Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Overtreatment of Low-Grade Ductal Carcinoma In Situ

Overtreatment of Low-Grade Ductal Carcinoma In Situ JAMA Surgery Survival Benefit of Breast Surgery for Low-Grade Ductal Carcinoma In Situ: A Population-Based Cohort Study Yasuaki Sagara, MD; Melissa Anne Mallory, MD; Stephanie Wong, MD; et al. Importance While the prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially following the introduction of breast-screening methods, the clinical significance of early detection and treatment for DCIS remains unclear. Objective To investigate the survival benefit of breast surgery for low-grade DCIS. Design, Setting, and Participants A retrospective longitudinal cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from October 9, 2014, to January 15, 2015, at the Dana-Farber/Brigham and Women’s Cancer Center. Between 1988 and 2011, 57 222 eligible cases of DCIS with known nuclear grade and surgery status were identified. Exposures Patients were divided into surgery and nonsurgery groups. Main Outcomes and Measures Propensity score weighting was used to balance patient backgrounds between groups. A log-rank test and multivariable Cox proportional hazards model was used to assess factors related to overall and breast cancer–specific survival. Results Of 57 222 cases of DCIS identified in this study, 1169 cases (2.0%) were managed without surgery and 56 053 cases (98.0%) were managed with surgery. With a median follow-up of 72 months from diagnosis, there were 576 breast cancer–specific deaths (1.0%). The weighted 10-year breast cancer–specific survival was 93.4% for the nonsurgery group and 98.5% for the surgery group (log-rank test, P < .001). The degree of survival benefit among those managed surgically differed according to nuclear grade (P = .003). For low-grade DCIS, the weighted 10-year breast cancer–specific survival of the nonsurgery group was 98.8% and that of the surgery group was 98.6% (P = .95). Multivariable analysis showed there was no significant difference in the weighted hazard ratios of breast cancer–specific survival between the surgery and nonsurgery groups for low-grade DCIS. The weighted hazard ratios of intermediate- and high-grade DCIS were significantly different (low grade: hazard ratio, 0.85; 95% CI, 0.21-3.52; intermediate grade: hazard ratio, 0.23; 95% CI, 0.14-0.42; and high grade: hazard ratio, 0.15; 95% CI, 0.11-0.23) and similar results were seen for overall survival. Conclusions and Relevance The survival benefit of performing breast surgery for low-grade DCIS was lower than that for intermediate- or high-grade DCIS. A prospective clinical trial is warranted to investigate the feasibility of active surveillance for the management of low-grade DCIS. JAMA Surg. 2015; 150(8):739-745 Ductal carcinoma in situ (DCIS) makes up approximately 20% to 25% of all breast cancers detected by mammographic screening programs. Such programs were set up to identify early invasive disease, so the large numbers of all grades of DCIS diagnosed were unexpected and unwelcome. As the natural history of untreated DCIS is largely unknown, its management is controversial; mammogram-detected DCIS is usually treated as if it is cancer, primarily with surgery. Adjuvant treatments may also be offered, which vary from hospital to hospital and from country to country.1 Surgery for DCIS has remained largely unchanged since the 1970s, and mastectomy is now performed more often than is seen with invasive cancer. It is 40 years since the inception of the first breast screening programs, and it is time to question the appropriateness and the outcomes of these management policies for screen-detected DCIS. Sagara and colleagues2 have scrutinized SEER data from 9 US states involving 57 222 women with a median 72 months’ follow-up from diagnosis. They showed that the vast majority of patients diagnosed with all grades of DCIS who did not receive surgery did not die from breast cancer. Of those patients who received surgery, 29% had a mastectomy. Among patients diagnosed with low-grade DCIS, the weighted 10-year breast cancer–specific survival of the nonsurgery group was 98.8%, and for patients having surgery, it was 98.6% (P = .95). Multivariate analysis also showed no significant difference in the weighted hazard ratios of breast cancer–specific survival between the surgery and nonsurgery groups for low-grade DCIS. There was also no overall survival benefit for patients with low-grade DCIS who had surgery compared with those who did not. The authors eloquently describe both the use of propensity score weighting and elucidate other potential problems in their article, such as limited information regarding patient characteristics and surgical margins, among others; but flaws notwithstanding, it seems more likely than not that we have been getting the treatment of low-grade DCIS wrong. Past management may have been determined with the best of intentions, but for several years now many clinicians, pathologists, statisticians, and others have voiced genuine concern about the likely overtreatment of screen-detected DCIS. Although independent reviews of screening programs3 concur that overtreatment exists, statisticians and epidemiologists do not agree about its magnitude and produce varying estimates.4 This leaves women of screening age, patients, and their surgeons with a dilemma that must be resolved with better prospective evidence gathered from multidimensional, comprehensive studies. This might not be easy, but with more women themselves recognizing the controversies surrounding DCIS,5 clinicians need to design prospective randomized trials of active monitoring with translational questions. This would give patients access to a “plan B,” namely trial participation, if they are unsure about surgery. The call by Sagara et al2 for a prospective clinical trial of active surveillance of low-grade DCIS in the United States might prove challenging, but as surgical equipoise is essential for successful trial recruitment, addressing initially the overtreatment of patients with low-grade DCIS might be the best strategy to gain surgeons’ acceptance and engagement. A unique environment exists within the United Kingdom enabling successful recruitment to such trials. The United Kingdom clinical culture is not quite as risk averse as that in the United States, and only a minority of the United Kingdom population receives screening or their medical treatment through insurance. This combination of factors permits more likelihood of enrollment in trials that offer patients less treatment despite this area being recognized as a difficult one for patients and physicians alike. The National Institute for Health Research Health Technology Assessment Programme has recently supported the Low Risk DCIS Study (LORIS) http://www.birmingham.ac.uk/loris. This important trial, driven by clinicians in partnership with patients from Independent Cancer Patients Voice, opened its feasibility phase in 2014. LORIS aims to enroll 932 patients with low-risk DCIS to standard treatment or active monitoring. Current recruitment is on target and shows yet again that women with breast cancer are brave, well informed, and altruistic. Such trials demand thoughtful planning before funding; in LORIS, the focus groups held with women who regularly underwent mammographic screening were invaluable and showed unequivocally that they needed the facts and uncertainties associated with DCIS communicated.6 Most welcomed an opportunity to participate in a trial addressing the issues. They highlighted the potential confusions caused by the terminology, so a survey of health care professionals was conducted to determine the best nomenclature to use in the trial when discussing DCIS.7 Finally, a DVD for women considering trial entry was made to explain the rationale and logic for the study in the even-handed manner demanded by such a controversial topic and which many clinicians find challenging. Active monitoring within LORIS requires large-volume core biopsies and a real-time central pathology review by expert DCIS pathologists from the United Kingdom National Sloane project to ensure that only patients with low-grade features are enrolled. Further safety features incorporate inclusion criteria designed to exclude women at higher risk of having accompanying higher-grade disease, such as the absence of a mass lesion clinically and on imaging. All patients are followed up with annual mammography, and appropriate patient-reported outcomes and health economic questions are embedded within the protocol. Pivotal to the trial is collection of tissue for translational work, and both tissue and imaging banks will provide unique future resources. The publication by Sagara and colleagues2 has provided an important platform on which, as they suggest, clinical trials of active monitoring can be successfully built. As reported in the recent Time magazine headline story,5 there are surgeons and patients across the United States ready to address these difficult issues. Women taking part in such studies will allow future generations worldwide to make informed choices based on data that currently are unavailable. Back to top Article Information Corresponding Author: Lesley Fallowfield, BSc, DPhil, University of Sussex, Sussex Health Outcomes Research & Education in Cancer, SHORE-C, University of Sussex, Falmer, East Sussex BN1 9RX, United Kingdom (l.j.fallowfield@sussex.ac.uk). Published Online: December 23, 2015. doi:10.1001/jamaoncol.2015.5026. Conflict of Interest Disclosures: Adele Francis is the Chief Investigator of LORIS. No other disclosures are reported. Funding/Support: Lesley Fallowfield is the primary investigator for the patient-reported outcomes and psychosocial substudy in the LORIS trial (ISRCTN27544579), which is funded by the National Health Service National Institute for Health Research Health Technology Assessment Programme. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. References 1. Dodwell D, Clements K, Lawrence G, et al; Sloane Project Steering Group. Radiotherapy following breast-conserving surgery for screen-detected ductal carcinoma in situ: indications and utilisation in the UK. Interim findings from the Sloane Project. Br J Cancer. 2007;97(6):725-729.PubMedGoogle ScholarCrossref 2. Sagara Y, Mallory MA, Wong S, et al. Survival benefit of breast surgery for low-grade ductal carcinoma in situ: a population-based cohort study. JAMA Surg. 2015;150(8):739-745.PubMedGoogle ScholarCrossref 3. Marmot MG, Altman DG, Cameron DA, Dewar JA, Thompson SG, Wilcox M; Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet. 2012;380(9855):1778-1786.PubMedGoogle ScholarCrossref 4. Jørgensen KJ, Gøtzsche PC. Who evaluates public health programmes? a review of the NHS Breast Screening Programme. J R Soc Med. 2010;103(1):14-20.PubMedGoogle ScholarCrossref 5. O’Connor S. Why doctors are rethinking breast-cancer treatment [published October 1, 2015]. http://time.com/4057310/breast-cancer-overtreatment/. Accessed November 18, 2015. 6. Fallowfield L, Francis A, Catt S, Mackenzie M, Jenkins V. Time for a low-risk DCIS trial: harnessing public and patient involvement. Lancet Oncol. 2012;13(12):1183-1185.PubMedGoogle ScholarCrossref 7. Fallowfield L, Matthews L, Francis A, Jenkins V, Rea D. Low grade Ductal Carcinoma in situ (DCIS): how best to describe it? Breast. 2014;23(5):693-696.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Oncology American Medical Association

Overtreatment of Low-Grade Ductal Carcinoma In Situ

JAMA Oncology , Volume 2 (3) – Mar 1, 2016

Loading next page...
 
/lp/american-medical-association/overtreatment-of-low-grade-ductal-carcinoma-in-situ-6AelDTjMQw
Publisher
American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2374-2437
eISSN
2374-2445
DOI
10.1001/jamaoncol.2015.5026
Publisher site
See Article on Publisher Site

Abstract

JAMA Surgery Survival Benefit of Breast Surgery for Low-Grade Ductal Carcinoma In Situ: A Population-Based Cohort Study Yasuaki Sagara, MD; Melissa Anne Mallory, MD; Stephanie Wong, MD; et al. Importance While the prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially following the introduction of breast-screening methods, the clinical significance of early detection and treatment for DCIS remains unclear. Objective To investigate the survival benefit of breast surgery for low-grade DCIS. Design, Setting, and Participants A retrospective longitudinal cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from October 9, 2014, to January 15, 2015, at the Dana-Farber/Brigham and Women’s Cancer Center. Between 1988 and 2011, 57 222 eligible cases of DCIS with known nuclear grade and surgery status were identified. Exposures Patients were divided into surgery and nonsurgery groups. Main Outcomes and Measures Propensity score weighting was used to balance patient backgrounds between groups. A log-rank test and multivariable Cox proportional hazards model was used to assess factors related to overall and breast cancer–specific survival. Results Of 57 222 cases of DCIS identified in this study, 1169 cases (2.0%) were managed without surgery and 56 053 cases (98.0%) were managed with surgery. With a median follow-up of 72 months from diagnosis, there were 576 breast cancer–specific deaths (1.0%). The weighted 10-year breast cancer–specific survival was 93.4% for the nonsurgery group and 98.5% for the surgery group (log-rank test, P < .001). The degree of survival benefit among those managed surgically differed according to nuclear grade (P = .003). For low-grade DCIS, the weighted 10-year breast cancer–specific survival of the nonsurgery group was 98.8% and that of the surgery group was 98.6% (P = .95). Multivariable analysis showed there was no significant difference in the weighted hazard ratios of breast cancer–specific survival between the surgery and nonsurgery groups for low-grade DCIS. The weighted hazard ratios of intermediate- and high-grade DCIS were significantly different (low grade: hazard ratio, 0.85; 95% CI, 0.21-3.52; intermediate grade: hazard ratio, 0.23; 95% CI, 0.14-0.42; and high grade: hazard ratio, 0.15; 95% CI, 0.11-0.23) and similar results were seen for overall survival. Conclusions and Relevance The survival benefit of performing breast surgery for low-grade DCIS was lower than that for intermediate- or high-grade DCIS. A prospective clinical trial is warranted to investigate the feasibility of active surveillance for the management of low-grade DCIS. JAMA Surg. 2015; 150(8):739-745 Ductal carcinoma in situ (DCIS) makes up approximately 20% to 25% of all breast cancers detected by mammographic screening programs. Such programs were set up to identify early invasive disease, so the large numbers of all grades of DCIS diagnosed were unexpected and unwelcome. As the natural history of untreated DCIS is largely unknown, its management is controversial; mammogram-detected DCIS is usually treated as if it is cancer, primarily with surgery. Adjuvant treatments may also be offered, which vary from hospital to hospital and from country to country.1 Surgery for DCIS has remained largely unchanged since the 1970s, and mastectomy is now performed more often than is seen with invasive cancer. It is 40 years since the inception of the first breast screening programs, and it is time to question the appropriateness and the outcomes of these management policies for screen-detected DCIS. Sagara and colleagues2 have scrutinized SEER data from 9 US states involving 57 222 women with a median 72 months’ follow-up from diagnosis. They showed that the vast majority of patients diagnosed with all grades of DCIS who did not receive surgery did not die from breast cancer. Of those patients who received surgery, 29% had a mastectomy. Among patients diagnosed with low-grade DCIS, the weighted 10-year breast cancer–specific survival of the nonsurgery group was 98.8%, and for patients having surgery, it was 98.6% (P = .95). Multivariate analysis also showed no significant difference in the weighted hazard ratios of breast cancer–specific survival between the surgery and nonsurgery groups for low-grade DCIS. There was also no overall survival benefit for patients with low-grade DCIS who had surgery compared with those who did not. The authors eloquently describe both the use of propensity score weighting and elucidate other potential problems in their article, such as limited information regarding patient characteristics and surgical margins, among others; but flaws notwithstanding, it seems more likely than not that we have been getting the treatment of low-grade DCIS wrong. Past management may have been determined with the best of intentions, but for several years now many clinicians, pathologists, statisticians, and others have voiced genuine concern about the likely overtreatment of screen-detected DCIS. Although independent reviews of screening programs3 concur that overtreatment exists, statisticians and epidemiologists do not agree about its magnitude and produce varying estimates.4 This leaves women of screening age, patients, and their surgeons with a dilemma that must be resolved with better prospective evidence gathered from multidimensional, comprehensive studies. This might not be easy, but with more women themselves recognizing the controversies surrounding DCIS,5 clinicians need to design prospective randomized trials of active monitoring with translational questions. This would give patients access to a “plan B,” namely trial participation, if they are unsure about surgery. The call by Sagara et al2 for a prospective clinical trial of active surveillance of low-grade DCIS in the United States might prove challenging, but as surgical equipoise is essential for successful trial recruitment, addressing initially the overtreatment of patients with low-grade DCIS might be the best strategy to gain surgeons’ acceptance and engagement. A unique environment exists within the United Kingdom enabling successful recruitment to such trials. The United Kingdom clinical culture is not quite as risk averse as that in the United States, and only a minority of the United Kingdom population receives screening or their medical treatment through insurance. This combination of factors permits more likelihood of enrollment in trials that offer patients less treatment despite this area being recognized as a difficult one for patients and physicians alike. The National Institute for Health Research Health Technology Assessment Programme has recently supported the Low Risk DCIS Study (LORIS) http://www.birmingham.ac.uk/loris. This important trial, driven by clinicians in partnership with patients from Independent Cancer Patients Voice, opened its feasibility phase in 2014. LORIS aims to enroll 932 patients with low-risk DCIS to standard treatment or active monitoring. Current recruitment is on target and shows yet again that women with breast cancer are brave, well informed, and altruistic. Such trials demand thoughtful planning before funding; in LORIS, the focus groups held with women who regularly underwent mammographic screening were invaluable and showed unequivocally that they needed the facts and uncertainties associated with DCIS communicated.6 Most welcomed an opportunity to participate in a trial addressing the issues. They highlighted the potential confusions caused by the terminology, so a survey of health care professionals was conducted to determine the best nomenclature to use in the trial when discussing DCIS.7 Finally, a DVD for women considering trial entry was made to explain the rationale and logic for the study in the even-handed manner demanded by such a controversial topic and which many clinicians find challenging. Active monitoring within LORIS requires large-volume core biopsies and a real-time central pathology review by expert DCIS pathologists from the United Kingdom National Sloane project to ensure that only patients with low-grade features are enrolled. Further safety features incorporate inclusion criteria designed to exclude women at higher risk of having accompanying higher-grade disease, such as the absence of a mass lesion clinically and on imaging. All patients are followed up with annual mammography, and appropriate patient-reported outcomes and health economic questions are embedded within the protocol. Pivotal to the trial is collection of tissue for translational work, and both tissue and imaging banks will provide unique future resources. The publication by Sagara and colleagues2 has provided an important platform on which, as they suggest, clinical trials of active monitoring can be successfully built. As reported in the recent Time magazine headline story,5 there are surgeons and patients across the United States ready to address these difficult issues. Women taking part in such studies will allow future generations worldwide to make informed choices based on data that currently are unavailable. Back to top Article Information Corresponding Author: Lesley Fallowfield, BSc, DPhil, University of Sussex, Sussex Health Outcomes Research & Education in Cancer, SHORE-C, University of Sussex, Falmer, East Sussex BN1 9RX, United Kingdom (l.j.fallowfield@sussex.ac.uk). Published Online: December 23, 2015. doi:10.1001/jamaoncol.2015.5026. Conflict of Interest Disclosures: Adele Francis is the Chief Investigator of LORIS. No other disclosures are reported. Funding/Support: Lesley Fallowfield is the primary investigator for the patient-reported outcomes and psychosocial substudy in the LORIS trial (ISRCTN27544579), which is funded by the National Health Service National Institute for Health Research Health Technology Assessment Programme. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. References 1. Dodwell D, Clements K, Lawrence G, et al; Sloane Project Steering Group. Radiotherapy following breast-conserving surgery for screen-detected ductal carcinoma in situ: indications and utilisation in the UK. Interim findings from the Sloane Project. Br J Cancer. 2007;97(6):725-729.PubMedGoogle ScholarCrossref 2. Sagara Y, Mallory MA, Wong S, et al. Survival benefit of breast surgery for low-grade ductal carcinoma in situ: a population-based cohort study. JAMA Surg. 2015;150(8):739-745.PubMedGoogle ScholarCrossref 3. Marmot MG, Altman DG, Cameron DA, Dewar JA, Thompson SG, Wilcox M; Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet. 2012;380(9855):1778-1786.PubMedGoogle ScholarCrossref 4. Jørgensen KJ, Gøtzsche PC. Who evaluates public health programmes? a review of the NHS Breast Screening Programme. J R Soc Med. 2010;103(1):14-20.PubMedGoogle ScholarCrossref 5. O’Connor S. Why doctors are rethinking breast-cancer treatment [published October 1, 2015]. http://time.com/4057310/breast-cancer-overtreatment/. Accessed November 18, 2015. 6. Fallowfield L, Francis A, Catt S, Mackenzie M, Jenkins V. Time for a low-risk DCIS trial: harnessing public and patient involvement. Lancet Oncol. 2012;13(12):1183-1185.PubMedGoogle ScholarCrossref 7. Fallowfield L, Matthews L, Francis A, Jenkins V, Rea D. Low grade Ductal Carcinoma in situ (DCIS): how best to describe it? Breast. 2014;23(5):693-696.PubMedGoogle ScholarCrossref

Journal

JAMA OncologyAmerican Medical Association

Published: Mar 1, 2016

Keywords: survival analysis,ductal carcinoma in situ,breast neoplasms,mammography,seer program,pathology,breast cancer,breast neoplasm screening,operative management of breast cancer,united kingdom,cancer surgery

References