© 2001 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 30, 103-108,
2001
© 2001 Oxford University Press
Who Should Not Receive Adjuvant Chemotherapy? International Databases
Affiliation of authors: Jonas Bergh, Radiumhemmet, Karolinska Institute and Hospital, Stockholm, Sweden, Marit Holmquist, Regional Oncological Centre, Uppsala, Sweden.
Correspondence: Jonas Bergh, M.D., Ph.D., Department of Oncology, Radiumhemmet, Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden (e-mail: jonas.bergh{at}cck.ki.s).
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ABSTRACT |
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 TopNotes Abstract IntroductionSelection of Patients for...DiscussionConclusionReferences |
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The optimal selection of patients for adjuvant therapy, avoiding overtreatment and undertreatment, of disease is a significant challenge in the management of early breast cancers. Population-based cohorts in Denmark and in two Swedish health care regions were investigated to identify patients with breast cancer who have a sufficiently low risk of recurrence without adjuvant therapy. Published data on different calcification patterns were also included from the randomized Swedish mammography two-county study. The Danish Breast Cancer Group's population-based registry revealed that patients with lymph node-negative and estrogen receptor- or progesterone receptor-positive cancers of histological grade I that were less than 20 mm in size had a 5-year survival rate similar to age-matched groups without breast cancer. Data from the Stockholm Breast Cancer Group identified a similar risk group (no information on cancer grade) with an approximate 10% risk of dying from breast cancer after 10 years without any adjuvant therapy. In women older than 50 years, approximately 20% died of other causes. Mammographically and lymph node-negative-detected cancers that are less than 15 mm in size generally have an excellent survival outcome, excluding patients with casting calcifications. Patients who have lymph node-negative breast cancers that are less than 20 mm in size, combined with estrogen receptor positivity, can be identified as a low-risk group. The vast majority of these patients are unlikely to benefit from the addition of conventional chemotherapy, but some of them may. The dilemma is that we cannot identify these patients prospectively because of the lack of relevant predictive factors for chemotherapy.
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INTRODUCTION |
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TopNotesAbstractIntroductionSelection of Patients for...DiscussionConclusionReferences |
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Systemic therapy with tamoxifen therapy and chemotherapy are the most important adjuvant modalities for improving the survival of women with primary breast cancer (1–3). A critical issue, however, is the identification of those patients who should be offered adjuvant chemotherapy based on a sufficiently high risk for recurrence. Scandinavian databases will be used in this article to identify breast cancer patients who potentially will be cured by only local or locoregional therapies, which makes the use of adjuvant therapy, especially chemotherapy, less necessary.
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SELECTION OF PATIENTS FOR ADJUVANT THERAPY—P OSSIBILITIES AND SHORTCOMINGS |
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TopNotesAbstractIntroductionSelection of Patients for...DiscussionConclusionReferences |
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Despite the stepwise improvements offered by the combination of different adjuvant therapies, major problems still exist regarding the selection of patients to whom such treatment should be offered. The critical problem is finding the optimal balance between overtreatment and undertreatment. One may accept overtreatment of relatively large patient groups if the long-term side effects are minimal. This seems to be the case for many of our standard chemotherapy regimens (2). Furthermore, economic cost–benefit analyses for standard adjuvant chemotherapy appear acceptable; the cost per year of life saved is lower than some other accepted medical interventions, especially when compared with other nonmedical procedures (4,5). The cutoff levels and recommendations for adjuvant therapy vary between countries and regions in the world, most likely reflecting differing medical, cultural, and economic assessments.
The lack of established predictive factors for chemotherapy is a major obstacle to improving outcomes. Many patients will relapse despite having received adjuvant chemo-endocrine therapy. Theoretically, relapse may not have occurred if alternate combinations of drugs, based on analyses of relevant predictive factors, were administered "up front." In the future, a detailed molecular "fingerprint" of each cancer could help to guide a tailored approach for each patient, together with an appreciation of individual pharmacokinetic variations (6–8). Recent data with the use of microarray technology demonstrate a very high degree of complexity (9). This should stimulate further research aimed at tailored therapy approaches.
International Databases
Information on the effects of adjuvant chemotherapy in breast cancer patients has traditionally been obtained from randomized studies. How representative the patients in randomized studies are compared with the general population, however, is less well-known. The selection bias of some clinical trials is most likely quite marked. A complementary approach to obtaining therapy and outcome data would be to study different population-based cancer and therapy registries, which are available in some parts of Europe. This review will discuss these registry results in some detail, with the aim of identifying patients unlikely to benefit from adjuvant chemotherapy.
Danish Breast Cancer Group (DBCG)
Established in 1977, the DBCG has carried out multiple national adjuvant and randomized studies. In parallel, they have created a registry of "all" new breast cancers occurring in Denmark since 1977. The registry contains some 60 000 reports. On the basis of 30 000 of the reported breast cancers, a low-risk group has been identified. Patients in the DBCG low-risk group had the following characteristics: having primary tumor size of less than or equal to 20 mm, having negative axillary lymph nodes, being Bloom–Richardson grade I, and being estrogen or progesterone receptor positive (
10 fmol/mg protein or 10% positive cells with the use of immunohistochemistry).
No adjuvant systemic therapy, tamoxifen therapy, or chemotherapy was given to this group. Radiotherapy was given to the scar area if the mastectomy operation was not radical, and it was also given to the remaining breast parenchyma in patients treated with breast-conserving surgery. The 5-year survival rate was calculated for this group. The premenopausal cohort had a 98% 5-year survival rate that was identical to that of a matched control group without breast cancer. The postmenopausal cohort had a 91% 5-year survival rate compared with a 92% 5-year survival rate for the control group (10) (Mouridsen H: personal communication) (Table 1
). On the basis of these figures, the addition of adjuvant therapy, especially chemotherapy, should be questioned. However, for this low-risk group, a 5-year follow-up period is too brief, as will be discussed.
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Regional Swedish Breast Cancer Registries Sweden has six health care regions with regional breast cancer registries that maintain information on primary tumor status as well as on primary therapy. Data have been obtained for this article from the two largest regions—Stockholm-Gotland and Uppsala-Örebro.
Stockholm Breast Cancer Group
The Stockholm Breast Cancer Group, Sweden, was established in 1976. Their database contains information on approximately 20 000 breast cancer patients (Rutqvist LE: personal communication). The population base is 1.9 million inhabitants. The registry has high coverage and follow-up of the breast cancers within the defined geographic region. A low-risk group was identified from a total of 15 842 patients undergoing primary surgery for breast cancer during the period from 1976 through 1996. The patients' status was followed up for events until December 31, 1997, and the data were matched against the nationwide death cause registry. The low-risk group from the Stockholm Breast Cancer Group had the following characteristics: having primary tumor size of less than 20 mm, having negative axillary lymph nodes, and being estrogen receptor positive (0.05 fmol/µg DNA).
A total of 1929 (12.2%) patients who had not received adjuvant systemic therapy were identified from the registry, which held information on 15 842 patients during the time period 1976 through 1996. The median follow-up period was 11.9 years for the 1929 patients, 500 of whom were younger than 50 years.
The overall survival rate at 10 years for the "postmenopausal" group was 70%, and the corresponding figure for those younger than 50 years was 89% (Fig. 1,a and b,Table 1
). The cumulative incidence of breast cancer deaths was approximately 10% for both age strata (Table 1). For the younger age group, most breast cancer deaths were recorded after 4 years of follow-up (Fig. 1, a). For women aged 50 years and older, non-breast cancer and breast cancer deaths increased linearly during the entire 10-year period. Approximately two thirds of deaths were non-breast cancer related (Fig. 1, b). The nearly 10% risk of dying of breast cancer for both age strata at 10 years would argue for the use of adjuvant hormonal therapy in estrogen receptor-positive tumors. Adjuvant tamoxifen therapy for 5 years will give a 47% porportional reduction of recurrence and should therefore be considered (1).
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Uppsala–Örebro Breast Cancer Group The regional breast cancer registry for the Uppsala–Örebro region was activated on September 1, 1992, by the Uppsala–Örebro Breast Cancer Study Group. The population base is approximately 1.9 million inhabitants. The registry did not initially contain information on preoperative therapy. For this report, only lymph node-negative patients treated during the time period from 1993 through 1998 were included. Of these, 3029 had not received postoperative adjuvant chemotherapy or tamoxifen therapy. The outcome for those patients was compared with mortality rates for age-matched groups. The relative survival rate is defined as the observed survival in the patient group divided by the expected survival rate of a comparable group in the general population followed during the same calendar years (11). All survival rates are presented with 95% confidence intervals (CIs).
Patients with a tumor size of less than 10 mm demonstrated an overall survival rate at 8 years of 87% (95% CI = 0.82 to 0.91) and a relative survival rate of 97% (95% CI = 0.92 to 1.01) based on 735 patients (Table 1). Nine hundred and seventy-seven patients with primary tumor sizes of 10–14 mm had an overall survival rate at 8 years of 85% (95% CI = 0.80 to 0.88) and a relative survival rate of 96% (95% CI = 0.91 to 1.0). For the 897 patients who had tumors sized 15–20 mm, the overall survival rate was 81% (95% CI = 0.75 to 0.85) at 8 years and the relative survival rate was 94% (95% CI = 0.88 to 0.99).
Five hundred twenty-three patients with a primary breast cancer sized 10–20 mm with positive estrogen receptors and low S phase were compared with 94 patients with a primary breast cancer with high S phase and negative estrogen receptors (Table 1). The 8-year overall survival rate for the first group was approximately 83% (95%CI = 0.75 to 0.89), for the latter group, it was 77% (95% CI = 0.63 to 0.87) (Fig. 2, a) (P = .048; Pearson log-rank test). The corresponding relative survival figures are depicted in a separate figure (Fig. 2, b), 95% for the low-risk group (95% CI = 0.86 to 1.01), and 88% for the high-risk group (95 % CI = 0.72 to 1.0) (P = .052; Pearson log-rank test).
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On the basis of the study of 1021 lymph node-negative patients with estrogen receptor-positive breast cancer 10–20 mm in size, the overall survival rate at 8 years was 84%. The corresponding value for estrogen receptor-negative cancers was 74%, based on the study of 291 patients. Indirect comparisons thus indicate that S phase added no prognostic information.
Identification of Low Risk Groups with the Use of Mammographic Patterns
From July 1977 through March 1986, a population-based and randomized mammography screening program was held in two Swedish counties. The study demonstrated a reduced breast cancer mortality rate for the screened group (12). The study has recently been updated with information on 2468 breast cancers (13). The authors conclude that mammography screening and histopathologic demonstration of axillary lymph node-negative breast cancers will enable the identification of a low-risk subgroup, which they believe should be recommended for less radical treatment. On the basis of these findings, the authors further investigated 343 primary breast cancers with a primary tumor size ranging from 1 to 14 mm (14). The long-term survival rate was determined to be 95% for the group of patients with a primary tumor size ranging from 1 to 9 mm without casting calcifications (14). However, 19 (14%) of 138 patients with tumors 1–9 mm in size had a specific type of calcification described as "casting" calcifications. These patients accounted for 73% of the breast cancer deaths (P<.001) in this analysis (14).
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DISCUSSION |
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TopNotesAbstractIntroductionSelection of Patients for...DiscussionConclusionReferences |
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Adjuvant hormonal therapy and chemotherapy alone and in combination have been instrumental in reducing breast cancer mortality rates by 25%–30% in the U.K. and the United States since 1970 (15). This positive development has been recorded during the last decade. This major improvement is likely explained by the use of adjuvant therapies, stage migration resulting from increased awareness, and screening mammography. The important message is that breast cancer mortality can be substantially reduced by different strategies. The use of adjuvant therapy has until now been restricted to lymph node-positive and lymph node-negative breast cancers with high-risk features. The potentially wider use of adjuvant therapy on larger patient groups may result in further absolute survival improvements, but the benefit–risk equation for the low-risk groups will be less favorable.
Patients with small breast cancers (<10–15 mm) without axillary lymph node metastases, combined with favorable biologic markers (histologic grade I, receptor positive, and low S phase), are likely to experience only a small additive effect of adjuvant chemotherapy in combination with tamoxifen therapy, yet this statement is challenged by the recent retrospective analysis of five National Surgical Adjuvant Breast and Bowel Project studies (16). This analysis of lymph node-negative breast cancer trials demonstrates a statistically significant survival improvement when chemotherapy is added to tamoxifen therapy and surgery, even in patients with estrogen receptor-positive cancers less than 1 cm in diameter (16). The overall survival rate after 8 years for the groups studied by the National Surgical Adjuvant Breast and Bowel Project who were treated with surgery alone is on the same order or slightly better than the population-based figure from the Uppsala–Örebro region.
The data from the two Swedish regions demonstrate that the mortality for the lymph node-negative group and the estrogen receptor-positive groups will occur only after several years of follow-up. These data argue strongly that 5 years of follow-up is too short, especially for the younger age group. Furthermore, the routine follow-up should be different for the low-risk groups with late-occurring relapses compared with patients at higher risk who usually relapse earlier.
The retrospective analysis of the Swedish two-county study indicates that different mammographic patterns may be used for selecting patients at very low risk versus those with a markedly higher risk, despite identical tumor size (14). Whether the calcification patterns can be generally applied and whether the selected high-risk patients will benefit from adjuvant therapy have yet to be demonstrated. The risk–benefit effects in medical and economic terms for treating low-risk patients with adjuvant chemotherapy have not been sufficiently investigated. Further studies are warranted.
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CONCLUSION |
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TopNotesAbstractIntroductionSelection of Patients for...DiscussionConclusionReferences |
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In conclusion, breast cancer demonstrates a wide span in malignancy potential and response to therapy, and adjuvant chemotherapy cannot be recommended for all patients with breast cancer. Those patients with lymph node-negative, estrogen receptor-positive small tumors should consider carefully the risk and benefits involved.
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NOTES |
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Supported by the Swedish Cancer Society.
The data from the Danish Breast Cancer Group were generously supplied by Professor Hennning Mouridsen, Copenhagen, Denmark. The data from the Stockholm-Gotland Breast Cancer Group were generously collected and transferred by the statistician Hemming Johansson and Associate Professor Lars Erik Rutqvist. The breast cancer registry data from the Uppsala-Örebro region were kindly supplied by the Uppsala-Örebro Breast Cancer Study Group and commented on by Professor Lars Holmberg and Associate Professor Leif Bergkvist. Professor Lazlo Tabar, Falun, Sweden, kindly supplied the mammography data.
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TopNotesAbstractIntroductionSelection of Patients for...DiscussionConclusionReferences |
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