E.J. Bantema-Joppe

The prognostic role of classical and nonclassical MHC class I expression in endometrial cancer

The aim of this study was to investigate classical MHC class I and nonclassical MHC (human leukocyte antigen‐G [HLA‐G]) expression in a large cohort of patients with endometrial cancer, to determine the prognostic value of these cell surface markers and their relation with clinicopathological variables. Tissue microarrays containing epithelial endometrial carcinoma tissue from 554 patients were stained for classical and nonclassical MHC class I using the following monoclonal antibodies: 4H84 (anti‐HLA‐G), β2‐m (anti‐beta‐2‐microglobulin) and HC‐10 (MHC class I antigen heavy chain). Expression data were linked to known clinicopathological characteristics and survival. HLA‐G upregulation and MHC class I downregulation in neoplastic cells was observed in 40% and 48%, respectively. Nonendometrioid tumor type, advanced stage disease (FIGO stage ≥II) and poorly or undifferentiated tumors were associated with MHC class I downregulation. Absence of HLA‐G expression was independently associated with MHC class I downregulation. In univariate analysis, MHC class I downregulation was a predictor of worse disease‐specific survival. Prognostic unfavorable tumor characteristics were correlated with downregulation of MHC class I expression in endometrial cancer cells. Furthermore, downregulated MHC class I has a negative impact on disease‐specific survival, observed in a large cohort of patients with endometrial cancer. As there seems to be a relation between classical and nonclassical MHC class I molecules (HLA‐G), further research is warranted to unravel this regulatory mechanism.

Simultaneous Integrated Boost Irradiation After Breast-Conserving Surgery: Physician-Rated Toxicity and Cosmetic Outcome at 30 Months' Follow-Up

PURPOSE To evaluate toxicity and cosmetic outcome (CO) in breast cancer survivors treated with three-dimensional conformal radiotherapy with a hypofractionated, simultaneous integrated boost (3D-CRT-SIB) and to identify risk factors for toxicity, with special focus on the impact of age. METHODS AND MATERIALS Included were 940 consecutive disease-free patients treated for breast cancer (Stage 0-III) with 3D-CRT-SIB, after breast-conserving surgery, from 2005 to 2010. Physician-rated toxicity (Common Terminology Criteria for Adverse Events version 3.0) and CO were prospectively assessed during yearly follow-up, up to 5 years after radiotherapy. Multivariate logistic regression analyses using a bootstrapping method were performed. RESULTS At 3 years, toxicity scores of 436 patients were available. Grade ≥ 2 fibrosis in the boost area was observed in 8.5%, non-boost fibrosis in 49.4%, pain to the chest wall in 6.7%, and fair/poor CO in 39.7% of cases. Radiotherapy before chemotherapy was significantly associated with grade ≥ 2 boost fibrosis at 3 years (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.3-6.0). Non-boost fibrosis was associated with re-resection (OR 2.2, 95% CI 1.2-4.0) and larger tumors (OR 1.1, 95% CI 1.0-1.1). At 1 year, chest wall pain was significantly associated with high boost dosage (OR 2.1, 95% CI 1.2-3.7) and younger age (OR 0.4, 95% CI 0.2-0.7). A fair/poor CO was observed more often after re-resection (OR 4.5, 95% CI 2.4-8.5), after regional radiotherapy (OR 2.9, 95% CI 1.2-7.1), and in larger tumors (OR 1.1, 95% CI 1.0-1.1). CONCLUSIONS Toxicity and CO are not impaired after 3D-CRT-SIB. Fibrosis was not significantly associated with radiotherapy parameters. Independent risk factors for fibrosis were chemotherapy after radiotherapy, re-resection, and larger tumor size. Re-resection was most predictive for worse CO. Age had an impact on chest wall pain occurrence.

Three-dimensional conformal hypofractionated simultaneous integrated boost in breast conserving therapy: Results on local control and survival

PURPOSE To report on local control and survival after breast conserving therapy (BCT) including three-dimensional conformal simultaneous integrated boost irradiation (3D-CRT-SIB) and on the influence of age on outcome. PATIENT AND METHODS For this study, 752 consecutive female breast cancer patients (stages I-III), treated with 3D-CRT-SIB at the University Medical Center Groningen from 2005 to 2008, were retrospectively identified. Median age was 58.4 (range 26-84) years. The SIB fractionation used was: 28×1.8Gy (whole breast) and 28×2.3Gy or 2.4Gy (tumour bed). Next to outcome, we estimated the effect of age on the recurrence-free period (RFP) by multivariate Cox regression survival analysis. RESULTS Median follow-up was 41 (range 3-65) months. Local control was 99.6% at 3 years (6 ipsilateral recurrences). The 3-year locoregional control, RFP and overall survival (OS) rates were 99.2%, 95.5%, and 97.1%, respectively. In multivariate analysis, tumours >2cm (hazard ratio (HR) 3.11; 95% confidence interval (CI) 1.57-6.17) and triple negativity (HR 3.03; 95% CI 1.37-6.67) and not age were associated with impaired RFP. CONCLUSIONS At 3 years, the 3D-CRT-SIB technique in BCT results in excellent local control and OS. Age was not a risk factor for any recurrence.

EARLY-STAGE YOUNG BREAST CANCER PATIENTS : IMPACT OF LOCAL TREATMENT ON SURVIVAL

PURPOSE In young women, breast-conserving therapy (BCT), i.e., lumpectomy followed by radiotherapy, has been associated with an increased risk of local recurrence. Still, there is insufficient evidence that BCT impairs survival. The aim of our study was to compare the effect of BCT with mastectomy on overall survival (OS) in young women with early-stage breast cancer. METHODS AND MATERIALS From two Dutch regional population-based cancer registries (covering 6.2 million inhabitants) 1,453 women <40 years with pathologically T1N0-1M0 breast cancer were selected. Cox regression survival analysis was used to study the effect of local treatment (BCT vs. mastectomy) stratified for nodal stage on survival and corrected for tumor size, age, period of diagnosis, and use of adjuvant systemic therapy. RESULTS With a median follow-up of 9.6 years, 10-year OS was 83% after BCT and 78% after mastectomy, respectively (unadjusted hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.09-1.72). In N0-patients, 10-year OS was 84% after BCT and 81% after mastectomy and local treatment was not associated with differences in OS (HR 1.19; 95% CI, 0.89-1.58; p = 0.25). Within the N1-patient group, OS was better after BCT compared with mastectomy, 79% vs. 71% at 10 years (HR 1.91; 95% CI, 1.28-2.84; p = 0.001) and in patients treated with adjuvant hormonal therapy (HR 0.34; 95% CI, 0.18-0.66; p = 0.001). CONCLUSIONS In this large population-based cohort of early-stage young breast cancer patients, 10-year OS was not impaired after BCT compared with mastectomy. Patients with 1 to 3 positive lymph nodes had better prognosis after BCT than after mastectomy.

Validation and Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast Cancer Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac Substructures

Purpose A relationship between mean heart dose (MHD) and acute coronary event (ACE) rate was reported in a study of patients with breast cancer (BC). The main objective of our cohort study was to validate this relationship and investigate if other dose-distribution parameters are better predictors for ACEs than MHD. Patients and Methods The cohort consisted of 910 consecutive female patients with BC treated with radiotherapy (RT) after breast-conserving surgery. The primary end point was cumulative incidence of ACEs within 9 years of follow-up. Both MHD and various dose-distribution parameters of the cardiac substructures were collected from three-dimensional computed tomography planning data. Results The median MHD was 2.37 Gy (range, 0.51 to 15.25 Gy). The median follow-up time was 7.6 years (range, 0.1 to 10.1 years), during which 30 patients experienced an ACE. The cumulative incidence of ACE increased by 16.5% per Gy (95% CI, 0.6 to 35.0; P = .042). Analysis showed that the volume of the left ventricle receiving 5 Gy (LV-V5) was the most important prognostic dose-volume parameter. The most optimal multivariable normal tissue complication probability model for ACEs consisted of LV-V5, age, and weighted ACE risk score per patient (c-statistic, 0.83; 95% CI, 0.75 to 0.91). Conclusion A significant dose-effect relationship was found for ACEs within 9 years after RT. Using MHD, the relative increase per Gy was similar to that reported in the previous study. In addition, LV-V5 seemed to be a better predictor for ACEs than MHD. This study confirms the importance of reducing exposure of the heart to radiation to avoid excess risk of ACEs after radiotherapy for BC.

Five year outcomes of hypofractionated simultaneous integrated boost irradiation in breast conserving therapy; patterns of recurrence

In 2005, we introduced hypofractionated 3-dimensional conformal radiotherapy with a simultaneous integrated boost (3D-CRT-SIB) technique after breast conserving surgery. In a consecutive series of 752 consecutive female invasive breast cancer patients (stages I-III) the 5-year actuarial rate for local control was 98.9%. This new technique gives excellent 5-year local control.

The impact of age on changes in quality of life among breast cancer survivors treated with breast-conserving surgery and radiotherapy

Background:The purpose of the study was to determine the impact of young age on health-related quality of life (HRQoL) by comparing HRQoL of younger and older breast cancer patients, corrected for confounding, and of young patients and a general Dutch population.Methods:The population consisted of breast cancer survivors (stage 0-III) after breast-conserving surgery and radiotherapy. Health-related quality of life was prospectively assessed using the EORTC QLQ-C30 and QLQ-BR23 questionnaires. The association between age (⩽50; 51–70; ⩾70 years) and HRQoL over time was analysed with mixed modelling. The clinical relevance of differences between/within age groups was estimated with Cohen’s D and consensus-based guidelines. The HRQoL data from the young patient cohort were compared with Dutch reference data at 3 years after radiotherapy.Results:A total of 1420 patients completed 3200 questionnaires. Median follow-up was 34 (range 6–70) months. Median age was 59 (range 28–85) years. Compared with older subjects, young women reported worse HRQoL in the first year after radiotherapy, but clinical relevance was limited. Three years after radiotherapy, HRQoL values in the younger group were equal to those in the reference population. Pain and fatigue after radiotherapy improved, with medium clinical relevance.Conclusions:Three years after radiotherapy for breast cancer, young age was not a risk factor for decreased HRQoL.

Radiation-induced fibrosis in the boost area after three-dimensional conformal radiotherapy with a simultaneous integrated boost technique for early-stage breast cancer: A multivariable prediction model

BACKGROUND AND PURPOSE To develop a multivariable prediction model for the risk of grade⩾2 fibrosis in the boost area after breast conserving surgery (BCS) followed by three-dimensional conformal radiotherapy (RT) with a simultaneous integrated photon boost (3D-CRT-SIB), five years after RT. MATERIAL AND METHODS This prospective cohort study included 1,030 patients treated with RT for breast cancer (stage 0-III), after BCS. Data regarding physician-rated fibrosis and dose-volume parameters were available in 546 patients. A multivariable logistic regression model for grade⩾2 fibrosis was generated. RESULTS At 5years, grade⩾2 fibrosis was observed in 13.4% of the patients. The multivariable analysis resulted in a prediction model for grade⩾2 fibrosis in the boost area including three independent variables: patient age, breast volume receiving⩾55Gy (V55 CTV breast) and the maximum radiation dose in the breast (Dmax). CONCLUSIONS A multivariable prediction model was developed including age, V55 CTV breast and Dmax for grade⩾2 fibrosis in the boost area after breast cancer RT using a 3D-CRT-SIB technique. This model can be used to estimate the risk of fibrosis and to optimize dose distributions aiming at reducing this risk.