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© 1999 American Society for Clinical Oncology Time Trends in Systemic Adjuvant Treatment for Node-Negative Breast CancerFrom the Direction de la Santé Publique, Régie Régionale de la Santé et des Services Sociaux de Montréal-Centre; Centre d'Oncologie, Centre Hospitalier de l'Université de Montréal, Campus Hôtel-Dieu; Département de Pathologie, Centre Hospitalier de l'Université de Montréal, Campus Saint-Luc, Montréal; Groupe de Recherche en Épidémiologie de l'Université Laval, Hôpital du Saint-Sacrement; and Département de Chirurgie, Hôpital du Saint-Sacrement, Québec, Canada. Address reprint requests to Nicole Hébert-Croteau, MD, PhD, Direction de la santé publique de Montréal-Centre, 4835, ave Christophe-Colomb, Montréal, Québec, H2J 3G8 Canada; email ncroteau{at}santepub-mtl.qc.ca
PURPOSE: We conducted a population-based study in Quebec, Canada, to assess longitudinal changes in systemic adjuvant therapy for node-negative breast cancer. MATERIALS AND METHODS: A stratified random sample was selected among women with newly diagnosed node-negative breast cancer in 1988, 1991, and 1993. Information on the patient, her tumor, source of care, and treatment was abstracted from medical charts. Patients were classified as being at minimal, moderate, or high risk of recurrence on the basis of criteria proposed at the 4th International Conference on Adjuvant Therapy of Primary Breast Cancer (St. Gallen, Switzerland, 1992), and systemic adjuvant treatment received was dichotomized as being consistent or not consistent with consensus recommendations. RESULTS: Overall, 1,578 cases of invasive breast carcinoma were reviewed. The proportion of patients who were given hormonal or cytotoxic treatment increased from 51.7% to 73.1% from 1988 to 1993. Virtually all women at minimal risk were treated in 1991 and 1993 according to the consensus statement. The proportions of women so treated were 75.0% and 65.4% in the moderate- and high-risk categories, respectively, in 1991. In 1993, these proportions were 71.4% and 67.0%, respectively. Omission of chemotherapy, especially in high-risk women with estrogen receptor–negative tumors who were 50 to 69 years of age, was the most frequent inconsistency with guidelines. CONCLUSION: Systemic adjuvant therapy for node-negative breast cancer has gained acceptance. Better understanding of the decision-making process, of the perception of the risks and benefits involved, and of the impact of alternative strategies for the dissemination of consensus recommendations are needed to promote the use of chemotherapy in specific categories of women who are at high risk of recurrence.
SINCE PUBLICATION of the 1988 Clinical Alert1 suggesting that women with node-negative breast cancer could benefit from systemic adjuvant treatment, several consensus conferences have defined recommendations for treatment of early-stage breast cancer. Approximately 70% of all new cases of breast cancer are free from nodal extension.2 Such guidelines are therefore likely to have implications for large numbers of women, more so in areas where screening by mammography is active. The 1990 National Institutes of Health Consensus Conference issued recommendations concerning the locoregional management of breast cancer that still represent current standards of care.3 For systemic adjuvant treatment, tumor size greater than 1 cm was then specified as the threshold beyond which such treatment should be considered after discussion of the associated risks and benefits with each patient. Successive consensus panels further refined recommendations for systemic adjuvant treatment.4,5 The 4th International Conference on Adjuvant Therapy of Primary Breast Cancer held in St. Gallen, Switzerland, in 1992 identified three groups of node-negative patients at distinct risk of recurrence, each with specific systemic treatment recommendations.4 The aim of the present study was to assess the evolution over time of the use of systemic adjuvant therapy for node-negative breast cancer and to compare systemic treatments given with the recommendations of the 1992 St. Gallen International Conference.
Study Population Patients were randomly selected among all new cases of breast cancer (International Classification of Diseases [ICD-9 ]codes 174.0 to 174.9 and 233.0) without regional or distant extension codes (ICD-9 196.0 to 199.9) reported to the Quebec tumor registry during the periods of April 1, 1988, to March 31, 1989, and April 1, 1991, to March 31, 1992. For the 1993 to 1994 time period, the Quebec hospital admission/discharge database was used, because data from the tumor registry for that year were not yet available at the time the study began. The hospital admission/discharge database includes information on both new and recurrent cases of breast cancer, and oversampling was performed to account for this. Only women residing in five major regions of Quebec (Montreal, Quebec, Chaudière/Appalaches, Laval, and Montérégie) were eligible. These regions account for more than 60% of the Quebec population.6 To compare medical practice between hospitals that are involved and those that are not involved in clinical research, the sample was stratified according to participation in multicenter clinical trials other than those sponsored by the pharmaceutical industry (National Surgical Adjuvant Breast and Bowel Project, Clinical Trials Group of the National Cancer Institute of Canada, and so on). Overall, 3,217 hospital admissions were selected. After elimination of noneligible cases or multiple admissions of the same patient, the final sample included 1,732 women with newly diagnosed breast cancer. We present here results for 1,578 women with invasive breast carcinoma (the 154 cases with ductal carcinoma-in-situ will be reported separately). Main reasons for exclusion were admission in a long-term or convalescent hospital; diagnostic errors; multiple registrations of the same patient; multiple primary tumors or recurrent breast tumors; cases with regional or distant extension; multicentric, inflammatory, or stage III or IV breast tumors; as well as women without confirmation of their disease at pathology. Tumors not originating from the mammary gland (eg, lymphomas) or having uncertain or nonmalignant behavior (eg, phyllodes tumors or lobular carcinomas-in-situ) were also excluded.
Data Collection
Study Variables
Patients were first assigned a risk category using the St. Gallen 1992 criteria.4 The first group at minimal risk of recurrence included noninvasive tumors, incidentally discovered small invasive tumors, and tumors of favorable histologic types (colloid, tubular, or papillary). All tumors measuring 1 cm or less with grade 1, 2, or missing were included in this category, except estrogen receptor–negative (ER-) tumors measuring 1 cm for which the mode of discovery was either unknown or clearly not incidental, which were classified as high risk. Moderate-risk patients were defined as having estrogen receptor–positive (ER+), grade 1 or 2 tumors greater than 1 cm but Patients who were on experimental protocol were automatically classified as having received treatment consistent with recommendations. Otherwise, systemic adjuvant treatments were classified as consistent with recommendations if women at minimal risk had received no treatment or tamoxifen only and if women at moderate risk had received tamoxifen alone. Compliance for high-risk women was defined by taking into account age and estrogen receptors as follows: women younger than 50 years of age who received chemotherapy (with or without tamoxifen), women between 50 and 69 years of age with ER- tumors who received chemotherapy (with or without tamoxifen), women between 50 and 69 years of age with ER+ tumors who received tamoxifen (with or without chemotherapy), women between 50 and 69 years of age with ER-unknown tumors who received chemotherapy and/or tamoxifen, and women 70 years or older who received tamoxifen (with or without chemotherapy) were considered as having had treatment consistent with recommendations.
Data Analysis
Table 1 lists characteristics of the study population. A total of 1,578 cases of node-negative invasive breast cancer were included in the study. Two thirds of cases (66.9%) were classified as stage I disease and 31.0% were stage II. Staging could not be performed due to lack of information in the chart in 2.2% of cases. In approximately 90% of tumors, size was estimated at pathology. Information regarding tumor grade was frequently absent from the chart, especially in hospitals that are not involved in clinical research (47.0% of cases in these hospitals v 22.2% in other centers). Hormone receptors were measured in approximately 80% of cases, and more than one half (57.4%) were classified as ER+. Women were classified as being at minimal risk of recurrence in 23.5% of cases, at moderate risk in 12.9%, and at high risk in 50.0%.
The vast majority of these women (84.3%) had surgery with breast preservation, whereas 15.3% had total breast ablation and less than 1% did not have any surgical intervention. Dissection of the axilla was performed in 1,259 cases (79.8% of the total), and 723 of these had at least 10 nodes examined at pathology. However, women who had no axillary dissection were all considered as being node-negative on the basis of their clinical examination, as indicated in the chart. Radiation therapy was given to 71.5% of all cases and 83.3% of women with breast preservation surgery. Definitive locoregional treatment, defined as total mastectomy with axillary dissection or breast-conserving surgery with both axillary dissection and radiation therapy, was therefore received by more than three quarters of patients (76.1%). In hospitals collaborating to multicenter clinical trials, the proportions of patients formally enrolled in such trials declined over time, from 29.7% in 1988, to 21.1% in 1991, and to 9.9% in 1993. The proportion of women who received systemic adjuvant treatment increased substantially from 1988 to 1991, from 51.7% to 72.8%, but this proportion remained stable thereafter (Table 2). From 1991 to 1993, almost three quarters of women with node-negative breast cancer were receiving some form of systemic therapy. This trend was largely attributable to the prescription of tamoxifen, taken by 43.6% and 64.0% of patients in 1988 and 1991, respectively. Similarly, use of chemotherapy increased between 1988 and 1991. In contrast, overall use of tamoxifen and chemotherapy changed little between 1991 and 1993.
The increase in tamoxifen use in the period of 1988 to 1991 was seen in virtually all categories of patients irrespective of age and tumor characteristics (Table 3). However, it was especially important in the group of women with ER- tumors, in which the proportion of tamoxifen users more than doubled, increasing from 20.1% in 1988 to 49.1% in 1991. Stability of tamoxifen use in 1991 and 1993 was also apparent in virtually all subgroups. On the other hand, trends in use of chemotherapy varied according to tumor characteristics. In women with tumors
In 1991, 75.7% of cases were already treated as recommended according to guidelines established in 1992 (Table 4). In 1993, this percentage remained essentially unchanged. After 1991, improvement in compliance with guidelines was seen only in women with very large tumors, increasing from 72.6% to 74.8% for women with tumors measuring 2.1 to 4 cm, and from 57.1% to 70.4% for women with tumors measuring more than 4 cm. In 1993, the proportion of women who received treatment consistent with guidelines was highest among women who were at minimal risk of recurrence (97.2% of invasive tumors and 100% of ductal carcinomas-in-situ) and lowest among women who were at high risk (67.0%).
Departures from the St. Gallen recommendations were mainly explained by low use of chemotherapy among women for whom it was the minimal recommended adjuvant treatment, ie, women having an indication of chemotherapy, whether or not tamoxifen was also given (Table 5). Many clinicians seem to prefer using tamoxifen alone in these high-risk cases. For instance, in 1993, 74.9% of women for whom tamoxifen was indicated as minimal systemic adjuvant therapy actually were prescribed this medication. By contrast, only 45.3% of those for whom chemotherapy was indicated as minimal adjuvant treatment actually received it. However, 25.9% of these women received tamoxifen alone.
The issue of undertreatment by chemotherapy affects primarily women who are 50 to 69 years of age with ER- tumors and a high risk of recurrence. In 1993, only 27.3% of these women received chemotherapy, even though chemotherapy was recommended as minimal adjuvant therapy. However, it was also observed among women younger than 50 years and at high risk of recurrence, where this proportion of women receiving chemotherapy reached 60.2%. In 1993, 36.4% and 16.9% of women from these two groups were prescribed tamoxifen alone.
From 1988 to 1991, use of systemic therapy in the management of node-negative breast cancer increased considerably in the regions studied. Consistency of treatments with 1992 international recommendations was already high in 1991, reaching 76% before the dissemination of these guidelines. From 1991 to 1993, the overall use of systemic treatments and consistency with recommendations remained essentially unchanged. However, prescription of chemotherapy continued to increase among women with a poor prognosis and decrease in those at low risk, showing a greater tendency to tailor use of adjuvant treatment according to risk of recurrence. The main discrepancy between systemic treatments received and those recommended is attributable to undertreatment of women at moderate or high risk of recurrence. Moreover, underuse of chemotherapy seems somewhat greater than underuse of tamoxifen. However, the extent of underuse is difficult to evaluate based on our data. First, given the limitations of the information available, true levels of use of systemic therapy, especially tamoxifen, may be underestimated. Information on systemic treatments is recorded in medical charts of different institutions and sometimes in the files of private clinics. For instance, cases first treated in smaller hospitals were often referred to larger centers with specialized resources in oncology where systemic treatments were initiated. This referral might not always be mentioned in the hospital chart where initial surgery was performed. Moreover, tamoxifen can be prescribed at follow-up visits in private clinics and may not be mentioned in the hospital records. We have attempted to upgrade our database by actively tracking all possible sources of information on systemic treatments given to women. Nevertheless, the levels of use of systemic adjuvant therapy that are reported here are still likely to be underestimates of true levels of use. Second, comorbidity and absolute or relative contraindications of systemic treatments were not taken into account. Information about contraindications to systemic therapy are not systematically recorded in medical charts. Contraindications could explain why some women did not receive systemic treatments as recommended. This factor might be especially important in explaining, at least in part, the relatively low use of chemotherapy in women older than 50 years.9-12 Third, in the late 1980s and early 1990s, concerns regarding the possibility of short- and long-term toxicity of systemic adjuvant chemotherapy probably represented a limitation to its use in this subgroup of cases given their high long-term survival. Data at 10 years of follow-up of the Early Breast Cancer Trialists' Collaborative Group13 clearly demonstrated the ability of polychemotherapy and tamoxifen to increase disease-free and overall survival in equal proportions among women with node-positive and node-negative disease. More recently, results at 5 years of follow-up for the National Surgical Adjuvant Breast and Bowel Project B-20 study confirmed the value of chemotherapy in virtually all subgroups of patients with breast cancer, although it failed to reach statistical significance in women 50 years or older for the majority of clinical end points.14 However, the absolute benefit of chemotherapy remains small in node-negative patients. Thus, after evaluation of risks and benefits, a relatively large proportion of women and their physicians may still decide to forego chemotherapy despite the results of clinical trials. Finally, the observed level of consistency with standards of care depends in part on the specific set of recommendations chosen as referent. For our purpose, the guidelines proposed at the 1992 St. Gallen conference had several advantages. The panel responsible for developing these guidelines included internationally recognized experts from North America as well as Europe. They were published in the middle of the period studied, allowing examination of time trends in practice patterns. Moreover, recommendations were sufficiently detailed and specific to allow comparison with actual practice. However, there remains some degree of uncertainty about the 1992 St. Gallen guidelines, especially with respect to the detailed definition of risk categories. A system of classification with a broader definition of the low-risk category would likely have resulted in a higher level of consistency with recommendations, but a classification with a broader definition of the high-risk category would have led to lower levels of consistency. Systemic treatment recommendations for women with node-negative breast cancer continue to vary according to risk of recurrence.15 However, information on the prognostic features needed to determine this risk was absent from many medical records in our own study. For instance, information regarding tumor grade was missing for 33% of cases. In addition, approximately 20% of our study population, mainly older women, did not undergo surgical exploration of the axilla. The importance of complete assessment of risk for recurrence to allow informed decision making about the use of adjuvant treatment therefore needs to be emphasized. The availability and quality of clinical data are critical to this issue. The increase in systemic treatments for node-negative breast cancer was closely linked in time with the publication of documents such as the 1988 Clinical Alert,1 articles regarding the first generation of clinical trials of systemic adjuvant therapy for node-negative breast cancer,16-19 and the Early Breast Cancer Trialists' Collaborative Group meta-analysis.13,20 These data appeared over a short interval and were widely disseminated in Quebec. Physicians seem to have responded quite rapidly to this new information. As compared with other Canadian provinces such as Ontario or British Columbia, use of systemic treatment among early-stage breast cancer patients in Quebec seems high.21 For example, in 1991, 28.4% and 17.5% of node-negative patients from Ontario and British Columbia received tamoxifen as compared with 64.0% in Quebec. For chemotherapy, these percentages were 7.1% and 9.6% respectively, compared with 18.4% in Quebec. After 1991, the medical literature and consensus-building initiatives seem to have had a smaller effect on practice patterns in this province. These results highlight the importance of the diffusion of new knowledge and consensus conference recommendations, mainly through medical journals, as a key determinant of clinical decision making by clinicians involved in the care of women with breast cancer.22,23 The major changes observed in patterns of care occurred in the absence of formally approved practice guidelines in the regions studied. The adoption of such guidelines might have led to higher levels of consistency of observed treatments with international recommendations. However, consensus conferences and practice guidelines in themselves have often been shown to have little influence on medical practice.22-24 This conclusion seems justified, although evaluative studies have often been impaired by use of data of low reliability (such as those derived from surveys or contained in administrative databases), lack of a control group, assessment only at a single point in time, and insufficient lag time between diffusion of the information and the evaluation of its impact.22,25-27 Several factors have been suggested to explain this limited impact, including inadequate dissemination strategies, disagreement in the medical community with the actual content of the guidelines, the importance of individualizing care to the needs and preferences of each patient, and the lack of organizational incentives to promote adoption of the recommended new practices.26-32 Thus practice guidelines may have improved consistency with recommendations if they had been coupled with an effective implementation strategy using multiple approaches.26,33 In conclusion, a longitudinal evaluation of treatment of node-negative breast cancer patients in Quebec suggests a substantial increase from 1988 to 1993 in the use of systemic adjuvant therapy. However, chemotherapy remained underutilized among women at high risk of recurrence. Our data suggest that education of health professionals and women about new knowledge appearing in the medical literature and dissemination of recommendations of international consensus conferences can rapidly improve the care of women with node-negative breast cancer.
Supported by the Fonds de la Recherche en Santé du Québec. We thank Andrée Christen, Ghislaine Gascon, Aline Pelletier, and Diane Roy, who assumed the supervision of data collection and review of medical charts, and Brigitte Simard and Ginette Gendron, who provided technical and secretarial assistance.
1. US National Cancer Institute: Clinical alert from the National Cancer Institute. Breast Cancer Res Treat 12:3-5, 1988[Medline]
2.
Ries L: Breast cancer stage distribution. J Natl Cancer Inst 87:1435, 1995 3. National Institute of Health: Treatment of early-stage breast cancer: NIH Consensus Conference. JAMA 265:391-395, 1991[Medline]
4.
Glick JH, Gelber RD, Goldhirsh A, et al: Meeting highlights: Adjuvant therapy for primary breast cancer. J Natl Cancer Inst 84:1479-1485, 1992
5.
Goldhirsch A, Wood WC, Senn HJ, et al: Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 87:1441-1445, 1995 6. Pageau M, Ferland M, Choinière R, et al: Indicateurs sociosanitaires: Le Québec et ses régions. Québec, Québec, Canada, Direction générale de la santé publique, Ministère de la Santé et des Services sociaux, Gouvernement du Québec, 1997 7. American Joint Committee on Cancer: Manual for Staging of Cancer (ed 4). Philadelphia, PA, JB Lippincott, 1992, pp 149-154 8. Levy PS, Lemeshow S: Sampling for Health Professionals. Belmont, CA, Lifetime Learning Publications, 1980 9. Morrow M: Breast disease in elderly women. Surg Clin North Am 74:145-161, 1994[Medline]
10.
Ballard-Barbash R, Potosky AL, Harlan LC, et al: Factors associated with surgical and radiation therapy for early stage breast cancer in older women. J Natl Cancer Inst 88:716-726, 1996 11. Muss HB: Breast cancer in older women. Semin Oncol 2:82-88, 1996 (suppl 1) 12. Law TM, Hesketh PJ, Porter KA, et al: Breast cancer in elderly women: Presentation, survival, and treatment options. Surg Clin North Am 76:289-308, 1996[Medline] 13. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339:1-15, 71-85, 1992
14.
Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89:1673-1682, 1997 15. Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer: Adjuvant systemic therapy for women with node-negative breast cancer. Can Med Assoc J 158:43-51, 1998 (suppl 3) 16. Fisher B, Redmond C, Dimitrov NV, et al: A randomized clinical trial evaluating methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 320:473-478, 1989[Abstract] 17. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor positive tumors. N Engl J Med 320:479-484, 1989[Abstract] 18. Mansour EG, Gray R, Shatila AH, et al: Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer. N Engl J Med 320:485-490, 1989[Abstract] 19. The Ludwig Breast Cancer Study Group: Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med 320:491-496, 1989[Abstract] 20. Early Breast Cancer Trialists' Collaborative Group: Effect of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer: An overview of 61 randomized trials among 28,896 women. N Engl J Med 319:1681-1692, 1988[Abstract] 21. Sawka C, Olivotto I, Coldman A, et al: The association between population-based treatment guidelines and adjuvant therapy for node-negative breast cancer. Br J Cancer 75:1534-1542, 1997[Medline] 22. Lomas J: Words without action? The production, dissemination and impact of consensus recommendations. Annu Rev Public Health 12:41-65, 1991[Medline] 23. Fineberg HV: Clinical evaluation: How does it influence medical practice? Bull Cancer 74:333-3346, 1987[Medline] 24. Grimshaw JM, Russell IT: Effect of clinical guidelines on medical practice: A systematic review of rigorous evaluations. Lancet 342:1317-1322, 1993[Medline] 25. Donabedian A: Evaluating the quality of medical care. Milbank Q 44:166-203, 1966 26. US Congress, Office of Technology Assessment: Identifying Health Technologies that Work: Searching for Evidence. Washington, DC, US Office of Technology Assessment, 1994, Publication OTA-H-608 27. Lomas J, Anderson GM, Dominck-Pierre K, et al: Do practice guidelines guide practice? The effect of a consensus statement on the practice of physicians. N Engl J Med 321:1306-1311, 1989[Abstract]
28.
Mooney G, Ryan M: Rethinking medical audit: The goal is efficiency. J Epidemiol Community Health 46:180-183, 1992
29.
Grilli R, Alexanian A, Apolone S, et al: The impact of treatment guidelines on actual practice in Italian general hospitals: The case of ovarian cancer. Ann Oncol 1:112-118, 1990 30. Grilli R, Apolone G, Marsoni S, et al: The impact of patient management guidelines on the care of breast, colorectal and ovarian cancer patients in Italy. Med Care 29:50-63, 1991[Medline] 31. Rosser WW, Palmer WH: Dissemination of guidelines on cholesterol: Effect on patterns of practice of general practitioners and family physicians in Ontario. Can Fam Physician 39:280-284, 1993[Medline]
32.
American Cancer Society: Survey of physicians' attitudes and practices in early cancer detection. CA Cancer J Clin 35:197-213, 1985 33. Davis DA, Taylor-Vaisey A: Translating guidelines into practice: A systematic review of theoretic concepts, practical experience and research evidence in the adoption of clinical practice guidelines. Can Med Assoc J 157:408-416, 1997[Abstract] Submitted March 16, 1998; accepted January 20, 1999. This article has been cited by other articles:
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 cm. Finally, the high-risk group included ER- tumors measuring 1 cm or more (except incidentally discovered tumors measuring 1 cm), ER+tumors greater than 2 cm, and grade 3 tumors. In this classification, histologic type and grade were considered before tumor size in defining risk. Consequently, tumors with colloid, tubular, or papillary histologic type measuring greater than 2 cm were considered as being at minimal risk, whereas grade 3 tumors were automatically classified as being at high risk of recurrence, regardless of size. 
