pre- and post-treatment electronic portal imaging was performed to calculate intrafraction prostate motion. Patient-specific PTV margins were derived and a 30 Gy (3 Gy/day) intensity modulated radiotherapy boost was delivered (Total dose = 72 Gy in 31 fractions; EQD2 = 81 Gy, α/β = 1.4).
Thirty-three patients completed treatment and were followed for a median of 7.2 years (range, 1.2 - 9.5). Seven patients (21%) developed Radiation Therapy Oncology Group (RTOG) late grade 2 GI toxicity and 1 patient (3%) developed late grade 2 GU toxicity. No patients developed late grade 3 GI or GU toxicity. To date, nine patients developed PSA relapse according to the Phoenix criteria. The actuarial five, seven and nine year biochemical control (BC) rates were 87% (95% confidence interval: 69-95), 77% (95% confidence interval: 56-89) and 66% (95% confidence interval: 42-82).
Our study demonstrates that the use of prostate fiducial markers in combination with a daily online image guidance protocol permits reduced, patient-specific PTV margins in a hypofractionated treatment scheme. This treatment planning and delivery strategy was well tolerated in the intermediate time frame. The use of very small PTV margins did not result in excessive failures when compared to other radiation regimens of similar radiobiological intensity.
[Show abstract][Hide abstract] ABSTRACT: Permanent breast seed implants (PBSIs) have been introduced as an alternative to whole breast irradiation with equivalent rates of tumour control but fewer associated morbidities. However, there is some suggestion that tumour location has an effect on cosmesis in patients having PBSI. Therefore, the aim of the present study was to determine whether tumour location can predict long-term cosmesis.
No preview · Article · Mar 2015 · Journal of Medical Imaging and Radiation Sciences
[Show abstract][Hide abstract] ABSTRACT: After breast conserving surgery, early stage breast cancer patients are currently treated with a wide range of radiation techniques including whole breast irradiation (WBI), accelerated partial breast irradiation (APBI) using high-dose rate (HDR) brachytherapy, or 3D-conformal radiotherapy (3D-CRT). This study compares the mean heart's doses for a left breast irradiated with different breast techniques. An anthropomorphic Rando phantom was modified with gelatin-based breast of different sizes and tumors located medially or laterally. The breasts were treated with WBI, 3D-CRT, or HDR APBI. The heart's mean doses were measured with Gafchromic films and controlled with optically stimulated luminescent dosimeters. Following the model reported by Darby (1), major cardiac were estimated assuming a linear risk increase with the mean dose to the heart of 7.4% per gray. WBI lead to the highest mean heart dose (2.99 Gy) compared to 3D-CRT APBI (0.51 Gy), multicatheter (1.58 Gy), and balloon HDR (2.17 Gy) for a medially located tumor. This translated into long-term coronary event increases of 22, 3.8, 11.7, and 16% respectively. The sensitivity analysis showed that the tumor location had almost no effect on the mean heart dose for 3D-CRT APBI and a minimal impact for HDR APBI. In case of WBI large breast size and set-up errors lead to sharp increases of the mean heart dose. Its value reached 10.79 Gy for women with large breast and a set-up error of 1.5 cm. Such a high value could increase the risk of having long-term coronary events by 80%. Comparison among different irradiation techniques demonstrates that 3D-CRT APBI appears to be the safest one with less probability of having cardiovascular events in the future. A sensitivity analysis showed that WBI is the most challenging technique for patients with large breasts or when significant set-up errors are anticipated. In those cases, additional heart shielding techniques are required.
Full-text · Article · Oct 2014 · Frontiers in Oncology
[Show abstract][Hide abstract] ABSTRACT: Background:
During breast-conserving surgery (BCS), surgeons increasingly perform full-thickness closure (FTC) to prevent seroma formation. This could potentially impair precision of target definition for boost and accelerated partial breast irradiation (APBI). The purpose of this study was to investigate the precision of target volume definition following BCS with FTC among radiation oncologists, using various imaging modalities.
Twenty clinical T1-2N0 patients, scheduled for BCS involving clip placement and FTC, were included in the study. Seven experienced breast radiation oncologists contoured the tumor bed on computed tomography (CT), magnetic resonance imaging (MRI) and fused CT-MRI datasets. A total of 361 observer pairs per image modality were analyzed. A pairwise conformity among the generated contours of the observers and the distance between their centers of mass (dCOM) were calculated.
On CT, median conformity was 44 % [interquartile range (IQR) 28-58 %] and median dCOM was 6 mm (IQR 3-9 mm). None of the outcome measures improved when MRI or fused CT-MRI were used. In two patients, superficial closure was performed instead of FTC. In these 14 image sets and 42 observer pairs, median conformity increased to 70 %.
Localization of the radiotherapy target after FTC is imprecise, on both CT and MRI. This could potentially lead to a geographical miss in patients at increased risk of local recurrence receiving a radiation boost, or for those receiving APBI. These findings highlight the importance for breast surgeons to clearly demarcate the tumor bed when performing FTC.
Full-text · Article · May 2014 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Purpose:
The authors' aims were to model how various factors influence radiation dose enhancement by gold nanoparticles (AuNPs) and to propose a new modeling approach to the dose enhancement factor (DEF).
The authors used Monte Carlo N-particle (MCNP 5) computer code to simulate photon and electron transport in cells. The authors modeled human breast cancer cells as a single cell, a monolayer, or a cluster of cells. Different numbers of 5, 30, or 50 nm AuNPs were placed in the extracellular space, on the cell surface, in the cytoplasm, or in the nucleus. Photon sources examined in the simulation included nine monoenergetic x-rays (10-100 keV), an x-ray beam (100 kVp), and (125)I and (103)Pd brachytherapy seeds. Both nuclear and cellular dose enhancement factors (NDEFs, CDEFs) were calculated. The ability of these metrics to predict the experimental DEF based on the clonogenic survival of MDA-MB-361 human breast cancer cells exposed to AuNPs and x-rays were compared.
NDEFs show a strong dependence on photon energies with peaks at 15, 30/40, and 90 keV. Cell model and subcellular location of AuNPs influence the peak position and value of NDEF. NDEFs decrease in the order of AuNPs in the nucleus, cytoplasm, cell membrane, and extracellular space. NDEFs also decrease in the order of AuNPs in a cell cluster, monolayer, and single cell if the photon energy is larger than 20 keV. NDEFs depend linearly on the number of AuNPs per cell. Similar trends were observed for CDEFs. NDEFs using the monolayer cell model were more predictive than either single cell or cluster cell models of the DEFs experimentally derived from the clonogenic survival of cells cultured as a monolayer. The amount of AuNPs required to double the prescribed dose in terms of mg Au/g tissue decreases as the size of AuNPs increases, especially when AuNPs are in the nucleus and the cytoplasm. For 40 keV x-rays and a cluster of cells, to double the prescribed x-ray dose (NDEF = 2) using 30 nm AuNPs, would require 5.1 ± 0.2, 9 ± 1, 10 ± 1, 10 ± 1 mg Au/g tissue in the nucleus, in the cytoplasm, on the cell surface, or in the extracellular space, respectively. Using 50 nm AuNPs, the required amount decreases to 3.1 ± 0.3, 8 ± 1, 9 ± 1, 9 ± 1 mg Au/g tissue, respectively.
NDEF is a new metric that can predict the radiation enhancement of AuNPs for various experimental conditions. Cell model, the subcellular location and size of AuNPs, and the number of AuNPs per cell, as well as the x-ray photon energy all have effects on NDEFs. Larger AuNPs in the nucleus of cluster cells exposed to x-rays of 15 or 40 keV maximize NDEFs.
[Show abstract][Hide abstract] ABSTRACT: To determine if older women with early stage breast cancer have sufficient decisional support during their breast cancer journey, a questionnaire-based study was conducted at the Sunnybrook Odette Cancer Centre, in Toronto, Ontario, Canada. Women with stages I and II breast cancer, ≥60 years, were contacted upon completion of their adjuvant treatment. A questionnaire was developed based on focus groups, the literature, and consultation with patients and a multidisciplinary team of experts. The questionnaire was divided into six domains as follows: (1) information support surrounding diagnosis, (2) impact of cancer diagnosis on the patient, (3) quality of interaction with healthcare team, (4) decisional support from the healthcare team, (5) additional information needs surrounding treatment decision, and (6) information support during radiation treatment. Ninety-two of 137 patients approached were included in the analysis. Ninety percent were > 60 years at the time of diagnosis and 65 % had stage I invasive breast cancer. The majority of women received adequate decisional support during their cancer journey. Approximately 90 % of women indicated that they received a high level of support during their cancer diagnosis. We found no significant differences in overall decisional support based on age at diagnosis, education level, ethnicity, or the presence of co-morbidities. However, participants desired additional educational resources such as a worksheet, consultation summary, or workbook to assist in making a treatment decision. The majority of participants felt that they had sufficient support while making a treatment decision for breast cancer.
No preview · Article · Oct 2013 · Journal of Cancer Education
[Show abstract][Hide abstract] ABSTRACT: The American Association of Physicists in Medicine Task Group No. 43 (AAPM TG-43) formalism is the standard for seeds brachytherapy dose calculation. But for breast seed implants, Monte Carlo simulations reveal large errors due to tissue heterogeneity. Since TG-43 includes several factors to account for source geometry, anisotropy and strength, we propose an additional correction factor, called the inhomogeneity correction factor (ICF), accounting for tissue heterogeneity for Pd-103 brachytherapy. This correction factor is calculated as a function of the media linear attenuation coefficient and mass energy absorption coefficient, and it is independent of the source internal structure. Ultimately the dose in heterogeneous media can be calculated as a product of dose in water as calculated by TG-43 protocol times the ICF. To validate the ICF methodology, dose absorbed in spherical phantoms with large tissue heterogeneities was compared using the TG-43 formalism corrected for heterogeneity versus Monte Carlo simulations. The agreement between Monte Carlo simulations and the ICF method remained within 5% in soft tissues up to several centimeters from a Pd-103 source. Compared to Monte Carlo, the ICF methods can easily be integrated into a clinical treatment planning system and it does not require the detailed internal structure of the source or the photon phase-space.
No preview · Article · Aug 2013 · Physics in Medicine and Biology