Margreet Baaijens

Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial

BACKGROUND The EORTC 10801 trial compared breast-conserving therapy (BCT) with modified radical mastectomy (MRM) in patients with tumours 5 cm or smaller and axillary node negative or positive disease. Compared with BCT, MRM resulted in better local control, but did not affect overall survival or time to distant metastases. We report 20-year follow-up results. METHODS The EORTC 10801 trial was open for accrual between 1980 and 1986 in eight centres in the UK, the Netherlands, Belgium, and South Africa. 448 patients were randomised to BCT and 420 to MRM. Randomisation was done centrally, stratifying patients by institute, carcinoma stage (I or II), and menopausal status. BCT comprised of lumpectomy and complete axillary clearance, followed by breast radiotherapy and a tumour-bed boost. The primary endpoint was time to distant metastasis. This analysis was done on all eligible patients, as they were randomised. FINDINGS After a median follow-up of 22·1 years (IQR 18·5-23·8), 175 patients (42%) had distant metastases in the MRM group versus 207 (46%) in the BCT group. Furthermore, 506 patients (58%) died (232 [55%] in the MRM group and 274 [61%] in the BCT group). No significant difference was observed between BCT and MRM for time to distant metastases (hazard ratio 1·13, 95% CI 0·92-1·38; p=0·23) or for time to death (1·11, 0·94-1·33; 0·23). Cumulative incidence of distant metastases at 20 years was 42·6% (95% CI 37·8-47·5) in the MRM group and 46·9% (42·2-51·6) in the BCT group. 20-year overall survival was estimated to be 44·5% (95% CI 39·3-49·5) in the MRM group and 39·1% (34·4-43·9) in the BCT group. There was no difference between the groups in time to distant metastases or overall survival by age (time to distant metastases: <50 years 1·09 [95% CI 0·79-1·51] vs ≥50 years 1·16 [0·90-1·50]; overall survival <50 years 1·17 [0·86-1·59] vs ≥50 years 1·10 [0·89-1·37]). INTERPRETATION BCT, including radiotherapy, offered as standard care to patients with early breast cancer seems to be justified, since long-term follow-up in this trial showed similar survival to that after mastectomy. FUNDING European Organisation for Research and Treatment of Cancer (EORTC).

Re-irradiation and hyperthermia after surgery for recurrent breast cancer

PURPOSE Evaluation of efficacy and side effects of combined re-irradiation and hyperthermia electively or for subclinical disease in the management of locoregional recurrent breast cancer. METHODS AND MATERIALS Records of 198 patients with recurrent breast cancer treated with re-irradiation and hyperthermia from 1993 to 2010 were reviewed. Prior treatments included surgery (100%), radiotherapy (100%), chemotherapy (42%), and hormonal therapy (57%). Ninety-one patients were treated for microscopic residual disease following resection or systemic therapy and 107 patients were treated electively for areas at high risk for local recurrences. All patients were re-irradiated to 28-36Gy (median 32) and treated with 3-8 hyperthermia treatments (mean 4.36). Forty percent of the patients received concurrent hormonal therapy. Patient and tumor characteristics predictive for actuarial local control (LC) and toxicity were studied in univariate and multivariate analysis. RESULTS The median follow-up was 42months. Three and 5year LC-rates were 83% and 78%. Mean of T90 (tenth percentile of temperature distribution), maximum and average temperatures were 39.8°C, 43.6°C, and 41.2°C, respectively. Mean of the cumulative equivalent minutes (CEM43) at T90 was 4.58min. Number of previous chemotherapy and surgical procedures were most predictive for LC. Cumulative incidence of grade 3 and 4 late toxicity at 5years was 11.9%. The number of thermometry sensors and depth of treatment volume were associated with acute hyperthermia toxicity. CONCLUSIONS The combination of re-irradiation and hyperthermia results in a high LC-rate with acceptable toxicity.

Local control rate after the combination of re-irradiation and hyperthermia for irresectable recurrent breast cancer: Results in 248 patients

BACKGROUND AND PURPOSE Randomized studies have shown that adding hyperthermia (HT) to re-irradiation (re-RT) improves treatment outcome for patients with breast cancer recurrences. We evaluated the efficacy and side effects in patients treated with re-RT and HT for irresectable locoregional breast cancer recurrences. MATERIAL AND METHODS From September 1996 to December 2011, 248 patients with a macroscopic breast cancer recurrence were treated with re-RT and HT. Radiotherapy (RT) was applied to a dose of 32 Gy in 4 Gy fractions, twice weekly. HT was prescribed once weekly after RT. Primary endpoints for this analysis were complete response (CR) and local control (LC). Secondary endpoints were overall survival (OS), and toxicity. Patient-, tumor-, and treatment-related characteristics predictive for the endpoints were identified in univariate and multivariate analyses. RESULTS The median follow-up period was 32 months. The CR rate was 70%. At 1, 3, and 5 years LC was 53%, 40% and 39%, and OS was 66%, 32%, and 18%, respectively. OS after 10 years was 10%. Thermal burns developed in 23% patients, healing with conservative measures. The incidence of 5 years late grade 3 toxicity was 1%. A few patients survived more than 10 years without evidence of disease. CONCLUSIONS The combination of re-RT and HT results in a high rate of long-term LC with acceptable late toxicity, and many patients remained locally controlled for the rest of their survival period.

Diagnostic and therapeutic ionizing radiation and the risk of a first and second primary breast cancer, with special attention for BRCA1 and BRCA2 mutation carriers: A critical review of the literature

Occurrence of breast cancer is a well-known long-term side effect of ionizing radiation (both diagnostic and therapeutic). The radiation-induced breast cancer risk increases with longer follow-up, higher radiation dose and younger age of exposure. The risk for breast cancer following irradiation for lymphomas is well known. Although data regarding the carcinogenic risk of adjuvant radiotherapy for a primary breast cancer are sparse, an increased risk is suggested with longer follow-up mainly when exposed at younger age. Particularly, patients with a BRCA1/2 mutation might be more sensitive for the deleterious effects of ionizing radiation due to an impaired capacity of repairing double strand DNA breaks. This might have consequences for the use of mammography in breast cancer screening, as well as the choice between breast conserving therapy including radiotherapy and mastectomy at primary breast cancer diagnosis in young BRCA1/2 mutation carriers. Good data regarding this topic, however, are scarce, mainly due to constraints in the design of performed studies. In this review, we will discuss the current literature on the association between ionizing radiation and developing breast cancer, with particular attention to patients with a BRCA1/2 mutation.

The tolerance of reirradiation and hyperthermia in breast cancer patients with reconstructions

Background: Breast cancer recurrences in previously irradiated areas are treated with reirradiation (reRT) and hyperthermia (HT). The aim of this retrospective study is to quantify the toxicity of HT in breast cancer patients with reconstruction. Methods: Between 1992 and 2009, 36 patients were treated with reRT with a scheme of 8 fractions of 4.0 Gy in 4 weeks, and HT on a total of 37 tissue reconstructions. The types of reconstructions were: split-thickness skin graft (15), transverse rectus abdominis myocutaneous flap (1), latissimus dorsi flap (14), rhomboid flap (1) or a combination of grafts and flaps (6). Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Patient, tumour, and treatment characteristics predictive for the endpoints were identified in univariate and multivariate analyses. The primary endpoint was HT toxicity. Secondary endpoints were acute and late radiotherapy (RT) toxicity, complete response (CR), local control (LC) and overall survival (OS). Results: The median follow-up time was 64 months. Grade 2 HT toxicity occurred in four patients and grade 3 in three. The three patients with grade 3 HT toxicity required reoperation. None of the evaluated parameters showed a significant relationship with HT toxicity. The CR rate in 15 patients with macroscopic disease was 80%. The 3 and 5 year LC rates were 74% and 69%; the median OS was 55 months. Conclusions: Combined reRT and HT in breast cancer patients with reconstruction is safe and effective.

Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer

BackgroundImproved breast cancer (BC) survival and evidence showing beneficial effects of internal mammary chain (IMC) irradiation underscore the importance of studying late cardiovascular effects of BC treatment.MethodsWe assessed cardiovascular disease (CVD) incidence in 14,645 Dutch BC patients aged <62 years, treated during 1970–2009. Analyses included proportional hazards models and general population comparisons.ResultsCVD rate-ratio for left-versus-right breast irradiation without IMC was 1.11 (95% CI 0.93–1.32). Compared to right-sided breast irradiation only, IMC irradiation (interquartile range mean heart doses 9–17 Gy) was associated with increases in CVD rate overall, ischaemic heart disease (IHD), heart failure (HF) and valvular heart disease (hazard ratios (HRs): 1.6–2.4). IHD risk remained increased until at least 20 years after treatment. Anthracycline-based chemotherapy was associated with an increased HF rate (HR = 4.18, 95% CI 3.07–5.69), emerging <5 years and remaining increased at least 10–15 years after treatment. IMC irradiation combined with anthracycline-based chemotherapy was associated with substantially increased HF rate (HR = 9.23 95% CI 6.01–14.18), compared to neither IMC irradiation nor anthracycline-based chemotherapy.ConclusionsWomen treated with anthracycline-based chemotherapy and IMC irradiation (in an older era) with considerable mean heart dose exposure have substantially increased incidence of several CVDs. Screening may be appropriate for some BC patient groups.

Effect of radiotherapy for breast cancer on the prognosis of a subsequent myocardial infarction

Authors contributed equally to this work. 1 Netherlands Cancer Institute, Epidemiology, Amsterdam, The Netherlands 2 Erasmus MCCancer Institute, Medical Oncology, Rotterdam, The Netherlands 3 Erasmus MCCancer Institute, Radiation Oncology, Rotterdam, The Netherlands 4 Netherlands Cancer Institute, Medical Oncology, Amsterdam, The Netherlands 5 Netherlands Cancer Institute, Surgery, Amsterdam, The Netherlands 6 Netherlands Cancer Institute, Radiation Oncology, Amsterdam, The Netherlands

SU‐GG‐T‐02: Clinical Application of the ENAL Set‐Up Correction Protocol to Compensate for Time Trends in Breast Cancer Treatments

Purpose: Clinical evaluation of the extended NAL (eNAL) set‐up protocol (deBoer2007) for breast cancer patients treated with an integrated boost technique. Method and Materials: For 80 breast cancer patients, two orthogonal planar kilovoltage images and one megavoltage image (for the medio‐lateral beam) were acquired per fraction throughout the treatment course (14 fractions on average). Based on registration of surgical clips in the lumpectomy cavity (4.3 on average) set‐up corrections were derived after the first three fractions and updated once a week thereafter using eNAL. The stability of the clips during the fractionated treatment was derived. Using a t‐test the correlation between clip migration and either the method of surgery or the time elapsed from last surgery was quantified. The impact of the eNAL protocol on the set‐up accuracy for both the tumor bed and the whole breast was evaluated. Results: During the fractionated treatment the mean distance between the clips and their center of mass (COM) reduced by 0.9 ± 1.2 mm (1 SD). The clip migration was not statistically different between patients treated within 100 days after surgery or afterwards (p=0.20). Compared to conventional breast surgery (closing the lumpectomy cavity superficially), clip migration after oncoplastic surgery (suturing the lumpectomy cavity) was slightly smaller, but not significantly different (p=0.13). Throughout the treatment course timetrends in the COM position of the clips >3mm were observed for 61% of the patients. Application of the eNAL protocol on clips resulted in residual systematic errors for the tumor bed of <1 mm in each direction, while the whole breast was treated within about 2 mm accuracy. Conclusion: Surgical clips can safely be used for position verification and correction. By compensating for time trends, the eNAL protocol resulted in better set‐up accuracies for both the tumor bed and the whole breast than the NAL protocol.