Paula H.M. Elkhuizen

Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial

BACKGROUND Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. METHODS Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033. FINDINGS Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001). INTERPRETATION A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. FUNDING Fonds Cancer, Belgium.

CLINICAL RESULTS OF IMAGE-GUIDED DEEP INSPIRATION BREATH HOLD BREAST IRRADIATION

PURPOSE To evaluate the feasibility, cardiac dose reduction, and the influence of the setup error on the delivered dose for fluoroscopy-guided deep inspiration breath hold (DIBH) irradiation using a cone-beam CT for irradiation of left-sided breast cancer patients. METHODS AND MATERIALS Nineteen patients treated according to the DIBH protocol were evaluated regarding dose to the ipsilateral breast (or thoracic wall), heart, (left ventricle [LV] and left anterior descending artery [LAD]), and lung. The DIBH treatment plan was compared to the free-breathing (FB) treatment planning and to the dose data in which setup error was taken into account (i.e., actual delivered dose). RESULTS The largest setup variability was observed in the direction perpendicular to the RT field (μ = -0.8 mm, Σ = 2.9 mm, σ = 2.0 mm). The mean (D(mean)) and maximum (D(max)) doses of the DIBH treatment plan was significantly lower compared with the FB treatment plan for the heart (34% and 25%, p < 0.001), LV (71% and 28%, p < 0.001), and LAD (52% and 39.8%, p < 0.001). For some patients, large differences were observed between the heart D(max) according to the DIBH treatment plan and the actual delivered dose (up to 71%), although D(max) was always smaller than the planned FB dose (mean group reduction = 29%, p < 0.001). CONCLUSION The image-guided DIBH treatment protocol is a feasible irradiation method with small setup variability that significantly reduces the dose to the heart, LV, and LAD.

Multiinstitutional study on target volume delineation variation in breast radiotherapy in the presence of guidelines

PURPOSE This study aims to determine magnitude, causes and consequences of post-operative breast tumour target volume delineation variation among radiation oncologists in the presence of guidelines. MATERIALS AND METHODS Excision cavities, CTVs and PTVs of eight breast cancer patients were delineated on CT scans by 13 Dutch radiation oncologists (observers) from 12 Dutch institutes participating in the international Young Boost Trial. Delineated volumes and conformity indices were determined. CTV delineation variation (SD) was determined for anatomically relevant regions. Non-parametric statistics were performed to establish effects of observers, patient characteristics and regions on delineation variation. RESULTS Even in the presence of delineation guidelines considerable delineation variation is present (0.24<SD<1.22 cm). Presence of clips or seroma reduced interobserver variation (0.24<SD<0.62 cm). Region-specific analysis showed distinct regions of higher variability per patient. This could not always be ascribed to anatomical features, suggesting interobserver variation is not solely due to lack of image quality. CONCLUSIONS In this study, interobserver delineation variation in breast tumour target volume delineation is larger than, e.g. setup inaccuracies and results from limited reliable visual guidance as well as interpretation differences between observers, despite guidelines. Reduction of delineation variation is essential in view of current developments in planning techniques, particularly for External Partial Breast Irradiation.

High Local Recurrence Risk After Breast-Conserving Therapy in Node-Negative Premenopausal Breast Cancer Patients Is Greatly Reduced by One Course of Perioperative Chemotherapy: A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group Study

PURPOSE Patients with invasive breast cancer may develop a local recurrence (LR) after breast-conserving therapy (BCT). Younger age has been found to be an independent risk factor for LR. Within a group of premenopausal node-negative breast cancer patients, we studied risk factors for LR and the effect of perioperative chemotherapy (PeCT) on LR. PATIENTS AND METHODS The European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized trial (EORTC 10854) to compare surgery followed by one course of PeCT (fluorouracil, doxorubicin, and cyclophosphamide) with surgery alone. From patients treated on this trial, we selected premenopausal patients with node-negative breast cancer who were treated with BCT to examine whether histologic characteristics and the expression of various proteins (estrogen receptor, progesterone receptor, p53, Ki-67, bcl-2, CD31, c-erbB-2/neu) are risk factors for subsequent LR. Also, the effect of one course of PeCT on the LR risk (LRR) was studied. RESULTS Using multivariate analysis, age younger than 43 years (relative risk [RR], 2.75; 95% confidence interval [CI], 1.46 to 5.18; P =.002), multifocal growth (RR, 3.34; 95% CI, 1.27 to 8.77; P =.014), and elevated levels of p53 (RR, 2. 14; 95% CI, 1.13 to 4.05; P =.02) were associated with higher LRR. Also, PeCT was found to reduce LRR by more than 50% (RR, 0.47; 95% CI, 0.25 to 0.86; P =.02). Patients younger than 43 years who received PeCT achieved similar LR rates as those of patients younger than 43 years who were treated with BCT alone. CONCLUSION In premenopausal node-negative patients, age younger than 43 years is the most important risk factor for LR after BCT; this risk is greatly reduced by one course of PeCT. The main reason for administering systemic adjuvant treatment is to improve overall survival. The important reduction of LR after BCT is an additional reason for considering systemic treatment in young node-negative patients with breast cancer.

Nomogram to predict ipsilateral breast relapse based on pathology review from the EORTC 22881-10882 boost versus no boost trial

BACKGROUND AND PURPOSE The EORTC 22881-10882 trial showed that for patients treated with breast conserving therapy (BCT), a 16Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. A model to estimate the risk of ipsilateral breast relapse (IBR) already exists, but now a model has been developed which takes boost treatment into account and is based on centrally reviewed pathology. MATERIALS AND METHODS A Cox model was developed based on central pathology review data and clinical data of 1603 patients from the EORTC 22881-10882 trial with a median follow-up of 11.5years. From a predefined set of variables, predictors with a maximal effect on 10-year IBR rate >4% were retained in the model. Bootstrap re-sampling was used to assess model calibration and discrimination. The results are presented in the form of a nomogram. RESULTS Apart from young age and no boost, presence of DCIS adjacent to the invasive tumor was associated with increased risk of IBR (HR 1.96, p=0.001). Patients with high grade invasive tumors were younger than patients with low/intermediate grade (p<0.0001). The nomogram includes histologic grade, DCIS, tumor diameter, age, tamoxifen, chemotherapy, and boost with a concordance probability estimate of 0.68. CONCLUSIONS The nomogram for predicting IBR 10years after BCT includes seven factors, with young age, presence of DCIS and boost treatment as the most dominant factors. The nomogram estimates IBR and confirms the importance of a boost dose. Combined with a model to predict fibrosis published previously, the nomogram presented here may assist in decision making for individual patients.

Has partial breast irradiation by IORT or brachytherapy been prematurely introduced into the clinic

In contrast to most new oncology treatments, wide clinical introduction of partial breast irradiation (PBI) is not based on level A trial evidence. Despite promising phase I/II data, new reports based upon large cohorts of patients mention more recurrences and/or complications from PBI compared with whole breast irradiation (WBI), necessitating more careful selection of patients for PBI while awaiting long term results of major clinical trials. In an attempt to improve this we give preoperative PBI within a prospective trial.

Predictive Factors for Local Recurrence in Breast Cancer

Risk factors for local recurrence in breast cancer after breast conserving therapy (BCT) differ from those for local recurrence after mastectomy. To better guide optimal treatment of individual patients, it is desirable to identify patients at high risk for local recurrence. Several clinical and histopathologic factors, such as young age and presence of ductal carcinoma in situ, are known to be predictors for local recurrence after BCT. After mastectomy, lymph node status and tumor size are dominant risk factors for local recurrence. The results of recent expression profiling studies have explained differences in prognosis and risk for local recurrence and also explained response to different therapies (adjuvant systemic therapy and radiotherapy). Because of the variation in different subtypes of breast cancer and the difference in amount of tumor burden remaining after surgery, finding robust predictive profiles is complex. In this review, we describe the predictive and prognostic factors for local recurrence after mastectomy and BCT and also describe the role of radiosensitivity in local recurrence.

Reducing interobserver variation of boost-CTV delineation in breast conserving radiation therapy using a pre-operative CT and delineation guidelines ☆

AIMS To investigate whether using a pre-operative CT scan (Preop-CT) (1) decreases interobserver variation of boost-CTV delineation in breast conserving therapy (BCT), and (2) influences the size of the delineated volumes. PATIENTS AND METHODS Thirty cT1-2N0-1 breast cancer patients underwent a CT-scan in radiation treatment position, prior to and after lumpectomy. Five observers delineated a boost-CTV, both with and without access to the Preop-CT. For each patient and for each observer pair, the conformity index (CI) and the distance between the centres of mass (COMd) for both boost volumes were calculated. In addition, all delineated volumes including the standard deviation (SD) with respect to the median delineation were calculated. RESULTS Using a Preop-CT reduced the mean COMd of the boost-CTV from 1.1cm to 1.0 cm (p<0.001). No effect was seen on the CI, but the boost-CTV volume reduced from 42 cc to 36 cc (p=0.005), implying a reduction of interobserver variation. We saw no significant change in the SD. CONCLUSION Use of a Preop-CT in BCT results in a modest but statistically significant reduction in interobserver variation of the boost-CTV delineations and in a significant reduction in the boost-CTV volume.

Breast-Conserving Therapy: Radiotherapy Margins for Breast Tumor Bed Boost

PURPOSE To quantify the interfraction position variability of the excision cavity (EC) and to compare the rib and breast surface as surrogates for the cavity. Additionally, we sought to determine the required margin for on-line, off-line and no correction protocols in external beam radiotherapy. METHODS AND MATERIALS A total of 20 patients were studied who had been treated in the supine position for 28 daily fractions. Cone-beam computed tomography scans were regularly acquired according to a shrinking action level setup correction protocol based on bony anatomy registration of the ribs and sternum. The position of the excision area was retrospectively analyzed by gray value cone-beam computed tomography-to-computed tomography registration. Subsequently, three setup correction strategies (on-line, off-line, and no corrections) were applied, according to the rib and breast surface registrations, to estimate the residual setup errors (systematic [Sigma] and random [sigma]) of the excision area. The required margins were calculated using a margin recipe. RESULTS The image quality of the cone-beam computed tomography scans was sufficient for localization of the EC. The margins required for the investigated setup correction protocols and the setup errors for the left-right, craniocaudal and anteroposterior directions were 8.3 mm (Sigma = 3.0, sigma = 2.6), 10.6 mm (Sigma = 3.8, sigma = 3.2), and 7.7 mm (Sigma = 2.7, sigma = 2.9) for the no correction strategy; 5.6 mm (Sigma = 2.0, Sigma = 1.8), 6.5 mm (Sigma = 2.3, sigma = 2.3), and 4.5 mm (Sigma = 1.5, sigma = 1.9) for the on-line rib strategy; and 5.1 mm (Sigma = 1.8, sigma = 1.7), 4.8 mm (Sigma = 1.7, sigma = 1.6), and 3.3 mm (Sigma = 1.1, sigma = 1.6) for the on-line surface strategy, respectively. CONCLUSION Considerable geometric uncertainties in the position of the EC relative to the bony anatomy and breast surface have been observed. By using registration of the breast surface, instead of the rib, the uncertainties in the position of the EC area were reduced.

Tumor bed delineation for external beam accelerated partial breast irradiation: A systematic review

In recent years, accelerated partial breast irradiation (APBI) has been considered an alternative to whole breast irradiation for patients undergoing breast-conserving therapy. APBI delivers higher doses of radiation in fewer fractions to the post-lumpectomy tumor bed with a 1-2 cm margin, targeting the area at the highest risk of local recurrence while sparing normal breast tissue. However, there are inherent challenges in defining accurate target volumes for APBI. Studies have shown that significant interobserver variation exists among radiation oncologists defining the lumpectomy cavity, which raises the question of how to improve the accuracy and consistency in the delineation of tumor bed volumes. The combination of standardized guidelines and surgical clips significantly improves an observers ability in delineation, and it is the standard in multiple ongoing external-beam APBI trials. However, questions about the accuracy of the clips to mark the lumpectomy cavity remain, as clips only define a few points at the margin of the cavity. This paper reviews the techniques that have been developed so far to improve target delineation in APBI delivered by conformal external beam radiation therapy, including the use of standardized guidelines, surgical clips or fiducial markers, pre-operative computed tomography imaging, and additional imaging modalities, including magnetic resonance imaging, ultrasound imaging, and positron emission tomography/computed tomography. Alternatives to post-operative APBI, future directions, and clinical recommendations were also discussed.