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© 2001 American Society for Clinical Oncology Understanding the Utility of Adjuvant Systemic Therapy for Primary Breast CancerFrom the Mayo Clinic, Rochester, MN. Address reprint requests to Charles L. Loprinzi, MD, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; email cloprinzi{at}mayo.edu
PURPOSE: Physicians and patients require quantitative information on the expected benefits of adjuvant therapy for primary breast cancer to make appropriate treatment decisions. To date, there has not been any widely available method for estimating the benefits from adjuvant systemic therapy, in terms of long-term disease-free survival probabilities, in patients with primary breast cancer. METHODS: Baseline prognostic information for primary breast cancer patients was estimated by asking 11 breast cancer specialists to complete a questionnaire on baseline prognosis and then using mean values. Data on the relative benefits of adjuvant therapy were culled from systematic reviews and randomized controlled trials. A computer algorithm was developed to calculate 10-year absolute outcome data. Results from this evaluation were compared with a previously described actuarial algorithm. RESULTS: Individual prognostic estimates varied within a group of breast cancer specialists, but mean values of their estimates closely followed published data. Translation of expected benefits of adjuvant therapy from relative to absolute terms was performed with a simple computer algorithm. The data were translated into tabular forms to facilitate user-friendly clinical use. CONCLUSION: The provided data should facilitate a better understanding of the absolute magnitude of benefit for available systemic adjuvant therapies in individual women with primary breast cancer. This should allow patients to make more informed decisions about their options.
ONCOLOGISTS, in conjunction with their patients, make decisions regarding adjuvant systemic therapy for primary breast cancer every day. Such decisions need to be individualized based on the characteristics of the primary tumor and the willingness of the patient to undergo toxicities for potential benefits. When asked about how treatment decisions are made, oncology experts routinely reply that patients need to be informed of the options and that they need to participate in the decision-making process. The question at hand is: How do physicians best inform themselves and their patients regarding the potential benefits associated with adjuvant systemic therapy for primary breast cancer? In a survey of women who had previously received adjuvant chemotherapy, only a minority of women remembered receiving any estimates regarding their prognosis with or without adjuvant systemic therapy, thus suggesting that there is room for improvement in providing patients with adequate information on adjuvant therapy.1 Currently, articles on adjuvant therapy routinely describe the benefits of adjuvant systemic therapy in terms of annual proportional reductions of risks of either recurrence or death related to the disease.2 This terminology does not seem to be well understood by many physicians, and it is certainly not well understood by the vast majority of patients. What then does the term "annual proportional reduction" mean? Basically, it refers to a lessening of a risk on a yearly basis. For example, if a patient’s risk for disease recurrence in a particular year was 20%, a 25% annual proportional reduction of that risk would result in that patient now having a risk of recurrence of 15% that year (5% is 25% of 20%, and that resultant 5% is subtracted from 20% to get 15%). We hope that the previous sentence is understandable to the reader but, if not, then our point is even better made: this terminology is confusing to many. In truth, things are made even more confusing if distant (eg, 10 years later) prognosis is desired. This is because, with annual proportional reductions, the baseline changes annually. If anyone questions the uncertainties that abound regarding the prognosis of a primary breast cancer patient without, or with, various systemic adjuvant therapies, all one needs to do is ask four to five oncology colleagues to estimate 10-year disease-free survival probabilities for a selected patient case. This will readily illustrate the wide variations of opinion in this area. To help physicians and patients make informed decisions, annual proportional risk reduction information needs to be translated into a more intuitive language. In an effort to overcome the difficulty in understanding this prognostic information, Dr Peter Ravdin developed a computer program (Adjuvant!) to better illustrate the potential benefits of adjuvant systemic therapy. Information regarding this program was published previously.3-5 Over the past few years, we examined Dr Ravdin’s pioneering work in an attempt to understand further how to present this information in a manner that is readily available for patient care. One option is to convey the available information in terms of how well a person will do 10 years hence. Although late relapses may occasionally occur, this information is more akin to the chance of the patient being cured of her disease and is more easily understood by physicians and patients.
To understand the potential benefits of adjuvant systemic therapy, the natural history of the primary disease process must be considered first. Although it is true that physicians do not have a very reproducible estimation of survival probabilities with various common disease scenarios affecting primary breast cancer patients,6 it is still essential that an attempt be made in this regard. The most important prognostic factor is the status of the axillary lymph nodes.7 The second most important factor is tumor size.8,9 Other factors, such as patient age, hormone receptor status, and ploidy, are less important than node status and tumor size.9-17 Given that we have a difficult time agreeing on prognosis when primarily using tumor size and lymph node status, evidence suggests that the use of other, less important, prognostic factors does not help clarify matters.6 Historical information suggests that patients with negative lymph nodes have a 10-year disease-free survival of approximately 60% to 75%, whereas patients with positive lymph nodes have a 10-year disease-free survival of approximately 25% to 30%.2,7,10 To understand better what established breast cancer medical oncologists estimate 10-year disease-free survival to be, on the basis of different lymph node and tumor size situations, 11 such oncologists were asked to complete a blank copy of Table 1. The numbers provided in Table 1 illustrate the averages of the oncologists’ responses for each square. The raw data used to derive Table 1 are provided in Table 2, illustrating once again6 that there is little uniformity in these predictions. Despite the disparity among the individual oncologists’ estimates, the average numbers provided in the last column of Table 2 seem to provide reasonable estimates of 10-year disease-free survivals in the different clinical scenarios. In contrast to the above method, Dr Ravdin’s Adjuvant! program uses Surveillance, Epidemiology, and End-Results data and a proprietary formula to estimate patient prognostic information.3-5 A comparison of our prognostic numbers from Table 1 with prognostic numbers for similar patients derived from Dr Ravdin’s Adjuvant! program is provided in Figure 1. This figure illustrates a remarkably good correlation between these two methods, with a tendency for slightly more optimistic baseline predictions from the Adjuvant! program.
Annual Reduction of Risk of Recurrence Information regarding the effect of different adjuvant systemic therapies on the annual reduction of risk of recurrence can be found in overview publications2,18 and from new data regarding the additional benefit from adding four cycles of paclitaxel to four cycles of standard doxorubicin/cyclophosphamide chemotherapy.19 These articles describe the effect of adjuvant chemotherapy, adjuvant tamoxifen, or both on disease recurrence ( Table 3) and death ( Table 4). The benefits from combined chemotherapy and tamoxifen are additive,2,18-20 which translates into multiplicative effects on proportional risk reductions. This is reflected in the estimates given for the combined treatment effects displayed in Tables 3 and 4. It is interesting that the proportional reductions in annual risks for recurrence, compared with death, are so different for the use of standard chemotherapy and tamoxifen in the overview analyses. For example, as shown in Tables 3 and 4, the annual reduction of the risk of recurrence for tamoxifen is 50%, whereas the annual reduction in the risk of death is one half that (ie, 25%). The reasons for this relatively wide discrepancy have not been clearly elucidated.
Translation of This Annual Reduction of Risk Into 10-Year Survival Outcomes Ten-year disease-free or overall survival can be calculated in a fashion similar to compound interest using our knowledge of the natural history and the proportional efficacy of different adjuvant therapies as main input parameters. This information can be provided in both numerical and graphical form by a simple computer program (Numeracy [available at http://mhs.mayo.edu/adjuvant]), which allows physicians to type in the patient’s expected 10-year overall or disease-free survival without adjuvant therapy and the estimated annual reduction in risk of death or recurrence with adjuvant therapies (Fig 2). The results generated from this computer program are summarized in Table 5. For younger women, this survival information can be provided without factoring in competing causes of death given that overall 10-year survival for patients younger than 69 years in the absence of breast cancer was 96% in one large overview of adjuvant therapy.2 For women older than 69 years or those with medical comorbidities, however, the program can factor in the mortality that would be associated with a woman who was otherwise healthy, based on causes of mortality other than breast cancer. Average 10-year mortality rates and expected survivals are provided for North American women of different ages in Table 6.
Assumptions About the Underlying Hazards Functions Used in the Computations The mathematical formulas used for the computations in our computer model are based on a few simple but nontrivial assumptions. Such assumptions include (1) constant annual risks for recurrence or breast cancer–specific mortality (the hazards functions), (2) constant baseline mortality rates without interference by adjuvant treatment, and (3) constant effects of adjuvant treatment on the annual risks over time. Arguments in support of these assumptions include the following: (a) a large meta-analysis of adjuvant therapies demonstrated that the shape of the hazards function had virtually no impact on long-term absolute benefits2; (b) adjuvant treatments had little, if any, effect on baseline non-breast cancer–related mortality causes2,20; (c) both chemotherapy and endocrine therapy have constant effects on overall mortality for 10 years and on recurrence for 5 years2,20; and (d) published hazards functions for mortality or recurrence show a peak within the first 0 to 4 years and then remain largely constant over years 5 through 9.21-23 The simple formulas used in our model to calculate 10-year outcomes are quite robust against variations introduced by modifying these assumptions. In the first logical step, the model calculates annual hazards rates for breast cancer–specific adverse events based on physician estimates of 10-year event-free survival. In a second step, the program uses the estimated proportional reduction of risk to calculate the 10-year event-free survival with adjuvant treatment. Non-breast cancer–related mortality is treated as a simple competing cause of death. In all instances, the hazards functions are assumed to be constant over time.
Comparison of Predicted Benefits With Numeracy Versus Adjuvant!
Sample Situations To illustrate how to use the presented information, two cases are presented. The first case is a 55-year-old woman with a 3.5-cm, node-negative, estrogen receptor–positive breast cancer who has received (or will receive) adequate local regional therapy. Using Table 1, this woman’s 10-year disease-free survival probability can be estimated as approximately 70% (rounding up from 69%). When we next examine the annual proportional risk reductions by adjuvant therapies, the question arises: should we use data regarding recurrence reduction (Table 3) or death reduction (Table 4)? To be conservative, we will first choose to use data regarding death reduction. (Because disease-free survival and overall survival at 10 years are very similar, we will use disease-free survival and survival interchangeably.) From Table 4, we note that this woman’s annual proportional reduction in death is 10%, 25%, and 35%, respectively, with the use of chemotherapy, tamoxifen, or both. Proceeding to Table 5, we observe that her 70% baseline 10-year disease-free survival probability (without adjuvant therapy) improves to 73%, 77%, or 79% with the use of standard chemotherapy (eg, doxorubicin/cyclophosphamide), tamoxifen, or both. Alternatively, if we used the more positive data regarding annual reductions of recurrence (Table 3), the corresponding percentages for her to be free of disease recurrence are 75%, 84%, and 87%. The second case is a 45-year-old woman with a 5-cm, estrogen receptor–negative breast cancer with seven of 15 involved axillary lymph nodes. Here, Table 1 predicts a 10-year disease-free survival probability of approximately 20%. Using Table 4, the annual proportional reduction in recurrent risk is 35% when using standard chemotherapy (eg, doxorubicin/cyclophosphamide) and 51% if paclitaxel is added. As shown in Table 5, this would improve that patient’s 10-year disease-free survival probability from 20% to 36% with standard chemotherapy and to 46% if taxane therapy was also given.
Absolute Benefits Based on Baseline Prognosis
Simplified Tables
Communication With the Patient The information generated from this approach can be provided as direct information to the patient, along with expected toxicities from different adjuvant systemic approaches. In doing so, we recommended that patients first be asked whether they would like to receive specific prognostic information. Most patients do claim to desire information that is as accurate as possible. Patients who receive specific prognostic information seem to have a better understanding of their disease process compared with those who are provided with general information only.24,25 A printout can be generated using a simple computer program to provide a graphic illustration of expected survival benefits (Fig 2).
Limitations In conclusion, the methodology described in this article or the computer program developed by Dr Ravdin3-5, 27 can be used to understand better the potential benefits from different adjuvant systemic therapies for patients with primary breast cancer. A similar methodology could well be applied to other oncology situations (eg, adjuvant therapy for primary colorectal cancer). The methodology is adaptable because estimates for baseline prognosis and/or for proportional benefits change with the emergence of new data from ongoing and future clinical trials.
We thank Dr Peter Ravdin for the use of his Adjuvant! program and for repeatedly helpful conversations regarding the subject.
1. Ravdin PM, Siminoff IA, Harvey JA: Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy. J Clin Oncol 16: 515-521, 1998[Abstract] 2. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352: 930-942, 1998[Medline] 3. Ravdin PM: How can prognostic and predictive factors in breast cancer be used in a practical way today? Recent Results Cancer Res 152: 86-93, 1998[Medline] 4. Ravdin PM: A computer program to assist in making breast cancer adjuvant therapy decisions. Semin Oncol 23: 43-50, 1996[Medline] 5. Ravdin PM: A computer-based program to assist in adjuvant therapy decisions for individual breast cancer patients. Bull Cancer 82: 561S-564S, 1995 (suppl 5) 6. Loprinzi CL, Ravdin PM, De Laurentiis M, et al: Do American oncologists know how to use prognostic variables for patients with newly diagnosed primary breast cancer? J Clin Oncol 12: 1422-1426, 1994[Abstract] 7. Fisher ER, Costantino J, Fisher B, et al: Pathologic finding from the National Surgical Adjuvant Breast Project (protocol 4): Discriminants for 15-year survival. Cancer 71: 2141-2150, 1993[Medline] 8. Rosen PP, Groshen S, Saigo PE, et al: Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: A study of 644 patients with median follow-up of 18 years. J Clin Oncol 7: 1239-1251, 1989[Abstract] 9. Rosner D, Lane WW: Should all patients with node-negative breast cancer receive adjuvant therapy? Identifying additional subsets of low-risk patients who are highly curable by surgery alone. Cancer 68: 1482-1494, 1991[Medline] 10. Fisher ER, Redmond C, Fisher B, et al: Prognostic factors in NSABP studies of women with node-negative breast cancer. J Natl Cancer Inst Monogr 11: 151-158, 1992 11. McQuire WL, Tandon AK, Allred DC, et al: Treatment decisions in axillary node-negative breast cancer patients. J Natl Cancer Inst Monogr 11: 173-180, 1992 12. Adami HO, Malker B, Holmbert L, et al: The relation between survival and age at diagnosis in breast cancer. N Engl J Med 315: 559-563, 1986[Abstract] 13. Host H, Lund E: Age as a prognostic factor in breast cancer. Cancer 57: 2217-2221, 1986[Medline] 14. Harris AL, Nicholson S, Sainsburgy R, et al: Epidermal growth factor receptor and other oncogenes as prognostic markers. J Natl Cancer Inst Monogr 11: 181-187, 1992
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Foekens JA, van Putten WL, Prtengen H, et al: Prognostic value of PS2 and cathepsin-D in 710 human primary breast tumors: Multivariate analysis. J Clin Oncol 11: 899-908, 1993
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Allred DC, Clark GM, Elledge R, et al: Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst 85: 200-206, 1993 17. Dressler LG, Eudey L, Gray R, et al: Prognostic potential of DNA flow cytometry measurements in node-negative breast cancer patients: Preliminary analysis of an intergroup study (INT-0076). J Natl Cancer Inst Monogr 11: 167-172, 1992 18. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351: 1451-1467, 1998[Medline] 19. Berry D, Demetri G, Cirrincione C, et al: Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level on the adjuvant chemotherapy of patients (PTS) with node-positive primary breast cancer (BC). Proc Am Soc Clin Oncol 17: 101a, 1998 (abstr 390A) 20. Early Breast Cancer Trialists’ Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339: 1-15, 1992[Medline] 21. Yakovlev AY, Tsodikov AD, Boucher K, et al: The shape of the hazard function in breast carcinoma: Curability of the disease revisited. Cancer 85: 1789-1798, 1999[Medline] 22. Hilsenbeck SG, Ravdin PM, de Moor CA, et al: Time-dependence of hazard ratios for prognostic factors in primary breast cancer. Breast Cancer Res Treat 52: 227-237, 1998[Medline]
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Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14: 2738-2746, 1996 24. Sheldon JM, Fetting JH, Siminoff LA: Offering the option of randomized clinical trials to cancer patients who overestimate their prognoses with standard therapies. Cancer Invest 11: 57-62, 1993[Medline] 25. Fetting JH, Siminoff LA, Piantadosi S, et al: Effect of patients’ expectations of benefit with standard breast cancer adjuvant chemotherapy on participation in a randomized clinical trial: A vignette study. J Clin Oncol 8: 1476-1482, 1990[Abstract] 26. National Center for Health Statistics: United States Decennial Life Tables for 1989-1991 (vol 1, no 1). Hyattsville, MD, National Center for Health Statistics, publication PHS 97-1150-1, 1997 27. Ravdin PM, Siminoff LA, Davis GJ, et al: Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 19:980-991, 2001 Submitted May 17, 2000; accepted September 28, 2000. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 v > 50 years) in two tables. Although they may initially take a few moments to digest, these tables can be an easier way to use the data in clinical practice once they are understood. 
