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Age as a prognostic factor for patients treated with definitive irradiation for early stage breast cancer
Int. J. Radiarion Oncology Biol. Phys.. Vol. Printed in the U.S.A. All rights reserved.
16, pp. 373-38
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I
??Original Contribution
AGE AS A PROGNOSTIC FACTOR FOR PATIENTS TREATED WITH DEFINITIVE IRRADIATION FOR EARLY STAGE BREAST CANCER LAWRENCE J. SOLIN, M.D.,* BARBARA FOWBLE, M.D.,* DELRAY J. SCHULTZ, AND ROBERT L. GOODMAN, M.D.*
M.A.t
University of Pennsylvania School of Medicine and the Fox Chase Cancer Center, Philadelphia, PA From 1977 to 1986,88 breast cancers in 86 women age I 35 years were treated with definitive irradiation following breast-conserving surgery. The records of these eases were reviewed and compared to 808 breast cancers in 798 women age 136 years treated similarly during the same time period. All women had AJC clinical Stages I or II invasive carcinoma of the breast and had undergone an axillary surgical staging procedure to determine pathologic lymph node staging prior to receiving definitive radiotherapy. There was no statistical difference between the younger and older women in terms of 5-year actuarial overall survival (94% vs. 90%), NED survival (78% vs. 81%) or relapse-free survival (70% vs. 77%). Although the younger women tended to have an earlier pattern of failure, the difference between the actuarial percentage of failures at 5 years for the two age groups was not significantly different for local only first failure (9% vs. 5%), regional only first failure (6% vs. 3%), and local and regional only first failure (0% vs. 1%). Subset analyses also did not show a difference between the younger and older patients. Although longer follow-up will be needed to confirm these observations, our 5-year results show that younger patients I age 35 do not have an adverse outcome in terms of survival, local control, or regional control when compared with older patients 2 age 36. Potential candidates for definitive irradiation following breast-conserving surgery should not be excluded for treatment solely on the basis of younger age zz 35 years. Breast cancer, Radiation therapy, Young women, Age.
INTRODUCTION
The purpose of this report is to examine the importance of age as a prognostic factor for patients treated with definitive irradiation following breast-conserving surgery for early stage breast cancer and to update our previous report. 35 Although there tended to be an earlier
Definitive irradiation with breast-conserving surgery is an accepted method of treatment for selected patients
with early stage breast cancer.‘,3-5*7,8,15,36,39,40 Although many prognostic factors have been identified for patients receiving definitive irradiation, the importance of age as a prognostic factor remains the topic of considerable controversy. Only minimal data have been reported on the use of radiotherapy treatment for younger women. Some studies have shown that the outcome of younger women is worse than for older women for such outcome parameters as local-regional failure,3T40disease-free survival,3 and overall survival.4 However, other studies, including our previous report of 3-year results, have found that age does not adversely impact on local-regional contro15,35*39 or survival35 for younger patients treated with definitive radiation therapy.
During the period 1977 to 1986, 88 of breast cancer in 86 women age I = 2 l-35 years, median = 32 years, and were treated with definitive irradiation
Presented at the Twenty-Ninth Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Boston, Massachusetts, October 19-23, 1987. * Department of Radiation Oncology. t Department of Biostatistics. Reprint requests to: Lawrence J. Solin, M.D., Department of Radiation Oncology, Fox Chase Cancer Center, Central and
Shelmire Avenues, Philadelphia, PA 19 111. Acknowledgements-The authors thank Gerald Hanks, M.D. for review ofthe manuscript and Leonard Braitman, Ph.D. and Edward Lusk, Ph.D. for review of the statistical analysis of the data. Mrs. Lisa Salerno provided secretarial assistance in the preparation of this manuscript. Accepted for publication 18 May 1988.
pattern of failure in the younger patients, our results did not show that younger women I age 35 have an adverse outcome in terms of survival, local control, and regional control at 5 years when compared with older women 2 age 36.
METHODS
373
AND
MATERIALS
consecutive cases 35 years (range mean = 32 years) following breast-
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conserving surgery for early stage breast cancer at the Hospital of the University of Pennsylvania and the Fox Chase Cancer Center. These cases were compared with 808 consecutive cases of breast cancer in 798 women age L 36 years (range = 36-85 years, median = 53 years, and mean = 54 years) treated similarly during the same time period. The analysis of cases for both younger women and older women was limited to patients who had invasive carcinoma of the breast, who were AJC clinical Stage I (Tl NO MO) or II (T2 NO MO, Tl Nl MO, or T2 Nl M0),23 who had complete removal of the primary breast tumor with an excisional biopsy or wider resection, and who had undergone an axillary surgical staging procedure to determine pathologic lymph node status. Treatment policies, criteria for patient selection, and an analysis of five year results have previously been reported.7*36 The records of the patients were reviewed for histology of the primary tumor, clinical T stage, clinical tumor size, clinical AJC stage, final pathology margin from the primary tumor excision, pathologic axillary lymph node status, pathologic AJC stage, survival status, first and overall site(s) of failure, menopausal status, and estrogen and progesterone receptor status of the primary tumor. Mean follow-up time was 40 months (range = l-102 months, median = 39 months) for women zz age 35 and 3 1 months (range = l-l 11 months, median = 26 months) for women 2 age 36. The surgical treatment included an excisional biopsy or wider resection of the primary tumor for all patients. A re-excisional biopsy was performed in 64% (56/88) of the younger women and 49% (397/808) of the older women at the time of the axillary lymph node dissection. In general, pathologic axillary lymph node status was determined using an anatomic lower axillary lymph node dissection of level I t- II. The radiation therapy treatment consisted of 4,5005,000 centigray (cGy) to the whole breast delivered by opposed tangential fields over 41 to 5 weeks using a 6 MV linear accelerator. A boost to the primary tumor bed was delivered to a total dose of 26,000 cGy in 98% (861 88) of the younger women (median total dose = 6200 cGy) and 95% (770/808) of the older women (median total dose = 6200 cGy) using either an iridium implant or electrons of varying energy. In lymph node positive patients, a third field was added to treat the axillary apex and supraclavicular region to a total dose of 4,600 cGy at a depth of 3 cm., and a posterior axillary boost was given to boost the mid-plane axilla to approximately 4,500-4,600 cGy. Adjuvant chemotherapy consisted in general of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) + prednisone.” For pathologically node negative patients, adjuvant chemotherapy was given to 9% (5/55) ofthe younger women and 4% (22/553) ofthe older women. For pathologically node positive patients, adjuvant chemotherapy was given to 91% (30/33) of the younger women and 7 1% ( 180/255) of the older women. Hormonal therapy consisting of tamoxifen was also
February 1989, Volume 16, Number 2
added as clinically indicated, generally for postmenopausal patients with positive lymph nodes and positive hormone receptors. Survival curves were determined using the KaplanMeier method” with the time period beginning at the onset of definitive radiation therapy, not at the time of diagnosis of carcinoma. For survival analysis, the sample point was the patient (total = 884). For analysis of local and regional control, the sample point was the treated breast (total = 896). For analysis of relapse-free survival (RFS), patients were required to be alive and continuously without evidence of disease in order not to be considered as a failure. For analysis of NED (no evidence of disease) survival, patients were required to be alive and without evidence of disease at the time of last follow-up examination in order not to be considered as a failure. Therefore, a patient who had been salvaged with mastectomy (with or without chemotherapy and/or radiotherapy) for an isolated local or local-regional failure was considered to be a failure for relapse-free survival, but not a failure for NED survival. Statistical comparisons between survival curves were performed using the Mantel-Cox test.** Local failure was defined as a failure within the treated breast. Regional failure was defined as a failure within the axillary, infraclavicular, supraclavicular, or internal mammary nodal regions. “Local only first failure” was scored as positive only for a local failure which occurred as the first and only site of failure without regional failure and without distant failure. “Regional only first failure” was scored as positive only for a regional failure which occurred as the first and only site of failure without local failure and without distant failure. “Local and regional only first failure” was scored as positive only for a patient who failed with both local and regional failure simultaneously as first failure and without distant failure. “Any local failure” was scored as positive for a local failure which occurred before, simultaneously with, or after regional and/or distant failure. “Any local and/or regional failure” was scored as positive for any local failure, any regional failure, or both which occurred before, simultaneously with, or after distant failure. “First failure with any local component” was scored as positive for a local failure which occurred before or simultaneously with regional and/or distant failure. Two patients who failed with distant metastases before local failure were not scored as failures under the definition of “first failure with any local component,” but these two patients were scored as failures for analysis of “any local failure” and “any local and/or regional failure.” For local and regional control, curves were determined using the Kaplan-Meier methodI with the time period beginning at the onset of definitive radiation therapy. Statistical comparisons between the actuarial percentage of failures at a given time point (e.g. at 5 years) were performed using a two sample test of proportions with appropriate standard errors.2’,34
Age as a prognostic factor 0 L. J. SOLIN etal. RESULTS
Table 1 shows the characteristics for the 896 breast cancers. There is no statistically significant difference between the two groups for pathology of the primary tumor, clinical T stage, clinical tumor size, clinical AJC stage, or pathologic axillary lymph node status (p > .14 for each comparison by Chi-square test). The final pathology margin from the primary tumor excision was defined as the pathology margin from a re-excisional biopsy if this was done or the pathology margin from the initial tumor excision if a re-excision was not done. The final
Table 1. Tumor characteristics Age 5 35 years (n = 88) Number Pathology Ductal Lobular Medullary Ductal/Lobular Colloid Other Clinical T Stage Tl T2 Clinical tumor size sl.Ocm l.l-2.0cm 2.1-3.0cm 3. I-4.0 cm 4. I-5.0 cm Unknown Clinical AJC Stage I II Pathologic N Stage NO Nl l-3 positive r4 positive Pathologic AJC Stage I II Estrogen receptor status Positive Negative Not done/Unknown Progesterone receptor status Positive Negative Not done/Unknown Final pathology margin Negative Positive Unknown Menopausal status Pre-menopausal Post-menopausal Pet-i-menopausal
Age 2 36 years (n = 808)
(%)
Number
(%)
(90) (1) (7) (1) (1) -
704 37 16 28 8 15
(87) (5) (2) (3) (1) (2)
475 333
(59) (41)
103 208 182 53 21 241
(13) (26) (23)
3:
(6) (19) (25) (7) (2) (41)
43 45
(49) (51)
448 360
(55) (45)
55
(62)
553
(68)
192 63
(24) (8)
79 1 6 1 1 44 44 5 17 22 6
25 8
::; (30)
33 55
(38) (62)
369 439
22 38 28
(25) (43) (32)
409 148 251
I:;; (31)
18 32 38
(20) (36) (43)
303 183 322
(38) (23) (40)
40 7 41
(45) (8) (47)
358 3;;
(44) (9) (47)
88 -
(100) -
275 468 65
(34) (58) (8)
315
pathology margin was also not significantly different (P = .92) between the two groups. A significant difference was found between the two groups for estrogen receptor status and progesterone receptor status (p < .OO1 for both comparisons) with the younger women showing more estrogen receptor and progesterone receptor negative tumors. All of the younger women were premenopausal whereas the older women were a mixture of premenopausal, postmenopausal and perimenopausal. Figure 1 shows survival outcome versus age. There is no significant difference for patients age I 35 years versus age 1 36 years for overall survival (Fig. l-A), NED survival (Fig. 1-B), or relapse-free survival (Fig. 1-C). Local and regional failure rates for the two age groups are given in Table 2. The difference between the actuarial percentage of failures at 5 years for the two age groups was not statistically significant for each of the comparisons between the two age groups. The local only first failure rate for the younger women was 9% versus 5% for the older women (95% confidence interval of the difference34 of -4% to + 12%). The younger patients showed an earlier pattern of failure (Table 3). However, the differences between the younger and older patients did not achieve statistical significance (Fischer’s exact test). Local only first failure curves are shown in Figure 2. Because of the earlier pattern of failure in the younger patients, the curves were statistically different (p = .04 using the Mantel-Cox test), but the difference between the actuarial percentage of failures at five years was not statistically significant (p = .36 using the two sample test of proportions) for the younger versus older women. The pattern for site(s) of first failure is detailed in Table 4. All of the six breast failures in the younger age group were local only first failures (Table 4) and five of the six occurred by 3 years. Four of the six failures were detected by the new appearance of suspicious microcalcifications on routine mammography without an associated palpable or mammographic mass, and two by physical examination. Four of the six patients with breast failure in the younger group are alive and NED at 0, 9, 10, and 48 months respectively after salvage therapy, and the other two with breast failure are dead from metastatic disease. To control for potentially confounding variables of older age and menopausal status on outcome, subset analysis was performed with comparison of three age groups of age I 35 years versus age 36-50 years versus age 2 5 1 years (Table 5). There were 327 patients with 333 treated breasts in the middle group of age 36-50 years, and 47 1 patients with 475 treated breasts in the oldest group of age L 5 1 years. In the middle group, 76% (253/333) were premenopausal, and in the oldest group, 89% (423/475) were postmenopausal. There were no statistically significant differences between the three age groups for each of the comparisons for overall, NED and relapse-free survival (p > .29 for each comparison using the Mantel-Cox test). The difference between the actuar-
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I. J. Radiation Oncology 0 Biology 0 Physics
----
Age
-Age
S
February 1989, Volume 16, Number 2
35
-_-_
L 36
NUMBER Age Aga
5 35 2 36
0
1
2
3
4
5
YEARS
5()-
-----
P
0
1
2
Age S
35
Age
36
3
2
<
35
>
36
RISK
Age <
35
86
70
60
41
20
16
Age
36
796
574 I
406 d
276
(63
106
I
2
4
5
L
O-
CJ
3
YEARS
Fig. I. Actuarial survival curves for patients age I 35 years vs. age 2 36 years. The numbers shown in each figure (A, B, and C) are the number of patients at risk by year intervals. There is no significant difference between the two curves in each figure (p = .73, .98, and .18 respectively for overall survival, NED survival, and relapse-free survival). (A) Overall survival. (B) NED (no evidence of disease) survival. (C) Relapse-free survival.
5; SE #!J
AT
Age Age
4
5
YEARS
ial percentage of failures for the three age groups was also not statistically significant at 5 years for each of the comparisons for local and regional failure (p > .20 for each comparison using the two sample test of proportions). To evaluate the effect of radiotherapy alone on local control, a subset analysis was performed of patients who were pathologically node negative and who did not receive chemotherapy (Table 6). Patients who received chemotherapy were excluded from this subset because the use of chemotherapy has been associated with a decreased risk of local recurrence.36 There were 48 patients with 50 treated breasts in the younger age group, and 527 patients with 53 1 treated breasts in the older age group. There was no statistical difference in the actuarial percentage of failures for the two age groups at 5 years for local or regional control (p > .12 for each comparison using the two sample test of proportions). To evaluate a group of patients with uniformly longer follow-up, a subset analysis was performed of patients who were treated through 1983 (Table 7). In this subgroup, there were 56 patients with 57 treated breasts in
the younger age group, and 365 patients with 369 treated breasts in the older age group. Mean follow-up time was 53 months (range = 7-102 months, median = 51 months) for women 5 age 35 and 51 months (range = 2-l 11 months, median = 49 months) for women 2 age 36. For surviving patients only, mean follow-up time was 55 months (range = 12-102 months, median = 5 1 months) for women I age 35 and 53 months (range = 3-l 11 months, median = 5 I months) for women 2 age 36. There was no statistically significant difference between the two age groups for each of the comparisons of survival (p > .12 for each comparison using the Mantel-Cox test). There was also no statistically significant difference between the actuarial percentage of failures for the two age groups for each of the comparisons for local and regional failure (p > .26 for each comparison using the two sample test of proportions). For the younger age group 5 35 years, the calculated value in Tables 2, 5, 6, and 7 for “any local failure” was 1% less than the value for “local only first failure” and for “first failure with any local component” because all
317
Ageas a prognosticfactor0 L. J. SOLIN et al. Table 2. Five year actuarial local and regional failure Age 5 35 years % First failure Local only Regional only Local and regional only First failure with any local component Any failure Local Local and/or regional
Age r 36 years %
9* 6
: 1
-
9*
8
8* 19
8 13
-_--
Age
5
35
-
Age
2
36
9%
p > .20 for each of the comparisons of age ZG35 years vs. age 2 36 years. * See last paragraph in Results.
0, 0
/‘;-3-----8 1
5% 2
3
4
5
YEARS
Fig. 2. Actuarial local only first failure curves for patients I age of the failures in the younger age group were “local only first failures” (Table 4) and because of differences in denominators due to censoring during the actuarial calculations of the different failure rates.
35 years versus r age 36 years. The error bars at 5 years overlap and show + 1 standard error. The actuarial percentage of failures at 5 years for the younger versus older patients was not statistically different (p = .36 using the two sample test of proportions). However, because of the earlier pattern of failure in the younger patients, the difference between the curves was statistically significant (p = .04 using the Mantel-Cox test).
DISCUSSION The significance of age as a prognostic factor for patients treated for early stage breast cancer remains the topic of considerable controversy. The importance of this report is to document that younger women 5 age 35 years do not have an adverse outcome in terms of survival, local control, and regional control when compared with older women 2 age 36 years for a large series of patients treated in a standardized fashion. All cases were well characterized in that all patients had undergone an axillary dissection so that pathologic staging was available for the two age groups and was found to be comparable (Table 1). There were no significant differences in the tumor characteristics between the two groups (Table 1) with the exceptions of estrogen receptor (ER), progesterone receptor (PR), and menopausal status. The younger age group had significantly more ER and PR negative
Table 3. Local and regional failures within three years Age I 35 years
First failure Local only Local and/or regional only Any failure Local Local and/or regional
tumors, and similar findings have been previously noted in other studies.‘4’18 There was an earlier pattern of failure in the younger women (Table 3 and Fig. 2). However, the difference in the actuarial percentage of failures at 5 years as compared to the older women was not statistically significant (Table 2 and Fig. 2). In view of the tendency towards an earlier pattern of failure and the fact that four of the six breast failures in the younger patients were detected by the new appearance of suspicious microcalcifications on routine mammography, our current recommendation is for very careful follow-up for younger patients, especially during the first 3 years with physical examination every 2-3 months and mammography every 6- 12 months. Although there is limited information regarding the outcome of treatment of younger women with definitive irradiation following breast-conserving surgery, a number of studies have shown that younger age is not an adverse prognostic factor. For Stage I and II cancers irradi-
Age 2 36 years
No.
(%)
No.
(%)
5/6* 719
(83) (78)
8/16 16/28
(SO) (57)
516 9112
(83) (75)
18/29 26144
(62) (59)
* Each fraction is the number of failures occurring within the first three years of follow-up divided by the total number of failures.
Table 4. Site(s) of first failure Site(s) Local only Regional only Distant only Local and regional Local and distant Regional and distant Local, regional, and distant No failure Total
Age I 35 years 6 3 I
Age 2 36 years
3 69
16 7 51 5 6 8 715
88
808
-
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I. J. Radiation Oncology 0 Biology 0 Physics
Table 5. Five year actuarial outcome for three age groups Age I 35 years %
Age 36-50 years %
94 78 70
88 81 75
91 81 78
5 3
5 2
Survival Overall NED Relapse-free First failure Local only Regional only Local and regional only First failure with any local component Any failure Local Local and/or regional
9* 6 -
1
9*
10
6
8*
10
6
15
11
p > .20 for all comparisons of age I 35 years vs. age 36-50 years vs. age 2 5 1 years. * See last paragraph in Results.
ated following excisional biopsy and lower axillary nodal staging, Clarke et al. found that the local-regional relapse rate was not different for patients age I 35 years versus age > 35 years in a multivariate analysis.5 For mainly Stage I and II cancers, van Limbergen et al. found that there was no difference for local control in patients age < 40 years versus 240 years on multivariate analysis, although there was a significant difference (78.7% versus >90%) on univariate analysis.39 In this study, the tumors in the younger patients were associated with a higher pathologic grading. A number of studies of patients treated with definitive irradiation have suggested that younger age is associated with increased local or local-regional recurrence rates, but that survival is generally not found to be worse in younger patients because of salvage therapy. In the study of Recht et aL3’ from the Joint Center for Radiation
Table 6. Five year actuarial outcome for the pathologic node negative, no chemotherapy subgroup Age I 35 years % First failure Local only Regional only Local and regional only First failure with any local component Any failure Local Local and/or regional
Table 7. Five year actuarial outcome for patients treated 1977- 1983
Age251 years %
2
19
February 1989, Volume 16, Number 2
Age 2 36 years %
14* 6 -
6
14*
8
13* 23
9 12
:
p > .12 for all comparisons of age I 35 years vs. age 2 36 years. * See last paragraph in Results.
Survival Overall NED Relapse-free First failure Local only Regional only Local and regional only First failure with any local component Any failure Local Local and/or regional
Age I 35 years %
Age 136 years %
92 77 69
89 81 77
7* 7 -
: 2
7*
8
6* 18
8 13
p > .12 for all comparisons of age I 35 years vs. age 2 36 years. * See last paragraph in Results.
Therapy, younger women I age 34 had an increased risk of local recurrence (26% at 5 years) when compared with older women 2 age 35 ( 10% at 5 years). However, 5-year survival (89% vs. 85% respectively) and freedom from distant metastases (77% vs. 8 1% respectively) were not different between the two groups. Kurtz et ~1.~’also found an increased risk of recurrence in the breast in patients younger than age 40 vs. older. However, the survival rates at 15 years were not different. Matthews et ~1.~~found that there were more local-regional failures for women 5 age 35 versus > age 35, but that there was no difference for the younger women treated with definitive irradiation versus mastectomy in terms of local-regional control, overall survival, and disease-free survival. Other studies have also suggested that age is a significant negative prognostic factor for patients treated with definitive irradiation in terms of local-regional recurrence3,‘T40and disease-free survival3 For patients treated surgically with mastectomy, there is also a significant controversy as to the importance of age relative to outcome. Multiple studies have shown no difference for younger versus older women with outcome generally measured in terms of survival.2~9~1 ‘,27,28*38 However, Haagensen found that patients under age 30 years had a worse prognosis when compared with his overall group of patients treated with radical mastectomy,’ 3 and other series of patients treated predominantly with surgery have also noted a poorer prognosis for younger patients. 19,30,33 The ability to preserve the treated breast following definitive irradiation is an important measure of the efficacy of treatment. The five year actuarial rates of local only first failure and local and regional only first failure for the younger patients I age 35 years in this study were 9% and 0% respectively (Table 2). The psychological motivation for breast preservation has been found to be im-
Age as a prognostic factor 0 L. J.
portant in patients receiving primary radiotherapy instead of mastectomy as treatment for early stage breast cancer.24,25Evidence for the importance of breast preservation, particularly in younger patients, is evidenced by the increased percentage of younger patients in radiotherapy series. In our current series, 9.7% (86/884) ofthe patients were rage 35 years. In historical series of all patients presenting with breast cancer, 2.7-4.3% were
%LIN
et
319
al.
youngest age group of 135 years does not have a worse outcome in terms of survival, local control, and regional control and that controlling for older age and menopausal status does not change the conclusions found when patients r age 36 years are considered as a single population. One of the limitations of this study is the relatively short follow-up period, and longer observations will be necessary to confirm that these findings continue to be valid over time. When a subset analysis was performed and restricted to patients with longer follow-up (Table 7) our results continued to show no difference in outcome for survival, local control, and regional control for younger versus older patients. Thus, our 5-year data suggest that younger women do not have an adverse outcome in terms of survival, local control, and regional control for younger versus older patients. For both the younger women I age 35 and the older women 2 age 36, the 5-year actuarial local only first failure rates (9% vs. 5% respectively) and any local failure rates (8% vs. 8% respectively) are all relatively low rates of failure following definitive irradiation of the breast. A definite strength of the present series is that it represents the outcome of contemporary treatment strategy. All patients had pathologic axillary nodal staging, 53% had assessment of resection margins of the primary tumor, and 5 1% had a re-excision of the primary tumor. Patients with positive nodes generally received multiagent adjuvant chemotherapy. Table 8 shows a comparison of the results of conservative surgery and radiation for early breast cancer in younger women from several major series which report breast or local recurrence rates separately from local-regional recurrence rates. Axillary dissection was not performed in all patients in any of the other series, and emphasis was not placed on re-excision or assessment of the resection margins of the primary tu-
Table 8. Results of definitive irradiation and conservative surgery for early stage breast cancer in younger women: Summary of series reporting breast recurrence rates
Age Period of treatment Number of treated breasts % Tl Lesions % Re-excision of the primary tumor % Evaluation of the pathology margin of the primary tumor % Axillary lymph node dissection % Pathologic N 1 axillae % Chemotherapy % Breast recurrence Actuarial at 5 years Crude N.S. = Not stated. * For younger and older women combined.
Recht3’
Matthews26
van Limbergen39
Kurtz2’
Solin (present series)
534 1968-81 47 53 N.S.
535 1955-83 72 N.S. N.S.
139 1966-79 N.S. 24* N.S.
139 1963-8 1 210 58 N.S.
135 1977-86 88 50 64
N.S. 85 40 32
N.S. 57* 29* N.S.
N.S. 60* N.S. 14*
N.S. 12
21 N.S.
26 23
N.S. 30 56 16
53 100 37 40
12 20
9 7
380
I. J. Radiation Oncology 0 Biology 0 Physics
mor in these earlier series. The relatively low breast recurrence rates for younger women in the present series may be related to these factors. Therefore, the incidence of breast recurrence for younger women who are appropriately selected for radiation therapy, who have had adequate excision of the primary tumor, and who have been treated appropriately with radiotherapy is reasonably small and acceptable. Definitive irradiation for younger patients should continue to be considered as an acceptable alternative to conventional mastectomy for appropriately selected and treated patients.
February 1989, Volume 16, Number 2
Although longer follow-up will be needed to confirm our findings, the results of this study show that younger women 5 age 35 years do not have an adverse survival outcome when compared with older women 2 age 36 years and that the actuarial percentage of local and regional failures at five years was not significantly different. Because of the trend towards an earlier pattern of failure in the younger women, careful follow-up is necessary. Potential candidates for definitive irradiation should not be excluded for treatment solely on the basis of younger age 5 35 years.
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Bedwinek, J.M., Perez, C.A., Kramer, S., Brady, L., Goodman, R., Grundy, G.: Irradiation as the primary management of Stage I and II adenocarcinoma of the breast. Can-
cerClin. Trials3: I l-18, 1980. 2. Birks, D.M., Crawford, G.M., Ellison, L.G., Johnstone,
F.R.C.: Carcinoma of the breast in women 30 years of age or less. Surg. Gynecol. Obstet. 137: 2 l-25, 1973. 3. Calle, R., Vilcoq, J.R., Zafrani, B., Vielh, P., Fourquet, A.: Local control and survival of breast cancer treated by limited surgery followed by irradiation. ht. J. Radiat. Oncol. Biol. Phys. 12: 873-878, 1986. 4. Clark, R.M., Wilkinson, R.H., Mahoney, L.J., Reid, J.G., MacDonald, W.D.: Breast cancer: A 21 year experience with conservative surgery and radiation. Int. J. Radiat. Oncol. Biol. Phys. 8: 967-975, 1982. 5. Clarke, D.H., Le, M.G., Sarrazin, D., Lacombe, M., Fontaine, F., Travagli, J., May-Levin, F., Contesso, G., Arriagada, R.: Analysis of local-regional relapses in patients with early breast cancers treated by excision and radiotherapy: Experience of the Institut Gustave-Roussy. Int. J. Radiat. Oncol. Biol. Phys. 11: 137-145, 1985. 6. Cutler, S.J., Young, J.L., Jr. (Eds.): Third national cancer survey: Incidence data. Natl. Cancer Inst. Monog. 41: 108, 1975. 7. Danoff, B.F., Haller, D.G., Glick, J-H., Goodman, R.L.: Conservative surgery and irradiation in the treatment of early breast cancer. Ann. Intern. Med. 102: 634-642, 1985. 8. Delouche, G., Bachelot, F., Premont, M., Kurtz, J.M.: Conservation treatment of early breast cancer: Long term results and complications. Int. J. Radiat. Oncol. Biol. Phys. 13: 29-34, 1987. 9. Early, T.K., Gallagher, J.Q., Chapman, K.E.: Carcinoma of the breast in women under 30 years of age. Am. J. Surg. 118: 832-834, 1969. 10. Glick, J.H., Danoff, B.F., Haller, D.G., Weiler, C., Goodman, R.L.: Adjuvant chemotherapy in patients undergoing definitive irradiation for primary breast cancer-The University of Pennsylvania experience. In Conservative Management of Breast Cancer: New Surgical and Radiotherapeutic Techniques, Harris, J.R., Hellman, S., and Silen W. (Eds.). Philadelphia, PA, J.B. Lippincott Co. 1983, pp. 3 1l-320. 11. Gogas, J., Skalkeas, G.: Prognosis of mammary carcinoma in young women. Surgery 78: 339-342,1975. 12. Haagensen, C.D.: Diseases of the Breast. W.B. Saunders Co., Philadelphia, PA. 1986, pp. 402-407. 13. Ibid., pp. 903-932. 14. Hahnel, R., Woodings, T., Vivian, A.B.: Prognostic value of estrogen receptors in primary breast cancer. Cancer 44: 67 l-675,1979.
15. Harris, J.R., Botnick, L., Bloomer, W.D., Chaffey, J.T., Hellman, S.: Primary radiation therapy for early breast cancer: The experience at the Joint Center for Radiation Therapy. Int. J. Radiat. Oncol. Biol. Phys. 7: 1549-1552, 1981. 16. Harris, J.R., Levene, M.B., Hellman, S.: The role of radiation therapy in the primary treatment of carcinoma of the breast. Sem. Oncol. 5: 403-416, 1978. 17. Kaplan, E.L., Meier, P.: Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53: 457-48 1, 1958. 18. Kiang, D.T., Kennedy, B.J.: Factors affecting estrogen receptors in breast cancer. Cancer 40: 157 l- 1576, 1977. 19. Kleinfeld, G., Haagensen, C.D., Cooley, E.: Age and menstrual status as prognostic factors in carcinoma of the breast. Ann. Surg. 157: 600-605, 1963. 20. Kurtz, J.M., Spitalier, J.M., Amalric, R., Brandone, H., Ayme, Y., Bressac, C., Hans, D.: Mammary recurrences in women younger than forty. Int. J. Radiat. Oncol. Bioi. Phys. 15: 27 l-276, 1988. 2 1. Lawless, J.F.: Statistical Models and Methods for Lifetime Data. New York, NY, John Wiley and Sons, 1982. 22. Mantel, N.: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50: 163-170, 1966. 23. Manual for Staging of Cancer, 2nd edition. Philadelphia, PA, J.B. Lippincott. 1983, pp. 127-134. 24. Margolis, G.J., Carabell, S.C., Goodman, R.L.: Psychological aspects of primary radiation therapy for breast carcinoma. Am. J. Clin. Oncol. 6: 533-538, 1983. 25. Margolis, G.J., Goodman, R.L., Rubin, A.: Psychological factors in the choice oftreatment for breast cancer (Abstr.). Int. J Radiat. Oncol. Biol. Phys. lZ(Suppl. I): 15 1, 1986. 26. Matthews, R.H., McNeese, M.D., Montague, E.D., Oswald, M.J.: Prognostic implications of age in breast cancer patients treated with tumorectomy and irradiation or with mastectomy. Int. J. Radiat. Oncol. Biol. Phys. 14: 659663, 1988. 27. Max, M.H., Klamer, T.W.: Breast cancer in 120 women under 35 years old: A lo-year community-wide survey. Am. Surg. 50: 23-25,1984. 28. Moore, S.W., Lewis, R.J.: Carcinoma of the breast in women 30 years of age and under. Surg. Gynecol. Obstet. 119: 1253-1255,1964. 29. Norris, H.J., Taylor, H.B.: Carcinoma of the breast in women less than 30 years old. Cancer 26: 953-959, 1970. 30. Noyes, R.D., Spanos, W.J., Montague, E.D.: Breast cancer in women aged 30 and under. Cancer 49: 1302-1307, 1982. 31. Recht, A., Connolly, J.L., Schnitt, S.J., Silver, B., Rose,
Age as a prognostic factor 0 L. .I. SOLINetal.
32.
33. 34. 35.
36.
37.
M.A., Love, S., Harris, J.R.: The effect of young age on tumor recurrence in the treated breast after conservative surgery and radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 14: 3-10, 1988. Rosen, P.P., Lesser, M.L., Kinne, D.W., Beattie, E.J.: Breast carcinoma in women 35 years of age or younger. Ann. Surg. 199: 133-142,1984. Schwartz, G.F., Zeok, J.V.: Carcinoma of the breast in young women. Am. J. Surg. 131: 570-574,1976. Simon, R.: Confidence intervals for reporting results of clinical trials. Ann. Znt.Med. 105: 429-435, 1986. Solin, L.J., Danoff, B.F., Pajak, T.F., Goodman, R.L.: Breast cancer in young women treated definitively with radiotherapy: An early report. Am. J. C/in. Oncol. 7: 431435, 1984. Solin, L.J., Fowble, B., Martz, K.L., Goodman, R.L.: Definitive irradiation for early stage breast cancer: The University of Pennsylvania experience. Int. J. Radiat. Oncol. Biol. Phys. 14: 235-242, 1988. Solin, L.J., Fowble, B., Martz, K., Pajak, T.F., Goodman, R.L.: Results of re-excisional biopsy of the primary tumor in preparation for definitive irradiation of patients with
38.
39.
40.
41.
42.
381
early stage breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 12: 721-725, 1986. Treves, N., Holleb, AL: A report of 549 cases of breast cancer in women 35 years of age or younger. Surg. Gynecol. Obstet. 107: 27 l-283, 1958. van Limbergen, E., van den Bogaert, W., van der Schueren, E., Rijnders, A.: Tumor excision and radiotherapy as primary treatment of breast cancer. Analysis of patient and treatment parameters and local control. Radiother. Oncol. 8: 1-9, 1987. Vilcoq, J.R., Calle, R., Stacey, P., Ghossein, N.A.: Theoutcome of treatment by tumorectomy and radiotherapy of patients with operable breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 7: 1327-1332, 1981. Wallgren, A., Silfversward, C.. Hultborn, A.: Carcinoma of the breast in women under 30 years of age. Cancer 40: 916-923. 1977. Young, J.L., Jr., Percy, C.L., Asire, A.J. (Eds.): Surveillance, epidemiology, and end results: Incidence and mortality data, 1973-77. Natl. Cancer Inst. Monog. 57: 70, 1981.
16, pp. 373-38
0360-O-3016/89 $3.00 + .oO Copyright 0 I989 Pergamon Press plc
I
??Original Contribution
AGE AS A PROGNOSTIC FACTOR FOR PATIENTS TREATED WITH DEFINITIVE IRRADIATION FOR EARLY STAGE BREAST CANCER LAWRENCE J. SOLIN, M.D.,* BARBARA FOWBLE, M.D.,* DELRAY J. SCHULTZ, AND ROBERT L. GOODMAN, M.D.*
M.A.t
University of Pennsylvania School of Medicine and the Fox Chase Cancer Center, Philadelphia, PA From 1977 to 1986,88 breast cancers in 86 women age I 35 years were treated with definitive irradiation following breast-conserving surgery. The records of these eases were reviewed and compared to 808 breast cancers in 798 women age 136 years treated similarly during the same time period. All women had AJC clinical Stages I or II invasive carcinoma of the breast and had undergone an axillary surgical staging procedure to determine pathologic lymph node staging prior to receiving definitive radiotherapy. There was no statistical difference between the younger and older women in terms of 5-year actuarial overall survival (94% vs. 90%), NED survival (78% vs. 81%) or relapse-free survival (70% vs. 77%). Although the younger women tended to have an earlier pattern of failure, the difference between the actuarial percentage of failures at 5 years for the two age groups was not significantly different for local only first failure (9% vs. 5%), regional only first failure (6% vs. 3%), and local and regional only first failure (0% vs. 1%). Subset analyses also did not show a difference between the younger and older patients. Although longer follow-up will be needed to confirm these observations, our 5-year results show that younger patients I age 35 do not have an adverse outcome in terms of survival, local control, or regional control when compared with older patients 2 age 36. Potential candidates for definitive irradiation following breast-conserving surgery should not be excluded for treatment solely on the basis of younger age zz 35 years. Breast cancer, Radiation therapy, Young women, Age.
INTRODUCTION
The purpose of this report is to examine the importance of age as a prognostic factor for patients treated with definitive irradiation following breast-conserving surgery for early stage breast cancer and to update our previous report. 35 Although there tended to be an earlier
Definitive irradiation with breast-conserving surgery is an accepted method of treatment for selected patients
with early stage breast cancer.‘,3-5*7,8,15,36,39,40 Although many prognostic factors have been identified for patients receiving definitive irradiation, the importance of age as a prognostic factor remains the topic of considerable controversy. Only minimal data have been reported on the use of radiotherapy treatment for younger women. Some studies have shown that the outcome of younger women is worse than for older women for such outcome parameters as local-regional failure,3T40disease-free survival,3 and overall survival.4 However, other studies, including our previous report of 3-year results, have found that age does not adversely impact on local-regional contro15,35*39 or survival35 for younger patients treated with definitive radiation therapy.
During the period 1977 to 1986, 88 of breast cancer in 86 women age I = 2 l-35 years, median = 32 years, and were treated with definitive irradiation
Presented at the Twenty-Ninth Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Boston, Massachusetts, October 19-23, 1987. * Department of Radiation Oncology. t Department of Biostatistics. Reprint requests to: Lawrence J. Solin, M.D., Department of Radiation Oncology, Fox Chase Cancer Center, Central and
Shelmire Avenues, Philadelphia, PA 19 111. Acknowledgements-The authors thank Gerald Hanks, M.D. for review ofthe manuscript and Leonard Braitman, Ph.D. and Edward Lusk, Ph.D. for review of the statistical analysis of the data. Mrs. Lisa Salerno provided secretarial assistance in the preparation of this manuscript. Accepted for publication 18 May 1988.
pattern of failure in the younger patients, our results did not show that younger women I age 35 have an adverse outcome in terms of survival, local control, and regional control at 5 years when compared with older women 2 age 36.
METHODS
373
AND
MATERIALS
consecutive cases 35 years (range mean = 32 years) following breast-
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conserving surgery for early stage breast cancer at the Hospital of the University of Pennsylvania and the Fox Chase Cancer Center. These cases were compared with 808 consecutive cases of breast cancer in 798 women age L 36 years (range = 36-85 years, median = 53 years, and mean = 54 years) treated similarly during the same time period. The analysis of cases for both younger women and older women was limited to patients who had invasive carcinoma of the breast, who were AJC clinical Stage I (Tl NO MO) or II (T2 NO MO, Tl Nl MO, or T2 Nl M0),23 who had complete removal of the primary breast tumor with an excisional biopsy or wider resection, and who had undergone an axillary surgical staging procedure to determine pathologic lymph node status. Treatment policies, criteria for patient selection, and an analysis of five year results have previously been reported.7*36 The records of the patients were reviewed for histology of the primary tumor, clinical T stage, clinical tumor size, clinical AJC stage, final pathology margin from the primary tumor excision, pathologic axillary lymph node status, pathologic AJC stage, survival status, first and overall site(s) of failure, menopausal status, and estrogen and progesterone receptor status of the primary tumor. Mean follow-up time was 40 months (range = l-102 months, median = 39 months) for women zz age 35 and 3 1 months (range = l-l 11 months, median = 26 months) for women 2 age 36. The surgical treatment included an excisional biopsy or wider resection of the primary tumor for all patients. A re-excisional biopsy was performed in 64% (56/88) of the younger women and 49% (397/808) of the older women at the time of the axillary lymph node dissection. In general, pathologic axillary lymph node status was determined using an anatomic lower axillary lymph node dissection of level I t- II. The radiation therapy treatment consisted of 4,5005,000 centigray (cGy) to the whole breast delivered by opposed tangential fields over 41 to 5 weeks using a 6 MV linear accelerator. A boost to the primary tumor bed was delivered to a total dose of 26,000 cGy in 98% (861 88) of the younger women (median total dose = 6200 cGy) and 95% (770/808) of the older women (median total dose = 6200 cGy) using either an iridium implant or electrons of varying energy. In lymph node positive patients, a third field was added to treat the axillary apex and supraclavicular region to a total dose of 4,600 cGy at a depth of 3 cm., and a posterior axillary boost was given to boost the mid-plane axilla to approximately 4,500-4,600 cGy. Adjuvant chemotherapy consisted in general of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) + prednisone.” For pathologically node negative patients, adjuvant chemotherapy was given to 9% (5/55) ofthe younger women and 4% (22/553) ofthe older women. For pathologically node positive patients, adjuvant chemotherapy was given to 91% (30/33) of the younger women and 7 1% ( 180/255) of the older women. Hormonal therapy consisting of tamoxifen was also
February 1989, Volume 16, Number 2
added as clinically indicated, generally for postmenopausal patients with positive lymph nodes and positive hormone receptors. Survival curves were determined using the KaplanMeier method” with the time period beginning at the onset of definitive radiation therapy, not at the time of diagnosis of carcinoma. For survival analysis, the sample point was the patient (total = 884). For analysis of local and regional control, the sample point was the treated breast (total = 896). For analysis of relapse-free survival (RFS), patients were required to be alive and continuously without evidence of disease in order not to be considered as a failure. For analysis of NED (no evidence of disease) survival, patients were required to be alive and without evidence of disease at the time of last follow-up examination in order not to be considered as a failure. Therefore, a patient who had been salvaged with mastectomy (with or without chemotherapy and/or radiotherapy) for an isolated local or local-regional failure was considered to be a failure for relapse-free survival, but not a failure for NED survival. Statistical comparisons between survival curves were performed using the Mantel-Cox test.** Local failure was defined as a failure within the treated breast. Regional failure was defined as a failure within the axillary, infraclavicular, supraclavicular, or internal mammary nodal regions. “Local only first failure” was scored as positive only for a local failure which occurred as the first and only site of failure without regional failure and without distant failure. “Regional only first failure” was scored as positive only for a regional failure which occurred as the first and only site of failure without local failure and without distant failure. “Local and regional only first failure” was scored as positive only for a patient who failed with both local and regional failure simultaneously as first failure and without distant failure. “Any local failure” was scored as positive for a local failure which occurred before, simultaneously with, or after regional and/or distant failure. “Any local and/or regional failure” was scored as positive for any local failure, any regional failure, or both which occurred before, simultaneously with, or after distant failure. “First failure with any local component” was scored as positive for a local failure which occurred before or simultaneously with regional and/or distant failure. Two patients who failed with distant metastases before local failure were not scored as failures under the definition of “first failure with any local component,” but these two patients were scored as failures for analysis of “any local failure” and “any local and/or regional failure.” For local and regional control, curves were determined using the Kaplan-Meier methodI with the time period beginning at the onset of definitive radiation therapy. Statistical comparisons between the actuarial percentage of failures at a given time point (e.g. at 5 years) were performed using a two sample test of proportions with appropriate standard errors.2’,34
Age as a prognostic factor 0 L. J. SOLIN etal. RESULTS
Table 1 shows the characteristics for the 896 breast cancers. There is no statistically significant difference between the two groups for pathology of the primary tumor, clinical T stage, clinical tumor size, clinical AJC stage, or pathologic axillary lymph node status (p > .14 for each comparison by Chi-square test). The final pathology margin from the primary tumor excision was defined as the pathology margin from a re-excisional biopsy if this was done or the pathology margin from the initial tumor excision if a re-excision was not done. The final
Table 1. Tumor characteristics Age 5 35 years (n = 88) Number Pathology Ductal Lobular Medullary Ductal/Lobular Colloid Other Clinical T Stage Tl T2 Clinical tumor size sl.Ocm l.l-2.0cm 2.1-3.0cm 3. I-4.0 cm 4. I-5.0 cm Unknown Clinical AJC Stage I II Pathologic N Stage NO Nl l-3 positive r4 positive Pathologic AJC Stage I II Estrogen receptor status Positive Negative Not done/Unknown Progesterone receptor status Positive Negative Not done/Unknown Final pathology margin Negative Positive Unknown Menopausal status Pre-menopausal Post-menopausal Pet-i-menopausal
Age 2 36 years (n = 808)
(%)
Number
(%)
(90) (1) (7) (1) (1) -
704 37 16 28 8 15
(87) (5) (2) (3) (1) (2)
475 333
(59) (41)
103 208 182 53 21 241
(13) (26) (23)
3:
(6) (19) (25) (7) (2) (41)
43 45
(49) (51)
448 360
(55) (45)
55
(62)
553
(68)
192 63
(24) (8)
79 1 6 1 1 44 44 5 17 22 6
25 8
::; (30)
33 55
(38) (62)
369 439
22 38 28
(25) (43) (32)
409 148 251
I:;; (31)
18 32 38
(20) (36) (43)
303 183 322
(38) (23) (40)
40 7 41
(45) (8) (47)
358 3;;
(44) (9) (47)
88 -
(100) -
275 468 65
(34) (58) (8)
315
pathology margin was also not significantly different (P = .92) between the two groups. A significant difference was found between the two groups for estrogen receptor status and progesterone receptor status (p < .OO1 for both comparisons) with the younger women showing more estrogen receptor and progesterone receptor negative tumors. All of the younger women were premenopausal whereas the older women were a mixture of premenopausal, postmenopausal and perimenopausal. Figure 1 shows survival outcome versus age. There is no significant difference for patients age I 35 years versus age 1 36 years for overall survival (Fig. l-A), NED survival (Fig. 1-B), or relapse-free survival (Fig. 1-C). Local and regional failure rates for the two age groups are given in Table 2. The difference between the actuarial percentage of failures at 5 years for the two age groups was not statistically significant for each of the comparisons between the two age groups. The local only first failure rate for the younger women was 9% versus 5% for the older women (95% confidence interval of the difference34 of -4% to + 12%). The younger patients showed an earlier pattern of failure (Table 3). However, the differences between the younger and older patients did not achieve statistical significance (Fischer’s exact test). Local only first failure curves are shown in Figure 2. Because of the earlier pattern of failure in the younger patients, the curves were statistically different (p = .04 using the Mantel-Cox test), but the difference between the actuarial percentage of failures at five years was not statistically significant (p = .36 using the two sample test of proportions) for the younger versus older women. The pattern for site(s) of first failure is detailed in Table 4. All of the six breast failures in the younger age group were local only first failures (Table 4) and five of the six occurred by 3 years. Four of the six failures were detected by the new appearance of suspicious microcalcifications on routine mammography without an associated palpable or mammographic mass, and two by physical examination. Four of the six patients with breast failure in the younger group are alive and NED at 0, 9, 10, and 48 months respectively after salvage therapy, and the other two with breast failure are dead from metastatic disease. To control for potentially confounding variables of older age and menopausal status on outcome, subset analysis was performed with comparison of three age groups of age I 35 years versus age 36-50 years versus age 2 5 1 years (Table 5). There were 327 patients with 333 treated breasts in the middle group of age 36-50 years, and 47 1 patients with 475 treated breasts in the oldest group of age L 5 1 years. In the middle group, 76% (253/333) were premenopausal, and in the oldest group, 89% (423/475) were postmenopausal. There were no statistically significant differences between the three age groups for each of the comparisons for overall, NED and relapse-free survival (p > .29 for each comparison using the Mantel-Cox test). The difference between the actuar-
376
I. J. Radiation Oncology 0 Biology 0 Physics
----
Age
-Age
S
February 1989, Volume 16, Number 2
35
-_-_
L 36
NUMBER Age Aga
5 35 2 36
0
1
2
3
4
5
YEARS
5()-
-----
P
0
1
2
Age S
35
Age
36
3
2
<
35
>
36
RISK
Age <
35
86
70
60
41
20
16
Age
36
796
574 I
406 d
276
(63
106
I
2
4
5
L
O-
CJ
3
YEARS
Fig. I. Actuarial survival curves for patients age I 35 years vs. age 2 36 years. The numbers shown in each figure (A, B, and C) are the number of patients at risk by year intervals. There is no significant difference between the two curves in each figure (p = .73, .98, and .18 respectively for overall survival, NED survival, and relapse-free survival). (A) Overall survival. (B) NED (no evidence of disease) survival. (C) Relapse-free survival.
5; SE #!J
AT
Age Age
4
5
YEARS
ial percentage of failures for the three age groups was also not statistically significant at 5 years for each of the comparisons for local and regional failure (p > .20 for each comparison using the two sample test of proportions). To evaluate the effect of radiotherapy alone on local control, a subset analysis was performed of patients who were pathologically node negative and who did not receive chemotherapy (Table 6). Patients who received chemotherapy were excluded from this subset because the use of chemotherapy has been associated with a decreased risk of local recurrence.36 There were 48 patients with 50 treated breasts in the younger age group, and 527 patients with 53 1 treated breasts in the older age group. There was no statistical difference in the actuarial percentage of failures for the two age groups at 5 years for local or regional control (p > .12 for each comparison using the two sample test of proportions). To evaluate a group of patients with uniformly longer follow-up, a subset analysis was performed of patients who were treated through 1983 (Table 7). In this subgroup, there were 56 patients with 57 treated breasts in
the younger age group, and 365 patients with 369 treated breasts in the older age group. Mean follow-up time was 53 months (range = 7-102 months, median = 51 months) for women 5 age 35 and 51 months (range = 2-l 11 months, median = 49 months) for women 2 age 36. For surviving patients only, mean follow-up time was 55 months (range = 12-102 months, median = 5 1 months) for women I age 35 and 53 months (range = 3-l 11 months, median = 5 I months) for women 2 age 36. There was no statistically significant difference between the two age groups for each of the comparisons of survival (p > .12 for each comparison using the Mantel-Cox test). There was also no statistically significant difference between the actuarial percentage of failures for the two age groups for each of the comparisons for local and regional failure (p > .26 for each comparison using the two sample test of proportions). For the younger age group 5 35 years, the calculated value in Tables 2, 5, 6, and 7 for “any local failure” was 1% less than the value for “local only first failure” and for “first failure with any local component” because all
317
Ageas a prognosticfactor0 L. J. SOLIN et al. Table 2. Five year actuarial local and regional failure Age 5 35 years % First failure Local only Regional only Local and regional only First failure with any local component Any failure Local Local and/or regional
Age r 36 years %
9* 6
: 1
-
9*
8
8* 19
8 13
-_--
Age
5
35
-
Age
2
36
9%
p > .20 for each of the comparisons of age ZG35 years vs. age 2 36 years. * See last paragraph in Results.
0, 0
/‘;-3-----8 1
5% 2
3
4
5
YEARS
Fig. 2. Actuarial local only first failure curves for patients I age of the failures in the younger age group were “local only first failures” (Table 4) and because of differences in denominators due to censoring during the actuarial calculations of the different failure rates.
35 years versus r age 36 years. The error bars at 5 years overlap and show + 1 standard error. The actuarial percentage of failures at 5 years for the younger versus older patients was not statistically different (p = .36 using the two sample test of proportions). However, because of the earlier pattern of failure in the younger patients, the difference between the curves was statistically significant (p = .04 using the Mantel-Cox test).
DISCUSSION The significance of age as a prognostic factor for patients treated for early stage breast cancer remains the topic of considerable controversy. The importance of this report is to document that younger women 5 age 35 years do not have an adverse outcome in terms of survival, local control, and regional control when compared with older women 2 age 36 years for a large series of patients treated in a standardized fashion. All cases were well characterized in that all patients had undergone an axillary dissection so that pathologic staging was available for the two age groups and was found to be comparable (Table 1). There were no significant differences in the tumor characteristics between the two groups (Table 1) with the exceptions of estrogen receptor (ER), progesterone receptor (PR), and menopausal status. The younger age group had significantly more ER and PR negative
Table 3. Local and regional failures within three years Age I 35 years
First failure Local only Local and/or regional only Any failure Local Local and/or regional
tumors, and similar findings have been previously noted in other studies.‘4’18 There was an earlier pattern of failure in the younger women (Table 3 and Fig. 2). However, the difference in the actuarial percentage of failures at 5 years as compared to the older women was not statistically significant (Table 2 and Fig. 2). In view of the tendency towards an earlier pattern of failure and the fact that four of the six breast failures in the younger patients were detected by the new appearance of suspicious microcalcifications on routine mammography, our current recommendation is for very careful follow-up for younger patients, especially during the first 3 years with physical examination every 2-3 months and mammography every 6- 12 months. Although there is limited information regarding the outcome of treatment of younger women with definitive irradiation following breast-conserving surgery, a number of studies have shown that younger age is not an adverse prognostic factor. For Stage I and II cancers irradi-
Age 2 36 years
No.
(%)
No.
(%)
5/6* 719
(83) (78)
8/16 16/28
(SO) (57)
516 9112
(83) (75)
18/29 26144
(62) (59)
* Each fraction is the number of failures occurring within the first three years of follow-up divided by the total number of failures.
Table 4. Site(s) of first failure Site(s) Local only Regional only Distant only Local and regional Local and distant Regional and distant Local, regional, and distant No failure Total
Age I 35 years 6 3 I
Age 2 36 years
3 69
16 7 51 5 6 8 715
88
808
-
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I. J. Radiation Oncology 0 Biology 0 Physics
Table 5. Five year actuarial outcome for three age groups Age I 35 years %
Age 36-50 years %
94 78 70
88 81 75
91 81 78
5 3
5 2
Survival Overall NED Relapse-free First failure Local only Regional only Local and regional only First failure with any local component Any failure Local Local and/or regional
9* 6 -
1
9*
10
6
8*
10
6
15
11
p > .20 for all comparisons of age I 35 years vs. age 36-50 years vs. age 2 5 1 years. * See last paragraph in Results.
ated following excisional biopsy and lower axillary nodal staging, Clarke et al. found that the local-regional relapse rate was not different for patients age I 35 years versus age > 35 years in a multivariate analysis.5 For mainly Stage I and II cancers, van Limbergen et al. found that there was no difference for local control in patients age < 40 years versus 240 years on multivariate analysis, although there was a significant difference (78.7% versus >90%) on univariate analysis.39 In this study, the tumors in the younger patients were associated with a higher pathologic grading. A number of studies of patients treated with definitive irradiation have suggested that younger age is associated with increased local or local-regional recurrence rates, but that survival is generally not found to be worse in younger patients because of salvage therapy. In the study of Recht et aL3’ from the Joint Center for Radiation
Table 6. Five year actuarial outcome for the pathologic node negative, no chemotherapy subgroup Age I 35 years % First failure Local only Regional only Local and regional only First failure with any local component Any failure Local Local and/or regional
Table 7. Five year actuarial outcome for patients treated 1977- 1983
Age251 years %
2
19
February 1989, Volume 16, Number 2
Age 2 36 years %
14* 6 -
6
14*
8
13* 23
9 12
:
p > .12 for all comparisons of age I 35 years vs. age 2 36 years. * See last paragraph in Results.
Survival Overall NED Relapse-free First failure Local only Regional only Local and regional only First failure with any local component Any failure Local Local and/or regional
Age I 35 years %
Age 136 years %
92 77 69
89 81 77
7* 7 -
: 2
7*
8
6* 18
8 13
p > .12 for all comparisons of age I 35 years vs. age 2 36 years. * See last paragraph in Results.
Therapy, younger women I age 34 had an increased risk of local recurrence (26% at 5 years) when compared with older women 2 age 35 ( 10% at 5 years). However, 5-year survival (89% vs. 85% respectively) and freedom from distant metastases (77% vs. 8 1% respectively) were not different between the two groups. Kurtz et ~1.~’also found an increased risk of recurrence in the breast in patients younger than age 40 vs. older. However, the survival rates at 15 years were not different. Matthews et ~1.~~found that there were more local-regional failures for women 5 age 35 versus > age 35, but that there was no difference for the younger women treated with definitive irradiation versus mastectomy in terms of local-regional control, overall survival, and disease-free survival. Other studies have also suggested that age is a significant negative prognostic factor for patients treated with definitive irradiation in terms of local-regional recurrence3,‘T40and disease-free survival3 For patients treated surgically with mastectomy, there is also a significant controversy as to the importance of age relative to outcome. Multiple studies have shown no difference for younger versus older women with outcome generally measured in terms of survival.2~9~1 ‘,27,28*38 However, Haagensen found that patients under age 30 years had a worse prognosis when compared with his overall group of patients treated with radical mastectomy,’ 3 and other series of patients treated predominantly with surgery have also noted a poorer prognosis for younger patients. 19,30,33 The ability to preserve the treated breast following definitive irradiation is an important measure of the efficacy of treatment. The five year actuarial rates of local only first failure and local and regional only first failure for the younger patients I age 35 years in this study were 9% and 0% respectively (Table 2). The psychological motivation for breast preservation has been found to be im-
Age as a prognostic factor 0 L. J.
portant in patients receiving primary radiotherapy instead of mastectomy as treatment for early stage breast cancer.24,25Evidence for the importance of breast preservation, particularly in younger patients, is evidenced by the increased percentage of younger patients in radiotherapy series. In our current series, 9.7% (86/884) ofthe patients were rage 35 years. In historical series of all patients presenting with breast cancer, 2.7-4.3% were
%LIN
et
319
al.
youngest age group of 135 years does not have a worse outcome in terms of survival, local control, and regional control and that controlling for older age and menopausal status does not change the conclusions found when patients r age 36 years are considered as a single population. One of the limitations of this study is the relatively short follow-up period, and longer observations will be necessary to confirm that these findings continue to be valid over time. When a subset analysis was performed and restricted to patients with longer follow-up (Table 7) our results continued to show no difference in outcome for survival, local control, and regional control for younger versus older patients. Thus, our 5-year data suggest that younger women do not have an adverse outcome in terms of survival, local control, and regional control for younger versus older patients. For both the younger women I age 35 and the older women 2 age 36, the 5-year actuarial local only first failure rates (9% vs. 5% respectively) and any local failure rates (8% vs. 8% respectively) are all relatively low rates of failure following definitive irradiation of the breast. A definite strength of the present series is that it represents the outcome of contemporary treatment strategy. All patients had pathologic axillary nodal staging, 53% had assessment of resection margins of the primary tumor, and 5 1% had a re-excision of the primary tumor. Patients with positive nodes generally received multiagent adjuvant chemotherapy. Table 8 shows a comparison of the results of conservative surgery and radiation for early breast cancer in younger women from several major series which report breast or local recurrence rates separately from local-regional recurrence rates. Axillary dissection was not performed in all patients in any of the other series, and emphasis was not placed on re-excision or assessment of the resection margins of the primary tu-
Table 8. Results of definitive irradiation and conservative surgery for early stage breast cancer in younger women: Summary of series reporting breast recurrence rates
Age Period of treatment Number of treated breasts % Tl Lesions % Re-excision of the primary tumor % Evaluation of the pathology margin of the primary tumor % Axillary lymph node dissection % Pathologic N 1 axillae % Chemotherapy % Breast recurrence Actuarial at 5 years Crude N.S. = Not stated. * For younger and older women combined.
Recht3’
Matthews26
van Limbergen39
Kurtz2’
Solin (present series)
534 1968-81 47 53 N.S.
535 1955-83 72 N.S. N.S.
139 1966-79 N.S. 24* N.S.
139 1963-8 1 210 58 N.S.
135 1977-86 88 50 64
N.S. 85 40 32
N.S. 57* 29* N.S.
N.S. 60* N.S. 14*
N.S. 12
21 N.S.
26 23
N.S. 30 56 16
53 100 37 40
12 20
9 7
380
I. J. Radiation Oncology 0 Biology 0 Physics
mor in these earlier series. The relatively low breast recurrence rates for younger women in the present series may be related to these factors. Therefore, the incidence of breast recurrence for younger women who are appropriately selected for radiation therapy, who have had adequate excision of the primary tumor, and who have been treated appropriately with radiotherapy is reasonably small and acceptable. Definitive irradiation for younger patients should continue to be considered as an acceptable alternative to conventional mastectomy for appropriately selected and treated patients.
February 1989, Volume 16, Number 2
Although longer follow-up will be needed to confirm our findings, the results of this study show that younger women 5 age 35 years do not have an adverse survival outcome when compared with older women 2 age 36 years and that the actuarial percentage of local and regional failures at five years was not significantly different. Because of the trend towards an earlier pattern of failure in the younger women, careful follow-up is necessary. Potential candidates for definitive irradiation should not be excluded for treatment solely on the basis of younger age 5 35 years.
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