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The EORTC 22881-10882 trial in 5178 conservatively treated early breast cancer patients showed that a 16 Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. To investigate predictors for the long-term risk of fibrosis, Cox regression models of the time to moderate or severe fibrosis were developed on a random set of 1797 patients with and 1827 patients without a boost, and validated in the remaining set. The median follow-up was 10.7 years. The risk of fibrosis significantly increased (P < 0.01) with increasing maximum whole breast irradiation (WBI) dose and with concomitant chemotherapy, but was independent of age. In the boost arm, the risk further increased (P < 0.01) if patients had post-operative breast oedema or haematoma, but it decreased (P < 0.01) if WBI was given with >6 MV photons. The c-index was around 0.62. Nomograms with these factors are proposed to forecast the long-term risk of moderate or severe fibrosis. [ABSTRACT FROM AUTHOR]

The EORTC 22922/10925 trial aimed to investigate the impact on overall survival (OS) of elective internal mammary and medial supraclavicular (IM-MS) radiation therapy (RT) in breast cancer stage I-III. Surgery for the primary tumour and axillary lymph nodes, chest wall RT, boost RT after whole breast RT in breast conserving therapy (BCT), RT to operated axilla, and systemic therapy were per physician's preference. The aim of the current analysis is to assess breast cancer outcomes according to different locoregional and systemic therapy used in the trial., Material/methods: Data with a median follow-up of 15.7 years were extracted from the trial's case report forms. Kaplan-Meier curves of disease-free and OS and cumulative incidence curves of breast cancer events were produced. An exploratory analysis of the effect of the type of locoregional and systemic therapy on breast cancer outcomes was conducted using the Cox model or the Fine & Gray model accounting for competing risks, both models being adjusted for baseline patient and disease characteristics and treatment. The significance level was set at 5 %, 2-sided., Results: Of the 4,004 patients included, 625 (16%) did not receive any postoperative systemic therapy, 1,185 (30%) received endocrine therapy only, 994 (25%) chemotherapy only, and 1,200 (30%) both chemotherapy and endocrine therapy, without differences between the randomisation arms. Administration and type of therapy was associated with age, menopausal status, clinical T- and N-stage and ER status (p < 0.0001). Local control was better with mastectomy (with/without postmastectomy RT) as compared to BCT, but mastectomy was associated with more distant metastasis (DM) as first event. Similarly, DM as first event occurred more in the BCT group that received a boost as compared to no boost and in those who received RT to the lower axillary level. IM-MS RT reduced significantly regional recurrences and improved disease-free survival in a sensitivity stratified analysis. OS was worse with mastectomy as compared to BCT and with irradiation of the axilla but better with sentinel node dissection and adjuvant combined chemo and hormonal therapy., Conclusion: Different components of therapy influenced the site of first event. IM-MS RT improved outcomes in different breast cancer outcomes were most probably related that the group were balanced due to the trial arms and stratification methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes., Design: Systematic review and meta-analysis., Data Sources: Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023)., Study Selection: Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions)., Data Extraction: Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration's tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively., Data Synthesis: Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran's Q test and I 2 statistic. Network meta-analysis was used to integrate all available evidence., Main Outcome Measures: The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics., Results: From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF., Conclusions: MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings., Systematic Review Registration: PROSPERO CRD42023460249., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; IC has received consulting fees from Pfizer, Novartis, Eli Lilly, Seagen, Gilead, Astra Zeneca, Daiichi Sankyo, and Menarini StemLine and is a clinical board member of the European Society for Radiotherapy and Oncology (unpaid); JQC has received funding from the Canadian Institutes of Health Research and honorariums from Roche, Pfizer, Novartis, AstraZeneca, Well Doc Alberta, Merck, La Roche-Posay, Knight, Seagen, Oncology Education, and Gilead; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The purpose of this study is to evaluate the influence of the extent of surgery and radiation therapy (RT) on the rates and sites of local (LR) and regional recurrences (RR) in the EORTC 22922/10925 trial., Patients and Methods: All data were extracted from the trial's individual patients' case report forms (CRF) and analysed with a median follow-up of 15.7 years. Cumulative incidence curves were produced for LR and RR accounting for competing risks: an exploratory analysis of the effect of the extent of surgical and radiation treatments on LR rate was conducted using the Fine & Gray model accounting for competing risks and adjusted for baseline patient and disease characteristics. The significance level was set at 5%, 2-sided. Frequency tables were used to describe the spatial location of LR and RR., Results: Out of 4004 patients included in the trial, 282 (7%) patients experienced LR and 165 (4.1%) RR, respectively. Cumulative incidence rate of LR at 15 years was lower after mastectomy (3.1%) compared to BCS + RT (7.3%) (F&G: HR (Hazard Ratio) = 0.421, 95%CI = 0.282-0.628, p-value < 0.0001). LR were similar up to 3 years for both mastectomy and BCS but continued to occur at a steady rate for BCS + RT, only. The spatial location of the recurrence was related to the locoregional therapy applied and the absolute gain of RT correlated to stage of disease and extent of surgery., Conclusions: The extent of locoregional therapies impacts significantly on LR and RR rates and spatial location., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. None of the authors has a conflict of interest related to this work]., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Objectives: To evaluate the representativeness of Dutch patients participating in the European Organization for Research and Treatment of Cancer EORTC boost-no-boost trial to the target breast cancer patient population., Methods: All female breast cancer patients diagnosed between 1989 and 1996, aged ≤70 years, treated with breast-conserving surgery and radiation therapy, were selected from the Netherlands Cancer Registry (NCR) and linked to the EORTC trial database. Baseline characteristics were compared between trial and non-trial participants, for the Dutch population and according to seven participating institutions. Kaplan-Meier curves and multivariable Cox regression were used to explore potential heterogeneity in overall survival between low, medium and high-volume institutes., Results: Overall, 20,880 patients were identified from the NCR: 2,445 of 2,602 (94%) trial participants could be linked, and 18,435 were treated outside the trial. Trial participants had similar age, morphology, topography, laterality and socioeconomic status as non-trial participants, but more often stage I (62.7% vs. 56.4%) tumours and less often adjuvant treatment (22.9% vs. 26.5%). Crude 20-year survival ranged from 52.5% to 57.4%, without significant differences in multivariable analyses., Conclusion: This case study showed that participants in the boost-no-boost trial well represented the Dutch target population. Data linkage comes with challenges, but can close the gap between research and clinical practice., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: The 15-year results of the EORTC 229922-10925 phase III trial showed a significant reduction in breast cancer mortality and breast cancer recurrences after internal mammary chain (IMC) and medio-supraclavicular irradiation. Unexpectedly, cardiac death was not increased, and the incidence of cardiac events did not differ between left- and right-sided cases, although target volume coverages and organ at risk doses were unknown. Therefore, a planning study was carried out comparing the past and the present, to eventually enable, thereafter, an increased therapeutic ratio of IMC irradiation., Materials and Methods: A planning study was carried out on target volume coverage and organ at risk doses for whole-breast irradiation (WBI) ± IMC comparing the results between two-dimensional radiotherapy (free-breathing), hybrid intensity-modulated radiotherapy (IMRT; breath-hold) and robust intensity-modulated proton therapy (IMPT; free-breathing) for 10 left-sided breast cancer cases. Two-dimensional radiotherapy consisted of two tangential wedged photon breast fields and mixed electron/photon beams for the IMC. Hybrid IMRT included two tangential photon breast fields (70%) complemented with IMRT (30%). IMPT plans were created using multi-field robust optimisation (5 mm set-up and 3% range uncertainties) with two (WBI) or three (WBI + IMC) beams., Results: Target volume dose objectives were met for hybrid IMRT and IMPT. For two-dimensional radiotherapy, target coverage was 97% and 83% for breast and IMC, respectively. The mean heart dose for WBI only was <2 Gy for all techniques. For WBI + IMC, heart doses (mean heart dose, mean left anterior descending region, volume of the heart receiving 5 Gy (V5) were significantly higher for two-dimensional radiotherapy when compared with contemporary techniques. The V5 left anterior descending region reduced from 100% (two-dimensional radiotherapy) to 70% and 20% for hybrid IMRT and IMPT, respectively., Conclusion: Contemporary radiotherapy techniques result in improved target volume coverage and significantly decreased heart doses for WBI + IMC radiotherapy. Hence, nowadays an increased therapeutic ratio of elective IMC irradiation may be anticipated., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Bolus serves as a tissue equivalent material that shifts the 95-100% isodose line towards the skin and subcutaneous tissue. The need for bolus for all breast cancer patients planned for postmastectomy radiation therapy (PMRT) has been questioned. The work was initiated by the faculty of the European SocieTy for Radiotherapy & Oncology (ESTRO) breast cancer courses and represents a multidisciplinary international breast cancer expert collaboration to optimize PMRT. Due to the lack of randomised trials evaluating the benefits of bolus, we designed a stepwise project to evaluate the existing evidence about the use of bolus in the setting of PMRT to achieve an international consensus for the indications of bolus in PMRT, based on the Delphi method., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Uncertainty about the benefit-risk ratio of regional lymph node irradiation led to varying clinical protocols. We investigated long-term late side effects after internal mammary and medial supraclavicular (IM-MS) lymph node irradiation to improve shared decision making., Methods: The multicenter European Organization for Research and Treatment of Cancer trial (ClinicalTrials.gov, NCT00002851) randomly assigned stage I-III breast cancer patients with involved axillary nodes and/or a medially located primary tumor. We analyzed late side effects both longitudinally at every follow-up and cross-sectionally at 5-year intervals. All statistical tests were 2-sided., Results: Between 1996 and 2004, 46 departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. Longitudinal follow-up data showed cumulative incidence rates at 15 years of 2.9% (95% confidence interval [CI] = 2.2% to 3.8%) vs 5.7% (95% CI = 4.7% to 6.9%) (P < .001) for lung fibrosis, 1.1% (95% CI = 0.7% to 1.7%) vs 1.9% (95% CI = 1.3% to 2.6%) (P = .07) for cardiac fibrosis, and 9.4% (95% CI = 8.0% to 10.8%) vs 11.1% (95% CI = 9.6% to 12.7%) (P = .04) for any cardiac disease when treated without or with IM-MS lymph node irradiation. There was no evidence for differences between left- and right-sided breast cancer (Wald χ2 test of treatment by breast side interaction, P = .33 and P = .35, for cardiac fibrosis and for any cardiac disease, respectively). The cumulative incidence probabilities of cross-sectionally reported side effects with a score of 2 or greater at 15 years were 0.1% (95% CI = 0.0% to 0.5%) vs 0.8% (95% CI = 0.4% to 1.4%) for pulmonary (P = .02), 1.8% (95% CI = 1.1% to 2.8%) vs 2.6% (95% CI = 1.8% to 3.7%) for cardiac (P = .15), and 0.0% (95% CI not evaluated) vs 0.1% (95% CI = 0.0% to 0.4%) for esophageal (P = .16), respectively. No difference was observed in the incidence of second malignancies, contralateral breast cancer, or cardiovascular deaths., Conclusions: The incidence of late pulmonary side effects was statistically significantly higher after IM-MS lymph node irradiation, as were some of the cardiac events, without a difference between left- and right-sided treatments. Absolute rates and differences were very low, without increased non-breast cancer-related mortality, even before introducing heart-sparing techniques., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: To promptly recognize and manage cardiovascular (CV) risk factors before, during, and after cancer treatment, decreasing the risk of cancer therapy-related cardiac dysfunction is crucial. After recent advances in breast cancer treatment, mortality rates from cancer have decreased, and the prevalence of survivors with a potentially higher CV disease risk has increased. Cardiovascular risks might be associated with the multimodal approach, including systemic therapies and breast radiotherapy (RT)., Observations: The heart disease risk seems to be higher in patients with tumors in the left breast, when other classic CV risk factors are present, and when adjunctive anthracycline-based chemotherapy is administered, suggesting a synergistic association. Respiratory control as well as modern RT techniques and their possible further refinement may decrease the prevalence and severity of radiation-induced heart disease. Several pharmacological cardioprevention strategies for decreasing cardiac toxic effects have been identified in several guidelines. However, further research is needed to ascertain the feasibility of these strategies in routine practice., Conclusions and Relevance: This review found that evidence-based recommendations are lacking on the modalities for and intensity of heart disease screening, surveillance of patients after RT, and treatment of these patients. A multidisciplinary and multimodal approach is crucial to guide optimal management.

Background: 10-year results from several studies showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. We present the scheduled 15-year analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, which aims to investigate the impact on overall survival of elective internal mammary and medial supraclavicular (IM-MS) irradiation., Methods: EORTC 22922/10925, a randomised, phase 3 trial done across 46 radiation oncology departments from 13 countries, included women up to 75 years of age with unilateral, histologically confirmed, stage I-III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumour. Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. Patients were randomly assigned (1:1) centrally using minimisation to receive IM-MS irradiation at 50 Gy in 25 fractions (IM-MS irradiation group) or no IM-MS irradiation (control group). Stratification was done for institution, menopausal status, site of the primary tumour within the breast, type of breast and axillary surgery, and pathological T and N stage. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival analysed according to the intention-to-treat principle. Secondary endpoints were disease-free survival, distant metastasis-free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after randomisation. This study is registered with ClinicalTrials.gov, NCT00002851., Findings: Between Aug 5, 1996, and Jan 13, 2004, we enrolled 4004 patients, of whom 2002 were randomly assigned to the IM-MS irradiation group and 2002 to the no IM-MS irradiation group. At a median follow-up of 15·7 years (IQR 14·0-17·6), 554 (27·7%) patients in the IM-MS irradiation group and 569 (28·4%) patients in the control group had died. Overall survival was 73·1% (95% CI 71·0-75·2) in the IM-MS irradiation group and 70·9% (68·6-72·9) in the control group (HR 0·95 [95% CI 0·84-1·06], p=0·36). Any breast cancer recurrence (24·5% [95% CI 22·5-26·6] vs 27·1% [25·1-29·2]; HR 0·87 [95% CI 0·77-0·98], p=0·024) and breast cancer mortality (16·0% [14·3-17·7] vs 19·8% [18·0-21·7]; 0·81 [0·70-0·94], p=0·0055) were lower in the IM-MS irradiation group than in the control group. No significant differences in the IM-MS irradiation group versus the control group were seen for disease-free survival (60·8% [95% CI 58·4-63·2] vs 59·9% [57·5-62·2]; HR 0·93 [95% CI 0·84-1·03], p=0·18), or distant metastasis-free survival (70·0% [67·7-72·2] vs 68·2% [65·9-70·3]; 0·93 [0·83-1·04], p=0·18). Causes of death between groups were similar., Interpretation: The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I-III breast cancer. However, this is not converted to improved overall survival., Funding: US National Cancer Institute, Ligue Nationale contre le Cancer, and KWF Kankerbestrijding., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: After 5 years of annual follow-up following breast cancer, Dutch guidelines are age based: annual follow-up for women <60 years, 60-75 years biennial, and none for >75 years. We determined how the risk of recurrence corresponds to these consensus-based recommendations and to the risk of primary breast cancer in the general screening population., Subjects, Materials, and Methods: Women with early-stage breast cancer in 2003/2005 were selected from the Netherlands Cancer Registry (n = 18,568). Cumulative incidence functions were estimated for follow-up years 5-10 for locoregional recurrences (LRRs) and second primary tumors (SPs). Risks were compared with the screening population without history of breast cancer. Alternative cutoffs for age were determined by log-rank tests., Results: The cumulative risk for LRR/SP was lower in women <60 years (5.9%, 95% confidence interval [CI] 5.3-6.6) who are under annual follow-up than for women 60-75 (6.3%, 95% CI 5.6-7.1) receiving biennial visits. All risks were higher than the 5-year risk of a primary tumor in the screening population (ranging from 1.4% to 1.9%). Age cutoffs <50, 50-69, and > 69 revealed better risk differentiation and would provide more risk-based schedules. Still, other factors, including systemic treatments, had an even greater impact on recurrence risks., Conclusion: The current consensus-based recommendations use suboptimal age cutoffs. The proposed alternative cutoffs will lead to a more balanced risk-based follow-up and thereby more efficient allocation of resources. However, more factors should be taken into account for truly individualizing follow-up based on risk for recurrence., Implications for Practice: The current age-based recommendations for breast cancer follow-up after 5 years are suboptimal and do not reflect the actual risk of recurrent disease. This results in situations in which women with higher risks actually receive less follow-up than those with a lower risk of recurrence. Alternative cutoffs could be a start toward risk-based follow-up and thereby more efficient allocation of resources. However, age, or any single risk factor, is not able to capture the risk differences and therefore is not sufficient for determining follow-up. More risk factors should be taken into account for truly individualizing follow-up based on the risk for recurrence., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era., Methods: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis., Results: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m 2 platinum dose administered (P trend  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure., Conclusions: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background and Purpose: The aim of this study was to assess the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on tumor response to preoperative chemoradiation for rectal cancer., Materials and Methods: Data on patients who received chemoradiation prior to surgery for rectal cancer between 2010 and 2015 were retrieved from linkage between the PHARMO Database Network, Dutch Pathology Registry and Netherlands Cancer Registry. Pathological complete response rates (pCR) were compared between patients who did or did not use ACEIs/ARBs during treatment. Multivariable analysis was performed using logistic regression., Results: Out of 345 patients, 92 patients (26.7%) used ACEIs/ARBs during treatment. Median age was 65 years (range 30-85). Older and male patients were more likely to use ACEIs/ARBs. pCR (ypT0N0) was observed in 17.4% of patients using ACEIs/ARBs compared to 14.6% of patients who did not use ACEIs/ARBs (p = 0.595). A good response (ypT0-1N0) was observed in 21.7% of ACEIs/ARBs patients vs. 19.4% of patients who did not use ACEIs/ARBs (p = 0.724). Multivariable analysis, taking into account background variables and co-medication, showed increased pCR in patients using beta-blockers (odds ratio 2.3, 95% confidence interval 1.0-5.4)., Conclusion: In this retrospective cohort, the use of ACEIs/ARBs was not associated with tumor response to preoperative chemoradiation in rectal cancer patients. Thereby, the suggested potentiating effect of ACEIS/ARBs could not be confirmed in our study. Further research could be directed to investigate a possible benefit of beta-blockers or other anti-hypertensive drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose Testicular cancer (TC) treatment increases risk of subsequent malignant neoplasms (SMNs). It is unknown whether changes in TC treatment over time have affected SMN risk. Methods Solid SMN risk was evaluated in a multicenter cohort comprising 5,848 1-year survivors treated for TC before age 50 years between 1976 and 2007. SMN incidence was compared with cancer incidence in the general population. Treatment-specific risks were assessed using multivariable regression in a case-cohort design. Results After a median follow-up of 14.1 years, 350 solid SMNs were observed, translating into a 1.8-fold (95% CI, 1.6-2.0) increased risk compared with general population rates. Solid SMN risk was increased in patients with seminoma and those with nonseminoma (standardized incidence ratio, 1.52 and 2.21, respectively). Patients with nonseminoma experienced increased risk of SMNs of the thyroid, lung, stomach, pancreas, colon, and bladder and of melanoma and soft tissue sarcoma, whereas those with seminoma experienced increased risk of SMNs of the small intestine, pancreas, and urinary bladder. The 25-year cumulative incidence of solid SMNs was 10.3% (95% CI, 9.0% to 11.6%). In multivariable analysis, platinum-based chemotherapy was associated with increased risk of a solid SMN (hazard ratio [HR], 2.40; 95% CI, 1.58 to 3.62), colorectal SMN (HR, 3.85; 95% CI, 1.67 to 8.92), and noncolorectal GI SMN (HR, 5.00; 95% CI, 2.28 to 10.95). Receipt of platinum 400 to 499 and ≥ 500 mg/m 2 increased solid SMN risk compared with surgery only (HR, 2.43; 95% CI, 1.40 to 4.23 and HR, 2.42; 95% CI, 1.50 to 3.90, respectively), whereas risk was not significantly increased with lower doses (HR, 1.75; 95% CI, 0.90 to 3.43). The HR of a GI SMN increased by 53% (95% CI, 26% to 80%) per 100 mg/m 2 of platinum-containing chemotherapy. The HR of an infradiaphragmatic SMN increased by 8% per Gray of radiation dose administered (95% CI, 6% to 9%; P < .001). Conclusion Radiotherapy and platinum-containing chemotherapy are associated with increased solid SMN risk, specifically with GI SMNs.

Purpose: Little is known about the occurrence, timing and prognostic factors for first and also subsequent local (LR), regional (RR) or distant (DM) breast cancer recurrence. As current follow-up is still consensus-based, more information on the patterns and predictors of subsequent recurrences can inform more personalized follow-up decisions., Methods: Women diagnosed with stage I-III invasive breast cancer who were treated with curative intent were selected from the Netherlands Cancer Registry (N = 9342). Extended Cox regression was used to model the hazard of recurrence over ten years of follow-up for not only site-specific first, but also subsequent recurrences after LR or RR., Results: In total, 362 patients had LR, 148 RR and 1343 DM as first recurrence. The risk of first recurrence was highest during the second year post-diagnosis (3.9%; 95% CI 3.5-4.3) with similar patterns for LR, RR and DM. Young age (<40), tumour size >2 cm, tumour grade II/III, positive lymph nodes, multifocality and no chemotherapy were prognostic factors for first recurrence. The risk of developing a second recurrence after LR or RR (N = 176) was significantly higher after RR than after LR (50 vs 29%; p < 0.001). After a second LR or RR, more than half of the women were diagnosed with a third recurrence., Conclusions: Although the risk of subsequent recurrence is high, absolute incidence remains low. Also, almost half the second recurrences are detected in the first year after previous recurrence and more than 80% are DM. This suggests that more intensive follow-up for early detection subsequent recurrence is not likely to be (cost-)effective.

Background: The Dutch guidelines advise to start radiation therapy (RT) within 5 weeks following breast-conserving surgery (BCS). However, much controversy exists regarding timing of RT. This study investigated its effect on 10-year disease-free survival (DFS) in a Dutch population-based cohort., Methods: All women diagnosed with primary invasive stage I-IIIA breast cancer in 2003 treated with BCS+RT were included. Two populations were studied. Population 1 excluded patients receiving chemotherapy before RT. Analyses were stratified for use of adjuvant systemic therapy (AST). Population 2 included patients treated with chemotherapy, and compared chemotherapy before (BCS-chemotherapy-RT) and after RT (BCS-RT-chemotherapy). DFS was estimated using multivariable Cox regression. Locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were secondary outcomes., Results: Population 1 (n=2759) showed better DFS and DMFS for a time interval of >55 than a time interval of <42 days. Patients treated with AST showed higher DFS for >55 days (hazards ratio (HR) 0.60 (95% confidence interval (CI): 0.38-0.94)) and 42-55 days (HR 0.64 (95% CI: 0.45-0.91)) than <42 days. Results were similar for DMFS, while timing did not affect LRRFS and OS. For patients without AST, timing was not associated with DFS, DMFS and LLRFS, but 10-year OS was significantly lower for 42-55 and >55 days compared to <42 days. In population 2 (n=1120), timing did not affect survival in BCS-chemotherapy-RT. In BCS-RT-chemotherapy, DMFS was higher for >55 than <42 days., Conclusions: Starting RT shortly after BCS seems not to be associated with a better long-term outcome. The common position that RT should start as soon as possible following surgery in order to increase treatment efficacy can be questioned.

Skin sparing mastectomy, a surgical procedure sparing a large portion of the overlying skin of the breast, and nipple-sparing mastectomy, sparing the whole nipple-areolar complex, are increasingly used, although their oncologic efficacy remains unclear. The aim of this study was to assess the radiation oncologists' opinions regarding the indications of radiation therapy (RT) after skin-sparing mastectomy and nipple-sparing mastectomy. Radiation oncology members of four national and international societies were invited to complete a questionnaire comprising of 22 questions to assess their opinions regarding RT indications in the context of skin-sparing and nipple-sparing mastectomy. A total of 298 radiation oncologists answered the questionnaire. 90.9% of respondents affirmed that breast cancer is one of their specializations. The majority declared that post-mastectomy RT is indicated for early-stage (stages I and II) breast cancer patients who present with risk factors for recurrence after skin-sparing or nipple-sparing mastectomy (87.2% and 80.2%, respectively). All suggested risk factors (tumor size, lymph node involvement, extracapsular extension, lymphovascular space invasion, positive surgical margins, triple negative tumor, multicentric tumor, and age) were considered as major elements (important or very important). There is no consensus regarding the necessity of evaluating residual breast tissue or the definition of residual breast tissue after mastectomy. All classic factors were considered as major elements, potentially influencing the decision to advice or not postoperative RT. Many uncertainties remain about the indications for RT after skin-sparing mastectomy or nipple-sparing mastectomy., (© 2016 Wiley Periodicals, Inc.)

Triple negative breast cancer refers to tumours lacking the expression of the three most used tumour markers, namely oestrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2). These cancers are known to carry a more dismal prognosis than the other molecular subtypes. Whether a more aggressive local-regional treatment is warranted or not in patients with triple-negative breast cancer is still a matter of debate. Indeed there remain a number of grey zones with respect to the optimization of the extent and the timing of surgery and radiation therapy (RT) in this patient population, also in consideration of the significant heterogeneity in biological behaviour and response to treatment identified for these tumours. The objective of this review is to provide an insight into the biological and clinical behaviour of triple-negative breast cancers and revisit the most recent advances in their management, focussing on local-regional treatments., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Up to 30% of patients who undergo radiation for intermediate- or high-risk localized prostate cancer relapse biochemically within 5 years. We assessed if biochemical disease-free survival (DFS) is improved by adding 6 months of androgen suppression (AS; two injections of every-3-months depot of luteinizing hormone-releasing hormone agonist) to primary radiotherapy (RT) for intermediate- or high-risk localized prostate cancer., Patients and Methods: A total of 819 patients staged: (1) cT1b-c, with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≥ 7, or (2) cT2a (International Union Against Cancer TNM 1997), with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread, with PSA ≤ 50 ng/mL, were centrally randomized 1:1 to either RT or RT plus AS started on day 1 of RT. Centers opted for one dose (70, 74, or 78 Gy). Biochemical DFS, the primary end point, was defined from entry until PSA relapse (Phoenix criteria) and clinical relapse by imaging or death of any cause. The trial had 80% power to detect hazard ratio (HR), 0.714 by intent-to-treat analysis stratified by dose of RT at the two-sided α = 5%., Results: The median patient age was 70 years. Among patients, 74.8% were intermediate risk and 24.8% were high risk. In the RT arm, 407 of 409 patients received RT; in the RT plus AS arm, 403 patients received RT plus AS and three patients received RT only. At 7.2 years median follow-up, RT plus AS significantly improved biochemical DFS (HR, 0.52; 95% CI, 0.41 to 0.66; P < .001, with 319 events), as well as clinical progression-free survival (205 events, HR, 0.63; 95% CI, 0.48 to 0.84; P = .001). In exploratory analysis, no statistically significant interaction between treatment effect and dose of RT could be evidenced (heterogeneity P = .79 and P = .66, for biochemical DFS and progression-free survival, respectively). Overall survival data are not mature yet., Conclusion: Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk cT1b-c to cT2a (with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread) prostatic carcinoma, treated by radiation., (© 2016 by American Society of Clinical Oncology.)

Background: Voluntary moderate deep inspiration breath-hold (vmDIBH) is widely used for left sided breast cancer patients. The purpose of this study was to investigate the usefulness of vmDIBH in local and locoregional radiation therapy (RT) of right-sided breast cancer., Materials and Methods: For fourteen right-sided breast cancer patients, 3D-conformal (3D-CRT) RT plans (i.e., forward IMRT) were calculated on free-breathing (FB) 3D-CRT(FB) and vmDIBHCT-scans, for local- as well as locoregional breast treatment, with and without internal mammary nodes (IMN). Dose volume parameters were compared., Results: For local breast treatment, no relevant reduction in mean lung dose (MLD) was found. For locoregional breast treatment without IMN, the average MLD reduced from 6.5 to 5.4 Gy (p < 0.005) for the total lung and from 11.2 to 9.7 Gy (p < 0.005) for the ipsilateral lung. For locoregional breast treatment with IMN, the average MLD reduced from 10.8 to 9.1 Gy (p < 0.005) for the total lung and from 18.7 to 16.2 Gy (p < 0.005) for the ipsilateral lung, whilea small reduction in mean heart dose of 0.4 Gy (p = 0.07) was also found., Conclusions: Breathing adapted radiation therapy in left-sided breast cancer patients is becoming widely introduced. As a result of the slight reduction in lung dose found for locoregional right-sided breast cancer treatment in this study, a slightly lower risk of pneumonitis and secondary lung cancer (in ever smoking patients) can be expected.In addition, for some patients the heart dose will also be reduced by more than 0.5 up to 2.6 Gy. We therefore suggest to also apply breath-hold for locoregional irradiation of right-sided breast cancer patients.

Background: Survivors of Hodgkin's lymphoma are at increased risk for treatment-related subsequent malignant neoplasms. The effect of less toxic treatments, introduced in the late 1980s, on the long-term risk of a second cancer remains unknown., Methods: We enrolled 3905 persons in the Netherlands who had survived for at least 5 years after the initiation of treatment for Hodgkin's lymphoma. Patients had received treatment between 1965 and 2000, when they were 15 to 50 years of age. We compared the risk of a second cancer among these patients with the risk that was expected on the basis of cancer incidence in the general population. Treatment-specific risks were compared within the cohort., Results: With a median follow-up of 19.1 years, 1055 second cancers were diagnosed in 908 patients, resulting in a standardized incidence ratio (SIR) of 4.6 (95% confidence interval [CI], 4.3 to 4.9) in the study cohort as compared with the general population. The risk was still elevated 35 years or more after treatment (SIR, 3.9; 95% CI, 2.8 to 5.4), and the cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4 to 51.5). The cumulative incidence of second solid cancers did not differ according to study period (1965-1976, 1977-1988, or 1989-2000) (P=0.71 for heterogeneity). Although the risk of breast cancer was lower among patients who were treated with supradiaphragmatic-field radiotherapy not including the axilla than among those who were exposed to mantle-field irradiation (hazard ratio, 0.37; 95% CI, 0.19 to 0.72), the risk of breast cancer was not lower among patients treated in the 1989-2000 study period than among those treated in the two earlier periods. A cumulative procarbazine dose of 4.3 g or more per square meter of body-surface area (which has been associated with premature menopause) was associated with a significantly lower risk of breast cancer (hazard ratio for the comparison with no chemotherapy, 0.57; 95% CI, 0.39 to 0.84) but a higher risk of gastrointestinal cancer (hazard ratio, 2.70; 95% CI, 1.69 to 4.30)., Conclusions: The risk of second solid cancers did not appear to be lower among patients treated in the most recent calendar period studied (1989-2000) than among those treated in earlier periods. The awareness of an increased risk of second cancer remains crucial for survivors of Hodgkin's lymphoma. (Funded by the Dutch Cancer Society.).

Introduction: We retrospectively investigated the possible influence of a simultaneous integrated boost (SIB), hypofractionation and oncoplastic surgery on cosmetic outcome in 125 patients with stage I-II breast cancer treated with breast conserving therapy (BCT)., Patients and Methods: The boost was given sequentially (55%) or by SIB (45%); fractionation was conventional (83%) or hypofractionated (17%); the surgical technique was a conventional lumpectomy (74%) or an oncoplastic technique (26%). We compared cosmetic results subjectively using a questionnaire independently completed by the patient and by the physician and objectively with the BCCT.core software. Independent-samples T-tests were used to compare outcome in different groups. Patients also completed the EORTC QLQ C30 and BR23., Results: Univariate analyses indicated no significant differences of the cosmetic results (P ≤ 0.05) for the type of boost or fractionation. However, the conventional lumpectomy group scored significantly better than the oncoplastic group in the BCCT.core evaluation, without a significant difference in the subjective cosmetic evaluation. Quality of life outcome was in favour of SIB, hypofractionation and conventional surgery., Conclusion: Our study indicates that the current RT techniques seem to be safe for cosmetic outcome and quality of life. Further investigation is needed to verify the possible negative influence of oncoplastic surgery on the cosmetic outcome and the quality of life as this technique is especially indicated for patients with an unfavourable tumour/breast volume ratio., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Trials failed to demonstrate additional value of completion axillary lymph node dissection in case of limited sentinel lymph node metastases in breast cancer patients undergoing breast conserving therapy. It has been suggested that the low regional recurrence rates in these trials might partially be ascribed to accidental irradiation of part of the axilla by whole breast radiation therapy, which precludes extrapolation of results to mastectomy patients. The aim of the randomized controlled BOOG 2013-07 trial is therefore to investigate whether completion axillary treatment can be safely omitted in sentinel lymph node positive breast cancer patients treated with mastectomy., Design: This study is designed as a non-inferiority randomized controlled multicentre trial. Women aged 18 years or older diagnosed with unilateral invasive clinically T1-2 N0 breast cancer who are treated with mastectomy, and who have a maximum of three axillary sentinel lymph nodes containing micro- and/or macrometastases, will be randomized for completion axillary treatment versus no completion axillary treatment. Completion axillary treatment can consist of completion axillary lymph node dissection or axillary radiation therapy. Primary endpoint is regional recurrence rate at 5 years. Based on a 5-year regional recurrence free survival rate of 98 % among controls and 96 % for study subjects, the sample size amounts 439 per arm (including 10 % lost to follow-up), to be able to reject the null hypothesis that the rate for study and control subjects is inferior by at least 5 % with a probability of 0.8. Results will be reported after 5 and 10 years of follow-up., Discussion: We hypothesize that completion axillary treatment can be safely omitted in sentinel node positive breast cancer patients undergoing mastectomy. If confirmed, this study will significantly decrease the number of breast cancer patients receiving extensive treatment of the axilla, thereby diminishing the risk of morbidity and improving quality of life, while maintaining excellent regional control and without affecting survival., Trial Registration: The BOOG 2013-07 study is registered in the register of ClinicalTrials.gov since April 10, 2014, Identifier: NCT02112682 .

Background: The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown., Methods: We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer., Results: Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest., Conclusions: In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).