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Originally published as JCO Early Release 10.1200/JCO.2004.07.018 on August 2 2004 © 2004 American Society of Clinical Oncology. Compliance With Consensus Recommendations for Systemic Therapy Is Associated With Improved Survival of Women With Node-Negative Breast CancerFrom the Direction des systèmes de soins et services, Institut national de santé publique du Québec; Programme d'oncologie, Hôpital Charles LeMoyne; Centre intégré de lutte contre le cancer de la Montérégie, Greenfield Park; Unité de recherche en santé des populations, Hôpital du Saint-Sacrement; Département de médecine sociale et préventive, Université Laval, Québec; Département de médecine sociale et préventive, Université de Montréal; and Département de chirurgie, Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada Address reprint requests to Nicole Hébert-Croteau, MD, PhD, Institut national de santé publique du Québec, 4835 ave. Christophe-Colomb, Montreal, Québec H2J 3G8, Canada; e-mail: Nicole.Hebert-Croteau{at}Inspq.qc.ca
PURPOSE: The impact of consensus recommendations for systemic therapy on outcome of disease is unclear. We evaluated if compliance with guidelines for systemic adjuvant treatment is associated with improved survival of women with node-negative breast cancer. PATIENTS AND METHODS: The study population included women diagnosed with invasive node-negative breast cancer in Québec, Canada, in 1988 to 1989, 1991 to 1992, and 1993 to 1994. Information was collected by chart review, linkage with administrative databases, and queries to attending physicians. Guidelines from the 1992 St Gallen conference were used as standard of care. Survival was estimated by Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Among 1,541 women, 358 died before December 1999. Median follow-up was 6.8 years. Seven-year event-free and overall survivals were 66% and 81%, respectively. Survival was 88%, 84%, and 74% in women at minimal, moderate, or high risk of recurrence. Virtually all women at minimal risk were treated according to the consensus (98.4% of 370). In comparison, adjusted hazard ratios of death were 1.0 (95% CI, 0.6 to 1.7) and 2.3 (95% CI, 1.3 to 4.0) among women at moderate risk treated according to the consensus or not, respectively. Among women at high risk, adjusted hazard ratios of death were 2.0 (95% CI, 1.4 to 2.8) and 2.7 (95% CI, 1.9 to 3.9), respectively. Both risk category (P < .0005) and compliance with guidelines (P < .0005) were independent significant predictors of survival. CONCLUSION: Treatment according to consensus recommendations is associated with improved survival of women with breast cancer in the community. Promoting the adoption of guidelines for treatment is an effective strategy for disease control.
Practice guidelines are used to improve quality of care, reduce inappropriate interventions, and control costs.1,2 Although several studies have shown reasonable compliance with consensus recommendations for treatment of breast cancer,3-8 their impact on survival remains unclear. A recent hospital-based investigation in Rhode Island showed higher recurrences and mortality at 5 years among women who received less than definitive prognostic evaluation or therapy.9 This is consistent with an extensive review of the available evidence that suggests a positive impact of clinical guidelines on both the process and outcome of care for several health conditions,10 although opposite views have been expressed.11 Overall, however, population-based evaluations of the effects of compliance with guidelines for multimodal therapy of breast cancer are lacking, especially among women with node-negative disease. We studied time trends in systemic adjuvant therapy among women diagnosed with localized breast cancer in Québec, Canada.7,12,13 The proportion of women receiving systemic treatment increased substantially between 1988 and 1991, from 44% to 64% for tamoxifen and from 12% to 18% for chemotherapy. Moreover, conformity of care with consensus guidelines increased from 64% in 1988 to 76% in 1991. We observed this cohort to evaluate if compliance with guidelines for systemic adjuvant therapy improved survival.
Study Population The sampling procedure has been described.7 Patients were randomly selected among all new cases of node-negative breast cancer reported to the Québec tumor registry (QTR) in 1988 to 1989 and 1991 to 1992, and to the province hospital discharge database in 1993 to 1994. These specific years were chosen to conduct a pattern-of-care study during the periods both before and 1 year after the 1990 National Institutes of Health and the 1992 St Gallen consensus conferences. The completeness of the QTR for breast cancer registration has been estimated at 98.8%.14 This registry uses the hospital discharge database as its sole source for patient identification. The sample was stratified according to hospital participation in collaborative clinical trials. Approximately 50% of patients with node-negative breast cancer registered in these databases were sampled. Residents of five regions were eligible: Montréal, Québec, Chaudière/Appalaches, Laval, and Montérégie, together accounting for 62% of the population of the province during this period.15 Main exclusions were multiple primary tumors; multicentric, inflammatory, in situ, and stage III, IV, or unknown breast tumors; and patients with regional extension at chart review, lack of pathologic confirmation of diagnosis, tumors not originating from the mammary gland (eg, lymphomas), or nonmalignant tumors (eg, lobular carcinoma in situ). Women lost to follow-up immediately after primary treatment (n = 37) were also excluded. The project was approved by the Commission d'accès à l'information du Québec, the directors of professional services in all hospitals, and research ethics committees.
Data Collection
Study Variables
Patients were assigned a risk category for recurrence at baseline using the St Gallen 1992 conference criteria,19 the only detailed consensus about node-negative breast cancer universally available in Québec during the study period. This classification used tumor size, invasiveness, grade, histology, estrogen receptor (ER) status, and mode of discovery. The algorithms defining risk of recurrence and compliance with recommended treatment have been published and are summarized in the Appendix.7 Briefly, women at minimal risk of recurrence were those with incidentally discovered small invasive tumors or tumors with colloid, tubular, or papillary histology. All invasive tumors measuring 1 cm or less with grade 1, 2, or unknown were included in this category, except ER-negative tumors of 1 cm with mode of discovery unknown or symptomatic, which were classified as high risk. Patients at moderate risk were women with ER-positive, grade 1 or 2 invasive tumors greater than 1 cm but Patients who were treated with an experimental protocol were automatically classified as having received treatment consistent with guidelines. Otherwise, systemic adjuvant treatments were classified as consistent with guidelines if women at minimal risk had received no treatment or tamoxifen only, and if women at moderate risk had received tamoxifen alone. For women at highrisk, those younger than age 50 years who received chemotherapy (with or without tamoxifen), women between age 50 and 69 years with ER-negative tumors who received chemotherapy (with or without tamoxifen), women between age 50 and 69 years with ER-positive tumors who received tamoxifen (with or without chemotherapy), women between age 50 and 69 years with ER status unknown who received tamoxifen and/or chemotherapy, and women 70 years or older who received tamoxifen (with or without chemotherapy) were considered as having been treated according to the guidelines.
Data Analysis Survival analysis was done using Kaplan-Meier estimates and Cox proportional hazards analysis of event-free, relapse-free, distant–disease-free, overall, and breast cancer–specific survivals. Events included in the computation of these outcomes were local, regional, or distant recurrences, and deaths as a result of any cause for relapse-free survival. Distant recurrences, second primary tumors, and deaths defined distant–disease-free survival. Any recurrence, second primary tumor, or death was included in the calculation of event-free survival. To avoid bias resulting from competing risks, only first events were used in the analysis.20 Time patients received follow-up was computed from the date of pathologic diagnosis and was censored at the last medical consultation in the analysis of recurrences. Women having moved out of the province were censored at the date they moved. Kaplan-Meier estimates of survival according to risk category and conformity of systemic treatment with guidelines, individually or combined, were compared by the log-rank test. Survival rates and their 95% CIs at specific years after diagnosis were estimated. Cox proportional hazards models used as a main independent variable the combined classification of risk and conformity of systemic treatment with guidelines. Several prognostic factors, including tumor size, grade, ER status, margin status, and lymphatic or vascular infiltration (which did not improve the prediction of the models once risk category and compliance with guidelines were taken into account) were omitted from the analysis; only age, comorbidity, and locoregional treatment were kept as adjustment variables. Hazard ratios are expressed in reference to the baseline category of women at minimal risk who received treatment consistent with guidelines. In all models, the proportionality assumption was verified both graphically and by maximum likelihood estimation using time-dependent covariates, and goodness of fit was assessed by residual analysis. A 5% level of statistical significance was used and all tests were bilateral.
Study Population Characteristics of the 1,541 women in the cohort are listed in Table 1. Discovery of the disease was triggered by symptoms in most patients. Only 32 women had a Charlson's comorbidity index of 2 or more. Tumor size was  1 cm in 25% of patients, 1 to 2 cm in 44% of patients, and larger than 2 cm in 31% of patients. Approximately 7% of tumors had favorable histology (colloid, tubular, or papillary tumor), 38% were grade 3, 58% were ER-positive, and 9% displayed lymphatic or vascular infiltration. Surgical margins were still involved with tumor in 18% of patients after the last surgery. Overall, 12% of women participated in a clinical trial. Only 15% had total mastectomy, and the majority had conservative surgery with (71%) or without (14%) radiation therapy. Dissection of the axilla was performed in 80% of patients. Risk of recurrence was minimal in 24%, moderate in 13%, and high in 51% of the cohort. Risk of recurrence could not be inferred because of incomplete information in the charts in 12% of patients. Almost two thirds of these women received treatment consistent with recommendations for their risk category. In the minimal-risk category, this proportion reached 98.4%. Table 2 summarizes systemic treatment received by 380 patients who were not treated according to the consensus.
Actuarial Estimates of Survival Table 3 lists events used in the analysis of event-free survival. Median follow-up was 6.8 years. Kaplan-Meier estimates of survival are shown in Figure 1. For the whole cohort, 7-year event-free, relapse-free, distant–disease-free, and overall survivals were 66% (95% CI, 63% to 69%), 70% (95% CI, 68% to 73%), 71% (95% CI, 68% to 73%), and 81% (95% CI, 78% to 83%; Table 4), respectively. Survival was better in women at minimal than intermediate risk, who themselves had better survival than women at high risk of recurrence. Women for whom a risk category could not be inferred at chart review had intermediate survival, as expected because this likely is a composite group of all categories. Associations of outcomes with risk were highly significant for event-free (P < .00005), relapse-free (P < .00005), distant–disease-free (P < .00005), and overall survivals (P < .00005), and this was unchanged by adjustment for systemic treatment received.
Survival was also better in women treated according to the consensus, although the difference was more obvious in the moderate-risk group in crude analysis. Conformity of treatment was significantly associated with event-free (P < .00005), relapse-free (P < .00005), distant–disease-free (P < .00005), and overall survivals (P < .00005), even after adjustment for risk category.
Multivariate Analyses of Survival
When the analysis was restricted to breast cancer–specific survival, hazard ratios were 1.9 (95% CI, 0.7 to 5.4) and 2.4 (95% CI, 0.7 to 9.1) among intermediate-risk women (for the comparison with women at minimal risk treated according to the consensus, P = .2 for both), and 5.5 (95% CI, 2.7 to 11.1) and 7.4 (95% CI, 3.6 to 15.2) in women at high risk (P < .0005 for both) treated according to the consensus or not, respectively, but the number of events in each stratum then became small. Finally, models including risk category, conformity with guidelines, and their interaction as distinct covariates were fitted, still adjusting for age, comorbidity, and locoregional treatment. Both risk category (likelihood ratio statistic comparing models with and without risk, P < .0005) and treatment according to the consensus (likelihood ratio statistic comparing models with and without conformity with guidelines, P < .0005) were significant independent predictors of survival. Interaction did not reach statistical significance. The hazard ratios of death as a result of any cause were 1.2 (95% CI, 0.8 to 1.9; P = .4) in women at moderate risk, 2.0 (95% CI, 1.4 to 2.8; P < .0005) in those at high risk, both relative to women at minimal risk, and 0.7 (95% CI, 0.5 to 0.9; P = .005) in individuals treated according to the consensus versus otherwise.
This study suggests that women treated for node-negative breast cancer according to consensus recommendations for systemic therapy experience a significant improvement in survival at 7 years. As expected, reduction of relapses, an important goal of therapy in node-negative breast cancer,21 was even more substantial. The systematic evaluation of the impact of guidelines for treatment of breast cancer is lacking. Given our study design, a direct causal relationship cannot be inferred because noncompliance with practice guidelines may be a surrogate for other determinants of poor outcomes. Nevertheless, the observed associations support the current movement for developing, updating, and disseminating such recommendations observed both internationally and regionally. Few investigations assessing the impact of compliance with guidelines have focused on outcomes of breast cancer using a population-based approach and individual patient data. Limitations in the completeness and validity of the information contained in the databases for this assessment is one reason,8,22 and this also applies to our study. We attempted to limit missing or inaccurate data by using multiple sources of information. In addition, Québec has a universal health care system, allowing longitudinal surveillance of hospital admissions and medical consultations. Nevertheless, it is plausible that some events treated on an ambulatory basis elsewhere than the hospital of primary care were missed by our strategy for tracking patients. Underestimation of tamoxifen use is also possible, given that this treatment could have been prescribed on an ambulatory basis and not reported by the clinicians at the time of our queries for information. Because these omissions are likely to be random, the resulting bias would be conservative. Another limitation is the short median follow-up of this cohort given its good prognosis. Given that most recurrences are expected within the first 5 years,23,24 lack of statistical power to detect a treatment difference would be more important for survival than for other outcomes. Finally, although our estimates were adjusted for comorbidity, we did not take into account functional status, a factor related to both treatment decision and survival. Meta-analyses of clinical trials show an improvement of 5.6% in 10-year survival with 5 years of tamoxifen treatment 25 and 2% with polychemotherapy26 in women with node-negative disease. Thus, our study supports the notion that, with respect to systemic adjuvant therapy for breast cancer, the benefit observed in clinical trials is expected on the field. Our data confirm the independent prognostic validity of the St Gallen classification of women with node-negative breast cancer. They also support its recent updates. Disease-free and overall survivals were similar in women at minimal and moderate risk in multivariate analysis. This lack of difference could be explained by some misclassification of risk, especially as a result of missing values of critical variables, such as tumor grade or ER status. The significant difference with the high-risk category, however, should be even more important without this problem. However, the 2001 consensus recognized only two categories of women at minimal and high risk.27 The prognostic factors used in this classification are routinely available and relatively free of the measurement problems reported with other biomarkers, which increase its applicability.28 Although most departures from guidelines in our series were from underuse of specific therapies, the development of new technologies, such as gene profiling, should allow a more accurate estimation of prognosis and reduce both over- and undertreatment.29,30 Compliance with guidelines depends in part on the method used to develop them. Formal consensus is one among several of these methods.31 For breast cancer, consensus conferences on primary therapy have been used extensively because new information accumulates rapidly. The process usually involves experts and rests on a rigorous evaluation of the available evidence, two conditions perceived to increase its scientific quality, therefore promoting compliance.1,30,31 Other factors stimulating the adoption of guidelines include their dissemination strategy and implementation of mechanisms for feedback and accountability.1,31,32 In contrast, discrepancies between guidelines published at similar periods of time and based on the same evidence are likely to reduce their individual impact and should be justified.33 Successive consensuses have defined increasingly liberal indications of systemic adjuvant treatment for breast cancer. The 2000 National Institutes of Health Consensus Development Conference,34 for example, recommended chemotherapy for women with tumors larger than 1 cm whatever their nodal status. The main deviation from guidelines in our study was absence of adjuvant chemotherapy when such therapy was indicated. We previously demonstrated7 that in 1993 to 1994, for example, 74.9% of women for whom tamoxifen was indicated received this treatment, whereas 2.4% were prescribed chemotherapy instead and 22.7% had no systemic treatment. In individuals having an indication of chemotherapy, however, only 45.3% received it, whereas 25.9% had only tamoxifen and 28.8% received no systemic adjuvant therapy. Many clinicians may be reluctant to offer toxic treatment to individuals with good prognosis, especially when other factors, such as comorbidity, are present. Undertreatment of older women, for example, has been demonstrated repeatedly.12,35,36 However, patients' preferences are also an important component of the therapeutic decision,37,38 and it has been shown that small absolute benefits can be important to women.39 The demonstration of better outcomes should be seen by clinicians as a strong argument to comply with consensus guidelines for treatment.
The appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF (via Adober Acrobat Readerr) version.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Served as an officer or member of the Board of a company: Jean Latreille, Roche, Aventis, Pfizer, Novartis, AstraZeneca.
Jacques Cantin, MD, deceased in 2002, was collaborator to this work. We acknowledge his contribution to this study and his lifelong commitment to breast cancer control. We thank Christine Beaulieu, Sylvie Bérubé, Magali Girard, Monika Lessard, Michèle Perron, and Brigitte Simard for assistance in data collection and analysis.
Supported by the Canadian Breast Cancer Research Alliance. Part of this work was presented at the 8th International Conference on Primary Therapy of Early Breast Cancer, St Gallen, Switzerland, March 12-15, 2003; at the American Society of Clinical Oncology 39th Annual Meeting, Chicago, IL, May 31-June 3, 2003; and at the Reasons for Hope Conference, Ottawa, Canada, October 25-27, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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3. Johnson TP, Ford L, Warnecke RB, et al: Effect of a National Cancer Institute clinical alert on breast cancer practice patterns. J Clin Oncol 12:1783-1788, 1994
4. Olivotto IA, Coldman AJ, Hislop TG, et al: Compliance with practice guidelines for node-negative breast cancer. J Clin Oncol 15:216-222, 1997 5. Guadagnoli E, Shapiro CL, Weeks JC, et al: The quality of care for treatment of early stage breast carcinoma. Cancer 83:302-309, 1998[CrossRef][Medline] 6. Lazovich DA, Solomon CC, Thomas DB, et al: Breast conservation therapy in the United States following the 1990 National Institutes of Health consensus development conference on the treatment of patients with early stage invasive breast carcinoma. Cancer 86:628-637, 1999[CrossRef][Medline]
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8. Malin JL, Schuster MA, Kahn KA, et al: Quality of breast cancer care: What do we know? J Clin Oncol 20:4381-4393, 2002 9. Lash TL, Silliman RA, Guadagnoli E, et al: The effect of less than definitive care on breast carcinoma recurrence and mortality. Cancer 89:1739-1747, 2000[CrossRef][Medline] 10. Grimshaw JM, Russell IT: Effect of clinical guidelines on medical practice: A systematic review of rigorous evaluation. Lancet 342:1317-1322, 1993[CrossRef][Medline] 11. Worrall G, Chaulk P, Freake D: The effects of clinical practice guidelines on patient outcomes in primary care: A systematic review. CMAJ 156:1705-1712, 1997[Abstract] 12. Hébert-Croteau N, Brisson J, Latreille J, et al: Compliance with consensus recommendations for the treatment of early stage breast carcinoma in elderly women. Cancer 85:1104-1113, 1999[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1 cm (except incidentally discovered tumors measuring 1 cm), ER-positive tumors greater than 2 cm, and grade 3 tumors. In this classification, histology and grade were considered before tumor size in defining risk. Therefore, colloid, tubular, or papillary tumors greater than 2 cm were still included in the minimal-risk group, whereas all grade 3 tumors were classified as high risk, regardless of tumor size. 
