Spot-scanning proton therapy for early breast cancer in free breathing versus deep inspiration breath-hold.

BACKGROUND AND PURPOSE: Proton therapy for breast cancer is usually given in free breathing (FB). With the use of deep inspiration breath-hold (DIBH) technique, the location of the heart is displaced inferiorly, away from the internal mammary nodes and, thus, the dose to the heart can potentially be reduced. The aim of this study was to explore the potential benefit of proton therapy in DIBH compared to FB for highly selected patients to reduce exposure of the heart and other organs at risk. We aimed at creating proton plans with delivery times feasible with treatment in DIBH. MATERIAL AND METHODS: Sixteen patients with left-sided breast cancer receiving loco-regional proton therapy were included. The FB and DIBH plans were created for each patient using spot-scanning proton therapy with 2-3 fields, robust and single field optimization. For the DIBH plans, minimum monitor unit per spot and spot spacing were increased to reduce treatment delivery time. RESULTS: All plans complied with target coverage constraints. The median mean heart dose was statistically significant reduced from 1.1 to 0.6 Gy relative biological effectiveness (RBE) by applying DIBH. No statistical significant difference was seen for mean dose and V17Gy RBE to the ipsilateral lung. The median treatment delivery time for the DIBH plans was reduced by 27% compared to the FB plans without compromising the plan quality. INTERPRETATION: The median absolute reduction in dose to the heart was limited. Proton treatment in DIBH may only be relevant for a subset of these patients with the largest reduction in heart exposure.

European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus recommendations on patient selection and dose and fractionation for external beam radiotherapy in early breast cancer.

High-quality randomised clinical trials testing moderately fractionated breast radiotherapy have clearly shown that local control and survival is at least as effective as with 2 Gy daily fractions with similar or reduced normal tissue toxicity. Fewer treatment visits are welcomed by patients and their families, and reduced fractions produce substantial savings for health-care systems. Implementation of hypofractionation, however, has moved at a slow pace. The oncology community have now reached an inflection point created by new evidence from the FAST-Forward five-fraction randomised trial and catalysed by the need for the global radiation oncology community to unite during the COVID-19 pandemic and rapidly rethink hypofractionation implementation. The aim of this paper is to support equity of access for all patients to receive evidence-based breast external beam radiotherapy and to facilitate the translation of new evidence into routine daily practice. The results from this European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus state that moderately hypofractionated radiotherapy can be offered to any patient for whole breast, chest wall (with or without reconstruction), and nodal volumes. Ultrafractionation (five fractions) can also be offered for non-nodal breast or chest wall (without reconstruction) radiotherapy either as standard of care or within a randomised trial or prospective cohort. The consensus is timely; not only is it a pragmatic framework for radiation oncologists, but it provides a measured proposal for the path forward to influence policy makers and empower patients to ensure equity of access to evidence-based radiotherapy.

Proton therapy for early breast cancer patients in the DBCG proton trial: planning, adaptation, and clinical experience from the first 43 patients.

BACKGROUND: The Danish Breast Cancer Group (DBCG) Proton Trial randomizes breast cancer patients selected on high mean heart dose (MHD) or high lung dose (V20Gy/V17Gy) in the photon plan between photon and proton therapy. This study presents the proton plans and adaptation strategy for the first 43 breast cancer patients treated with protons in Denmark. MATERIAL AND METHODS: Forty-four proton plans (one patient with bilateral cancer) were included; 2 local and 42 loco-regional including internal mammary nodes (IMN). Nineteen patients had a mastectomy and 25 a lumpectomy. The prescribed dose was either 50 Gy in 25 fractions (n = 30) or 40 Gy in 15 fractions (n = 14) wherefrom five received simultaneous integrated boost to the tumor bed. Using 2-3 en face proton fields, single-field optimization, robust optimization and a 5 cm range shifter ensured robustness towards breathing motion, setup- and range uncertainties. An anatomical evaluation was performed by evaluating the dose after adding/removing 3 mm and 5 mm tissue to/from the body-outline and used to define treatment tolerances for anatomical changes. RESULTS: The nominal and robust criteria were met for all patients except two. The median MHD was 1.5 Gy (0.5-3.4 Gy, 50 Gy) and 1.1 Gy (0.0-1.5 Gy, 40 Gy). The anatomical evaluations showed how 5 mm shrinkage approximately doubled the MHD while 5 mm swelling reduced target coverage of the IMN below constraints. Ensuring 3-5 mm robustness toward swelling was prioritized but not always achieved by robust optimization alone emphasizing the need for a distal margin. Twenty-eight patients received plan adaptation, eight patients received two, and one received five. CONCLUSION: This proton planning strategy ensured robust treatment plans within a pre-defined level of acceptable anatomical changes that fulfilled the planning criteria for most of the patients and ensured low MHD.

Patient-reported outcomes in postmenopausal breast cancer survivors - comparisons with normative data.

BACKGROUND: Survival rates for breast cancer (BC) are increasing, leading to growing interest in treatment-related late-effects. The aim of the present study was to explore late effects using Patient-Reported Outcome Measures in postmenopausal BC survivors in standard follow-up care. The results were compared to age- and gender-matched data from the general Danish population. MATERIAL AND METHODS: Postmenopausal BC survivors in routine follow-up care between April 2016 and February 2018 at the Department of Oncology, Aarhus University Hospital, Denmark were asked to complete the EORTC QLQ-C30 and BR23 questionnaires together with three items on neuropathy, myalgia, and arthralgia from the PRO-CTCAE. Patients were at different time intervals from primary treatment, enabling a cross-sectional study of reported late effects at different time points after primary treatment. The time intervals used in the analysis were year ≤1, 1-2, 2-3, 3-4, 4-5 and 5+. The QLQ-C30 results were compared with reference data from the general Danish female population. Between-group differences are presented as effect sizes (ESs) (Cohen's d). RESULTS: A total of 1089 BC survivors participated. Compared with the reference group, BC survivors reported better global health status 2-3 and 4-5 years after surgery (d = 0.26) and physical functioning 2-3 years after (0.21). Poorer outcomes in BC survivors compared with the reference group were found for cognitive functioning (0-4 and 5+ years), fatigue (0-2 years), insomnia (1-3 years), emotional functioning (3-4 years), and social functioning (≤1 year after surgery) with ESs ranging from 0.20 to 0.41. For the remaining outcomes, no ESs exceeded 0.20. CONCLUSION: Only small to medium ESs were found for better global health and physical functioning and poorer outcomes for cognitive functioning, fatigue, insomnia, emotional functioning, and social functioning in postmenopausal BC survivors, who otherwise reported similar overall health-related quality of life compared with the general Danish female population.

Patterns in detection of recurrence among patients treated for breast cancer.

PURPOSE: The Danish follow-up program for breast cancer (BC) patients has recently been changed. Today most patients are offered open access to an outpatient clinic, whereas the scheduled visits are phased out. This strategy has been studied in regards to psychological and health-related quality of life outcomes, but not in regards to detection of recurrence and survival. The aim of this study was to quantify the recurrences detected at scheduled outpatient visits in Denmark before the implementation of revised follow-up guidelines. METHODS: We conducted a cross-sectional study among 310 patients with recurrent BC. Information was retrieved on tumor characteristics, type of visit when recurrence was detected, recurrence localization, symptoms reported, and duration of symptoms from the Danish Breast Cancer Group database and medical records. RESULTS: The recurrences were locoregional (26%), locoregional and distant (15%), or distant (59%). Among patients still in outpatient follow-up (n = 199), recurrence was detected at a patient-requested extra outpatient visit (15%), by the general practitioner or other specialist (47%), at a scheduled outpatient visit (21%), or on a scheduled mammogram (11%). Among patients with recurrences detected at scheduled outpatient visits, the majority (88%) reported symptoms related to the recurrence. Most frequent symptoms were pain (37%), dyspnoea (15%), and fatigue (12%). CONCLUSIONS: One-fifth of BC recurrences among patients attending outpatient follow-up were detected at scheduled outpatient visits. Very few of these were asymptomatic. Whether there will be a delay in detection of the symptomatic recurrences when the number of visits is reduced is unknown.

Spatial location of local recurrences after mastectomy: a systematic review.

PURPOSE: We performed a systematic review to document the spatial location of local recurrences (LR) after mastectomy. METHODS: A PubMed search was conducted in August 2019 for the following terms: breast [Title/Abstract] AND cancer [Title/Abstract] AND recurrence [Title/Abstract] AND mastectomy [Title/Abstract]. The search was filtered for English language. Exclusion criteria included studies that did not specify the LR location or studies reporting LR associated with inflammatory breast cancer, or other breast cancers such as phyllodes tumours, lymphoma or associated with sarcoma/angiosarcoma. RESULTS: A total of 3922 titles were identified, of which 21 publications were eligible for inclusion in the final analysis. A total of 6901 mastectomy patients were included (range 25-1694). The mean LR proportion was 3.5%. Among the total of 351 LR lesions, 81.8% were in the subcutaneous tissue and the skin, while 16% were pectoral muscle recurrences. CONCLUSION: Local recurrences are mostly located within the subcutaneous tissue and the skin, assumed to result from unrecognized/subclinical tumour foci left behind after mastectomy, surgical implantation of tumour cells in the wound/scar and/or tumour emboli within the subcutaneous lymphatics. Pectoral muscle recurrences are less frequent and may be attributed to residual disease along the posterior surgical margin and/or lymphatic involvement.

Residual Glandular Breast Tissue After Mastectomy: A Systematic Review.

BACKGROUND: The goal of mastectomy is remove all of the glandular breast tissue (BGT) without compromising skin flaps viability. The purpose of this systematic review was to localize and/or estimate the amount of residual BGT (rBGT) after mastectomy and to identify factors that could be related to rBGT and/or residual disease. METHODS: We conducted a PubMed search. The report was subdivided according to the method used to evaluate the presence of rBGT. A total of 16 publications were included in our final report. Two main methods for identifying rBGT included imaging (i.e., MRI scan) and histological evaluation at the time of mastectomy. RESULTS: The rate of rBGT was reported in up to 100% of the patients and was found to be associated mainly with the type of surgical resection, indication, and surgeon's expertise. Residual breast tissue can be found in all areas of the remaining chest wall, mostly in the skin-flaps, and more frequently underneath the nipple-areola complex.

Adjuvant radiotherapy does not affect hemostasis.

Cancer is associated with increased risk of venous thromboembolic disease. Venous thromboembolic disease accounts for a substantial addition to morbidity and mortality rates in cancer patients and is the second leading cause of death in cancer patients, exceeded only by the underlying cancer. Only few previous studies have investigated the influence of radiotherapy on hemostasis and whether radiotherapy in itself causes an increased risk of venous thromboembolic disease. The aim was to investigate if adjuvant radiotherapy affects hemostasis after surgery and chemotherapy in patients with breast cancer. Radiotherapy consisted of either 40 Gy/15 fractions or 50 Gy/25 fractions. Blood samples were obtained from 39 consecutive women before and immediately after the first, the intermediate, and the final radiation fraction. Platelet function was measured using impedance aggregometry, and thrombin generation was determined in platelet-poor plasma using calibrated automated thrombogram. Furthermore, P-selectin, international normalized ratio, fibrinogen, activated partial thromboplastin time, coagulation factor VIII, von Willebrand factor, C-reactive protein (CRP), and soluble thrombomodulin were measured before and after radiation treatment. Platelet aggregation was within reference interval before initiation of radiotherapy, and remained unaffected during the radiation course. Neither serum P-selectin, thrombin generation, fibrinogen, coagulation factor VIII, von Willebrand factor, CRP nor thrombomodulin were substantially influenced by radiation treatment. The present study showed that radiotherapy did not affect hemostasis, neither by a single radiation dose nor during the radiation course, in early breast cancer patients receiving adjuvant radiotherapy.

Forty years of landmark trials undertaken by the Danish Breast Cancer Cooperative Group (DBCG) nationwide or in international collaboration.

BACKGROUND: Over the past 40 years the Danish Breast Cancer Cooperative Group (DBCG) has made significant contributions to improve outcome and to make treatment of patients with early breast cancer more tolerable through nationwide and international trials evaluating loco-regional and systemic treatments. These trials have been instrumental to establish standards for the treatment of early breast cancer. METHODS: The DBCG 82 trials had a global impact by documenting that the significant gain in loco-regional recurrence from postmastectomy radiation added to systemic therapy was associated with a reduction in distant recurrence and mortality in high-risk pre- and postmenopausal patients. The DBCG trials comparing breast conserving surgery and radiotherapy with mastectomy and more recently the trial of internal mammary node irradiation also had a major impact of practice. The trials initiated by the DBCG 40 years ago on tamoxifen and cyclophosphamide based chemotherapy became instrumental for the development of adjuvant systemic therapy not only due to their positive results but by sharing these important data with other members of the Early Breast Cancer Trialist' Collaborative Group (EBCTCG). Trials from the DBCG have also been important for highlighting the relative importance of anthracyclines and taxanes in the adjuvant setting. Furthermore, DBCG has made a major contribution to the development of aromatase inhibitors and targeted adjuvant treatment for human epidermal growth factor receptor 2 positive breast cancers. RESULTS: The substantial impact of these treatment improvements is illustrated by a 46.7% 10-year overall survival of early breast cancer patients treated in 1978-1987 compared to 71.5% for patients treated 2008-2012. CONCLUSIONS: The trials conducted and implemented by the DBCG appear to have a major impact on the substantial survival improvements in breast cancer.

DBCG hypo trial validation of radiotherapy parameters from a national data bank versus manual reporting.

INTRODUCTION: The current study evaluates the data quality achievable using a national data bank for reporting radiotherapy parameters relative to the classical manual reporting method of selected parameters. METHODS: The data comparison is based on 1522 Danish patients of the DBCG hypo trial with data stored in the Danish national radiotherapy data bank. In line with standard DBCG trial practice selected parameters were also reported manually to the DBCG database. Categorical variables are compared using contingency tables, and comparison of continuous parameters is presented in scatter plots. RESULTS: For categorical variables 25 differences between the data bank and manual values were located. Of these 23 were related to mistakes in the manual reported value whilst the remaining two were a wrong classification in the data bank. The wrong classification in the data bank was related to lack of dose information, since the two patients had been treated with an electron boost based on a manual calculation, thus data was not exported to the data bank, and this was not detected prior to comparison with the manual data. For a few database fields in the manual data an ambiguity of the parameter definition of the specific field is seen in the data. This was not the case for the data bank, which extract all data consistently. CONCLUSIONS: In terms of data quality the data bank is superior to manually reported values. However, there is a need to allocate resources for checking the validity of the available data as well as ensuring that all relevant data is present. The data bank contains more detailed information, and thus facilitates research related to the actual dose distribution in the patients.

Loco-regional morbidity after breast conservation and axillary lymph node dissection for early breast cancer with or without regional nodes radiotherapy, perspectives in modern breast cancer treatment: the Skagen Trial 1 is active.

BACKGROUND: Axillary lymph node dissection (ALND) and adjuvant radiotherapy (RT) in early breast cancer are associated with a risk of morbidity, including lymphedema and impaired shoulder mobility. The aim of this study was to evaluate loco-regional morbidity after breast conserving surgery (BCS), ALND, taxane-based chemotherapy and whole breast irradiation (WBI) with or without regional nodes RT. MATERIAL AND METHODS: Eligible patients had BCS and ALND from 2007 to 2012 followed by adjuvant taxane-based chemotherapy and if indicated, trastuzumab and endocrine treatment. The RT consisted of WBI and regional nodes RT in case of ≥ pN1 disease (group 1) and WBI only in case of pN0-1(mic) disease (group 2). The dose was 50 Gy in 25 fractions. The patients were invited to participate in a cross-sectional study evaluating morbidity. RESULTS: Of the 347 eligible patients, 277 patients (79%) accepted the invitation. Of these, 185 patients (67%) belonged to group 1 and 92 patients (33%) to group 2. The median time from RT to evaluation of morbidity was 3.3 years (group 1) and 4.3 years (group 2). In group 1, 34 patients (18%) and in group 2, 15 patients (16%) had ≥2 cm enlargement in circumference of ipsilateral upper or lower arm (p = .67). The frequence of impairment of ipsilateral shoulder abduction to ≤120° was 3% in both groups and of shoulder flexion to ≤120° was 1% and 2% (group 1 versus 2). No difference in patient reported outcome measure (PROM) data regarding heaviness or enlargement of ipsilateral upper and lower arm or mobility and sensory disturbances. CONCLUSION: The risk of lymphedema was low in patients after ALND and not related to use of regional nodes RT. Impairment of shoulder function was rare, and no differences in PROM were detected regarding use or not of regional nodes RT.

Setup error and motion during deep inspiration breath-hold breast radiotherapy measured with continuous portal imaging.

BACKGROUND: The position and residual motion of the chest wall of breast cancer patients during treatment in deep inspiration breath-hold (DIBH) were investigated. MATERIAL AND METHODS: The study included 58 left-sided breast cancer patients treated with DIBH three-dimensional (3D) conformal radiotherapy in 15 or 25 fractions. The DIBH levels were monitored using an external marker block placed on the chest, either shifted 5 cm to the right at the level of the xiphoid process (Group 1, 27 consecutive patients) or placed medially on the inferior part of the sternum (Group 2, 31 consecutive patients). At every third treatment fraction, continuous portal images were acquired. The time-resolved chest wall position during treatment was compared with the planned position to determine the inter-fraction setup errors and the intra-fraction motion of the chest wall. RESULTS: The DIBH compliance was 95% during both recruitment periods. A tendency of smaller inter-fraction setup errors and intra-fraction motion was observed for group 2 (medial marker block position). However, apart from a significantly reduced inter-field random shift (σ = 1.7 mm vs. σ = 0.9 mm, p = 0.005), no statistically significant differences between the groups were found. In a combined analysis, the group mean inter-fraction setup error was M = - 0.1 mm, with random and systematic errors of σ = 1.7 mm and Σ = 1.4 mm. The group mean inter-field shift was M = 0.0 (σ = 1.3 mm and Σ = 1.1 mm) and the group mean standard deviation of the intra-field motion was 0.5 mm. The absolute setup error had a maximum of 16.3 mm, exceeding 5 mm in 2.2% of the imaged fields. CONCLUSION: Compared to free breathing treatments, the primary benefit of the DIBH technique was the separation of the heart from the target rather than more accurate targeting. Despite a small gating window, occasional large errors in the chest wall position were observed for some patients, illustrating limitations of the external marker block as surrogate in a broad patient population.

Radiotherapy for breast cancer.

In early breast cancer, adjuvant moderately hypofractionated regimens are recommended for both whole breast, partial breast and locoregional irradiation which abbreviates the overall treatment time, as argued in this review. Gating is recommended as well as the use of a simultaneous integrated boost when indicated. A tangential field set-up is standard, however, for challenging cases volumetric modulated arc therapy techniques, or referral for proton therapy, may be considered. In the metastatic setting, stereotactic radiotherapy is a promising treatment option for oligometastatic disease.

Through Clinicians Eyes: Use of an In-consultation Patient Decision Aid in Radiation Treatment for Early Breast Cancer. A Qualitative Study.

INTRODUCTION: Shared decision making (SDM) has become a crucial element on the political agenda and represents a vital aspect of modern healthcare. However, successful implementation of SDM highly depends on the attitude of clinicians towards SDM. The overall aim of our study was to explore the experience of oncologists and nurses with SDM using the Decision Helper, an in-consultation decision aid, at four Danish radiotherapy departments. METHODS: Semi-structured interviews were conducted with 20 clinicians. The participants were selected using purposive sampling to include nurses and oncologists, male and female, with different levels of experience with SDM and clinical work. The analysis was a data-driven, iterative process with inductive coding of all interviews and meaning condensation. RESULTS: Two main themes emerged: "Using the Decision Helper changes the consultation" and "Change of attitude among Danish oncologists." Each of the two themes included four elaborative subthemes, which are reported with supporting citations in this paper. In brief, the use of SDM and the Decision Helper should ideally be adjusted to the individual patient and depends highly on the oncologist. The participants described ambitions towards "making the right decision for this patient at this time." The healthcare system, however, has pitfalls that may hinder SDM, e.g., rigid interpretation of guideline-based recommendations. CONCLUSION: Using an in-consultation Decision Helper has the potential for individualized, structured patient engagement in decision making. There is a need for patient decision aids in clinical guidelines to ensure patient engagement in decision making.

Shared decision making with breast cancer patients - does it work? Results of the cluster-randomized, multicenter DBCG RT SDM trial.

BACKGROUND AND PURPOSE: Shared decision making (SDM) is a patient engaging process advocated especially for preference-sensitive decisions, such as adjuvant treatment after breast cancer. An increasing call for patient engagement in decision making highlights the need for a systematic SDM approach. The objective of this trial was to investigate whether the Decision Helper (DH), an in-consultation patient decision aid, increases patient engagement in decisions regarding adjuvant whole breast irradiation. MATERIAL AND METHODS: Oncologists at four radiotherapy units were randomized to practice SDM using the DH versus usual practice. Patient candidates for adjuvant whole breast irradiation after breast conserving surgery for node-negative breast cancer were eligible. The primary endpoint was patient-reported engagement in the decision process assessed with the Shared Decision Making Questionnaire (SDM-Q-9) (range 0-100, 4 points difference considered clinical relevant). Other endpoints included oncologist-reported patient engagement, decisional conflict, fear of cancer recurrence, and decision regret after 6 months. RESULTS: Of the 674 included patients, 635 (94.2%) completed the SDM-Q-9. Patients in the intervention group reported higher level of engagement (median 80; IQR 68.9 to 94.4) than the control group (71.1; IQR 55.6 to 82.2; p < 0.0001). Oncologist-reported patient engagement was higher in the invention group (93.3; IQR 82.2 to 100) compared to control group (73.3; IQR 60.0 to 84.4) (p < 0.0001). CONCLUSION: Patient engagement in medical decision making was significantly improved with the use of an in-consultation patient decision aid compared to standard. The DH on adjuvant whole breast irradiation is now recommended as standard of care in the Danish guideline.

Legal termination of a pregnancy resulting from transplanted cryopreserved ovarian tissue due to cancer recurrence.

PURPOSE: To report on a woman who conceived naturally and had a normal intrauterine pregnancy following transplantation of frozen/thawed ovarian tissue but decided to have an early abortion due to recurrence of breast cancer. METHODS: The patient was diagnosed breast cancer and received antineoplastic treatment that forced her into premature ovarian insufficiency and infertility. Ovarian tissue cryopreserved prior to chemotherapy was transplanted following cancer treatment restoring fertility and regular menstrual cycles. RESULTS: The patient conceived 6 month after transplantation. However, she experienced recurrence of breast cancer and decided on legal termination of the pregnancy in the first trimester. DISCUSSION: The obtained pregnancy only 6 month following transplantation underlines the ability of the procedure. The recurrence occurred near the original site of the tumor and was most unlikely related to the transplantation. The activity of the transplanted tissue is likely to be destroyed by the renewed antineoplastic treatment she will receive. However, she still has the majority of one ovary cryostored and may later want to undergo additional transplantation to regain fertility or to have menstrual cycles back.