Oncological outcome, postoperative complications, and mammographic changes after intraoperative radiotherapy with electrons (IOERT) as a boost in a large single-institution cohort of breast cancer patients.

Advantages of using intraoperative radiotherapy with electrons (IOERT) as a boosting modality in breast-conserving therapy include the direct visualization of the tumor bed, a reduced skin dose, and patient convenience. We report oncological outcome, postoperative complication rate, and mammographic changes on follow-up imaging in women treated at our institution with IOERT as a boost modality in breast-conserving therapy for early-stage breast carcinoma. Between January 2007 and June 2018, 763 consecutive patients were enrolled. During breast-conserving surgery, an IOERT boost of 9 Gy was applied, followed by whole breast irradiation (WBI). At a median follow-up of 62.2 months (range: 0.5-135), 13 in-breast recurrences were observed, yielding a local tumor control rate of 98.4% at 5 years. In multivariable analysis, high tumor grading was predictive for local recurrence (HR = 5.6; 95%CI: 1.19-26.2). A total of 27 (3.5%) patients developed any kind of postoperative complication. None of the tumor characteristics nor any of the IOERT technical parameters were predictive for development of a postoperative complication. On follow-up imaging, 145 patients with mammographic changes BIRADS score ≥3 were found of which 50.3% required a biopsy. Only 17 patients had positive biopsies; none of the IOERT parameters were predictive for false-positive imaging. A 9 Gy IOERT boost combined with postoperative WBI provided outstanding local control rates, was well-tolerated, with limited postoperative complications. However, radiologists must be aware of a presumable higher prevalence of mammographic changes after IORT as a boost.

Is the use of a preoperative computed tomography beneficial to reduce the interobserver variability of the CTVboost delineation for breast radiation therapy?

PURPOSE: To determine whether the use of a preoperative (preop) computed tomography (CT) reduces (1) the clinical target volume boost (CTVboost) and (2) the interobserver variability (IOV) of the delineated CTVboost in breast radiation therapy. METHODS AND MATERIALS: In patients treated with breast-conserving therapy, 3 CT scans in treatment position were performed: (1) preop; (2) after surgery, prechemotherapy (postop); and (3) postchemotherapy (postchemo). Six radiation-oncologists delineated the tumor bed and CTVboost before and after fusion of the preop CT. To assess the IOV, the Jaccard index was used. Linear mixed models were performedfor all analyses. RESULTS: Eighty-two lumpectomy cavities were evaluated in 22 patients. No difference in CTVboost using the fusion of the preop CT (50.0 cm3; 95% confidence interval [CI], 35.6-64.4) compared with no fusion (49.0 cm3; 95% CI, 34.6-63.4) (P = .6) was observed. A significant increase in IOV was shown with the fusion of the preop CT; the mean Jaccard index of the CTVboost delineation of postop and postchemo CT together without the fusion of the preop CT was 0.53 (95% CI, 0.49-0.57) versus 0.50 (95% CI, 0.46-0.53) with fusion (P < .0001). CONCLUSIONS: There is no benefit of using a preop CT to reduce the volume or the interobserver variability of the delineated CTVboost for breast radiation therapy.

Boost delineation in breast radiation therapy: Isotropic versus anisotropic margin expansion.

PURPOSE: The purpose of this article is to compare isotropic and anisotropic margin expansion with regard to the size of the clinical target volume boost (CTVboost) and the interobserver variability (IOV). METHODS AND MATERIALS: Lumpectomy cavities marked with 3 or more surgical clips were delineated by 6 radiation oncologists who specialized in breast radiation therapy. CTVboost anisotropic was created by manually expanding the tumor bed with an anisotropic margin of 15 mm (20 mm in case of extensive intraductal component) minus the surgical free margins in 6 directions (anteroposterior, craniocaudal, and superoinferior). For the CTVboost isotropic, the tumor bed was enlarged with an isotropic margin of 15 mm (20 mm in case of extensive intraductal component) minus the minimal surgical free margin. The volumes of the delineated CTVboost (cm3) were measured. To assess the IOV, the Jaccard index (JI), defined as the intersection divided by the size of the union of the sample sets, was used (ideal value = 1). The JI was calculated for each case and each observer pair. Linear mixed models were used for all analyses. RESULTS: A total of 444 delineated tumor beds were evaluated. The mean volume of the CTVboost almost doubled by expanding the tumor bed with an isotropic margin compared with anisotropic margins (CTVboost isotropic 94 mL [12.5-331.0] vs CTVboost anisotropic 50 mL [3.2-332.7]; P = .0006). The IOV, assessed by the JI, significantly decreased by using isotropic versus anisotropic margin expansion (JICTV boost isotropic 0.73 [0.02-0.92] vs JICTV boost anisotropic 0.51 [0.0-0.8]; P< .0001). Because of the known positive correlation of the IOV and larger volumes, we corrected for CTVboost volumes. With this correction, the difference in IOV remains highly significant (P < .0001) in favor of isotropic margin expansion. CONCLUSIONS: The use of anisotropic margin expansion from tumorbed to CTVboost isotropic significantly reduced the volume of the delineated CTVboost with a factor of 1.9 compared with isotropic margin expansion, but it substantially increased the interobserver variability.

Dose-response relationships within the parotid gland after radiotherapy for head and neck cancer.

BACKGROUND AND PURPOSE: To determine the salivary function, after parotid-sparing radiotherapy (RT), of different regions within the parotid gland and to evaluate dose-function relationships within the parotid glands and between patients. PATIENTS AND METHODS: Sixteen head and neck cancer patients, irradiated between September 1999 and November 2000 using a conformal parotid-sparing technique, were included in this study. Before RT and 7 months after RT (range 6-10 months), a salivary gland scintigraphy was performed in all patients combined with a single photon emission computed tomography (SPECT). The salivary excretion fraction (SEF) was measured, after stimulation, in 8-12 transverse 5mm SPECT slices of each parotid. Loss of salivary excretion fraction (dSEF %) of these slices was calculated as the proportion of SEF after RT as compared to SEF before RT. Since the planning CT-scan and the SPECT-scintigraphy were performed in the same treatment position, the dose to a transverse slice within the parotid gland could be matched to the loss of salivary excretion fraction of that respective slice. A non-linear model was fitted to the dose-loss of function data and the dose resulting in 50% loss of salivary excretion fraction (D50) was calculated. RESULTS: Before RT, all but one patient presented with normal salivary excretion fractions (SEF) of both parotid glands. Within the same parotid gland, the SEF's of the different slices were almost equal. Seven months after RT, the reduction in SEF was statistically significant (P-value<0.0001). A significant difference in loss of salivary excretion fraction (dSEF) was also observed between both parotid glands (P<0.0001) as a result of the parotid-sparing technique. When plotting the dSEF of a slice versus the dose given to that slice, doses as low as 10-15 Gy could result in a serious loss of function (dSEF>50%). After fitting a non-linear model to these plots, the mean dose resulting in 50% loss of salivary excretion fraction (D50) 7 months after RT was 22.5 Gy. A large inter-patient variability was found in D50. CONCLUSIONS: Salivary SPECT is a useful tool for the evaluation of the salivary function of different slices within the parotid gland. Before irradiation, the different slices within one parotid gland act as functional sub-units contributing equally to the function of the entire gland. Seven months after an average dose of 22.5 Gy (D50) the functional sub-unit has lost 50% of its excretion fraction. The high inter-patient variability in D50 and the observation that low doses (10-15 Gy) can induce serious loss of function should prompt us in the clinic to reduce the dose to the parotids even lower than the threshold of 22.5 Gy.

Subclinical cardiotoxicity detected by strain rate imaging up to 14 months after breast radiation therapy.

PURPOSE: Strain rate imaging (SRI) is a new echocardiographic modality that enables accurate measurement of regional myocardial function. We investigated the role of SRI and troponin I (TnI) in the detection of subclinical radiation therapy (RT)-induced cardiotoxicity in breast cancer patients. METHODS AND MATERIALS: This study prospectively included 75 women (51 left-sided and 24 right-sided) receiving adjuvant RT to the breast/chest wall and regional lymph nodes. Sequential echocardiographs with SRI were obtained before RT, immediately after RT, and 8 and 14 months after RT. TnI levels were measured on the first and last day of RT. RESULTS: Mean heart and left ventricle (LV) doses were both 9 ± 4 Gy for the left-sided patients and 4 ± 4 Gy and 1 ± 0.4 Gy, respectively, for the right-sided patients. A decrease in strain was observed at all post-RT time points for left-sided patients (-17.5% ± 1.9% immediately after RT, -16.6% ± 1.4% at 8 months, and -17.7% ± 1.9% at 14 months vs -19.4% ± 2.4% before RT, P<.01) but not for right-sided patients. When we considered left-sided patients only, the highest mean dose was given to the anterior left ventricular (LV) wall (25 ± 14 Gy) and the lowest to the inferior LV wall (3 ± 3 Gy). Strain of the anterior wall was reduced after RT (-16.6% ± 2.3% immediately after RT, -16% ± 2.6% at 8 months, and -16.8% ± 3% at 14 months vs -19% ± 3.5% before RT, P<.05), whereas strain of the inferior wall showed no significant change. No changes were observed with conventional echocardiography. Furthermore, mean TnI levels for the left-sided patients were significantly elevated after RT compared with before RT, whereas TnI levels of the right-sided patients remained unaffected. CONCLUSIONS: In contrast to conventional echocardiography, SRI detected a regional, subclinical decline in cardiac function up to 14 months after breast RT. It remains to be determined whether these changes are related to clinical outcome. In the meantime, we encourage the use of radiation techniques that minimize the exposure of the anterior LV wall in left-sided patients.

Changes in pulmonary function up to 10 years after locoregional breast irradiation.

PURPOSE: To evaluate the long-term impact of locoregional breast radiotherapy (RT) on pulmonary function tests (PFTs). METHODS AND MATERIALS: This study included 75 women who underwent postoperative locoregional breast RT. PFTs were performed before RT and 3, 6, and 12 months and 8 to 10 years after RT. By use of univariate and multivariate analyses, the impact of treatment- and patient-related factors on late changes in PFTs was evaluated. RESULTS: During the first year after RT, all PFTs significantly worsened at 3 to 6 months after RT (p < 0.05). At 12 months, forced vital capacity (FVC), vital capacity (VC), and forced expiratory volume in 1 second (FEV(1)) recovered almost to baseline values, whereas total lung capacity (TLC) and diffusion capacity of carbon monoxide (DL(CO)) recovered only slightly and were still found to be decreased compared with baseline (p < 0.05). At 8 to 10 years after RT, mean reductions in FEV(1) of 4% (p = 0.03) and in VC, DL(CO), and TLC of 5%, 9%, and 11% (all p < 0.0001), respectively, were observed compared with pre-RT values. On multivariate analysis, tamoxifen use negatively affected TLC at 8 to 10 years after RT (p = 0.033), whereas right-sided irradiation was associated with a late reduction in FEV(1) (p = 0.027). For FEV(1) and DL(CO), an early decrease was predictive for a late decrease (p = 0.003 and p = 0.0009, respectively). CONCLUSIONS: The time course of PFT changes after locoregional RT for breast cancer follows a biphasic pattern. An early reduction in PFTs at 3 to 6 months with a partial recovery at 12 months after RT is followed by a late, more important PFT reduction up to 8 to 10 years after RT. Tamoxifen use may have an impact on this late decline in PFTs.

Conformal locoregional breast irradiation with an oblique parasternal photon field technique.

We evaluated an isocentric technique for conformal irradiation of the breast, internal mammary, and medial supra-clavicular lymph nodes (IM-MS LN) using the oblique parasternal photon (OPP) technique. For 20 breast cancer patients, the OPP technique was compared with a conventional mixed-beam technique (2D) and a conformal partly wide tangential (PWT) technique, using dose-volume histogram analysis and normal tissue complication probabilities (NTCPs). The 3D techniques resulted in a better target coverage and homogeneity than did the 2D technique. The homogeneity index for the IM-MS PTV increased from 0.57 for 2D to 0.90 for PWT and 0.91 for OPP (both p < 0.001). The OPP technique was able to reduce the volume of heart receiving more than 30 Gy (V(30)), the cardiac NTCP, and the volume of contralateral breast receiving 5 Gy (V(5)) compared with the PWT plans (all p < 0.05). There is no significant difference in mean lung dose or lung NTCP between both 3D techniques. Compared with the PWT technique, the volume of lung receiving more than 20 Gy (V(20)) was increased with the OPP technique, whereas the volume of lung receiving more than 40 Gy (V(40)) was decreased (both p < 0.05). Compared with the PWT technique, the OPP technique can reduce doses to the contralateral breast and heart at the expense of an increased lung V(20).

Acute radiation effects on cardiac function detected by strain rate imaging in breast cancer patients.

PURPOSE: To investigate the occurrence of early radiation-induced changes in regional cardiac function using strain rate imaging (SRI) by tissue Doppler echocardiography. METHODS AND MATERIALS: We included 20 left-sided and 10 right-sided breast cancer patients receiving radiotherapy (RT) to the breast or chest wall. Standard echocardiography and SRI were performed before RT (baseline), immediately after RT (post-RT), and at 2 months follow-up (FUP) after RT. Regional strain (S) and strain rate (SR) values were obtained from all 18 left ventricular (LV) segments. Data were compared to the regional radiation dose. RESULTS: A reduction in S was observed post-RT and at FUP in left-sided patients (S(post-RT): -17.6 ± 1.5%, and S(FUP): -17.4 ± 2.3%, vs. S(baseline): -19.5 ± 2.1%, p < 0.001) but not in right-sided patients. Within the left-sided patient group, S and SR were significantly reduced after RT in apical LV segments (S(post-RT): -15.3 ± 2.5%, and S(FUP): -14.3 ± 3.7%, vs. S(baseline): -19.3 ± 3.0%, p < 0.01; and SR(post-RT): -1.06 ± 0.15 s(-1), and SR(FUP): -1.16 ± 0.28 s(-1), vs. SR(baseline): -1.29 ± 0.27 s(-1), p = 0.01), but not in mid- or basal segments. Furthermore, we observed that segments exposed to more than 3 Gy showed a significant decrease in S after RT (S(post-RT): -16.1 ± 1.6%, and S(FUP): -15.8 ± 3.4%, vs. S(baseline): -18.9 ± 2.6%, p < 0.001). This could not be observed in segments receiving less than 3 Gy. CONCLUSIONS: SRI shows a dose-related regional decrease in myocardial function after RT. It might be a useful tool in the evaluation of modern RT techniques, with respect to cardiac toxicity.

Clinical outcome of coronary stenting after thoracic radiotherapy: a case-control study.

OBJECTIVE: Patients with lymphoma, lung or breast neoplasia show significant improvement in their disease-specific survival after radiotherapy (RT), but these benefits may be offset by delayed effects of irradiation of the heart. We compared clinical outcome after coronary stenting in patients with neoplastic disease and previous thoracic RT with matched patients without previous RT. DESIGN: Single-centre retrospective case-control study. Patients and methods Each patient with former thoracic RT undergoing coronary stenting between June 1998 and June 2005 was matched to two control patients according to several known prognostic factors (gender, age, available follow-up, stented vessel, drug-eluting stent use, unstable coronary disease, renal insufficiency, diabetes, bifurcational disease, stent length and size and ejection fraction). Main outcome measures Major adverse cardiac events (MACE) were defined as the composite of cardiac death, acute myocardial infarction (AMI) and target lesion revascularisation (TLR) and were assessed at latest follow-up and compared using Cox regression analyses. RESULTS: 41 patients underwent coronary stenting at 6+/-4 years after RT. Clinical outcome at 5+/-2 years after stenting was compared with outcome in 82 matched patients. For all-cause mortality, the hazard ratio for RT versus no RT was 4.2 (95% CI 1.8 to 9.5; p=0.0006). For cardiac mortality, the estimated hazard ratio was 4.2 (95% CI 1.0 to 17.0; p=0.0451). No significant differences were detected in terms of AMI, TLR, MACE or stent thrombosis. CONCLUSIONS: Our findings suggest an increased risk of all-cause and cardiac mortality in patients who underwent coronary stent implantation after previous thoracic RT. Verification in larger patient populations is warranted.

Regional lymph node irradiation in breast cancer.

A recent meta-analysis, published by the Early Breast Cancer Trialists' Collaborative Group, demonstrated a clear survival advantage of post-operative radiotherapy on the breast, chest wall and regional lymphatics in node-positive disease. The extensive target volume in locoregional irradiation of breast cancer, in close proximity to the heart and lungs, complicates treatment planning. The breast or chest wall fields need to match the supraclavicular/axillary and parasternal fields, at the subclavicular and parasternal matchline, respectively. Dose distribution near the junction area is often inhomogeneous, and under- and over-dosage can occur, which can lead to recurrences and complications. This paper describes briefly the indications, complications and target localization concerning regional lymph node radiotherapy and discusses more extensively the advantages and disadvantages of the most frequently used treatment techniques.