Cardiac toxicity is an important sequela of breast radiotherapy. However, the relationship between dose to cardiac structures and subsequent toxicity has not been well defined, partially due to ...variations in substructure delineation, which can lead to inconsistent dose reporting and the failure to detect potential correlations. Here we have developed a heart atlas and evaluated its effect on contour accuracy and concordance.
A detailed cardiac computed tomography scan atlas was developed jointly by cardiology, cardiac radiology, and radiation oncology. Seven radiation oncologists were recruited to delineate the whole heart, left main and left anterior descending interventricular branches, and right coronary arteries on four cases before and after studying the atlas. Contour accuracy was assessed by percent overlap with gold standard atlas volumes. The concordance index was also calculated. Standard radiation fields were applied. Doses to observer-contoured cardiac structures were calculated and compared with gold standard contour doses. Pre- and post-atlas values were analyzed using a paired t test.
The cardiac atlas significantly improved contour accuracy and concordance. Percent overlap and concordance index of observer-contoured cardiac and gold standard volumes were 2.3-fold improved for all structures (p < 0.002). After application of the atlas, reported mean doses to the whole heart, left main artery, left anterior descending interventricular branch, and right coronary artery were within 0.1, 0.9, 2.6, and 0.6 Gy, respectively, of gold standard doses.
This validated University of Michigan cardiac atlas may serve as a useful tool in future studies assessing cardiac toxicity and in clinical trials which include dose volume constraints to the heart.
To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes.
The American Society of Clinical Oncology, American Society for ...Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process.
Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria.
Patients with newly diagnosed BC and
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mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in
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or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in
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carriers. Radiation therapy should not be withheld in
carriers. For patients with germline
mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in
carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in
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carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.
Radiation dose-volume effects in the heart Gagliardi, Giovanna; Constine, Louis S; Moiseenko, Vitali ...
International journal of radiation oncology, biology, physics,
03/2010, Volume:
76, Issue:
3 Suppl
Journal Article
Peer reviewed
The literature is reviewed to identify the main clinical and dose-volume predictors for acute and late radiation-induced heart disease. A clear quantitative dose and/or volume dependence for most ...cardiac toxicity has not yet been shown, primarily because of the scarcity of the data. Several clinical factors, such as age, comorbidities and doxorubicin use, appear to increase the risk of injury. The existing dose-volume data is presented, as well as suggestions for future investigations to better define radiation-induced cardiac injury.
An unmet clinical need in breast cancer management is the accurate identification of patients who will benefit from adjuvant radiotherapy. We hypothesized that integration of postradiation clonogenic ...survival data with gene expression data across breast cancer cell (BCC) lines would generate a radiation sensitivity signature (RSS) and identify patients with tumors refractive to conventional therapy.
Using clonogenic survival assays, we identified the surviving fraction (SF-2Gy) after radiation across a range of BCC lines. Intrinsic radiosensitivity was correlated to gene expression using Spearman correlation. Functional analysis was performed in vitro, and enriched biologic concepts were identified. The RSS was generated using a Random Forest model and was refined, cross-validated, and independently validated in additional breast cancer datasets.
Clonogenic survival identifies a range of radiosensitivity in human BCC lines (SF-2Gy 77%-17%) with no significant correlation to the intrinsic breast cancer subtypes. One hundred forty-seven genes were correlated with radiosensitivity. Functional analysis of RSS genes identifies previously unreported radioresistance-associated genes. RSS was trained, cross-validated, and further refined to 51 genes that were enriched for concepts involving cell-cycle arrest and DNA damage response. RSS was validated in an independent dataset and was the most significant factor in predicting local recurrence on multivariate analysis, outperfoming all clinically used clinicopathologic features.
We derive a human breast cancer-specific RSS with biologic relevance and validate this signature for prediction of locoregional recurrence. By identifying patients with tumors refractory to standard radiation this signature has the potential to allow for personalization of radiotherapy.
Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. ...It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation.
We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181.
Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5–11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94–1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7–5·7) in the APBI group versus 3·9% (3·1–5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group.
APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women.
National Cancer Institute, US Department of Health and Human Services.
To quantify the multi-institutional and multiobserver variability of target and organ-at-risk (OAR) delineation for breast-cancer radiotherapy (RT) and its dosimetric impact as the first step of a ...Radiation Therapy Oncology Group effort to establish a breast cancer atlas.
Nine radiation oncologists specializing in breast RT from eight institutions independently delineated targets (e.g., lumpectomy cavity, boost planning target volume, breast, supraclavicular, axillary and internal mammary nodes, chest wall) and OARs (e.g., heart, lung) on the same CT images of three representative breast cancer patients. Interobserver differences in structure delineation were quantified regarding volume, distance between centers of mass, percent overlap, and average surface distance. Mean, median, and standard deviation for these quantities were calculated for all possible combinations. To assess the impact of these variations on treatment planning, representative dosimetric plans based on observer-specific contours were generated.
Variability in contouring the targets and OARs between the institutions and observers was substantial. Structure overlaps were as low as 10%, and volume variations had standard deviations up to 60%. The large variability was related both to differences in opinion regarding target and OAR boundaries and approach to incorporation of setup uncertainty and dosimetric limitations in target delineation. These interobserver differences result in substantial variations in dosimetric planning for breast RT.
Differences in target and OAR delineation for breast irradiation between institutions/observers appear to be clinically and dosimetrically significant. A systematic consensus is highly desirable, particularly in the era of intensity-modulated and image-guided RT.
Most women with breast cancer who undergo breast-conserving surgery receive whole-breast irradiation. We examined whether the addition of regional nodal irradiation to whole-breast irradiation ...improved outcomes.
We randomly assigned women with node-positive or high-risk node-negative breast cancer who were treated with breast-conserving surgery and adjuvant systemic therapy to undergo either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) (nodal-irradiation group) or whole-breast irradiation alone (control group). The primary outcome was overall survival. Secondary outcomes were disease-free survival, isolated locoregional disease-free survival, and distant disease-free survival.
Between March 2000 and February 2007, a total of 1832 women were assigned to the nodal-irradiation group or the control group (916 women in each group). The median follow-up was 9.5 years. At the 10-year follow-up, there was no significant between-group difference in survival, with a rate of 82.8% in the nodal-irradiation group and 81.8% in the control group (hazard ratio, 0.91; 95% confidence interval CI, 0.72 to 1.13; P=0.38). The rates of disease-free survival were 82.0% in the nodal-irradiation group and 77.0% in the control group (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Patients in the nodal-irradiation group had higher rates of grade 2 or greater acute pneumonitis (1.2% vs. 0.2%, P=0.01) and lymphedema (8.4% vs. 4.5%, P=0.001).
Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence. (Funded by the Canadian Cancer Society Research Institute and others; MA.20 ClinicalTrials.gov number, NCT00005957.).
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