Radiotherapy and Oncology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Adjuvant radiotherapy after breast conserving surgery – A comparative effectiveness research study Stefanie Corradini a,⇑, Maximilian Niyazi a, Olivier M. Niemoeller a, Minglun Li a, Falk Roeder a, Renate Eckel b, Gabriele Schubert-Fritschle b, Heike R. Scheithauer a, Nadia Harbeck c,d, Jutta Engel b, Claus Belka a a c
Department of Radiation Oncology; b Munich Cancer Registry (MCR) of the Munich Cancer Centre (MCC) at the Department of Medical Informatics, Biometry and Epidemiology (IBE); Breast Center, Department of Obstetrics and Gynecology; and d Comprehensive Cancer Center (CCC-LMU), University of Munich, Germany
a r t i c l e
i n f o
Article history: Received 22 January 2014 Received in revised form 23 July 2014 Accepted 21 August 2014 Available online xxxx Keywords: Breast cancer Breast conserving surgery Radiotherapy Comparative effectiveness research Outcome
a b s t r a c t Purpose: The purpose of this retrospective outcome study was to validate the effectiveness of postoperative radiotherapy in breast conserving therapy (BCT) and to evaluate possible causes for omission of radiotherapy after breast conserving surgery (BCS) in a non-trial population. Methods: Data were provided by the population-based Munich Cancer Registry. The study included epidemiological data of 30.811 patients diagnosed with breast cancer from 1998 to 2012. The effect of omitting radiotherapy was analysed using Kaplan–Meier-estimates and Cox proportional hazard regression. Variables predicting omission of radiotherapy were analysed using multivariate logistic regression. Results: Use of postoperative radiotherapy after BCS was associated with significant improvements in local control and survival. 10-year loco-regional recurrence-free-survival was 90.8% with postoperative radiotherapy vs. 77.6% with surgery alone (p < 0.001). 10-year overall survival rates were 55.2% with surgery alone vs. 82.2% following postoperative radiotherapy (p < 0.001). Variables predicting omission of postoperative radiotherapy included advanced age (women P80 years; OR: 0.082; 95% CI: 0.071– 0.094, p < 0.001). Conclusions: This study shows a decrease in local control and a survival disadvantage if postoperative radiotherapy after breast conserving surgery is omitted in an unselected cohort of primary breast cancer patients. Due to its epidemiological nature, it cannot answer the question in whom postoperative radiotherapy can be safely omitted. Ó 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2014) xxx–xxx
Over the past decades, optimal management of early breast cancer has often attracted controversy. During the 1960s and 1970s, the dominant tradition had been radical mastectomy. Large randomised controlled trials published in the early 1980s first proved that breast conserving surgery (BCS) followed by postoperative radiotherapy (breast conserving therapy, BCT) was an alternative treatment for women with early breast cancer [1,2]. Women treated with breast conserving surgery followed by radiotherapy showed a significant decrease in local recurrences rates, as compared to breast conserving surgery alone. Moreover, BCT showed equal overall survival rates compared to radical mastectomy in long-term follow-up [3–6]. Thus, postoperative radiotherapy became mandatory after breast conserving surgery and to date, BCT has become the treatment of choice for early breast cancer.
⇑ Corresponding author. Address: Department of Radiation Oncology, University of Munich, Marchioninistraße 15, 81377 Munich, Germany. E-mail address: [email protected] (S. Corradini).
Nevertheless, the expanding body of research sometimes makes it difficult for clinicians to be aware of every potential novelty and how to incorporate it critically into real-world practice. Therefore, interdisciplinary consensus-based guidelines [7] provide statements, recommendations and explicit management instructions to assist clinicians with the successful implementation of new treatment strategies into clinical practice. However, health care decision-making is complex and therefore treatment decisions in daily practice are not always taken in accordance with evidencebased recommendations. In general, little is known why clinicians may not follow guidelines. There are a variety of barriers to guideline adherence, including lack of outcome expectancy [8,9]. If a physician believes that a recommendation will not lead to an improved outcome, the physician will less likely adhere to the guideline [9]. Lack of consideration of external validity is another explanation for the widespread underuse of treatments, that were shown to be beneficial in controlled trials [8]. Randomised trials provide the least biased estimates to compare treatments and are
http://dx.doi.org/10.1016/j.radonc.2014.08.027 0167-8140/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Corradini S et al. Adjuvant radiotherapy after breast conserving surgery – A comparative effectiveness research study. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.08.027
2
Breast conserving therapy – A comparative effectiveness research study
the gold standard of efficacy research in oncology. Unfortunately, their results do not always correspond to what is seen in realworld settings or in effectiveness research [10]. Clinicians have to pick from a range of possible treatment options, recognising that the best choice may vary across patients [11]. For this purpose, in clinical oncology, data of cancer registries are suited to analyse real patient populations in everyday clinical scenarios and to monitor the uptake of new treatments [12]. The aim of the present study was to evaluate the implementation and benefit of postoperative radiotherapy in BCT in routine clinical practice outside of clinical trials. A further purpose was to identify possible reasons related to omission of recommended radiotherapy.
Patients and methods Data sources Data were provided by the Munich Cancer Registry (MCR) [13]. The MCR is the population-based clinical cancer registry of Upper Bavaria and in part of Lower Bavaria (Southern Germany). Its catchment area has been enlarged from 2.3 million inhabitants to 3.8 million in 2002 and to 4.6 million in 2007. The MCR routinely collects data on patient’s demographics, primary tumour site, extent of disease (TNM), histology, treatment and follow-up. Cancer diagnosis, tumour morphology and stage at diagnosis are registered according to official classifications (ICD10, ICD-0-3, TNM classification of Malignant Tumours). Survival information is maintained systematically through death certificates.
Cohort selection Between 1998 and 2012 the MCR registered epidemiological population-based records on 30.811 female patients diagnosed with breast cancer, who underwent breast conserving surgery. Data did not include patients with male sex (n = 347), histology of lymphoma (n = 57) or sarcoma (n = 96), primary metastasis (n = 655), or with unknown date of initial diagnosis (e.g. tumours from death certificate information only [DCO]) (n = 2.656). The ‘‘Radiotherapy facilities cohort’’ is a subgroup of the population-based cohort, and consisted of 21.724 women treated at any radiotherapy department (n = 17) within Munich and the surrounding areas from 1998 to 2012. The second subgroup analysed in the present study consisted of 2.719 women treated at the single institution ‘‘Department of Radiation Oncology LMU’’ from 1998 to 2012. All patients in the two subgroups were presented or treated at a radiotherapy department throughout the course of their disease. Patients who refused the recommended postoperative radiotherapy of the breast were included in the study.
Statistical analyses and endpoints Statistical analyses were conducted using IBM SPSS Statistics 21.0 and SAS (Statistical Analysis System), Version 9.2. The study population was analysed regarding the impact of omitting postoperative radiotherapy after BCS on outcome. The Kaplan–Meier method was used to describe the effect of postoperative radiotherapy on overall survival (OS), loco-regional recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) and estimates were compared using the log-rank test. Relative survival was calculated by the ratio of the overall survival rate to the expected survival rate. Relative survival was used as an estimate for cancer specific survival. These statistical analyses were performed for primary tumours with invasive histology only. Prognostic factors related to OS, LRFS and DRFS were analysed by Cox proportional hazard regression models. Moreover, factors
predicting omission of postoperative radiotherapy were determined by multivariate logistic regression model. Results Baseline patient characteristics Patient and treatment characteristics for the three cohorts are summarised in Table 1. Median age at diagnosis was 60.9 years in the population-based cohort, with 16.6% of patients aged between 70 and 79 years and 6.1% of patients P80 years. In contrast, patients in the Department of Radiation Oncology LMU cohort were slightly younger at time of initial diagnosis, with a median age of 58.9 years and 15.0% of patients aged between 70 and 79 years and only 1.8% of patients aged P80 years. The population-based cohort presented with pathological tumour stage pTis in 10.1% (2937/29,068), pT1 in 62.5% (18,167/29,068), pT2 in 25.8% (7504/29,068), pT3 in 0.9% (253/29,068) and pT4 in 0.7% (207/ 29,068). Tumour stage was mostly balanced between the cohorts. Low tumour grade (G1) was present in 16.0% (4497/28,172) in the population-based cohort. The proportion was higher in the Department of Radiation Oncology LMU cohort, presenting with 18.5% (467/2526) of patients with grade 1 tumours. Nodal involvement (N+) was present in 25.6% (7536/29,384) in the populationbased cohort, which was comparable to the Radiotherapy facilities cohort presenting with 26.4% (5550/20,984) and the Department of Radiation Oncology LMU cohort with 24.3% (638/2625) positive nodal status. Overall, 86.3% (26,595/30,811) of the patients in the population-based cohort were treated with postoperative radiotherapy as part of BCT. A significant increase of postoperative radiotherapy was documented over time. While in 1998 only 81.0% of patients in the population-based cohort received postoperative radiotherapy after BCS, the proportion rose to 90.7% in 2012. In contrast, overall 97.2% (21,104/21,724) in the Radiotherapy facilities cohort and 97.6% (2655/2719) in the Department of Radiation Oncology LMU cohort were treated with postoperative radiotherapy – presenting with higher rates of radiotherapy. The standard radiotherapy regimen at the Department of Radiation Oncology of the University of Munich (LMU), was whole-breast irradiation (50.4 Gy in 28 fractions) followed by a boost of 10–16 Gy to the tumour bed. Alternative schedules, as hypofractionated radiotherapy [14–16], were rarely used. Overall, application of adjuvant chemotherapy and/or endocrine therapy was comparable in the three cohorts. Loco-regional recurrence-free survival The 10-year LRFS rate was 90.8% in patients receiving postoperative radiotherapy after BCS, compared to 77.6% in patients in whom radiotherapy was omitted – presenting more frequently with local failure (p < 0.001) (Table 2, Fig. 1A). These findings were comparable to the results of the two subgroups. The Radiotherapy facilities cohort presented with a 10-year LRFS of 90.6% for BCS with additional radiotherapy (p < 0.001), and the Department of Radiation Oncology LMU cohort with a 10-year LRFS of 92.9% (p < 0.001). In contrast, in both subgroups the surgery only group had elevated recurrence rates, presenting with 10-year local recurrence free survival rates of 42.0% and 43.9%, respectively (Table 2). As expected, for node positive patients with 63 positive lymph nodes LRFS was 87.0% after 10 years and with >3 positive lymph nodes 80.5%, respectively. In contrast, 10-year local recurrence free survival in node negative patients was 90.8% (p < 0.001, data not shown). Multivariate Cox analysis (Table 3) for local recurrence free survival identified postoperative radiotherapy (hazard ratio [HR], 0.350; 95% confidence interval [CI], 0.309–0.397, p < 0.001) as a
Please cite this article in press as: Corradini S et al. Adjuvant radiotherapy after breast conserving surgery – A comparative effectiveness research study. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.08.027
3
S. Corradini et al. / Radiotherapy and Oncology xxx (2014) xxx–xxx
Table 1 Cohort characteristics of the epidemiological population-based data of the Munich Cancer Registry, and the two subgroups: radiotherapy facilities cohort and Department of Radiation Oncology LMU cohort. BCS: breast conserving surgery. Population-based cohort 1998–2012 30,811 patients
Age at diagnosis (years)
Tumour size
Nodal status
Grade
Radiotherapy Chemotherapy Endocrine therapy
*
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Adjuvant radiotherapy after breast conserving surgery – A comparative effectiveness research study Stefanie Corradini a,⇑, Maximilian Niyazi a, Olivier M. Niemoeller a, Minglun Li a, Falk Roeder a, Renate Eckel b, Gabriele Schubert-Fritschle b, Heike R. Scheithauer a, Nadia Harbeck c,d, Jutta Engel b, Claus Belka a a c
Department of Radiation Oncology; b Munich Cancer Registry (MCR) of the Munich Cancer Centre (MCC) at the Department of Medical Informatics, Biometry and Epidemiology (IBE); Breast Center, Department of Obstetrics and Gynecology; and d Comprehensive Cancer Center (CCC-LMU), University of Munich, Germany
a r t i c l e
i n f o
Article history: Received 22 January 2014 Received in revised form 23 July 2014 Accepted 21 August 2014 Available online xxxx Keywords: Breast cancer Breast conserving surgery Radiotherapy Comparative effectiveness research Outcome
a b s t r a c t Purpose: The purpose of this retrospective outcome study was to validate the effectiveness of postoperative radiotherapy in breast conserving therapy (BCT) and to evaluate possible causes for omission of radiotherapy after breast conserving surgery (BCS) in a non-trial population. Methods: Data were provided by the population-based Munich Cancer Registry. The study included epidemiological data of 30.811 patients diagnosed with breast cancer from 1998 to 2012. The effect of omitting radiotherapy was analysed using Kaplan–Meier-estimates and Cox proportional hazard regression. Variables predicting omission of radiotherapy were analysed using multivariate logistic regression. Results: Use of postoperative radiotherapy after BCS was associated with significant improvements in local control and survival. 10-year loco-regional recurrence-free-survival was 90.8% with postoperative radiotherapy vs. 77.6% with surgery alone (p < 0.001). 10-year overall survival rates were 55.2% with surgery alone vs. 82.2% following postoperative radiotherapy (p < 0.001). Variables predicting omission of postoperative radiotherapy included advanced age (women P80 years; OR: 0.082; 95% CI: 0.071– 0.094, p < 0.001). Conclusions: This study shows a decrease in local control and a survival disadvantage if postoperative radiotherapy after breast conserving surgery is omitted in an unselected cohort of primary breast cancer patients. Due to its epidemiological nature, it cannot answer the question in whom postoperative radiotherapy can be safely omitted. Ó 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2014) xxx–xxx
Over the past decades, optimal management of early breast cancer has often attracted controversy. During the 1960s and 1970s, the dominant tradition had been radical mastectomy. Large randomised controlled trials published in the early 1980s first proved that breast conserving surgery (BCS) followed by postoperative radiotherapy (breast conserving therapy, BCT) was an alternative treatment for women with early breast cancer [1,2]. Women treated with breast conserving surgery followed by radiotherapy showed a significant decrease in local recurrences rates, as compared to breast conserving surgery alone. Moreover, BCT showed equal overall survival rates compared to radical mastectomy in long-term follow-up [3–6]. Thus, postoperative radiotherapy became mandatory after breast conserving surgery and to date, BCT has become the treatment of choice for early breast cancer.
⇑ Corresponding author. Address: Department of Radiation Oncology, University of Munich, Marchioninistraße 15, 81377 Munich, Germany. E-mail address: [email protected] (S. Corradini).
Nevertheless, the expanding body of research sometimes makes it difficult for clinicians to be aware of every potential novelty and how to incorporate it critically into real-world practice. Therefore, interdisciplinary consensus-based guidelines [7] provide statements, recommendations and explicit management instructions to assist clinicians with the successful implementation of new treatment strategies into clinical practice. However, health care decision-making is complex and therefore treatment decisions in daily practice are not always taken in accordance with evidencebased recommendations. In general, little is known why clinicians may not follow guidelines. There are a variety of barriers to guideline adherence, including lack of outcome expectancy [8,9]. If a physician believes that a recommendation will not lead to an improved outcome, the physician will less likely adhere to the guideline [9]. Lack of consideration of external validity is another explanation for the widespread underuse of treatments, that were shown to be beneficial in controlled trials [8]. Randomised trials provide the least biased estimates to compare treatments and are
http://dx.doi.org/10.1016/j.radonc.2014.08.027 0167-8140/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Corradini S et al. Adjuvant radiotherapy after breast conserving surgery – A comparative effectiveness research study. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.08.027
2
Breast conserving therapy – A comparative effectiveness research study
the gold standard of efficacy research in oncology. Unfortunately, their results do not always correspond to what is seen in realworld settings or in effectiveness research [10]. Clinicians have to pick from a range of possible treatment options, recognising that the best choice may vary across patients [11]. For this purpose, in clinical oncology, data of cancer registries are suited to analyse real patient populations in everyday clinical scenarios and to monitor the uptake of new treatments [12]. The aim of the present study was to evaluate the implementation and benefit of postoperative radiotherapy in BCT in routine clinical practice outside of clinical trials. A further purpose was to identify possible reasons related to omission of recommended radiotherapy.
Patients and methods Data sources Data were provided by the Munich Cancer Registry (MCR) [13]. The MCR is the population-based clinical cancer registry of Upper Bavaria and in part of Lower Bavaria (Southern Germany). Its catchment area has been enlarged from 2.3 million inhabitants to 3.8 million in 2002 and to 4.6 million in 2007. The MCR routinely collects data on patient’s demographics, primary tumour site, extent of disease (TNM), histology, treatment and follow-up. Cancer diagnosis, tumour morphology and stage at diagnosis are registered according to official classifications (ICD10, ICD-0-3, TNM classification of Malignant Tumours). Survival information is maintained systematically through death certificates.
Cohort selection Between 1998 and 2012 the MCR registered epidemiological population-based records on 30.811 female patients diagnosed with breast cancer, who underwent breast conserving surgery. Data did not include patients with male sex (n = 347), histology of lymphoma (n = 57) or sarcoma (n = 96), primary metastasis (n = 655), or with unknown date of initial diagnosis (e.g. tumours from death certificate information only [DCO]) (n = 2.656). The ‘‘Radiotherapy facilities cohort’’ is a subgroup of the population-based cohort, and consisted of 21.724 women treated at any radiotherapy department (n = 17) within Munich and the surrounding areas from 1998 to 2012. The second subgroup analysed in the present study consisted of 2.719 women treated at the single institution ‘‘Department of Radiation Oncology LMU’’ from 1998 to 2012. All patients in the two subgroups were presented or treated at a radiotherapy department throughout the course of their disease. Patients who refused the recommended postoperative radiotherapy of the breast were included in the study.
Statistical analyses and endpoints Statistical analyses were conducted using IBM SPSS Statistics 21.0 and SAS (Statistical Analysis System), Version 9.2. The study population was analysed regarding the impact of omitting postoperative radiotherapy after BCS on outcome. The Kaplan–Meier method was used to describe the effect of postoperative radiotherapy on overall survival (OS), loco-regional recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) and estimates were compared using the log-rank test. Relative survival was calculated by the ratio of the overall survival rate to the expected survival rate. Relative survival was used as an estimate for cancer specific survival. These statistical analyses were performed for primary tumours with invasive histology only. Prognostic factors related to OS, LRFS and DRFS were analysed by Cox proportional hazard regression models. Moreover, factors
predicting omission of postoperative radiotherapy were determined by multivariate logistic regression model. Results Baseline patient characteristics Patient and treatment characteristics for the three cohorts are summarised in Table 1. Median age at diagnosis was 60.9 years in the population-based cohort, with 16.6% of patients aged between 70 and 79 years and 6.1% of patients P80 years. In contrast, patients in the Department of Radiation Oncology LMU cohort were slightly younger at time of initial diagnosis, with a median age of 58.9 years and 15.0% of patients aged between 70 and 79 years and only 1.8% of patients aged P80 years. The population-based cohort presented with pathological tumour stage pTis in 10.1% (2937/29,068), pT1 in 62.5% (18,167/29,068), pT2 in 25.8% (7504/29,068), pT3 in 0.9% (253/29,068) and pT4 in 0.7% (207/ 29,068). Tumour stage was mostly balanced between the cohorts. Low tumour grade (G1) was present in 16.0% (4497/28,172) in the population-based cohort. The proportion was higher in the Department of Radiation Oncology LMU cohort, presenting with 18.5% (467/2526) of patients with grade 1 tumours. Nodal involvement (N+) was present in 25.6% (7536/29,384) in the populationbased cohort, which was comparable to the Radiotherapy facilities cohort presenting with 26.4% (5550/20,984) and the Department of Radiation Oncology LMU cohort with 24.3% (638/2625) positive nodal status. Overall, 86.3% (26,595/30,811) of the patients in the population-based cohort were treated with postoperative radiotherapy as part of BCT. A significant increase of postoperative radiotherapy was documented over time. While in 1998 only 81.0% of patients in the population-based cohort received postoperative radiotherapy after BCS, the proportion rose to 90.7% in 2012. In contrast, overall 97.2% (21,104/21,724) in the Radiotherapy facilities cohort and 97.6% (2655/2719) in the Department of Radiation Oncology LMU cohort were treated with postoperative radiotherapy – presenting with higher rates of radiotherapy. The standard radiotherapy regimen at the Department of Radiation Oncology of the University of Munich (LMU), was whole-breast irradiation (50.4 Gy in 28 fractions) followed by a boost of 10–16 Gy to the tumour bed. Alternative schedules, as hypofractionated radiotherapy [14–16], were rarely used. Overall, application of adjuvant chemotherapy and/or endocrine therapy was comparable in the three cohorts. Loco-regional recurrence-free survival The 10-year LRFS rate was 90.8% in patients receiving postoperative radiotherapy after BCS, compared to 77.6% in patients in whom radiotherapy was omitted – presenting more frequently with local failure (p < 0.001) (Table 2, Fig. 1A). These findings were comparable to the results of the two subgroups. The Radiotherapy facilities cohort presented with a 10-year LRFS of 90.6% for BCS with additional radiotherapy (p < 0.001), and the Department of Radiation Oncology LMU cohort with a 10-year LRFS of 92.9% (p < 0.001). In contrast, in both subgroups the surgery only group had elevated recurrence rates, presenting with 10-year local recurrence free survival rates of 42.0% and 43.9%, respectively (Table 2). As expected, for node positive patients with 63 positive lymph nodes LRFS was 87.0% after 10 years and with >3 positive lymph nodes 80.5%, respectively. In contrast, 10-year local recurrence free survival in node negative patients was 90.8% (p < 0.001, data not shown). Multivariate Cox analysis (Table 3) for local recurrence free survival identified postoperative radiotherapy (hazard ratio [HR], 0.350; 95% confidence interval [CI], 0.309–0.397, p < 0.001) as a
Please cite this article in press as: Corradini S et al. Adjuvant radiotherapy after breast conserving surgery – A comparative effectiveness research study. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.08.027
3
S. Corradini et al. / Radiotherapy and Oncology xxx (2014) xxx–xxx
Table 1 Cohort characteristics of the epidemiological population-based data of the Munich Cancer Registry, and the two subgroups: radiotherapy facilities cohort and Department of Radiation Oncology LMU cohort. BCS: breast conserving surgery. Population-based cohort 1998–2012 30,811 patients
Age at diagnosis (years)
Tumour size
Nodal status
Grade
Radiotherapy Chemotherapy Endocrine therapy
*
