Model-Based Selection for Proton Therapy in Breast Cancer: Development of the National Indication Protocol for Proton Therapy and First Clinical Experiences.

AIMS: Proton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences. MATERIALS AND METHODS: A national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy. RESULTS: The model of Darby et al. (N Engl J Med 2013; 368:987-82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021. CONCLUSION: The NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands.

A patient decision aid for breast cancer patients deciding on their radiation treatment, no change in decisional conflict but better informed choices.

BACKGROUND AND PURPOSE: In selected breast cancer patients, radiation treatment (RT) lowers the recurrence risk, with minor or no improvement of survival. In these patients, the choice to undergo RT is considered a preference-sensitive decision. To facilitate shared decision-making (SDM) for this choice, a patient decision aid was made. We aimed to evaluate the effect of the PtDA on decisional conflict. MATERIAL AND METHODS: We performed a multi-center pre- and post-intervention study (BRASA-trial). The first 214 patients made a choice without support of the PtDA; the subsequent 189 patients received a link to the PtDA. The primary endpoint was decisional conflict; secondary endpoints were perceived SDM and knowledge on treatment options. Patients filled out questionnaires immediately after, and three months after their decision. Data were analyzed with multi-level regression analysis. RESULTS: After correcting for the difference in age and educational level, the mean (±SD) decisional conflict for the intervention group (27.3 ± 11.4) was similar to the control group (26.8 ± 11.4; difference = 0.86, 95 %CI 1.67,3.36) three months after their decision. This also applied to perceived SDM. Patients exposed to the PtDA pursued additional treatment less often (45% vs 56%, odds ratio 0.59, 95 %CI 0.37,0.95) and scored significantly higher on the knowledge test (7.4 ± 2.5 vs 6.1 ± 2.7, corrected difference = 1.0, 95 %CI 0.50,1.49). There was no significant increase in consultation time. CONCLUSIONS: Handing out the PtDA was not associated with improved scores in decisional conflict or perceived SDM, but it was associated with a choice for less additional treatment and better knowledge about the treatment options.

Variation in the Use of Boost Irradiation in Breast-Conserving Therapy in the Netherlands: The Effect of a National Guideline and Cofounding Factors.

AIMS: To determine the variation in radiation therapy boost use in a nationwide study following adjustment of a national guideline in 2011, as well as to address the relationship to patient, tumour and radiation therapy institutional factors. MATERIALS AND METHODS: All invasive breast cancers and non-invasive breast cancers (ductal carcinoma in situ; DCIS) that received external whole-breast radiation between 2011 and 2016 were selected from the Netherlands Cancer Registry. Box plots were used to evaluate variation over time and logistic regression was carried out to address other factors influencing the variation. Funnel plots were constructed, with unadjusted and adjusted data for patient and tumour factors significantly affecting the use of a boost. RESULTS: For breast cancer patients (n = 45,207), the proportion receiving a boost and its range decreased over the years from 37.3-92.7% in 2011 to 28.3-65.4% in 2016. This trend was not observed in DCIS patients (n = 6,844). Young age, large tumours, high grade and the absence of tumour-free resection margins were associated with boost use for both breast cancer and DCIS. For breast cancer, triple-negative tumour subtype and metastatic lymph node involvement were also associated with boost use. Institutional factors did not influence the use of a boost and institutional variation remained substantial after case-mix adjustments. CONCLUSION: Following adjustment of a nationwide implemented guideline, variation in radiation therapy boost use decreased in patients with breast cancer but not in patients with DCIS. Several tumour and patient characteristics were associated with boost use. Substantial institutional variation could not be explained by differences in patient, tumour or predefined institutional characteristics.

Is DCIS breast cancer, and how do I treat it?

Ductal carcinoma in situ (DCIS) is a pre-invasive stage of breast cancer with a heterogeneous clinical behaviour. Since the introduction of mammographic screening programmes, the incidence of DCIS has shown a dramatic increase. Treatment should focus on the prevention of progression to invasive disease. If progression occurs, poorly differentiated DCIS frequently gives rise to grade III invasive breast cancer, whereas well differentiated DCIS more often recurs as grade I invasive disease. However, at present, validated diagnostic test are lacking to predict progression accurately. The majority of women with DCIS are suitable for breast conserving therapy. Obtaining clear surgical margins is the most important goal of a local excision. Radiotherapy is effective in reducing the risk of local recurrence with about 50 % in all subgroups of patients with DCIS. (Breast cancer specific) survival of women with DCIS is excellent, and radiotherapy does not further improve this. Future research should be directed in enabling to select women who have a high risk of--invasive--recurrence, so in which radiotherapy should be standard part of the breast conserving approach, and those women with a more indolent lesion, in which after surgery a watchful waiting approach can be followed.

Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast.

Individual patient data were available for all four of the randomized trials that began before 1995, and that compared adjuvant radiotherapy vs no radiotherapy following breast-conserving surgery for ductal carcinoma in situ (DCIS). A total of 3729 women were eligible for analysis. Radiotherapy reduced the absolute 10-year risk of any ipsilateral breast event (ie, either recurrent DCIS or invasive cancer) by 15.2% (SE 1.6%, 12.9% vs 28.1% 2 P <.00001), and it was effective regardless of the age at diagnosis, extent of breast-conserving surgery, use of tamoxifen, method of DCIS detection, margin status, focality, grade, comedonecrosis, architecture, or tumor size. The proportional reduction in ipsilateral breast events was greater in older than in younger women (2P < .0004 for difference between proportional reductions; 10-year absolute risks: 18.5% vs 29.1% at ages <50 years, 10.8% vs 27.8% at ages ≥ 50 years) but did not differ significantly according to any other available factor. Even for women with negative margins and small low-grade tumors, the absolute reduction in the 10-year risk of ipsilateral breast events was 18.0% (SE 5.5, 12.1% vs 30.1%, 2P = .002). After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality.

Effects of patient selection on the applicability of results from a randomised clinical trial (EORTC 10853) investigating breast-conserving therapy for DCIS.

Selection of patients for randomised clinical trials may have a large impact on the applicability of the study results to the general population presenting the same disorder. However, clinical characteristics and outcome data on non-entered patients are usually not available. The effects of patient selection for the EORTC 10853 trial investigating the role of radiotherapy in breast conserving therapy for ductal carcinoma in situ have been studied, in an analysis of all patients treated for ductal carcinoma in situ in five participating institutes. The reasons for not entering patients were evaluated and treatment results of the randomised patients were compared to those not entered. A total of 910 patients were treated for ductal carcinoma in situ. Of these, 477 (52%) were ineligible, with the size of the lesion being the main reason for ineligibility (30% of all ductal carcinoma in situ). Of the 433 eligible patients, 278 (64%) were randomised into the trial. The main reasons for non-entry of eligible patients were either physicians' preference for one of the treatment arms (26%) or patients' refusal (9%). These percentages showed significant variation among the institutes. At 4 years follow-up, those patients not entered in the trial and treated with local excision and radiotherapy, had higher local recurrence rates than the patients randomised in the trial and treated with the same approach, (17 vs 2%, P=0.03). The patients treated with local excision alone had equal local recurrence rates (11% in both groups). Selection of patients may explain the differences in outcome of the randomised patients, and those not-entered. Thus, the results of this trial may not be applicable to all patients with ductal carcinoma in situ.

Variations in diagnostic and therapeutic procedures in a multicentre, randomized clinical trial (EORTC 10853) investigating breast-conserving treatment for DCIS.

AIMS: To evaluate the diagnostic and therapeutic procedures which were followed in a European Organization for Research and Treatment of Cancer (EORTC) randomized clinical trial investigating the role of radiotherapy in breast-conserving treatment (BCT) for ductal carcinoma in situ (DCIS) of the breast. METHODS: The medical files of 824 of the 1010 randomized patients (82%) were reviewed during site visits to 30 participating institutes. RESULTS: Large variations occurred, particularly in the surgical procedures and histopathological work-up which were performed. Important risk factors like tumour size and margin status were poorly quantified in the medical files. CONCLUSIONS: These findings emphasize the need for establishing uniform guidelines for diagnostic and therapeutic procedures for DCIS, and for clearly defined risk factors for recurrence after BCT for DCIS. Because of its randomized nature, the main question of the trial, i.e. the effect of radiotherapy on the risk of local recurrence, will not be influenced by variation. The risk of local recurrence in itself, and hence the success of BCT for DCIS, may however be influenced by the quality of the initial procedures that were conducted.

Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853.

PURPOSE: In view of the increasing number of patients treated with breast-conserving treatment (BCT) for ductal carcinoma-in-situ (DCIS), risk factors for recurrence and metastasis should be identified. PATIENTS AND METHODS: Clinical and pathologic characteristics from patients with DCIS in the European Organization for Research and Treatment of Cancer trial 10853 (excision with or without radiotherapy) were related to the risk of recurrence. Pathologic features were derived from a central review of 863 of the 1,010 randomized cases (85%). The median follow-up was 5.4 years. RESULTS: Factors associated with an increased risk of local recurrence in the multivariate analysis were young age (< or = 40 years) (hazard ratio, 2.14; P =.02), symptomatic detection of DCIS (hazard ratio, 1.80; P =.008), growth pattern (solid and cribriform) (hazard ratios, 2.67 and 2.69, respectively; P =.012), involved margins (hazard ratio, 2.07; P =.0008), and treatment by local excision alone (hazard ratio, 1.74; P =.009). The risk of invasive recurrence was not related to the histologic type of DCIS (P =.63), but the risk of distant metastasis was significantly higher in poorly differentiated DCIS compared with well-differentiated DCIS (hazard ratio, 6.57; P =.01). CONCLUSION: Patients with poorly differentiated DCIS have a high risk of distant metastasis after invasive local recurrence. Margin status is the most important factor in the success of BCT for DCIS; additionally, young age and symptomatic detection of DCIS have negative prognostic value.

Breast-conserving therapy for Paget disease of the nipple: a prospective European Organization for Research and Treatment of Cancer study of 61 patients.

BACKGROUND: The purpose of the current study was to assess the outcome of breast-conserving therapy by means of a cone excision and radiotherapy in patients with Paget disease of the nipple without associated invasive breast carcinoma. METHODS: Between 1987 and 1998, 61 eligible patients were registered in the European Organization for Research and Treatment of Cancer Study 10873. The majority of patients (97%) presented without an associated palpable mass. At histologic examination, the majority (93%%) of patients had an underlying ductal carcinoma in situ (DCIS); in the remaining 7%, only Paget disease was found. Treatment was comprised of a complete excision of the nipple-areolar complex including the underlying breast tissue with tumor free margins, followed by external irradiation to the whole breast (50 gray in 25 fractions). The primary endpoint was local recurrence. RESULTS: At a median follow-up of 6.4 years, 4 of the 61 patients developed a recurrence in the treated breast (1 patient with DCIS and 3 patients with invasive disease). One patient with an invasive local recurrence died of disseminated breast carcinoma. The 5-year local recurrence rate was 5.2% (95% confidence interval, 1.8-14.1%). CONCLUSIONS: Breast-conserving therapy is a feasible alternative for patients with Paget disease and a limited extent of underlying DCIS. To achieve good local control, treatment should be comprised of a complete excision of the nipple-areolar complex including the underlying disease, followed by irradiation to the whole breast.

Histological type and marker expression of the primary tumour compared with its local recurrence after breast-conserving therapy for ductal carcinoma in situ.

We have investigated primary ductal carcinomas in situ (DCIS) of the breast and their local recurrences after breast-conserving therapy (BCT) for histological characteristics and marker expression. Patients who were randomized in the EORTC trial 10853 (wide local excision versus excision plus radiotherapy) and who developed a local recurrence were identified. Histology was reviewed for 116 cases; oestrogen and progesterone receptor status, and HER2/ neu and p53 overexpression were assessed for 71 cases. Comparing the primary DCIS and the invasive or non-invasive recurrence, concordant histology was found in 62%, and identical marker expression in 63%. Although 11% of the recurrences developed at a distance from the primary DCIS, nearly all these showed the same histological and immunohistochemical profile. 5 patients developed well-differentiated DCIS or grade I invasive carcinoma after poorly differentiated DCIS. Although these recurrences occurred in the same quadrant as the primary DCIS, they may be considered as second primary tumours. Only 4 patients developed poorly differentiated DCIS or grade III invasive carcinoma after well differentiated DCIS. We conclude that in most cases the primary DCIS and its local recurrence are related histologically or by marker expression, suggesting that local recurrence usually reflects outgrowth of residual DCIS; progression of well differentiated DCIS towards poorly differentiated DCIS or grade III invasive carcinoma is a non-frequent event.

Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast is a disorder that has become more common since it may manifest as microcalcifications that can be detected by screening mammography. Since selected women with invasive cancer can be treated safely with breast conservation therapy it is paradoxical that total mastectomy has remained the standard treatment for DCIS. We did a randomised phase III clinical trial to investigate the role of radiotherapy after complete local excision of DCIS. METHODS: Between 1986 and 1996, women with clinically or mammographically detected DCIS measuring less than or equal to 5 cm were treated by complete local excision of the lesion and then randomly assigned to either no further treatment (n=503) or to radiotherapy (n=507; 50 Gy in 5 weeks to the whole breast). The median duration of follow-up was 4.25 years (maximum 12.0 years). All analyses were by intention to treat. FINDINGS: 500 patients were followed up in the no further treatment group and 502 in the radiotherapy group. In the no further treatment group 83 women had local recurrence (44 recurrences of DCIS, and 40 invasive breast cancer). In the radiotherapy group 53 women had local recurrences (29 recurrences of DCIS, and 24 invasive breast cancer). The 4-year local relapse-free was 84% in the group treated with local excision alone compared with 91% in the women treated by local excision plus radiotherapy (log rank p=0.005; hazard ratio 0.62). Similar reductions in the risk of invasive (40%, p=0.04) and non-invasive (35%, p=0.06) local recurrence were seen. CONCLUSIONS: Radiotherapy after local excision for DCIS, as compared with local excision alone, reduced the overall number of both invasive and non-invasive recurrences in the ipsilateral breast at a median follow-up of 4.25 years.

Low risk of locoregional recurrence of primary breast carcinoma after treatment with a modification of the Halsted radical mastectomy and selective use of radiotherapy.

BACKGROUND: The purpose of the current study was to evaluate the locoregional recurrence rate after treatment of patients with operable breast carcinoma with a modification of the Halsted radical mastectomy and the selective use of radiotherapy and to identify risk factors for locoregional recurrence. METHODS: Between 1979-1987, 691 consecutive patients underwent mastectomy after a negative biopsy of the axillary apical lymph nodes. The median age of the patients was 59 years (range, 26-89 years). The clinical tumor size was < 2 cm in 72 patients, 2-5 cm in 387 patients, and >5 cm in 169 patients; 16 patients had a T4 tumor. Surgery was comprised of a modification of the Halsted radical mastectomy, including at least part of the pectoralis major muscle and the entire pectoralis minor muscle, in 573 patients; 303 patients had positive axillary lymph nodes. Adjuvant radiotherapy to the chest wall and regional lymph nodes was given to 74 patients, whereas an additional 414 patients underwent irradiation to the internal mammary and medial supraclavicular lymph nodes. The median follow-up was 91 months. RESULTS: The actuarial overall survival rate was 82% at 5 years and 63% at 10 years. The 10-year chest wall and regional lymph node control rates, including patients with prior distant failures, were 95% and 94%, respectively. The only two significant prognostic factors for locoregional recurrence on multivariate analysis were lymph node status and pathologic tumor size. CONCLUSIONS: Excellent locoregional control can be achieved with a modified technique of radical mastectomy in patients with negative apical biopsy and the selective use of comprehensive radiotherapy. These results may serve as a reference outcome for comparison with other locoregional treatment strategies.