Benefit of respiratory gating in the Danish Breast Cancer Group partial breast irradiation trial.

BACKGROUND AND PURPOSE: Partial breast irradiation (PBI)has beenthe Danish Breast Cancer Group(DBCG) standard for selected breast cancer patients since 2016 based onearlyresults from the DBCG PBI trial.During trial accrual, respiratory-gated radiotherapy was introduced in Denmark. This study aims to investigate the effect of respiratory-gating on mean heart dose (MHD). PATIENTS AND METHODS: From 2009 to 2016 the DBCG PBI trial included 230 patientswith left-sided breast cancer receiving external beam PBI, 40 Gy/15 fractions/3 weeks.Localization of the tumor bed on the planning CT scan, the use of respiratory-gating, coverage of the clinical target volume (CTV), and doses to organs at risk were collected. RESULTS: Respiratory-gating was used in 123 patients (53 %). In 176 patients (77 %) the tumor bed was in the upper and in 54 patients (23 %) in the lower breast quadrants. The median MHD was 0.37 Gy (interquartile range 0.26-0.57 Gy), 0.33 Gy (0.23-0.49 Gy) for respiratory-gating, and 0.49 Gy (0.31-0.70 Gy) for free breathing, p < 0.0001. MHD was < 1 Gy in 206 patients (90 %) and < 2 Gy in 221 patients (96 %). Respiratory-gating led to significantly lower MHD for upper-located, but not for lower-located tumor beds, however, all MHD were low irrespective of respiratory-gating. Respiratory-gating did not improve CTV coverage or lower lung doses. CONCLUSIONS: PBI ensured a low MHD for most patients. Adding respiratory-gating further reduced MHD for upper-located but not for lower-located tumor beds but did not influence target coverage or lung doses. Respiratory-gating is no longer DBCG standard for left-sided PBI.

Volume matters: Breast induration is associated with irradiated breast volume in the Danish Breast Cancer Group phase III randomized Partial Breast Irradiation trial.

PURPOSE: The relation between breast induration grade 2-3 at 3 years after radiation therapy and irradiated breast volume was investigated for patients in the Danish Breast Cancer Group (DBCG) Partial Breast Irradiation (PBI) trial. METHODS Treatment plan data was obtained from the Danish radiotherapy plan database. Dosimetric parameters for breast and organs at risk were determined. Breast induration data was obtained from the DBCG database. The volume of the whole breast (CTVp_breast) treated to various dose levels was determined for treatment plans in both arms. Logistic regression was used to assess the frequency of induration on breast volume irradiated to ≥40 Gy. RESULTS PBI and WBI was given to 433 and 432 patients, respectively. Median and interquartile ranges (IQR) for CTVp_breast were 710 mL (467-963 mL; PBI) and 666 mL (443-1012 mL; WBI) (p = 0.98). Median and IQR for CTVp_breast treated to ≥40 Gy was 24.9% (18.6-32.6%; PBI) and 59.8% (53.6-68.5%; WBI). Grade 2-3 induration was observed in 5% (PBI) and 10% (WBI) of the patients. A dose-response relationship was established between irradiated breast volume and frequency of breast induration. From the model, 5% and 10% risks of breast induration were observed for ≥40 Gy delivered to CTVp_breast volumes of 177 mL (95%CI, 94-260 mL) and 426 mL (95%CI, 286-567 mL), respectively. CONCLUSION The frequency of breast induration increased significantly with increasing irradiated breast volume, strongly favouring small volumes and PBI. Thus, treated breast volume - not the breast size itself - is the risk factor for induration. This is the first report directly linking the 40 Gy irradiated breast volume to breast induration.

Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The Danish Breast Cancer Group Partial Breast Irradiation Trial.

PURPOSE: On the basis of low risk of local recurrence in elderly patients with breast cancer after conservative surgery followed by whole breast irradiation (WBI), the Danish Breast Cancer Group initiated the noninferiority external-beam partial breast irradiation (PBI) trial (ClinicalTrials.gov identifier: NCT00892814). We hypothesized that PBI was noninferior to WBI regarding breast induration. METHODS: Patients operated with breast conservation for relatively low-risk breast cancer were randomly assigned to WBI versus PBI, and all had 40 Gy/15 fractions. The primary end point was 3-year grade 2-3 breast induration. RESULTS: In total, 865 evaluable patients (434 WBI and 431 PBI) were enrolled between 2009 and 2016. Median follow-up was 5.0 years (morbidity) and 7.6 years (locoregional recurrence). The 3-year rate of induration was 9.7% for WBI and 5.1% for PBI (P = .014). Large breast size was significantly associated with induration with a 3-year incidence of 13% (WBI) and 6% (PBI) for large-breasted patients versus 6% (WBI) and 5% (PBI) for small-breasted patients. PBI showed no increased risk of dyspigmentation, telangiectasia, edema, or pain, and patient satisfaction was high. Letrozole and smoking did not increase the risk of radiation-associated morbidity. Sixteen patients had a locoregional recurrence (six WBI and 10 PBI; P = .28), 20 patients had a contralateral breast cancer, and eight patients had distant failure (five WBI and three PBI). A nonbreast second cancer was detected in 73 patients (8.4%), and there was no difference between groups. CONCLUSION: External-beam PBI for patients with low-risk breast cancer was noninferior to WBI in terms of breast induration. Large breast size was a risk factor for radiation-associated induration. Few recurrences were detected and unrelated to PBI.

Internal Mammary Node Irradiation in Patients With Node-Positive Early Breast Cancer: Fifteen-Year Results From the Danish Breast Cancer Group Internal Mammary Node Study.

PURPOSE: The Danish Breast Cancer Group Internal Mammary Node study demonstrated improved 8-year overall survival (OS) with internal mammary node irradiation (IMNI) in patients with node-positive early breast cancer. Here, we present long-term results from the Danish Breast Cancer Group Internal Mammary Node study cohort. PATIENTS AND METHODS: This nationwide, prospective cohort study allocated patients with node-positive early breast cancer to adjuvant radiotherapy with or without IMNI depending on cancer laterality. Patients with right-sided cancer received IMNI. Patients with left-sided cancer were treated without IMNI because of risk of radiation-induced heart disease. Other treatment was independent of laterality. The primary study end point was OS. Secondary end points were distant recurrence and breast cancer mortality. Analyses were by intention to treat. RESULTS: During 2003-2007, 3,089 women were allocated to IMNI (right-sided, n = 1,491) or no IMNI (left-sided, n = 1,598). With a median follow-up of 14.8 years, 589 patients with and 701 patients without IMNI had died. The corresponding 15-year OS rates were 60.1% and 55.4%. The adjusted hazard ratio (HR) for death was 0.86 (95% CI, 0.77 to 0.96; P = .007) in favor of IMNI. The 15-year risk of developing distant recurrence was 35.6% (523 recurrences) and 38.6% (602 recurrences) with vs. without IMNI (adjusted HR, 0.88 [95% CI, 0.79 to 0.99; P = .04]). The 15-year breast cancer mortality with IMNI was 31.7% (467 deaths) compared with 33.9% (537 deaths) without IMNI (adjusted HR, 0.88 [95% CI, 0.78 to 1.00; P = .05]). The distribution of other deaths was similar across groups. CONCLUSION: In patients with node-positive early breast cancer treated with IMNI or without IMNI depending on breast cancer laterality, IMNI reduced the risk of distant recurrence and death from breast cancer, thereby improving long-term survival.

Joint Estimation of Cardiac Toxicity and Recurrence Risks After Comprehensive Nodal Photon Versus Proton Therapy for Breast Cancer.

PURPOSE: The study aims to perform joint estimation of the risk of recurrence caused by inadequate radiation dose coverage of lymph node targets and the risk of cardiac toxicity caused by radiation exposure to the heart. Delivered photon plans are compared with realistic proton plans, thereby providing evidence-based estimates of the heterogeneity of treatment effects in consecutive cases for the 2 radiation treatment modalities. METHODS AND MATERIALS: Forty-one patients referred for postlumpectomy comprehensive nodal photon irradiation for left-sided breast cancer were included. Comparative proton plans were optimized by a spot scanning technique with single-field optimization from 2 en face beams. Cardiotoxicity risk was estimated with the model of Darby et al, and risk of recurrence following a compromise of lymph node coverage was estimated by a linear dose-response model fitted to the recurrence data from the recently published EORTC (European Organisation for Research and Treatment of Cancer) 22922/10925 and NCIC-CTG (National Cancer Institute of Canada Clinical Trials Group) MA.20 randomized controlled trials. RESULTS: Excess absolute risk of cardiac morbidity was small with photon therapy at an attained age of 80 years, with median values of 1.0% (range, 0.2%-2.9%) and 0.5% (range, 0.03%-1.0%) with and without cardiac risk factors, respectively, but even lower with proton therapy (0.13% [range, 0.02%-0.5%] and 0.06% [range, 0.004%-0.3%], respectively). The median estimated excess absolute risk of breast cancer recurrence after 10 years was 0.10% (range, 0.0%-0.9%) with photons and 0.02% (range, 0.0%-0.07%) with protons. The association between age of the patient and benefit from proton therapy was weak, almost non-existing (Spearman rank correlations of -0.15 and -0.30 with and without cardiac risk factors, respectively). CONCLUSIONS: Modern photon therapy yields limited risk of cardiac toxicity in most patients, but proton therapy can reduce the predicted risk of cardiac toxicity by up to 2.9% and the risk of breast cancer recurrence by 0.9% in individual patients. Predicted benefit correlates weakly with age. Combined assessment of the risk from cardiac exposure and inadequate target coverage is desirable for rational consideration of competing photon and proton therapy plans.

Reduced lung dose and improved inspiration level reproducibility in visually guided DIBH compared to audio coached EIG radiotherapy for breast cancer patients.

INTRODUCTION: Patients with left-sided breast cancer with lymph node involvement have routinely been treated with enhanced inspiration gating (EIG) for a decade at our institution. In a transition from EIG to deep inspiration breath hold (DIBH) we compared the two techniques with focus on target coverage, dose to organs at risk and reproducibility of the inspiration level (IL). MATERIAL AND METHODS: Twenty-four patients were computed tomography (CT) scanned with EIG and DIBH. For DIBH we used visual feedback and for EIG audio coaching, both during scan and treatment. Treatment plans for 50 Gy over 25 fractions were calculated. Seventeen of the patients were included in the analysis of reproducibility. They were audio coached for one minute before beam-on in DIBH at nine treatment sessions. These respiration curves were analysed with average maximum IL and standard deviation (SD) for the EIG part of the respiratory signal, and mean IL and SD for the DIBH. Comparison of dosimetric and respiration parameters were performed with the Wilcoxon signed rank-sum test. RESULTS: In DIBH, the ipsilateral lung volume increased further compared to EIG (p < 0.0004, mean increase 11%). This lead to a 9% mean reduction (p = 0.002) of the ipsilateral lung volume receiving 20 Gy (V20 Gy). We found no other significant dosimetric differences between the two methods. The reproducibility of the IL was better with the DIBH method, observed as a significantly smaller SD in most patients (p < 0.04 for 16 of 17 patients). CONCLUSION: The DIBH method resulted in a significantly larger lung volume and lower ipsilateral lung V20 Gy compared to EIG. The IL for visually guided DIBH was more reproducible than audio-coached EIG. Based on these findings, the DIBH technique is our new breathing adaptation standard for radiotherapy of patients with left-sided breast cancer with lymph node involvement.

Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: national guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group.

UNLABELLED: During the past decade planning of adjuvant radiotherapy (RT) of early breast cancer has changed from two-dimensional (2D) to 3D conformal techniques. In the planning computerised tomography (CT) scan both the targets for RT and the organs at risk (OARs) are visualised, enabling an increased focus on target dose coverage and homogeneity with only minimal dose to the OARs. To ensure uniform RT in the national prospective trials of the Danish Breast Cancer Cooperative Group (DBCG), a national consensus for the delineation of clinical target volumes (CTVs) and OARs was required. MATERIAL AND METHODS: A CT scan of a breast cancer patient after surgical breast conservation and axillary lymph node (LN) dissection was used for delineation. During multiple dummy-runs seven experienced radiation oncologists contoured all CTVs and OARs of interest in adjuvant breast RT. Two meetings were held in the DBCG Radiotherapy Committee to discuss the contouring and to approve a final consensus. The Dice similarity coefficient (DSC) was used to evaluate the delineation agreement before and after the consensus. RESULTS: The consensus delineations of CTVs and OARs are available online and a table is presented with a contouring description of the individual volumes. The consensus provides recommendations for target delineation in a standard patient both in case of breast conservation or mastectomy. Before the consensus, the average value of the DSC was modest for most volumes, but high for the breast CTV and the heart. After the consensus, the DSC increased for all volumes. CONCLUSION: The DBCG has provided the first national guidelines and a contouring atlas of CTVs and OARs definition for RT of early breast cancer. The DSC is a useful tool in quantifying the effect of the introduction of guidelines indicating improved inter-delineator agreement. This consensus will be used by the DBCG in our prospective trials.

Supraclavicular recurrence after early breast cancer: a curable condition?

The prognosis of ipsilateral supraclavicular lymph node recurrence after early breast cancer appears to be worse than for other loco-regional recurrences, but better than for distant metastases. The purpose of the present study was to investigate the relationship between different types of salvage treatment and primary patient characteristics, treatment response, and survival after supraclavicular recurrence (SR) in a large patient population. From the Danish Breast Cancer Cooperative Group treatment database 1977-2003, 305 patients were identified with SR without distant disease as site of first recurrence. Salvage treatment types as well as other factors were related to response and survival. The median follow-up time for progression after SR was 25 months. Complete remission was 76% among patients receiving excision surgery, 67% with combined loco-regional and systemic therapy, and 48% with systemic therapy alone. Median progression-free survival (PFS) and overall survival was 18 and 29 months, respectively. The 5-year PFS probability was 15%. In univariate analysis, combination salvage therapy, negative nodal status and low malignancy grade were related to longer PFS. In multivariate analysis, salvage therapy and malignancy grade remained independent factors for survival. In conclusion, the prognosis of SR is generally poor. However, it appears to be a curable condition. An independent marker of improved outcome is local and systemic combination salvage treatment, which can be considered.

Interfractional changes in tumour volume and position during entire radiotherapy courses for lung cancer with respiratory gating and image guidance.

INTRODUCTION: With the purpose of implementing gated radiotherapy for lung cancer patients, this study investigated the interfraction variations in tumour size and internal displacement over entire treatment courses. To explore the potential of image guided radiotherapy (IGRT) the variations were measured using a set-up strategy based on imaging of bony landmarks and compared to a strategy using in room lasers, skin tattoos and cupper landmarks. MATERIALS AND METHODS: During their six week treatment course of 60Gy in 2Gy fractions, ten patients underwent 3 respiratory gated CT scans. The tumours were contoured on each CT scan to evaluate the variations in volumes and position. The lung tumours and the mediastinal tumours were contoured separately. The positional variations were measured as 3D mobility vectors and correlated to matching of the scans using the two different strategies. RESULTS: The tumour size was significantly reduced from the first to the last CT scan. For the lung tumours the reduction was 19%, p=0.03, and for the mediastinal tumours the reduction was 34%, p=0.0007. The mean 3D mobility vector and the SD for the lung tumours was 0.51 cm (+/-0.21) for matching using bony landmarks and 0.85 cm (+/-0.54) for matching using skin tattoos. For the mediastinal tumours the corresponding vectors and SD's were 0.55 cm (+/-0.19) and 0.72 cm (+/-0.43). The differences between the vectors were significant for the lung tumours p=0.004. The interfractional overlap of lung tumours was 80-87% when matched using bony landmarks and 70-76% when matched using skin tattoos. The overlap of the mediastinal tumours were 60-65% and 41-47%, respectively. CONCLUSIONS: Despite the use of gating the tumours varied considerably, regarding both position and volume. The variations in position were dependent on the set-up strategy. Set-up using IGRT was superior to set-up using skin tattoos.

Can audio coached 4D CT emulate free breathing during the treatment course?

BACKGROUND: The image quality of 4DCT depends on breathing regularity. Respiratory audio coaching may improve regularity and reduce motion artefacts. We question the safety of coached planning 4DCT without coaching during treatment. We investigated the possibility of coaching to a more stable breathing without changing the breathing amplitude. The interfraction variation of the breathing cycle amplitude in free and coached breathing was studied as well as the possible impact of fatigue on longer coaching sessions. METHODS: Thirteen volunteers completed respiratory audio coaching on 3 days within a 2 week period. An external marker system monitoring the motion of the thoraco-abdominal wall was used to track the respiration. On all days, free breathing and two coached breathing curves were recorded. We assumed that free versus coached breathing from day 1 (reference session) simulated breathing during an uncoached versus coached planning 4DCT, respectively, and compared the mean breathing cycle amplitude to the free versus coached breathing from day 2 and 3 simulating free versus coached breathing during treatment. RESULTS: For most volunteers it was impossible to apply coaching without changes in breathing cycle amplitude. No significant decrease in standard deviation of breathing cycle amplitude distribution was seen. Generally it was not possible to predict the breathing cycle amplitude and its variation the following days based on the breathing in the reference session irrespective of coaching or free breathing. We found a significant tendency towards an increased breathing cycle amplitude variation with the duration of the coaching session. CONCLUSION: These results suggest that large interfraction variation is present in breathing amplitude irrespective of coaching, leading to the suggestion of daily image guidance for verification of respiratory pattern and tumour related motion. Until further investigated it is not recommendable to use coached 4DCT for planning of a free breathing treatment course.

Cardiac and pulmonary complication probabilities for breast cancer patients after routine end-inspiration gated radiotherapy.

PURPOSE: Substantial reductions of radiation doses to heart and lung can be achieved using breathing adaptation of adjuvant radiotherapy following conservative surgery for breast cancer. The purpose of this study was to estimate the radiobiological implications after routine use of an end-inspiration gated treatment, and to compare the results with predictions based on pre-clinical CT-studies. PATIENTS AND METHODS: Nineteen consecutive patients with axillary lymph node-positive left-sided breast cancer were referred for adjuvant radiotherapy after breast conserving surgery. Treatment was performed with gating in the end-inspiration phase of audio-coached enhanced free breathing. The target intended to encompass the remaining breast, ipsilateral internal mammary and periclavicular nodes, and the prescription dose was 48Gy in 24 fractions. A three-field mono-isocentric conformal technique using deep tangentials and a supraclavicular field was employed. NTCPs were calculated using the relative seriality model for the heart, and the model proposed by Burman et al. for the lung. The observed values were compared to those predicted from two previous CT-studies for a deep inspiration breath-hold technique and an uncoached end-inspiration gating technique. RESULTS: The ipsilateral lung V(50) (relative volume receiving more than 50% of the prescription dose) had a median value of 23.7% (range 10.8-35.1%) over the patient population. The corresponding median lung pneumonitis probability was 1.1% (range 0-14%). The median heart V(50) was 0.8% (range 0-19.1%) with a corresponding median cardiac mortality NTCP of 0.1% (range 0-5.7%). These results compare well with the predictions of our previous CT-studies. There is a significant reduction in dose to the left anterior descending coronary artery for the enhanced end-inspiration gating technique compared to the uncoached end-inspiration technique employed in the CT-studies. CONCLUSIONS: In a routine clinical practice involving adjuvant breast radiotherapy gated in an enhanced end-inspiration phase, remarkably low doses to organs at risk are observed. The corresponding cardiac and pulmonary complication risks are of the order of 1% and smaller.

Reduction of cardiac and pulmonary complication probabilities after breathing adapted radiotherapy for breast cancer.

PURPOSE: Substantial reductions of cardio-pulmonary radiation doses can be achieved using voluntary deep inspiration breath-hold (DIBH) or free breathing inspiration gating (IG) in radiotherapy after conserving surgery for breast cancer. The purpose of this study is to evaluate the radiobiological implications of such dosimetric benefits. METHODS AND MATERIALS: Patients from previously reported studies were pooled for a total of 33 patients. All patients underwent DIBH and free breathing (FB) scans, and 17 patients underwent an additional IG scan. Tangential conformal treatment plans covering the remaining breast, internal mammary, and periclavicular nodes were optimized for each scan, prescription dose 48 Gy. Normal tissue complication probabilities were calculated using the relative seriality model for the heart, and the model proposed by Burman et al. for the lung. RESULTS: Previous computed tomography studies showed that both voluntary DIBH and IG provided reduction of the lung V50 (relative volume receiving more than 50% of prescription dose) on the order of 30-40%, and a 80-90% reduction of the heart V50 for left-sided cancers. Corresponding pneumonitis probability of 28.1% (range, 0.7-95.6%) for FB could be reduced to 2.6% (range, 0.1-40.1%) for IG, and 4.3% (range, 0.1-59%) for DIBH. The cardiac mortality probability could be reduced from 4.8% (range, 0.1-23.4%) in FB to 0.5% (range, 0.1-2.6%) for IG and 0.1% (range, 0-3.0%) for DIBH. CONCLUSIONS: Remarkable potential is shown for simple voluntary DIBH and free breathing IG to reduce the risk of both cardiac mortality and pneumonitis for the common technique of adjuvant tangential breast irradiation.

The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) in pulmonary adenocarcinoma: relation to prognosis.

In a lung cancer population comprising tumor tissue from 99 pulmonary adenocarcinoma patients, the relationship between tumor tissue level of the complex formed of urokinase (uPA) and its type-1 inhibitor (PAI-1) and survival was studied. The study included patient material previously investigated for the prognostic impact of PAI-1 on survival. Standard clinical parameters were available and the patients had a median survival time of 25 months. An ELISA established to measure preformed uPA-PAI-1 complexes was applied to the tumor extracts and previously measured data on uPA and PAI-1 levels were available. The amounts of uPA-PAI-1 complex measured in pulmonary adenocarcinoma tissue were within the same range as previously reported in breast cancer tissue (0.11-5.74 ng/mg protein). uPA and PAI-1 levels were weakly correlated to the uPA-PAI-1 complex, r = 0.52 and r = 0.47, respectively, and no relation was found between uPA-PAI-1 complex and any of the clinical parameters. However, a significant prognostic impact of PAI-1 on prognosis was demonstrated (HR = 1.62, p = 0.04). Patients with high PAI-1 and low uPA-PAI-1 complex were found to have a significantly poorer survival than patients with low PAI-1 and high uPA-PAI-1 complex (HR = 3.06, p = 0.01). This is the first investigation of the prognostic impact of uPA-PAI-1 complex in a tumor type other than breast cancer, showing low levels of uPA-PAI-1 complex in combination with high levels of PAI-1 to be associated with poor prognosis. To understand these interactions and the clinical importance of the tissue levels of uPA, PAI-1 and uPA-PAI-1 complex, the results suggest further exploratory studies of the components in pulmonary adenocarcinomas and other cancers.

Breathing adapted radiotherapy for breast cancer: comparison of free breathing gating with the breath-hold technique.

BACKGROUND AND PURPOSE: Adjuvant radiotherapy after breast-conserving surgery for breast cancer implies a risk of late cardiac and pulmonary toxicity. This is the first study to evaluate cardiopulmonary dose sparing of breathing adapted radiotherapy (BART) using free breathing gating, and to compare this respiratory technique with voluntary breath-hold. PATIENTS AND METHODS: 17 patients were CT-scanned during non-coached breathing manoeuvre including free breathing (FB), end-inspiration gating (IG), end-expiration gating (EG), deep inspiration breath-hold (DIBH) and end-expiration breath-hold (EBH). The Varian Real-time Position Management system (RPM) was used to monitor respiratory movement and to gate the scanner. For each breathing phase, a population based internal margin (IM) was estimated based on average chest wall excursion, and incorporated into an individually optimised three-field mono-isocentric wide tangential photon field treatment plan for each scan. The target included the remaining breast, internal mammary nodes and periclavicular nodes. RESULTS: The mean anteroposterior chest wall excursion during FB was 2.5mm. For IG and EG, the mean excursions within gating windows were 1.1 and 0.7 mm, respectively, whereas for DIBH and EBH the excursions were 4.1 and 2.6mm, respectively. For patients with left-sided cancer, the median heart volume receiving more than 50% of the prescription dose was reduced from 19.2% for FB to 2.8% for IG and 1.9% for DIBH, and the median left anterior descending (LAD) coronary artery volume was reduced from 88.9% to 22.4% for IG and 3.6% for DIBH. Simultaneously, the median ipsilateral relative lung volume irradiated to >50% of the prescribed target dose for both right- and left-sided cancers was reduced from 45.6% for FB to 29.5% for IG and 27.7% for DIBH. For EBH and EG, both the irradiated heart, LAD and lung volumes increased compared to FB. CONCLUSIONS: This is the first study to demonstrate the dosimetric benefits of free breathing gated breast cancer radiotherapy. IG compared favourably with DIBH, substantially reducing cardiac doses simultaneous with significant pulmonary tissue sparing.

Breathing adapted radiotherapy of breast cancer: reduction of cardiac and pulmonary doses using voluntary inspiration breath-hold.

BACKGROUND AND PURPOSE: Adjuvant radiotherapy of breast cancer using wide tangential photon fields implies a risk of late cardiac and pulmonary toxicity. This CT-study evaluates the detailed potential dosimetric consequences of applying breathing adapted radiotherapy (BART), and the feasibility of a monitored voluntary breath-hold technique for right-sided as well as for left-sided tumours. PATIENTS AND METHODS: After breast-conserving surgery, 16 patients were CT-scanned in distinct respiratory phases using the varian real-time position management system for the monitoring of respiratory anterioposterior chest wall excursion. Each patient underwent three scans: during free breathing (FB), voluntary expiration breath-hold (EBH) and voluntary deep inspiration breath-hold (DIBH). For each scan, an optimised treatment plan was designed with conformal tangential fields encompassing the clinical target volume (CTV) of the breast and ipsilateral internal mammary nodes, and an anterior supraclavicular field. RESULTS: Breath-hold was well accepted by the patients, with a median duration of 24 s for both EBH and DIBH. The mean anterioposterior chest wall excursions were 2.5, 2.6 and 4.1 mm during FB, EBH and DIBH, respectively. During EBH, the mean front chest wall position was 2.7 mm posterior to its mid-FB position, and during DIBH 12.6 mm anterior to its mid-FB position. For right-sided tumours, the median ipsilateral relative lung volume receiving >50% of the prescribed CTV dose was 39, 49 and 32% for FB, EBH and DIBH, respectively. For left-sided tumours, the corresponding percentages were 37, 46 and 31%. The median heart volume receiving >50% of the prescription dose was reduced from 8% for FB to 1% for DIBH, and the median left anterior descending coronary artery volume was reduced from 54 to 5%. CONCLUSIONS: Irradiated cardiac volumes can consistently be reduced for left-sided breast cancers using DIBH for wide tangential treatment fields. Additionally, substantial dose reductions in the lung are observed for both right- and left-sided tumours.

Tumor tissue concentrations of the proteinase inhibitors tissue inhibitor of metalloproteinases-1 (TIMP-1) and plasminogen activator inhibitor type 1 (PAI-1) are complementary in determining prognosis in primary breast cancer.

The purpose of this study was to investigate the association between tumor tissue levels of total tissue inhibitor of metalloproteinases-1 (TIMP-1) and prognosis in patients with primary breast cancer and to analyze whether measurement of TIMP-1 in tumor extracts added prognostic information to that obtained from measurements of urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 (PAI-1). An established sandwich enzyme-linked immunosorbent assay was thoroughly validated for the measurement of total TIMP-1 in tumor tissue extracts and used to determine levels of total TIMP-1 in 341 detergent-extracted tumor tissue samples from patients with primary breast cancer. The median age of the patients was 56 years (range, 29-75 years), and 164 were lymph node-negative, and 177 were lymph node-positive. The median follow-up time of the patients was 8.5 years (range, 7.3-11.3 years), and during follow-up 153 patients experienced recurrence of disease, and 136 patients died. In univariate survival analysis, we found a significant association between tumor tissue TIMP-1 level and both shorter recurrence-free survival (p = 0.0004) and shorter overall survival (p = 0.03). In multivariate survival analysis, higher tumor tissue TIMP-1 levels significantly and independently predicted shorter recurrence-free survival (p < 0.05, hazard ratios >1, comparing quartiles II-IV with I). In addition, we found that measurement of TIMP-1 levels added prognostic information to that obtained from measurement of PAI-1. In conclusion, high levels of TIMP-1 in tumor tissue extracts are significantly associated with a poor prognosis in patients with primary breast cancer. Furthermore TIMP-1 adds prognostic information to that obtained from PAI-1. However, further validation in independent data sets is needed.