Affiliations of authors: T. G. Karrison, D. J. Ferguson,Departments of Health Studies and Surgery, University of Chicago, IL; P. Meier, Columbia University, New York, NY.
Correspondence to: Theodore G. Karrison, Ph.D., Department of Health Studies, MC2007, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637.
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ABSTRACT |
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INTRODUCTION |
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The pathologic stage at which the patient is treated usually makes a larger difference in recurrence rate and survival than do variations in treatment. We have therefore stratified our analyses according to pathologic stage but have combined all types of radical mastectomy. (Given the retrospective nature of the data and the many potential confounding variables, we draw no conclusions regarding the benefits of any particular therapy.) The longest intervals between primary treatment and recurrence, the limits of dormancy, determine the length of follow-up required to establish curability. Better methods of detecting residual cancer cells and indicating their malignant potential may, in time, give more reliable signs than those already in use that an early or late recurrence is likely. Our data derive from clinical and radiologic recognition of recurrence, verified by microscopic pathology when indicated.
The limit of dormancy is related to but not identical with the statistical definition of curability, which addresses whether patients ever reach a point at which they no longer have an excess mortality risk relative to the general population (4). This approach avoids the problems typically encountered in dating recurrences and, since estimates are based on all-cause mortality, also avoids the ambiguities and uncertainties involved in assigning causes of death (5). This time point should occur several years after the majority of recurrences, depending upon the distribution of time to death from breast cancer following a recurrence. Recurrences after this point should be very rare, and the patient who survives to this time could reasonably be regarded as cured of her disease. Previous studies of curability in breast cancer have been performed by Brinkley and Haybittle (6,7), Duncan and Kerr (8), Easson and Russell (9), and Pocock et al. (4). These studies have generally found that there is significant excess mortality even 15-20 years after initial therapy, and thus long-term follow-up is required to establish curability. In this report, we analyze the recurrence and excess mortality rates of a large patient cohort undergoing mastectomy at the University of Chicago Hospitals over a period spanning four decades from 1945 through mid-1987. With the assistance of our tumor registry and through personal contact, we were able to maintain follow-up of 20 years or more in more than 350 patients and beyond 30 years in more than 100 patients.
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PATIENTS AND METHODS |
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Demographic, medical history, and clinical/pathologic data were abstracted from patient charts and maintained in a computerized database. Pathologic staging was according to the American Joint Commission 1988, TNM (tumor-node-metastasis) criteria (10). Briefly, stage I includes patients with tumors 2 cm or less in diameter and who have no axillary lymph node involvement; stage IIA includes patients with tumors 2 cm or less in diameter and who have lymph node involvement or patients with tumors between 2 and 5 cm but who have no lymph node involvement; stage IIB consists of patients with tumors between 2 and 5 cm in diameter and who have lymph node involvement or patients with tumors larger than 5 cm in diameter and who have no node involvement; and stage III includes patients with tumors up to 5 cm in diameter and who have metastasis to axillary lymph nodes that are fixed to one another or other structures, patients with tumors larger than 5 cm and who have metastasis to either movable or fixed axillary lymph nodes, patients with tumors of any size that extend to the chest wall, or patients who have metastasis to internal mammary lymph nodes or the highest axillary lymph node. Patients with distant metastases are classified as stage IV and are not included. Follow-up information regarding tumor recurrences, life-death status, and cause of death was obtained with the assistance of the tumor registry as well as through personal contact with the patient or her local physician. Recurrence or its absence was diagnosed by query to the patient or physician, by biopsy, bone or liver scan, on x-ray, or at autopsy. When first recurrences were recorded in two loci, one was selected with the following priority: systemic, skeletal, internal mammary, supraclavicular, or local (i.e., within the field of the operation used for that patient). Follow-up for life-death status was complete (i.e., the patient was known to have died or was last contacted after January 1, 1996) for 1232 (80%) of the patients. The National Death Index (11) was searched to obtain additional information regarding the status of the patients lost to follow-up prior to 1996. Dates of death were thus determined for an additional 36 patients, bringing the completion rate to 82%. Among the 279 patients who were lost to follow-up, 70 were last known alive between 1.5 months and 10 years after their mastectomy, 108 between 10 and 20 years, 64 between 20 and 30 years, and 37 more than 30 years after surgery. Sixty-five of these patients were between 80 and 96 years old at the time of their last recorded examination.
About a quarter of the patients were given preventive radiation (6.2% of stage I, 19% of stage IIA, 32% of stage IIB, and 38% of stage III). Smaller numbers were given preventive chemotherapy (5.1%, 11%, 17%, and 28%, respectively) or endocrine treatment (4.8%, 18%, 23%, and 26%, respectively) according to the preferences of various oncologists. We include these women in all of the analyses. (A subgroup analysis of 832 women who underwent mastectomy without any other local or systemic therapy gave similar results.)
Summary tabulations of the number of disease recurrences by site and deaths by cause (when available) are provided for each postoperative year. We estimated the hazard rate for first recurrence or death from breast cancer using the actuarial estimator (12). For this analysis, patients who died from other or unknown causes without a known recurrence were censored at the time of death. Overall survival curves, for which the end point was death from all causes, were calculated using the Kaplan-Meier (13) product-limit estimator. The logrank test (14) and the Cox proportional hazards regression model (15) were used to compare survival rates among different groups. Plots of the log cumulative hazard functions indicated that the proportional hazards model provided an adequate fit to the data. Observed mortality rates were then compared with the expected mortality rates for an age-, race-, and sex-matched normal population using life tables obtained from U.S. Vital Statistics Reports encompassing the years during the period from 1945 through 1988 (16-25). Statistical evaluation of observed and expected death rates was performed as described by Pocock et al. (4). Specifically, the ratio of the observed number of deaths from all causes to the expected number of deaths in the general population was calculated for successive 5-year intervals, beginning at the time of mastectomy. We followed this by determination of the excess death rate, defined as the difference between the observed and expected number of deaths divided by the patient-years at risk. Ninety-five percent confidence intervals (95% CIs) for the true excess death rates were derived by assuming that the observed number of deaths follows a Poisson distribution. CIs that do not include zero indicate a death rate in the patients with breast cancer that differs from that in the general population at the P<.05 level of significance. All P values are two-sided.
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RESULTS |
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The number of first recurrences by site (local, skeletal, visceral,
supraclavicular, internal mammary, or site unknown), censored
observations, and deaths by cause (breast cancer, other causes, or
cause unknown) that occurred within each postoperative year are listed
in Table 1. It is apparent that recurrences are
concentrated in the first years after mastectomy and that they are rare
after 20 years. The last known recurrence was detected 27 years after
mastectomy and the last recorded death from breast cancer was 29 years
after surgery. The patient dying of breast cancer at 29 years had a
recurrence at 22 years and had also developed a contralateral tumor. In
the two patients dying of breast cancer at 27 years, one had a
recurrence at 16 years (as well as a contralateral tumor) and the other
a recurrence at 25 years. Most of the 647 patients who died of breast
cancer had a previously detected recurrence; however, 146 patients died
of breast cancer without a previously identified recurrence. A
recurrence was reported in only five of the patients who died of other
or unknown causes. Among the 296 other causes of death, 48 were
nonbreast cancers, 57 were cardiovascular related, and 191 were from
other causes without a known recurrence from breast cancer.
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Overall survival curves for patients at pathologic stages I, IIA, IIB,
and III are shown in Fig. 2, B. Differences in survival across the
different pathologic stages were highly significant (P = .0001
[logrank test]). Patients at pathologic stage I had 10-, 20-, and
30-year survival rates of 78.9% (95% CI = 74.4-83.4),
52.8% (95% CI = 46.6-59.0), and 34.9% (95% CI =
27.9-41.8), respectively. At pathologic stage IIA, these were
63.6% (95% CI = 59.4-67.9), 42.4% (95% CI =
37.6-47.2), and 26.7% (95% CI = 21.3-32.1), respectively; at
stage IIB, 47.6% (95% CI = 42.7-52.5), 29.9% (95% CI
=
25.0-34.7), and 18.5% (95% CI = 13.8-23.3), respectively; and
at stage III, 25.4% (95% CI = 20.6-30.3), 14.2% (95%
CI = 9.8-18.5), and 7.0% (95% CI = 3.0-11.1), respectively.
There was no evidence of any racial differences in survival (P
= .944, adjusting for pathologic stage and year of surgery [likelihood
ratio test]). See Heimann et al. (26) for a more
detailed analysis of this issue.
Table 2, A-D, compare the observed mortality rates
in successive 5-year intervals with the expected mortality rates
obtained from the U.S. life tables matched for age, race, sex (female),
and year of surgery (within 5 years) for the four-stage strata. Of
interest, for patients with stage I breast cancer, the observed death
rate is not statistically significantly greater than the expected rate
in any 5-year interval, including the initial period following
mastectomy. This is in accord with the relatively low recurrence/breast
cancer death rates seen in Fig. 1
and suggests that radical mastectomy
is a curative surgery for most stage I cases. However, the observed
number of deaths exceeds the expected number in all 5-year intervals
except the last, and thus there may exist a small excess death rate in
these early stage patients that is detectable only with a much larger
sample size.
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Finally, for patients with stage III cancer, the excess death rate is very high15% per year in the first 5 years after surgery and more than 9% per year in years 5-10, before falling to a little less than 4% per year between years 10 and 15. After 15 years, the difference is no longer statistically significant, but again the numbers are small and consequently the CIs are fairly broad.
Based on these analyses, there is strong evidence for excess mortality throughout the first 15 years after mastectomy in patients with stage II and III cancers. Furthermore, examination of excess mortality on a yearly basis after year 15 reveals differences that are fairly consistently positive over the ensuing 5-10 years in all pathologic stage groups. Although not statistically significant, this suggests that excess mortality may continue to exist beyond year 15. Pathologic stage had a major effect on the death rate during the first 15 years, but after 15 years, the observed death rates were actually fairly similarbetween about 3% and 7% per yearacross the different pathologic stages, in agreement with the findings reported in Pocock et al. (4). Pooling the data after 15 years over the four pathologic stage groupings, we detected a statistically significant excess death rate of 1.2% per year (95% CI = 0.28-2.12 per year; P = .009) in the 15-20-year interval and, again, examination of the yearly data revealed nonstatistically significant, but continuing, excess mortality in each of years 21, 22, 23, and 24.
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DISCUSSION |
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Metastatic cells may be present after surgery but remain dormant for several reasons. They may be unable to invade blood or lymph node vessels; they may be unable to induce angiogenesis and/or revascularization (28,29) with the balance between angiogenic and antiangiogenic stimuli favoring antiangiogenesis; apoptosis predominates; cell cycle regulatory proteins function normally so that there is no loss of cell cycle control (30); or a balance between growth-inducing and growth-inhibiting factors in the tumor microenvironment favors inhibition. Changes in any of these factors could result in tumor growth at a later time.
When mastectomy patients die without any evidence of recurrence,
apparently of other causes, a search for persisting cancer is not
usually made, and in any case it is difficult to rule out. Indeed, one
popular theory has it that all breast cancers contain dormant as well
as active cancer cells, although the dormant cells may never become
overt (31). Evidence qualifying this idea is provided by
follow-up beyond 25 years, after which time clinically apparent
recurrences, being nearly absent in our study and that by Friedl and
Herfarth are probably very rare. There is little excess mortality in
the pathologic stage I cases even in the first years after surgery,
which suggests that local treatment eliminated the tumor and that no
cells had metastasized. We also did not find a significant excess rate
of deaths after 20 years based on nearly 2000 cumulative years of
follow-up. A limitation of our data, however, is the lack of complete
follow-up in 18% of the cases. If individuals lost to follow-up
were at increased risk of death, then our estimates of excess risk
would be too low. On the basis of our CIs, we cannot rule out the
possibility that a small excess mortality exists even into the third
decade after mastectomy. Nonetheless, at least some of the patients
must have had no persisting disease or disease that remained localized.
Interestingly, the high hazard rate for recurrence or death from breast
cancer in patients with stage IIB and stage III disease drops
substantially after the first several years (Fig. 1), but for the
latter group remains relatively high throughout most of the second decade.
Recurrences that appear after radical mastectomyexcept if they are
small, local lesionsare usually followed by death from cancer within
a few years. Only 49 (9.3%) of 529 recurrences were first observed
more than 10 years after mastectomy, as shown in Table 1. No death from
breast cancer has been observed in our series after 25 years, except
among patients who had a recurrence or a contralateral cancer within
that 25-year period.
The quality and the extent of surgical treatment need to be taken into account when evaluating recurrence and survival of patients with mammary cancer (32). A diagnosis of recurrence is difficult to establish after partial mastectomy because the procedure may miss part of a multicentric cancer. We did not attempt analysis of dormancy in these patients.
In conclusion, recurrence of mammary carcinoma after various types of radical mastectomy occurred only rarely after 20 years, and the mortality rate after 20 years was not significantly different from that of the nondiseased population. The limit of dormancy appears to be between 20 and 25 years, and the patient surviving that long without recurrence or contralateral cancer is probably cured. Although the period of dormancy may be quite long, patients with very early stage disease have an excellent prognosis, and most recurrences and excess deaths in patients with stage II-III tumors occur within the first 10 years after mastectomy.
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NOTES |
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Manuscript received February 9, 1998; revised October 8, 1998; accepted November 2, 1998.
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