Locoregional breast radiotherapy including IMN: optimizing the dose distribution using an automated non-coplanar VMAT-technique.

BACKGROUND: Volumetric Modulated Arc Therapy (VMAT) offers better conformity, homogeneity and sparing of the heart and ipsilateral lung for locoregional radiotherapy in left-sided breast cancer compared to three-dimensional conformal radiotherapy (3D-CRT). However, conventional coplanar VMAT (cVMAT) can result in higher doses to the normal tissue on the contralateral side. This study investigates a non-coplanar VMAT-technique (ncVMAT) to mitigate this issue. MATERIAL AND METHODS: CT series of 20 left sided breast cancer patients were included for planning of locoregional breast radiotherapy including internal mammary nodes (IMN). Three treatment plans; 3D-CRT, cVMAT and ncVMAT, were generated for each patient with a prescription dose of 40.05 Gy in 15 fractions. Both VMAT-techniques consisted of a single arc in the axial plane, while ncVMAT included an additional arc in the sagittal plane. All plans were optimized to cover the clinical target volume (CTV) by 38.05 Gy for the breast and 36.05 Gy for lymph nodes, with as low as possible dose to organs at risk. RESULTS: Full CTV coverage was achieved for all plans. Both cVMAT and ncVMAT delivered more conformal and homogeneous target doses than 3D-CRT. Doses to the heart and ipsilateral lung were significantly lower with ncVMAT compared to both cVMAT and 3D-CRT. ncVMAT reduced doses to both the contralateral breast and lung compared to cVMAT and achieved levels similar to 3D-CRT for the contralateral breast and moderately higher doses for the contralateral lung. Delivery of high doses (>30 Gy) to the contralateral side was completely avoided with ncVMAT, contrary to the results for cVMAT and 3D-CRT. CONCLUSION: ncVMAT reduced doses to the heart and ipsilateral lung as compared to both cVMAT and 3D-CRT. All contralateral dose metrics were reduced with the novel ncVMAT technique compared to cVMAT, and the mean contralateral breast doses were similar to 3D-CRT.

A comparison of conventional and dynamic radiotherapy planning techniques for early-stage breast cancer utilizing deep inspiration breath-hold.

BACKGROUND: For breast cancer patients, radiotherapy increases the risk of cardiac disease. Conventional three-dimensional conformal radiotherapy (3D-CRT) in deep inspiration breath-hold (DIBH) has demonstrated substantial reduction in cardiac doses as compared to treatment in free breathing. The purpose of this treatment planning study is to investigate if dynamic techniques in combination with DIBH could improve the quality of the treatment plans and further reduce the doses to the heart and other organs at risk for early-stage breast cancer patients. MATERIAL AND METHODS: CT series in DIBH of 16 patients from a previous study were used. For each patient, treatment plans were generated with the following three techniques: 3D-CRT, tangential intensity-modulated radiotherapy (tIMRT) and volumetric modulated arc therapy with partial arcs (pVMAT). The treatment planning was performed focusing on planning target volume (PTV) coverage, V95% >95%. Dose-volume histograms were calculated and compared. Doses to the heart, left anterior descending (LAD) coronary artery, ipsilateral and contralateral lung as well as the contralateral breast (CB) were assessed. RESULTS: All plans fulfilled the criterion on PTV coverage. Compared to 3D-CRT, the dynamic plans obtained better dose homogeneity and conformity. The mean heart dose was similar for 3D-CRT and tIMRT, 1.3 and 1.1 Gy, respectively, but significantly higher for pVMAT, 1.6 Gy. The median V25 Gy to the heart was 0% for all techniques. The LAD doses were generally lower with the dynamic techniques. The mean doses to the ipsi- and contralateral lung and CB were similar with tIMRT and 3D-CRT but significantly higher with pVMAT. V20 Gy to the ipsilateral lung was significantly lower with tIMRT compared to 3D-CRT. CONCLUSION: tIMRT and 3D-CRT with DIBH are better techniques for sparing heart tissue and other organs at risk without compromising target coverage in early-stage breast cancer irradiation compared to VMAT.

Palliative pelvic radiotherapy for symptomatic rectal cancer - a prospective multicenter study.

BACKGROUND AND PURPOSE: Palliative pelvic radiotherapy (PPRT) is used to treat locally advanced rectal cancer (RC) although symptomatic effects and toxicities are poorly documented. Aims were to evaluate symptom severity, quality of life (QOL) and toxicity after PPRT. MATERIAL AND METHODS: Fifty-one patients with symptomatic primary or recurrent RC prescribed PPRT with fractions of 3 Gy to 30-39 Gy were included. Primary outcome was severity of target symptoms (TS) 12 weeks after PPRT. Pelvic symptom burden, toxicity, and QOL were assessed. Response was defined as patient-reported TS improvement or resolution. RESULTS: Pain (n = 24), rectal dysfunction (n = 16), and hematochezia (n = 9) were the most common TSs. Overall response rate among evaluable patients 12 weeks after PPRT was 28/33 (85%). Eighteen patients did not complete the study follow-up, 16 due to deteriorating health. TS responses were 10/13 (77%) for pain, 9/10 (90%) for rectal dysfunction, and 8/8 for hematochezia. Non-target pelvic symptom severity decreased and median QOL scores remained stable. There was no grade 4 toxicity. Median survival was nine months. CONCLUSIONS: In the majority of patients with symptomatic primary or recurrent RC, PPRT with 30-39 Gy contributes to pelvic symptom relief, with little toxicity. Patients prescribed PPRT of RC have limited life expectancy. Future studies should investigate simplification of PPRT.

Pulmonary function tests - an easy selection method for respiratory-gated radiotherapy in patients with left-sided breast cancer.

PURPOSE: The purpose of this study was to establish a feasible and convenient method for selection of the subset of patients with left-sided breast cancer for whom respiratory-gated radiotherapy (RT) would be necessary to meet the national recommendation regarding radiation dose to the heart. MATERIAL AND METHODS: The volume of heart receiving a dose equal to or higher than 25 Gy (V25Gy), the mean heart dose (Dmean) and total lung volume (TLV-CT) were obtained from treatment plans based on computer tomography (CT) series recorded during free breathing (FB), and the correlation between dose to the heart and TLV-CT was studied. Second, the correlation between TLV-CT and TLV defined from three pulmonary function tests (PFTs); spirometry, gas diffusion and plethysmograhy, was evaluated. RESULTS: Dose to the heart (V25Gy and Dmean) decreased with increasing TLV-CT. Pearson's correlation coefficient (r) for TLV-CT versus V25Gy and Dmean was equal (r = -0.809, p < 0.01) for patients planned for tangential breast RT only, and r = -0.853 and -0.861 (p < 0.01) for patients planned for loco-regional RT. Regression analysis showed good correlation between TLV-CT and TLV calculated from pulmonary function tests (R(2) ≥ 0.717, p < 0.01). CONCLUSION: TLV defined by routine pulmonary function tests can be used to identify the subset of left-sided breast cancer patients who require respiratory-gated RT.

Effects of scheduled exercise on cancer-related fatigue in women with early breast cancer.

While physical activity during cancer treatment is found beneficial for breast cancer patients, evidence indicates ambiguous findings concerning effects of scheduled exercise programs on treatment-related symptoms. This study investigated effects of a scheduled home-based exercise intervention in breast cancer patients during adjuvant chemotherapy, on cancer-related fatigue, physical fitness, and activity level. Sixty-seven women were randomized to an exercise intervention group (n = 33, performed strength training 3x/week and 30 minutes brisk walking/day) and a control group (n = 34, performed their regular physical activity level). Data collection was performed at baseline, at completion of chemotherapy (Post1), and 6-month postchemotherapy (Post2). Exercise levels were slightly higher in the scheduled exercise group than in the control group. In both groups, cancer-related fatigue increased at Post1 but returned to baseline at Post2. Physical fitness and activity levels decreased at Post1 but were significantly improved at Post2. Significant differences between intervention and control groups were not found. The findings suggest that generally recommended physical activity levels are enough to relief cancer-related fatigue and restore physical capacity in breast cancer patients during adjuvant chemotherapy, although one cannot rule out that results reflect diminishing treatment side effects over time.

Essential requirements for reporting radiation therapy in breast cancer clinical trials: An international multi-disciplinary consensus endorsed by the European Society for Radiotherapy and Oncology (ESTRO).

The European Society for Radiotherapy and Oncology (ESTRO) has advocated the establishment of guidelines to optimise precision radiotherapy (RT) in conjunction with contemporary therapeutics for cancer care. Quality assurance in RT (QART) plays a pivotal role in influencing treatment outcomes. Clinical trials incorporating QART protocols have demonstrated improved survival rates with minimal associated toxicity. Nonetheless, in routine clinical practice, there can be variability in the indications for RT, dosage, fractionation, and treatment planning, leading to uncertainty. In pivotal trials reporting outcomes of systemic therapy for breast cancer, there is limited information available regarding RT, and the potential interaction between modern systemic therapy and RT remains largely uncharted. This article is grounded in a consensus recommendation endorsed by ESTRO, formulated by international breast cancer experts. The consensus was reached through a modified Delphi process and was presented at an international meeting convened in Florence, Italy, in June 2023. These recommendations are regarded as both optimal and essential standards, with the latter aiming to define the minimum requirements. A template for a case report form (CRF) has been devised, which can be utilised by all clinical breast cancer trials involving RT. Optimal requirements include adherence to predefined RT planning protocols and centralised QART. Essential requirements aim to reduce variations and deviations from the guidelines in RT, even when RT is not the primary focus of the trial. These recommendations underscore the significance of implementing these practices in both clinical trials and daily clinical routines to generate high-quality data.

Regional radiotherapy after primary systemic treatment for cN+ breast cancer patients.

Pathologic complete response (pCR) after Primary Systemic Treatment (PST) for breast cancer is associated with excellent long-term outcomes. With increasing use of PST, the indication for regional nodal irradiation (RNI) has been challenged. The aim of this paper is to review the literature on de-escalation of RNI in patients treated with PST. We found no level 1 evidence on de-escalation of RNI after PST, but several randomized trials are ongoing. Consequently, current de-escalation strategies are based on cohort studies. These studies showed that in patients with low nodal tumour burden (LNTB) (≤3 suspicious nodes at imaging) prior to PST, and ypN0 based on Axillary Lymph Node Dissection (ALND), omission of RNI resulted in very low regional recurrences (RR) without compromising survival. In patients with LNTB and ypN0 based on Sentinel Lymph Node Biopsy (SLNB), omission of axillary treatment also resulted in low RR; the majority of these patients received local radiotherapy. Similarly, in patients with ypN1 (ALND) disease, omission of RNI resulted in low 5-year RR rates. Low RR-rates were also found in the few studies replacing ALND by RNI, in patients with ypN1 (SLNB) disease. In patients with high nodal tumour burden prior to PST and ypN0 (SLNB), replacing ALND by RNI also resulted in low RR. Due to the limited number of patients, these data should be interpreted with caution. We conclude that although level 1 evidence is lacking, de-escalation of RNI after PST can be considered in selected cases.

Protocol for the T-REX-trial: tailored regional external beam radiotherapy in clinically node-negative breast cancer patients with 1-2 sentinel node macrometastases - an open, multicentre, randomised non-inferiority phase 3 trial.

INTRODUCTION: Modern systemic treatment has reduced incidence of regional recurrences and improved survival in breast cancer (BC). It is thus questionable whether regional radiotherapy (RT) is still beneficial in patients with sentinel lymph node (SLN) macrometastasis. Postoperative regional RT is associated with an increased risk of arm morbidity, pneumonitis, cardiac disease and secondary cancer. Therefore, there is a need to individualise regional RT in relation to the risk of recurrence. METHODS AND ANALYSIS: In this multicentre, prospective randomised trial, clinically node-negative patients with oestrogen receptor-positive, HER2-negative BC and 1-2 SLN macrometastases are eligible. Participants are randomly assigned to receive regional RT (standard arm) or not (intervention arm). Regional RT includes the axilla level I-III, the supraclavicular fossa and in selected patients the internal mammary nodes. Both groups receive RT to the remaining breast. Chest-wall RT after mastectomy is given in the standard arm, but in the intervention arm only in cases of widespread multifocality according to national guidelines. RT quality assurance is an integral part of the trial.The trial aims to include 1350 patients between March 2023 and December 2028 in Sweden and Norway. Primary outcome is recurrence-free survival (RFS) at 5 years. Non-inferiority will be declared if outcome in the de-escalation arm is not >4.5 percentage units below that with regional RT, corresponding to an HR of 1.41 assuming 88% 5-year RFS with standard treatment. Secondary outcomes include locoregional recurrence, overall survival, patient-reported arm morbidity and health-related quality of life. Gene expression analysis and tumour tissue-based studies to identify prognostic and predictive markers for benefit of regional RT are included. ETHICS AND DISSEMINATION: The trial protocol is approved by the Swedish Ethics Authority (Dnr-2022-02178-01, 2022-05093-02, 2023-00826-02, 2023-03035-02). Results will be presented at scientific conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05634889.

Coping After Breast Cancer: Protocol for a Randomized Controlled Trial of Stress Management eHealth Interventions.

BACKGROUND: One-third or more of breast cancer survivors report stress and other psychological and physical complaints that can negatively impact their quality of life. Psychosocial stress management interventions, shown to mitigate the negative impact of these complaints, can now be delivered as accessible and convenient (for the patient and provider) eHealth interventions. In this randomized controlled trial (RCT), Coping After Breast Cancer (CABC), 2 modified versions of the stress management eHealth intervention program StressProffen were created: one with predominantly cognitive behavioral stress management content (StressProffen-cognitive behavioral therapy intervention [StressProffen-CBI]) and another with predominantly mindfulness-based stress management content (StressProffen-mindfulness-based intervention [StressProffen-MBI]). OBJECTIVE: This study aims to investigate the effects in breast cancer survivors of using StressProffen-CBI and StressProffen-MBI compared with a control group (treatment as usual). METHODS: Women diagnosed with breast cancer (stage I-III, unequivocally human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors) or ductal carcinoma in situ (DCIS) aged 21-69 years who completed the Cancer Registry of Norway-initiated health survey on quality of life are invited to the CABC trial about 7 months after diagnosis. Women who give consent to participate are randomized (1:1:1) to either the StressProffen-CBI, StressProffen-MBI, or control group. Both StressProffen interventions consist of 10 modules of stress management content delivered through text, sound, video, and images. The primary outcome is between-group changes in perceived stress at 6 months, assessed with Cohen 10-item Perceived Stress Scale. The secondary outcomes comprise changes in quality of life, anxiety, depression, fatigue, sleep, neuropathy, coping, mindfulness, and work-related outcomes approximately 1, 2, and 3 years after diagnosis. Long-term effects of the interventions on work participation, comorbidities, relapse or new cancers, and mortality will be assessed using data from national health registries. RESULTS: Recruitment is scheduled from January 2021 to May 2023. The goal is to recruit 430 participants (100 in each group). As of April 14 2023, 428 participants have been enrolled. CONCLUSIONS: The CABC trial is possibly the largest ongoing psychosocial eHealth RCT in patients with breast cancer. If 1 or both interventions prove to be effective in reducing stress and improving psychosocial and physical complains, the StressProffen eHealth interventions could be beneficial, inexpensive, and easily implementable tools for breast cancer survivors when coping with late effects after cancer and cancer treatments. TRIAL REGISTRATION: Clinicaltrials.gov NCT04480203; https://clinicaltrials.gov/ct2/show/NCT04480203. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47195.

Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer.

INTRODUCTION: Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNA-damaging chemotherapy in breast cancer. ATM (Ataxia Telangiectasia Mutated protein) is the key activator of p53 and Chk2 in response to genotoxic stress. Here, we sought to evaluate ATM's potential role in resistance to chemotherapy. METHODS: We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status. RESULTS: While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5). CONCLUSIONS: Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.

Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival.

INTRODUCTION: Presence of disseminated tumor cells (DTCs) in bone marrow (BM) and circulating tumor cells (CTC) in peripheral blood (PB) predicts reduced survival in early breast cancer. The aim of this study was to determine the presence of and alterations in DTC- and CTC-status in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy (NACT) and to evaluate their prognostic impact. METHODS: Bone marrow and peripheral blood were collected before NACT (BM1: n = 231/PB1: n = 219), at surgery (BM2: n = 69/PB2: n = 71), and after 12 months from start of NACT (BM3: n = 162/PB3: n = 141). Patients were included from 1997 to 2003 and followed until 2009 (or ten years follow-up). DTC- and CTC-status were determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. The prognostic significance of DTCs/CTCs was assessed by univariate and multivariate Cox-regression analyses. RESULTS: Before NACT, DTCs and CTCs were detected in 21.2% and 4.9% of the patients, respectively. At surgery, 15.9% and 1.4% had DTC- and CTC-presence, compared to 26.5% and 4.3% at 12 months from start of NACT. Of patients for whom DTC results both before NACT and at 12 months were available, concordant results were observed in 68%, and 14 out of 65 had positive DTC-status at both time points. Presence of ≥ 1 DTC 12 months from start of NACT, but not at other time points, predicted reduced disease-free survival (DFS; HR 2.3, p = 0.003), breast cancer-specific survival (BCSS; HR 3.0, p < 0.001) and overall survival (OS; HR 2.8, p < 0.001). Before NACT, presence of ≥ 3 DTCs was also associated with unfavorable outcome, and reduced BCSS was observed for CTC-positive patients (HR 2.2, p = 0.046). In multivariate analysis, DTC status (

Disseminated tumor cells as selection marker and monitoring tool for secondary adjuvant treatment in early breast cancer. Descriptive results from an intervention study.

BACKGROUND: Presence of disseminated tumor cells (DTCs) in bone marrow (BM) after completion of systemic adjuvant treatment predicts reduced survival in breast cancer. The present study explores the use of DTCs to identify adjuvant insufficiently treated patients to be offered secondary adjuvant treatment intervention, and as a surrogate marker for therapy response. METHODS: A total of 1121 patients with pN1-3 or pT1c/T2G2-3pN0-status were enrolled. All had completed primary surgery and received 6 cycles of anthracycline-containing chemotherapy. BM-aspiration was performed 8-12 weeks after chemotherapy (BM1), followed by a second BM-aspiration 6 months later (BM2). DTC-status was determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. If DTCs were present at BM2, docetaxel (100 mg/m², 3qw, 6 courses) was administered, followed by DTC-analysis 1 month (BM3) and 13 months (BM4) after the last docetaxel infusion. RESULTS: Clinical follow-up (FU) is still ongoing. Here, the descriptive data from the study are presented. Of 1085 patients with a reported DTC result at both BM1 and BM2, 94 patients (8.7%) were BM1 positive and 83 (7.6%) were BM2 positive. The concordance between BM1 and BM2 was 86.5%. Both at BM1 and BM2 DTC-status was significantly associated with lobular carcinomas (p = 0.02 and p = 0.03, respectively; chi-square). In addition, DTC-status at BM2 was also associated with pN-status (p = 0.009) and pT-status (p = 0.03). At BM1 28.8% and 12.8% of the DTC-positive patients had ≥2 DTCs and ≥3 DTCs, respectively. At BM2, the corresponding frequencies were 47.0% and 25.3%. Of 72 docetaxel-treated patients analyzed at BM3 and/or BM4, only 15 (20.8%) had persistent DTCs. Of 17 patients with ≥3 DTCs before docetaxel treatment, 12 patients turned negative after treatment (70.6%). The change to DTC-negativity was associated with the presence of ductal carcinoma (p = 0.009). CONCLUSIONS: After docetaxel treatment, the majority of patients experienced disappearance of DTCs. As this is not a randomized trial, the results can be due to effects of adjuvant (docetaxel/endocrine/trastuzumab) treatment and/or limitations of the methodology. The clinical significance of these results awaits mature FU data, but indicates a possibility for clinical use of DTC-status as a residual disease-monitoring tool and as a surrogate marker of treatment response. TRIAL REGISTRATION: Clin Trials Gov NCT00248703.

Radiation during deep inspiration allows loco-regional treatment of left breast and axillary-, supraclavicular- and internal mammary lymph nodes without compromising target coverage or dose restrictions to organs at risk.

BACKGROUND AND PURPOSE: Loco-regional radiotherapy of left-sided breast cancer represents a treatment planning challenge when the internal mammary chain (IMC) lymph nodes are included in the target volume. This treatment planning study evaluates the reduction in cardiopulmonary doses when radiation is given during deep inspiration breath-hold (DIBH). This was achieved without compromising dose coverage to the planning target volume (PTV). PATIENTS AND METHODS: Seventeen patients with early breast cancer, referred for adjuvant radiotherapy, were included. For each patient two computed tomography (CT)-scans were acquired; the first during free breathing (FB) and the second during DIBH. The scans were monitored by the Varian RPM respiratory gating system. Audio-visual guidance was used. The treatment planning of the two CT studies was performed focusing on good coverage (V95% > 98%) of the PTV. Doses to the heart, left anterior descending (LAD) coronary artery, lungs and contralateral breast were assessed. RESULTS: With equal PTV coverage, average mean heart dose was reduced from 6.2 Gy to 3.1 Gy in DIBH plans as compared to FB. Average volume receiving 25 Gy or more (V25Gy) was reduced from 6.7% to 1.2%, and the number of patients with V25Gy > 5% was reduced from 8 to 1 utilizing DIBH. The average mean dose to the LAD coronary artery was reduced from 25.0 Gy to 10.9 Gy. The average ipsilateral lung volume receiving 20 Gy or more (V20Gy) was reduced from 44.5% to 32.7% with DIBH. In 11 of the DIBH plans V20Gy was lower than 35%, in accordance with national guidelines, while none of the FB plans fulfilled this recommendation. CONCLUSION: Respiratory gated radiotherapy during DIBH is a suitable technique for loco-regional breast irradiation even when IMC lymph nodes are included in the PTV. Cardiopulmonary doses are considerably decreased for all dose levels without compromising the dose coverage to PTV.

Cardiac and pulmonary dose reduction for tangentially irradiated breast cancer, utilizing deep inspiration breath-hold with audio-visual guidance, without compromising target coverage.

BACKGROUND AND PURPOSE: cardiac disease and pulmonary complications are documented risk factors in tangential breast irradiation. Respiratory gating radiotherapy provides a possibility to substantially reduce cardiopulmonary doses. This CT planning study quantifies the reduction of radiation doses to the heart and lung, using deep inspiration breath-hold (DIBH). PATIENTS AND METHODS: seventeen patients with early breast cancer, referred for adjuvant radiotherapy, were included. For each patient two CT scans were acquired; the first during free breathing (FB) and the second during DIBH. The scans were monitored by the Varian RPM respiratory gating system. Audio coaching and visual feedback (audio-visual guidance) were used. The treatment planning of the two CT studies was performed with conformal tangential fields, focusing on good coverage (V(95)>98%) of the planning target volume (PTV). Dose-volume histograms were calculated and compared. Doses to the heart, left anterior descending (LAD) coronary artery, ipsilateral lung and the contralateral breast were assessed. RESULTS: compared to FB, the DIBH-plans obtained lower cardiac and pulmonary doses, with equal coverage of PTV. The average mean heart dose was reduced from 3.7 to 1.7 Gy and the number of patients with >5% heart volume receiving 25 Gy or more was reduced from four to one of the 17 patients. With DIBH the heart was completely out of the beam portals for ten patients, with FB this could not be achieved for any of the 17 patients. The average mean dose to the LAD coronary artery was reduced from 18.1 to 6.4 Gy. The average ipsilateral lung volume receiving more than 20 Gy was reduced from 12.2 to 10.0%. CONCLUSION: respiratory gating with DIBH, utilizing audio-visual guidance, reduces cardiac and pulmonary doses for tangentially treated left sided breast cancer patients without compromising the target coverage.

Dose evaluation and risk estimation for secondary cancer in contralateral breast and a study of correlation between thorax shape and dose to organs at risk following tangentially breast irradiation during deep inspiration breath-hold and free breathing.

PURPOSE: To assess the impact of using breathing adapted radiotherapy on contralateral breast (CB) dose, to relate the thorax shape with the dose to the organs at risk (OARs) and to predict the risk for induced malignancies in CB using linear and non-linear models, following tangential irradiation of breast. MATERIAL AND METHODS: Sixteen patients with stage I-II breast cancer treatment planned with tangential fields using deep inspiration breath hold (DIBH) and free breathing (FB) techniques were included in this analysis. The dose results mainly based on DVH analysis were compared. Four parameters were defined to describe thoracic shape. Excess relative risk (ERR) for cancer induction in CB, employing linear and non-linear models was calculated. RESULTS: Average CB volumes exposed to a dose of 1 Gy is 1.3 times higher in DIBH plans than in FB plans. No significant difference in average V3Gy and V5Gy for DIBH and FB plans is observed. The average mean CB dose for DIBH and FB plans is 0.33 and 0.28 Gy, respectively. No correlation between thorax shape parameters and mean OARs dose is observed. The estimated average mean ERR with linear model is lower in FB plans (0.12) than for the DIBH plans (0.14). The estimated ERR with non-linear model is 0.14 for DIBH plans and 0.15 for FB plans. CONCLUSION: No significant difference in CB dose between DIBH and FB plans is observed. The four thorax shape parameters defined in this study can not be related to the dose at OARs using DIBH and FB radiation techniques. The ERR estimates for secondary CB cancer are nearly the same for FB and DIBH planning when using a linear and non-linear risk prediction models.

Low Z-4OHtam concentrations are associated with adverse clinical outcome among early stage premenopausal breast cancer patients treated with adjuvant tamoxifen.

Low steady-state levels of active tamoxifen metabolites have been associated with inferior treatment outcomes. In this retrospective analysis of 406 estrogen receptor-positive breast cancer (BC) patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z-endoxifen and Z-4-hydroxy-tamoxifen (Z-4OHtam), with treatment outcomes in an independent cohort of BC patients. Among all patients, metabolite levels did not affect survival. However, in the premenopausal subgroup receiving tamoxifen alone (n = 191) we confirmed an inferior BC -specific survival in patients with the previously described serum concentration threshold of Z-4OHtam ≤ 3.26 nm (HR = 2.37, 95% CI = 1.02-5.48, P = 0.039). The 'dose-response' survival trend in patients categorized to ordinal concentration cut-points of Z-4OHtamoxifen (≤ 3.26, 3.27-8.13, > 8.13 nm) was also replicated (P-trend log-rank = 0.048). Z-endoxifen was not associated with outcome. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and BC outcome in an independent patient cohort. Premenopausal patients receiving 5-year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness.

Clinical oncology module for the ESTRO core curriculum.

INTRODUCTION: Clinical oncologists are physicians with the competencies to manage cancer patients through the entire disease pathway combining the competencies of radiation and medical oncologists. The 4th edition of the European Society for Radiotherapy and Oncology Core Curriculum for Radiation Oncology/Radiotherapy (ESTRO curriculum) has received wide support by the clinical oncology community. The aim was to develop a clinical oncology module that could be combined with the ESTRO curriculum to enable clinical oncology trainees to follow a single curriculum. MATERIALS AND METHODS: A range of stakeholders including National Society representatives, an oncologist from a low- middle-income country, and a recently appointed specialist, developed and commented on iterations of the curriculum. Further modifications were made by the ESTRO Education Council. RESULTS: The module is based on the CanMEDS 2015 framework and identifies 20 enabling competencies in the Medical Expert role that are required in addition to the ESTRO curriculum for the training of clinical oncologists. Recommendations are made for the levels of Entrustable Professional Activities (EPAs) to be attained by the end of training. CONCLUSIONS: The Clinical Oncology module, when combined with the ESTRO curriculum, covers the entire cancer pathway rather than being modality specific. It is hoped it will aid in the development of comparable standards of training in clinical oncology across Europe and may also have utility in low- and middle-income countries as well as providing a single curriculum for trainees.

[Recurrence and survival after breast-conserving treatment of breast cancer]. / Residiv og overlevelse etter brystbevarende behandling av brystkreft.

BACKGROUND: The objective of this retrospective study was to determine, within one institution, local relapse rate and survival for women with early-stage breast cancer treated with breast-conserving surgery followed by radiotherapy. MATERIAL AND METHODS: All women with infiltrating early-stage breast cancer who underwent post-operative whole breast irradiation at our institution in the period 14.06.99-8.03.2002 were included in the study. A CT-based 3D dose calculation was performed in all patients. RESULTS: 222 women received 50 Gy whole-breast irradiation after breast-conserving surgery in the study period. 51 patients received adjuvant systemic therapy according to national guidelines. Median age at diagnosis was 59 years (34-82 years). Median tumour size was 12 mm (1-30 mm) and 86.5 % of the patients were N0. During a follow-up (median) of 96 months (28-111 months), local recurrence was observed in three of 222 patients (1.4 %; 95 % CI [0.5-4.4 %]) in the ipsilateral breast. The estimated 8-year breast-cancer specific survival was 95 % and total survival was 90 %. INTERPRETATION: Our data demonstrate excellent local disease control in women with low-risk early-stage breast cancer (about 25 % were on adjuvant systemic therapy) who undergo breast-conserving surgery and 50 Gy whole-breast irradiation.

Hypofractionated Versus Standard Fractionated Radiotherapy in Patients With Early Breast Cancer or Ductal Carcinoma In Situ in a Randomized Phase III Trial: The DBCG HYPO Trial.

PURPOSE: Given the poor results using hypofractionated radiotherapy for early breast cancer, a dose of 50 Gy in 25 fractions (fr) has been the standard regimen used by the Danish Breast Cancer Group (DBCG) since 1982. Results from more recent trials have stimulated a renewed interest in hypofractionation, and the noninferiority DBCG HYPO trial (ClincalTrials.gov identifier: NCT00909818) was designed to determine whether a dose of 40 Gy in 15 fr does not increase the occurrence of breast induration at 3 years compared with a dose of 50 Gy in 25 fr. PATIENTS AND METHODS: One thousand eight hundred eighty-two patients > 40 years of age who underwent breast-conserving surgery for node-negative breast cancer or ductal carcinoma in situ (DCIS) were randomly assigned to radiotherapy at a dose of either 50 Gy in 25 fr or 40 Gy in 15 fr. The primary end point was 3-year grade 2-3 breast induration assuming noninferiority regarding locoregional recurrence. RESULTS: A total of 1,854 consenting patients (50 Gy, n = 937; 40 Gy, n = 917) were enrolled from 2009-2014 from eight centers. There were 1,608 patients with adenocarcinoma and 246 patients with DCIS. The 3-year rates of induration were 11.8% (95% CI, 9.7% to 14.1%) in the 50-Gy group and 9.0% (95% CI, 7.2% to 11.1%) in the 40-Gy group (risk difference, -2.7%; 95% CI, -5.6% to 0.2%; P = .07). Systemic therapies and radiotherapy boost did not increase the risk of induration. Telangiectasia, dyspigmentation, scar appearance, edema, and pain were detected at low rates, and cosmetic outcome and patient satisfaction with breast appearance were high with either no difference or better outcome in the 40-Gy cohort compared with the 50-Gy cohort. The 9-year risk of locoregional recurrence was 3.3% (95% CI, 2.0% to 5.0%) in the 50-Gy group and 3.0% (95% CI, 1.9% to 4.5%) in the 40-Gy group (risk difference, -0.3%; 95% CI, -2.3% to 1.7%). The 9-year overall survival was 93.4% (95% CI, 91.1% to 95.1%) in the 50-Gy group and 93.4% (95% CI, 91.0% to 95.2%) in the 40-Gy group. The occurrence of radiation-associated cardiac and lung disease was rare and not influenced by the fractionation regimen. CONCLUSION: Moderately hypofractionated breast irradiation of node-negative breast cancer or DCIS did not result in more breast induration compared with standard fractionated therapy. Other normal tissue effects were minimal, with similar or less frequent rates in the 40-Gy group. The 9-year locoregional recurrence risk was low.

The expression of p53, bcl-2, bax, fas and fasL in the primary tumour and lymph node metastases of breast cancer.

PURPOSE. It is unknown to what extent lymph node metastases differ from primary tumours of breast cancer. Our aim was to investigate the similarity between primary breast tumours and the matching lymph node metastases in 59 breast cancer patients. EXPERIMENTAL DESIGN. Immunohistochemical stainings of p53, bax, bc-l2, fas and fasL were performed in primary tumours and the parallel lymph node metastases. RESULTS. When using a cut point of 10%, the concordance between primary tumours and parallel lymph node metastases in the expression of p53 was 85%, bcl-2 79%, bax 69%, fas 59% and fasL 43%. In most tumours the staining status of p53, bcl-2 and bax in the primary tumour and the corresponding lymph node did not change more than 20%. However, these variables could fluctuate in both directions. In 15-25% of the cases, nodal expression was more than 20% lower than in the primary tumours, while in 10-17% of the cases, nodal expression was more than 20% higher than in the primary tumours. In half of the tumours, fas status did not change. Most fasL positive tumours lost positivity in the lymph node metastases or showed positively staining cancer cells only in the peripheral region of the node. A phenotype analysis of combined information of tumour fas/tumour fasL/nodal fas/nodal fasL expression (+/ - ) was assessed. The most frequently observed phenotype was tumour fas - /tumour fasL + /nodal fas - /nodal fasL- (22% of the tumours), although almost all combinations were seen. CONCLUSIONS. The expression of p53, bax, bcl - 2, fas and fasL is not maintained in the matching lymph node metastases of breast cancer. Large studies comparing the expression of relevant tumour biology factors in primary tumours and parallel lymph node metastases and their impact on therapy outcome, especially in the adjuvant setting, are warranted.