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Comprehensive Locoregional Treatment and Systemic Therapy for Postmastectomy Isolated Locoregional Recurrence
Int. J. Radiation Oncology Biol. Phys., Vol. 72, No. 5, pp. 1456–1464, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
doi:10.1016/j.ijrobp.2008.03.042
CLINICAL INVESTIGATION
Breast
COMPREHENSIVE LOCOREGIONAL TREATMENT AND SYSTEMIC THERAPY FOR POSTMASTECTOMY ISOLATED LOCOREGIONAL RECURRENCE SUNG-HSIN KUO, M.D., PH.D.,*x{k CHIUN-SHENG HUANG, M.D., PH.D.,y WUN-HON KUO, M.D.,y ANN-LII CHENG, M.D., PH.D.,*zx KING-JENG CHANG, M.D., PH.D.,y x{ AND JASON CHIA-HSIEN CHENG, M.D., PH.D.* Departments of *Oncology, y Surgery, and z Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; x Cancer Research Center and {Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; and k Department of Oncology, National Taiwan University Hospital Yun-Lin Branch, Yunlin, Taiwan Purpose: To assess the impact of comprehensive locoregional therapy and systemic therapy on disease control and survival for postmastectomy patients with isolated locoregional recurrence (ILRR). Methods and Materials: A total of 115 postmastectomy breast cancer patients treated for ILRR were included. Of the patients, 98 underwent comprehensive locoregional treatment (local tumor excision plus postoperative radiotherapy), and 17 received definitive radiotherapy alone. Involved-field radiotherapy was given to 69 patients, whereas entire-field radiotherapy (both involved-field and elective-field, involving the chest wall and regional lymphatics) was given to 46 patients. Systemic therapy consisting of hormone therapy, chemotherapy, or both was given to 69% of patients. Results: Patients treated with comprehensive locoregional treatment had a significantly better 5-year invasive disease–free survival (IDFS) and overall survival (OS) after ILRR than patients treated with definitive radiotherapy alone (IDFS rate, 51% vs. 16%, p = 0.006; OS rate, 62% vs. 37%, p = 0.017). Patients with the most comprehensive locoregional treatment (recurrent tumor excision and entire-field radiotherapy) and systemic therapy had a significantly better 5-year IDFS and OS than patients given either treatment or neither treatment (IDFS rate, 52% vs. 39%, p = 0.011; OS rate, 63% vs. 50%, p = 0.026). Multivariate analysis revealed that positive axillary lymph nodes, Grade III tumor, negative estrogen and progesterone receptor status at primary diagnosis, disease-free interval of less than 2 years, and less comprehensive locoregional treatment were significantly associated with worse IDFS and OS. Conclusions: Use of comprehensive locoregional therapy and systemic therapy can achieve good survival outcome in a substantial proportion of postmastectomy patients with ILRR. Ó 2008 Elsevier Inc. Locoregional recurrence, Survival, Breast cancer, Surgery, Radiotherapy, Metastasis.
Postmastectomy patients with ILRR are often treated with combined-modality therapy, including wide excision of recurrent tumor, radiotherapy, and systemic therapy. However the optimal management for patients with ILRR remains controversial (6–8). The rate of second local failure after local excision alone is very high, and therefore the need for radiotherapy after surgical excision is mandatory. In addition the efficacy of local control by radiotherapy seems to be related to the recurrence sites as well as the irradiated tumor volume (9–11). Even with the use of aggressive locoregional treatment without adjuvant systemic therapy for postmastectomy patients with ILRR in the past decade, most patients eventually develop distant metastasis (12–14). Specifically, postmastectomy patients with ILRR carrying unfavorable
INTRODUCTION Although the majority of postmastectomy patients having isolated locoregional recurrence (ILRR) present with considerable morbidity and subclinical disseminated disease (1, 2), a substantial proportion of patients can enjoy an unexpected long-term survival after curative therapy. Recent studies have demonstrated that the 5-year overall survival (OS) is approximately 40% in postmastectomy patients with ILRR treated with curative intent (3, 4). Local failure is associated with an increase in mortality. In addition, the time distribution of distant metastasis is significantly different between patients with local failure and local control (5). These findings suggest that an ILRR itself may be an independent predictor of subsequent distant metastasis. Reprint requests to: Jason Chia-Hsien Cheng, M.D., Ph.D., Department of Oncology, National Taiwan University Hospital, No. 7 Chung-Shan South Rd, Taipei, Taiwan. Tel: 886-2-2312-3456, ext 6696; Fax: 886-2-2371-1174; E-mail: [email protected]
Conflict of interest: none. Received Nov 20, 2007, and in revised form March 4, 2008. Accepted for publication March 10, 2008. 1456
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prognoses (such as combined chest wall and regional lymph node recurrence, and short disease-free interval), have higher incidences of distant metastasis and worse survival (1, 4). Under these circumstances, it would seem reasonable that a combination of comprehensive locoregional tumor excision, radiotherapy, and systemic therapy to improve locoregional control and to decrease systemic metastasis is warranted. It has been demonstrated that the widespread use of adjuvant systemic therapy after well locoregional treatment can increase the survival rates of primary breast cancer (15). These data suggest that postmastectomy patients with ILRR might potentially be cured by comprehensive locoregional treatment and systemic therapy. In this study, we investigated whether the most comprehensive locoregional treatment (recurrent tumor excision and entire-field (i.e., involved and/or elective field) radiotherapy and systemic therapy can improve clinical outcome of these patients. In addition, the prognostic factors of survival were analyzed. METHODS AND MATERIALS Patients and clinical characteristics Postmastectomy breast cancer patients who had not received any adjuvant radiotherapy and who were treated for ILRR without simultaneous evidence of distant metastasis were selected from the Cancer Registry of National Taiwan University Hospital for the period between 1992 and 2003. Presence of ILRR was defined as any relapse within the ipsilateral chest wall, axilla, the supra- or infraclavicular fossa, and the parasternal internal mammary region without distant disease at the time of diagnosis of recurrence. All recurrences were histologically confirmed by excision biopsy, incision biopsy, or fine-needle aspiration. Patients who had ILRR were treated by surgical excision followed by radiotherapy (comprehensive locoregional treatment) or definitive radiotherapy. In this series, 82 of 84 patients (98%) with chest wall or axillary recurrence underwent comprehensive locoregional treatment, whereas 16 of 31 patients (52%) with supra-/infraclavicular fossa or multiple site recurrence were given with definitive radiotherapy. Among the 115 patients with ILRR, 98 patients underwent comprehensive locoregional treatment (local tumor excision plus postoperative radiotherapy), and 17 received definitive radiotherapy alone. The use of systemic therapy with hormone therapy, systemic chemotherapy, or both at the time of ILRR was very much based on individual physician’s judgment and patient preference.
Radiotherapy technique A 60Co machine or 6-MV linear accelerator was used to deliver radiotherapy to the involved field, elective fields, or both. The area of involved-field radiotherapy included chest wall, supra- / infraclavicular region, axilla, or internal mammary region containing the recurrent tumor. The area of elective-field radiotherapy included the uninvolved chest wall and supra- /infraclavicular lymphatics, as well as the axillary or internal mammary lymphatics if there was gross recurrent disease shown on the imaging studies in these two regions. Because this retrospective review spans over a decade, the radiotherapy techniques varied considerably. In the early days of this protocol, involved-field radiotherapy was frequently used, although more recently entire-field radiotherapy has been used. Patients with chest wall recurrence were typically treated with either tangential photon beams or en face electron beams.
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Patients with supra-/infraclavicular or axillary recurrence were usually treated with a single anterior field or the opposed anterior– posterior/posterior–anterior fields. Choice of technique, as mentioned previously, was based on anatomic considerations and the judgment of the treating physicians. Radiation doses varied from 30 Gy in 10 fractions to 66 Gy in 33 fractions, with the most frequently used dose being at least 50 Gy.
Statistical analysis Follow-up data available as of June 30, 2006, were analyzed. The second locoregional failure was defined as any recurrence within the ipsilateral chest wall and/or regional draining lymphatics after radical treatment for initial ILRR. Distant metastasis–free survival was measured from the date of original diagnosis of ILRR to the date of distant recurrence. Invasive disease–free survival (IDFS) was measured from the date of diagnosis of ILRR to the date of ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence, death attributable to any cause, contralateral invasive breast cancer, and second primary, nonbreast invasive cancer (16). The OS was calculated from the diagnosis of ILRR to the day of death attributable to breast cancer, cause other than breast cancer, or unknown cause at the last follow-up date (16). Survival was estimated using the Kaplan-Meier product-limit method; for survival data 95% confidence intervals were given where indicated. Survival was compared between groups using the log-rank test. The Chi-square test and Fisher’s exact test were used to compare the clinicopathologic parameters between two groups. The following variables and categories were used for the univariate analyses and Cox regression analyses: tumor size, lymph nodal status, histologic grade, estrogen receptor status, and progesterone receptor status at primary diagnosis, time to ILRR, site of ILRR, target volume of radiotherapy, and use of systemic therapy after ILRR. The level of significance was chosen as 5%, and all p values were two-tailed.
RESULTS Patterns and treatment of recurrence A total of 115 patients, with a median age of 48 years (range, 24–75 years), met the criteria for inclusion in the study. The majority of recurrences occurred at the chest wall and around the mastectomy scar (69 patients, 60%). Supra- or infraclavicular lymph node recurrence represented 22% of all ILRR (25 patients), axillary failure 13% (15 patients), and multiple locoregional recurrences 5% (6 patients). Clinicopathologic features in these patients at the time of original diagnosis are listed in Table 1. At the primary diagnosis, the median number of nodes examined was 14 (range, 5–40). Of the patients, 67% had more than 10 axillary nodes excised. The median number of positive nodes was five (range, one to 28). In the patients with one to three positive nodes, the involved nodal ratio was 0.29. Among 15 patients with axillary recurrence, the medium number of nodes examined at primary diagnosis was 13 (range, seven to 25). At the time of ILRR, 14 of 15 patients with axillary recurrence received local tumor excision, including axillary clearance. Among them, the median number of nodes examined at ILRR was three (range, one to 13), and the median number of positive nodes at ILRR was one (range, one to 13). Although there is clear evidence for an impact of the postmastectomy radiotherapy (PMRT) in patients with high-risk
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Table 1. Clinicopathologic features at initial diagnosis and treatment of all postmastectomy patients with isolated locoregional recurrence (ILRR) Characteristic Patient age at diagnosis (y) Median Range Tumor size at initial diagnosis (cm) 2 >2–5 >5 No. of nodes positive at initial diagnosis 0 1–3 4 Tumor grade at initial diagnosis 1 2 3 Unknown Hormone receptor status at initial diagnosis ER and/or PR: positive ER and PR: negative Unknown Locoregional treatment of ILRR Comprehensive locoregional treatment (surgery and radiotherapy) Radiotherapy alone Systemic treatment after ILRR None Chemotherapy Hormone therapy Sequential chemotherapy and hormone therapy
No. (%) 48 24–75 28 (24) 66 (57) 21 (19) 41 (36) 30 (26) 44 (38) 24 (21) 56 (49) 28 (24) 7 (6) 73 (64) 35 (30) 7 (6) 98 (85) 17 (15) 36 (30) 26 (23) 31 (27) 22 (20)
Abbreviations: ER = estrogen receptor; PR = progesterone receptor.
factors (e.g., four or more involved nodes, a locally advanced primary tumor, lymphatic vessel invasion, possible large tumor size, and a positive margin), a substantial proportion of our highest-risk patients did not receive PMRT because of physician attitude or patient refusals, especially among patients undergoing mastectomy between 1985 and 1995. This retrospective review spans more than a decade, which may be one of the reasons why a relatively higher percentage of our postmastectomy ILRR patients with tumors greater than 5 cm and/or with more than three metastatic lymph nodes did not receive adjuvant PMRT at the time of their primary diagnosis. Among the 115 patients with ILRR, post-ILRR radiotherapy alone was given to 36. Post-ILRR radiotherapy was combined with hormonal therapy in 31 patients, with systemic chemotherapy in 26, and with both systemic modalities in 22 (Table 1). The chemotherapy in these patients was either an anthracycline-based, taxane-containing, or vinorelbinecontaining regimen. The systemic hormone regimen contained one or more of the following: tamoxifen, goserelin, letrozole, or anastrozole. Involved-field radiotherapy was given to 69 patients, whereas entire-field radiotherapy was given to 46 patients (Table 2). Among patients receiving comprehensive locoregional treatment, involved-field radiotherapy was given to 59 patients, and entire-field radiotherapy was given to 39 (Table 2). At the time of ILRR, 87
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(76%) of 115 patients received a radiation dose of 50 Gy or more, whereas 28 patients received a dose of less than 50 Gy. Among them, 6 patients received 39 Gy in 13 fractions (a biologically equivalent dose of 50 Gy in 2-Gy fractions). Clinicopathologic features and treatment variation To investigate whether patient and tumor variables could potentially result in differential outcomes in postmastectomy patients with ILRR who received radiotherapy alone, those who received surgery and involved-field radiotherapy, and those who received surgery and entire-field radiotherapy, we compared patients and tumor characteristics in these three subgroups. We found that the patients in these three subgroups were similar in terms of age, tumor size, number of positive axillary lymph nodes, tumor grade, and hormone receptor status at primary diagnosis, as well as radiation dose at ILRR, except that the patients in the radiotherapy-alone group had a significantly higher percentage of recurrence in the supra-/infraclavicular fossa (Table 2). Survival outcomes At the end of the follow-up period (median, 46.2 months; range, 32–150 months), 43 patients had died and 72 patients were alive. The median OS from initial diagnosis of breast cancer for all patients was 159 months (95% CI, 137–182); actuarial 5- and 10-year survival rates after primary treatment were 79% and 59%, respectively. The median OS after ILRR was 106 months (95% CI, 51–161), and the 5-year survival rate was 57% (Fig. 1). The median IDFS after ILRR was 52 months (95% CI, 27–77), and the 5-year IDFS rate was 46% (Fig. 1). Locoregional control and treatment variation Of the 115 patients, 20 (17%) had a second ILRR after locoregional treatment. Moreover, 48 (42%) of 115 patients subsequently developed distant metastases. Bone, liver, lung, and brain were the most common sites of distant medastasis. As shown in Table 3, the second ILRR was significantly rare in patients treated with comprehensive locoregional treatment using the entire-field design. Similarly the 5-year rate of time to freedom from second recurrence after ILRR was 97% in patients with such a comprehensive locoregional treatment (i.e., surgery and postoperative entire-field radiotherapy), as compared with 81% in patients with surgical excision followed by involved-field radiotherapy and 40% in patients with definitive radiotherapy alone (p = 0.028). The second ILRR and distant metastasis rates respectively were 6.5% and 26.1% in patients treated with entire-field radiotherapy, as compared with 24.6% and 52.2% in patients treated with involved-field radiotherapy alone, irrespective of surgical treatment (second ILRR, p = 0.012; second distant metastasis, p = 0.005). Prognostic factors analysis The influence of primary tumor characteristics, recurrence pattern after ILRR, and treatment factors after ILRR on IDFS and OS were tested by univariate analyses. The correlation of
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Table 2. Clinicopathologic features at initial diagnosis and treatment variation of all postmastectomy patients with isolated locoregional recurrence (ILRR) Characteristic No. of patients Patient age at diagnosis (y) Median Range Tumor size at initial diagnosis (cm) 2 >2–5 >5 No. of nodes positive at initial diagnosis 0 1–3 4 Tumor grade at initial diagnosis 1 2 3 Unknown Hormone receptor status at initial diagnosis ER and/or PR: positive ER and PR: negative Unknown ILRR area Chest wall and around the mastectomy scar Axillary area Supra- or infraclavicular area and multiple ILRR Radiation dose (Gy)* $50 <50
Surgery + comprehensive RT, n (%)
Surgery + involved-field RT, n (%)
RT alone, n (%)
39 (34)
59 (51)
17 (15)
10 (26) 23 (59) 6 (15)
13 (22) 37 (64) 9 (14)
5 (30) 6 (35) 6 (35)
0.200
15 (38) 10 (26) 14 (38)
21 (36) 18 (30) 20 (34)
5 (29) 2 (12) 10 (59)
0.369
10 (26) 16 (41) 11 (28) 2 (5)
11 (19) 33 (56) 12 (20) 3 (6)
3 (18) 7 (41) 5 (29) 2 (12)
0.485
28 (72) 9 (23) 2 (5)
39 (66) 17 (29) 3 (5)
6 (35) 9 (53) 2 (12)
0.123
21 (54) 9 (23) 9 (23)
48 (81) 4 (7) 7 (12)
0 (0) 2 (12) 15 (88)
<0.001
35 (90) 4 (10)
45 (76) 14 (24)
13 (77) 4 (23)
0.223
p Value
48 24–75
Abbreviations: ER = estrogen receptor; PR = progesterone receptor; RT = radiotherapy. * Biologically equivalent dose of 50 Gy in 2-Gy fractions.
5-year OS and IDFS with the various prognostic factors is listed in Table 4. Number of positive axillary lymph nodes, tumor grade, hormone receptor status at primary diagnosis, disease-free interval, and combined use of comprehensive lo-
Fig. 1. Overall survival (OS) and invasive disease–free survival (IDFS) after isolated locoregional recurrence for all postmastectomy patients.
coregional and systemic treatment were significantly associated with IDFS; in contrast, primary tumor size, site of recurrence, irradiated target volume, and systemic therapy for recurrence were not associated with IDFS. Number of positive axillary lymph nodes, tumor grade, hormone receptor status at primary diagnosis, disease-free interval, and combined use of comprehensive locoregional and systemic treatment were significantly associated with OS, whereas primary tumor size, site of recurrence, irradiated target volume, and systemic therapy for recurrence were not significantly associated with OS. In multivariate analysis, positive axillary lymph nodes, Grade II/III tumor, negative hormone receptor status at primary diagnosis, short diseasefree interval, and use of comprehensive locoregional treatment were significantly associated with OS (Table 5). In addition, positive axillary lymph nodes, Grade II/III tumor, negative hormone receptor status at primary diagnosis, short disease-free interval, and use of comprehensive locoregional treatment remained statistically significant in predicting IDFS (Table 5). As shown in Table 4, with regard to local treatment modality, patients treated with recurrent tumor excision and radiotherapy for ILRR had significantly better 5-year IDFS and OS after ILRR than those treated with definitive radiotherapy alone (IDFS rate, 51% vs. 16%, p = 0.006; OS rate,
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Table 3. Second isolated locoregional recurrence (ILRR) and locoregional treatment %3000
Entire-field RT and excision of recurrent tumor
Involved-field RT and excision of recurrent tumor
Involved- or entire-field RT alone
39 2 (5.1%)
59 12 (20.3%)
17 6 (35.3%)
0 1 1 0 97%
4 4 3 1 81%
2 2 1 1 40%
No. of patients Incidence of second ILRR* Failure site of second ILRR Chest wall (n) Axilla (n) Supra- or infraclavicular region (n) Multiple second ILRR (n) 5-Year rate of time to freedom from second ILRRy
Abbreviations: ILRR = isolated locoregional recurrence; RT = radiotherapy. * p = 0.016. y p = 0.028.
62% vs. 37%, p = 0.017). Patients treated with entire-field locoregional radiotherapy showed a trend toward better 5-year OS but nonsignificantly different IDFS rates of 63% and 60%, as compared with 54% (p = 0.064) and 39% (p =
0.278), respectively, in patients treated with involved-field radiotherapy alone (Table 4). Furthermore, patients who were given additional systemic therapy showed a nonsignificantly better 5-year OS (60%) than those who were not given
Table 4. Results of univariate analysis of primary tumor characteristics and treatment factors for survival of patients with isolated locoregional recurrence (ILRR) Characteristic Tumor size at initial diagnosis (cm) <2 2–5 >5 No. of nodes positive at initial diagnosis 0 1–3 $4 Tumor grade at initial diagnosis 1 2 3 Hormone receptor status at initial diagnosis ER and/or PR: positive ER and PR: negative Site of ILRR Chest wall Axilla Supra- or infraclavicular region or multiple sites Disease-free interval (y) <2 $2 Locoregional treatment Surgery + entire-field RT Surgery + involved-field RT RT alone Irradiated volume Involved field Entire field Systemic treatment after ILRR None Chemotherapy, hormone therapy, or both Comprehensive locoregional and systemic treatment Both Either or none
5-Year IDFS after ILRR
p Value
5-Year OS after ILRR
p Value
60% 44% 28%
0.285
76% 54% 40%
0.096
70% 36% 32%
0.007
81% 48% 44%
0.029
64% 44% 30%
0.014
74% 58% 36%
0.010
56% 26%
0.016
66% 40%
0.034
61% 52% 26%
0.080
63% 55% 45%
0.179
28% 58%
0.002
37% 70%
0.001
66% 45% 16%
0.004
69% 60% 37%
0.012
39% 60%
0.064
54% 63%
0.279
40% 48%
0.140
50% 60%
0.085
52% 39%
0.011
63% 50%
0.026
Abbreviations: ER = estrogen receptor; IDFS = invasive disease–free survival; OS = overall survival; PR = progesterone receptor; RT = radiotherapy.
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Table 5. Multivariate analysis of prognostic factors in survival after postmastectomy isolated locoregional recurrence (ILRR) Disease-free survival Factor Grade II or III vs. I Lymph node status Positive vs. negative Hormone receptor status ER () and PR () vs. ER (+) and/or PR (+) Disease-free interval (y) <2 vs. ($2 years) Comprehensive locoregional treatment received No vs. yes
Overall survival
HR
95% CI
p
HR
95% CI
p
1.90
1.07–3.37
0.029
2.31
1.22–4.36
0.010
2.76
1.39–5.48
0.004
2.75
1.22–6.21
0.015
2.37
1.31–4.30
0.004
2.42
1.23–4.77
0.010
2.07
1.19–3.61
0.010
3.03
1.59–5.78
0.001
1.77
1.02–3.07
0.042
2.04
1.06–3.90
0.032
Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; PR = progesterone receptor.
additional systemic therapy (50%; p = 0.085). Similarly, the 5-year IDFS rate for patients with additional systemic therapy was 48%, compared with 40% for patients without systemic therapy (p = 0.140). As shown in Figs. 2 and 3, patients treated with the most comprehensive locoregional treatment (i.e., a combination of recurrent tumor excision and entirefield radiotherapy) and the additional systemic therapy after ILRR had the best 5-year OS and IDFS as compared with those who received either treatment alone or neither treatment (OS rate, 63% vs. 50%, p = 0.026; IDFS rate, 52% vs. 39%, p = 0.011). Given that the suboptimal dose of radiation might be associated with decreased survival in postmastectomy patients with ILRR, we tried to elucidate whether comprehensive locoregional treatment (recurrent tumor excision and entirefield radiotherapy at optimal doses) remained an independent prognostic factor for patients receiving optimal doses of
Fig. 2. Overall survival (OS) after isolated locoregional recurrence, by treatment modalities (treatment with the most comprehensive locoregional treatment and systemic therapy combined [solid lines] vs. less comprehensive treatment [dotted lines]).
radiation (93 patients with a biologically equivalent dose of 50–60 Gy in 2-Gy fractions). Of these patients who received optimal doses of radiation, we found that patients treated with recurrent-tumor excision and radiotherapy for ILRR had a significantly better 5-year IDFS and OS after ILRR than those treated with definitive radiotherapy alone (IDFS rate, 56% vs. 20%, p = 0.012; OS rate, 64% vs. 26%, p = 0.016). Furthermore patients treated with the most comprehensive locoregional treatment (i.e., combination of recurrent-tumor excision and entire-field radiotherapy) and the additional systemic therapy after ILRR had the best 5-year OS and IDFS as compared with patients who received either treatment alone or neither treatment (OS rate, 64% vs. 46%, p = 0.031; IDFS rate, 58% vs. 39%, p = 0.035). With the analysis of this subgroup of patients using optimal doses, we emphasize the potentially favorable outcome in ILRR patients with the
Fig. 3. Invasive disease–free survival (IDFS) after isolated locoregional recurrence, by treatment modalities (treatment with the most comprehensive locoregional treatment and systemic therapy combined [solid lines] vs. less comprehensive treatment [dotted lines]).
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most comprehensive locoregional treatment, including field design and dose selection. DISCUSSION Use of PMRT) for highest-risk breast cancer patients have been established on the basis of the results of randomized trials and meta-analyses (17–19). Several treatment guidelines, such as the American Society of Clinical Oncology guidelines (20), the American Society for Therapeutic Radiology and Oncology guidelines (21), and the Canadian Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer (22), have been developed to help physicians to choose appropriate adjuvant radiotherapy for postmastectomy patients, based on patient and tumor characteristics. Given that PMRT and adjuvant systemic chemotherapy in highest-risk patients results in decreased ILRR rates and improved overall survival, the incidence of ILRR is decreasing in a recent decade. However, most postmastectomy patients with ILRR, even those with aggressive locoregional treatment but without systemic therapy, will eventually develop distant metastasis. Therefore, it is very unlikely that there will be any prospective clinical study or even good retrospective study with a large number of patients to define the role of most comprehensive locoregional treatment (recurrent tumor excision and entire-field radiotherapy) and systemic therapy in postmastectomy patients with ILRR. Our study represents one of the first moves toward this direction. In the present study, we conducted a long-term comprehensive follow-up study of 115 postmastectomy patients with ILRR and demonstrated that a substantial proportion of postmastectomy patients with ILRR had an unexpected long-term IDFS and OS after comprehensive locoregional and systemic therapy. Furthermore, we found that lymph node status, histologic grade, hormone status at primary diagnosis, the time interval to ILRR, and the use of comprehensive locoregional treatment are independent prognostic factors for clinical outcome of postmastectomy patients with ILRR. Postmastectomy patients with ILRR tend to have high incidence of morbidity and subsequent systemic dissemination (2–4). In contrast to the systemic disease control, these patients can have their locoregional disease control by complete excision of the tumor and post–operative radiotherapy. Patients receiving radiotherapy after the excision of local recurrent tumor have better local control than those without radiotherapy (23–26). Notably, our study showed that patients with chest wall recurrence had a marginally better OS and IDFS than those with recurrence at the other sites. For example, our patients with chest wall or axilla recurrence were often treated with comprehensive locoregional treatment, whereas most patients with supra-/infraclavicular fossa or multiple site recurrence were given with radiotherapy only. These findings are in line with previous studies reporting that patients with chest wall recurrence alone do better than those with supra-/infraclavicular nodal recurrence or recurrence at multiple lymphatic regions (27, 28). Hence the relatively limited number of our patients and selection bias
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may confound the interpretation. It appears that radiotherapy alone, for example, in our patients with higher percentage of recurrence in the supraclavicular/infraclavicular fossa, would independently influence their outcome. For example, a recent evaluation of importance in treating the LRR for postmastectomy patients entering into the DBCG 82b and 82c trials has shown that the combination of surgery and radiotherapy at the time of ILRR increased the persistent locoregional control; and that the supra/infraclavicular failure is still a poor prognostic factor for survival (4). Importantly, in their analyses, most patients with chest wall or axillary failures alone were offered a curative loco-regional treatment (surgery with and without radiotherapy), whereas most patients with supra/infraclavicular failure were offered systemic therapy or radiotherapy only (4). In the present study, postmastectomy patients with tumors greater than 5 cm and/or with more than three metastatic lymph nodes at their primary diagnosis may lack a sufficient adjuvant PMRT, and therefore had a poor prognosis after ILRR than patients without these risks. Indeed, in 1988, an analysis of failure patterns of postmastectomy patients has recommended that the routine use of PMRT for patients with four or more involved axillary nodes or tumors greater than 5 cm, given their relatively high risk of locoregional recurrence and distant metastases (29). However a recent retrospective analysis of a population–based cohort study of T1 to T2, node-positive breast cancer patients treated with mastectomy between 1988 and 1995, from the linked Surveillance, Epidemiology, and End Results database, showed that the use of PMRT was surprisingly low (30). In that analysis, only 26% of patients with more than three metastatic lymph nodes received PMRT, indicating that PMRT was underused in the late 1980s and in the early 1990s (30). This finding is in line with our findings that a proportion of our postmastrectomy ILRR patients with tumor greater than 5 cm and/or with more than three metastatic lymph nodes did not receive adjuvant PMRT at their primary diagnosis (between 1985 and 1995). Although our postmastectomy patients with tumors greater than 5 cm and/or with more than three metastatic lymph nodes at the time of their primary diagnosis lack a sufficient adjuvant radiation treatment (i.e., PMRT), these patients with ILRR may still have a chance of longterm survival (5-year IDFS rate, 32%; 5-year OS, 47%) after comprehensive locoregional and systemic treatment with surgery, entire-field radiotherapy, and adjuvant systemic therapy. These findings encourage the use of comprehensive locoregional treatment and systemic therapy for postmastectomy patients with ILRR. Our data indicate that patients undergoing entire-field radiotherapy sustained lower rates of second ILRR. Because the regional lymph nodes may harbor micrometastasis, it is reasonable to irradiate nodal regions, eradicate the potential micrometastasis, and thereby improve locoregional control and patient survival. Recent reports have also demonstrated that patients with ILRR at the chest wall who received additional elective radiation to the uninvolved nodal regions had significantly lower rates of second local recurrence than those
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who received involved-field radiation alone (10, 11, 31, 32). These results support our finding that entire-field (i.e., involved- and elective-field) radiotherapy reduced the rate of second ILRR from 26.1% to 6.5%, and further decreased the rate of distant metastasis from 52.2% to 24.6%. Several studies assessing the association between the interval to recurrence and prognosis in postmastectomy patients with ILRR have suggested that patients with late recurrence (>2 years after the original diagnosis) had much better prognoses than those with earlier recurrence (3, 9, 32, 33). In a recent study of 213 patients with ILRR after breast-conservatation surgery or mastectomy, patients with early chest wall recurrence had a worse prognosis than those with late recurrence (34). Although some of our patients were not treated with PMRT in the earlier days of our protocol, those patients with earlier ILRR as well as positive axillary lymph node findings, higher tumor grade, and negative hormone receptor status had significantly worse survival. Therefore the usefulness of PMRT for these patients with high-risk tumor characteristics demands emphasis. In addition these prognostic factors can aid physicians in clinical decision making regarding the use of adjuvant systemic chemotherapy or hormone therapy at the time of ILRR. Our postmastectomy patients had a 5-year OS rate of 63% and an IDFS rate of 54% after receiving aggressive locoregional treatment either with or without systemic therapy. These observations are similar to, or even better than, published series on ILRR with OS rates in the range of 42% to 79% (4, 30, 35, 36), as well as earlier series on postmastectomy ILRR with rates of 20% to 50% (11, 13, 31, 37). Although the impact of systemic chemotherapy or hormone therapy after curative locoregional therapy on locoregional control and prevention of distant metastasis is difficult to determine in this retrospective study, these findings may guide clinicians in the use of adjuvant systemic therapy after locoregional treatment, especially for higher-risk patients (38). The
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use of adjuvant hormone therapy is supported by a recent randomized trial that demonstrated improvement in IDFS but no impact on OS (36). Moreover, another study comparing locoregional therapy alone with locoregional therapy and chemotherapy combined found a trend toward improved IDFS and OS in postmastectomy patients with ILRR (39). The role of systemic chemotherapy in the treatment of ILRR patients is still of great relevance, however, because of the small patient numbers and heterogeneous patient populations (40, 41). A limitation of this study is that confounding factors likely were present in this series. For example, patients treated more recently tend to receive more comprehensive locoregional treatment and better screening for occult metastases than previous patients with ILRR. It is of note that our patients with ILRR who underwent the most comprehensive locoregional and systemic therapies had significantly better OS and IDFS than patients treated with either locoregional therapy or systemic therapy alone. These findings encourage the use of comprehensive locoregional treatment and systemic therapy for postmastectomy patients with ILRR. This combination therapy not only helps to achieve local disease control, but also to prevent distant metastasis and further improve clinical outcomes. The role of systemic therapy after comprehensive locoregional treatment should be underscored in future trials for postmastectomy patients after ILRR, especially in the era of new chemotherapy regimens and hormones. CONCLUSION In conclusion, treatment for isolated locoregional recurrent breast cancer after mastectomy is challenging but may potentially be curative. Postmastectomy patients with ILRR may still have a chance of long-term survival after comprehensive locoregional and systemic treatment using surgery, entirefield radiotherapy, and adjuvant systemic therapy.
REFERENCES 1. Aberizk WJ, Silver B, Henderson IC, et al. The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 1986;58:1214–1218. 2. Buchanan CL, Dorn PL, Fey J, et al. Locoregional recurrence after mastectomy: Incidence and outcomes. J Am Coll Surg 2006;203:469–474. 3. Schmoor C, Sauerbrei W, Bastert G, et al. Role of isolated locoregional recurrence of breast cancer: Results of four prospective studies. J Clin Oncol 2000;18:1696–1708. 4. Nielsen HM, Overgaard M, Grau C, et al. Loco-regional recurrence after mastectomy in high-risk breast cancer-risk and prognosis. An analysis of patients from the DBCG 82 b&c randomization trials. Radiother Oncol 2006;79:147–155. 5. Fortin A, Larochelle M, Laverdiere J, et al. Local failure is responsible for the decrease in survival for patients with breast cancer treated with conservative surgery and postoperative radiotherapy. J Clin Oncol 1999;17:101–109. 6. Clemons M, Hamilton T, Mansi J, et al. Management of recurrent locoregional breast cancer: Oncologist survey. Breast 2003; 12:328–337.
7. Fentiman IS, Matthews PN, Davison OW, et al. Survival following local skin recurrence after mastectomy. Br J Surg 1985;72:14–16. 8. Recht A, Come S, Troyan S, et al. Local-regional recurrence after mastectomy or breast-conserving therapy. In: Harris JR, Lippman ME, Morrow M, editors. Diseases of the breast. Philadelphia, PA: Lippincott Williams & Wilkins; 2000. p. 731–748. 9. Clemons M, Danson S, Hamilton T, et al. Locoregionally recurrent breast cancer: Incidence, risk factors and survival. Cancer Treat Rev 2001;27:67–82. 10. Halverson KJ, Perez CA, Kuske RR, et al. Isolated locoregional recurrence of breast cancer following mastectomy: Radiotherapeutic management. Int J Radiat Oncol Biol Phys 1990;19: 851–858. 11. Schwaibold F, Fowble BL, Solin LJ, et al. The results of radiation therapy for isolated local regional recurrence after mastectomy. Int J Radiat Oncol Biol Phys 1991;21:299–310. 12. Kamby C, Sengelov L. Pattern of dissemination and survival following isolated locoregional recurrence of breast cancer. Breast Cancer Res Treat 1997;45:181–192.
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13. Magno L, Bignardi M, Micheletti E, et al. Analysis of prognostic factors in patients with isolated chest wall recurrence of breast cancer. Cancer 1987;60:240–244. 14. Stadler B, Kogelnik D. Local control and outcome of patients treated for isolated chest wall recurrence of breast cancer. Radiother Oncol 1987;8:105–111. 15. Colozza M, de Azambuja E, Cardoso F, et al. Breast cancer: Achievements in adjuvant systemic therapies in the pregenomic era. Oncologist 2006;11:111–125. 16. Hudis CA, Barlow WE, Costantino JP, et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: The STEEP system. J Clin Oncol 2007;25: 2127–2132. 17. Clarke M, Collins R, Darby S. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;366:2087–2106. 18. Lee MC, Jagsi R. Postmastectomy radiation therapy: Indications and controversies. Surg Clin North Am 2007;87:511–526. 19. Chung CS, Harris JR. Post-mastectomy radiation therapy: Translating local benefits into improved survival. Breast 2007;16(Suppl 2):S78–S83. 20. Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19:1539–1569. 21. Harris JR, Halpin-Murphy P, McNeese M, et al. Consensus statement on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys 1999;44:989–990. 22. Truong PT, Olivotto LA, Whelan TJ, et al. Clinical practice guidelines for the care and treatment of breast cancer: 16. Locoregional post-mastectomy radiotherapy. Can Med Assoc J 2004;170:1263–1273. 23. Donegan WL. Local and regional recurrence. In: Donegan WL, Spratt JS, editors. Cancer of the breast. 5th ed. Philadelphia: WB Saunders; 2002. p. 825–839. 24. Dahlstrom K, Andersson A, Andersen M. Wide local excision of recurrent breast cancer in the thoracic wall. Cancer 1993; 72:774–777. 25. Eek R, Falkson C. Extended survival in 80 patients without operable locoregionally recurrent breast cancer treated with chemotherapy. Am J Clin Oncol 1998;21:501–504. 26. Janjan N, McNeese M, Buzdar A, et al. Management of locoregional recurrent breast cancer. Cancer 1986;58:1552–1556. 27. Ciatto S. Detection of breast cancer local recurrences. Ann Oncol 1995;6(Suppl 2):23–26. 28. Willner J, Kiricuta IC, Kolbl O. Locoregional recurrence of breast cancer following mastectomy: Always a fatal event? Results of univariate and multivariate analysis. Int J Radiat Oncol Biol Phys 1997;37:853–863.
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29. Fowble B, Gray R, Gilchrist K, et al. Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 1988;6:1107–1117. 30. Smith BD, Smith GL, Haffty BG. Postmastectomy radiation and mortality in women with T1–2 node-positive breast cancer. J Clin Oncol 2005;23:1409–1419. 31. Chen K, Montague E, Oswald M. Results of irradiation in the treatment of locoregional breast cancer recurrence. Cancer 1985;56:1269–1273. 32. Schuck A, Konemann S, Matthees B, et al. Radiotherapy in the treatment of locoregional relapses of breast cancer. Br J Radiol 2002;75:663–669. 33. Van Dongen J, Voogd AC, Fentiman IS, et al. Long term results of a randomized trial comparing breast conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000;92:1143–1150. 34. Moran MS, Haffty BG. Local-regional breast cancer recurrence: Prognostic groups based on patterns of failure. Breast J 2002;8: 81–87. 35. Ballo MT, Strom EA, Prost H, et al. Loco-regional control of recurrent breast carcinoma after mastectomy: Does hyperfractionated accelerated radiotherapy improve local control. Int J Radiat Oncol Biol Phys 1999;44:105–112. 36. Waeber M, Gertsch-Castiglione M, Dietrich D, et al. Adjuvant therapy after excision and radation of isolated postmastectomy locoregional breast cancer recurrence: Definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation. Ann Oncol 2003;14:1215–1221. 37. Andry G, Suciu S, Vico P, et al. Locoregional recurrences after 649 modified radical mastectomies: Incidence and significance. Eur J Surg Oncol 1989;15:476–485. 38. Borner M, Bacchi M, Goldhirsch A, et al. First isolated locoregional recurrence following mastectomy for breast cancer: Results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. Swiss Group for Clinical Cancer Research. J Clin Oncol 1994;12: 2071–2077. 39. Haylock B, Coppin C, Jackson J, et al. Locoregional first recurrence after mastectomy: Prospective cohort studies with and without immediate chemotherapy. Int J Radiat Oncol Phys 2000;46:355–362. 40. Deutsch M, Parsons J, Mittal B. Radiation therapy for localregional recurrent breast carcinoma. Int J Radiat Oncol Biol Phys 1986;12:2061–2065. 41. Halverson K, Perez C, Kuske R, et al. Locoregional recurrence of breast cancer: A retrospective comparison of irradiation alone vs. irradiation and systemic therapy. Am J Clin Oncol 1992;15: 93–101.
doi:10.1016/j.ijrobp.2008.03.042
CLINICAL INVESTIGATION
Breast
COMPREHENSIVE LOCOREGIONAL TREATMENT AND SYSTEMIC THERAPY FOR POSTMASTECTOMY ISOLATED LOCOREGIONAL RECURRENCE SUNG-HSIN KUO, M.D., PH.D.,*x{k CHIUN-SHENG HUANG, M.D., PH.D.,y WUN-HON KUO, M.D.,y ANN-LII CHENG, M.D., PH.D.,*zx KING-JENG CHANG, M.D., PH.D.,y x{ AND JASON CHIA-HSIEN CHENG, M.D., PH.D.* Departments of *Oncology, y Surgery, and z Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; x Cancer Research Center and {Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; and k Department of Oncology, National Taiwan University Hospital Yun-Lin Branch, Yunlin, Taiwan Purpose: To assess the impact of comprehensive locoregional therapy and systemic therapy on disease control and survival for postmastectomy patients with isolated locoregional recurrence (ILRR). Methods and Materials: A total of 115 postmastectomy breast cancer patients treated for ILRR were included. Of the patients, 98 underwent comprehensive locoregional treatment (local tumor excision plus postoperative radiotherapy), and 17 received definitive radiotherapy alone. Involved-field radiotherapy was given to 69 patients, whereas entire-field radiotherapy (both involved-field and elective-field, involving the chest wall and regional lymphatics) was given to 46 patients. Systemic therapy consisting of hormone therapy, chemotherapy, or both was given to 69% of patients. Results: Patients treated with comprehensive locoregional treatment had a significantly better 5-year invasive disease–free survival (IDFS) and overall survival (OS) after ILRR than patients treated with definitive radiotherapy alone (IDFS rate, 51% vs. 16%, p = 0.006; OS rate, 62% vs. 37%, p = 0.017). Patients with the most comprehensive locoregional treatment (recurrent tumor excision and entire-field radiotherapy) and systemic therapy had a significantly better 5-year IDFS and OS than patients given either treatment or neither treatment (IDFS rate, 52% vs. 39%, p = 0.011; OS rate, 63% vs. 50%, p = 0.026). Multivariate analysis revealed that positive axillary lymph nodes, Grade III tumor, negative estrogen and progesterone receptor status at primary diagnosis, disease-free interval of less than 2 years, and less comprehensive locoregional treatment were significantly associated with worse IDFS and OS. Conclusions: Use of comprehensive locoregional therapy and systemic therapy can achieve good survival outcome in a substantial proportion of postmastectomy patients with ILRR. Ó 2008 Elsevier Inc. Locoregional recurrence, Survival, Breast cancer, Surgery, Radiotherapy, Metastasis.
Postmastectomy patients with ILRR are often treated with combined-modality therapy, including wide excision of recurrent tumor, radiotherapy, and systemic therapy. However the optimal management for patients with ILRR remains controversial (6–8). The rate of second local failure after local excision alone is very high, and therefore the need for radiotherapy after surgical excision is mandatory. In addition the efficacy of local control by radiotherapy seems to be related to the recurrence sites as well as the irradiated tumor volume (9–11). Even with the use of aggressive locoregional treatment without adjuvant systemic therapy for postmastectomy patients with ILRR in the past decade, most patients eventually develop distant metastasis (12–14). Specifically, postmastectomy patients with ILRR carrying unfavorable
INTRODUCTION Although the majority of postmastectomy patients having isolated locoregional recurrence (ILRR) present with considerable morbidity and subclinical disseminated disease (1, 2), a substantial proportion of patients can enjoy an unexpected long-term survival after curative therapy. Recent studies have demonstrated that the 5-year overall survival (OS) is approximately 40% in postmastectomy patients with ILRR treated with curative intent (3, 4). Local failure is associated with an increase in mortality. In addition, the time distribution of distant metastasis is significantly different between patients with local failure and local control (5). These findings suggest that an ILRR itself may be an independent predictor of subsequent distant metastasis. Reprint requests to: Jason Chia-Hsien Cheng, M.D., Ph.D., Department of Oncology, National Taiwan University Hospital, No. 7 Chung-Shan South Rd, Taipei, Taiwan. Tel: 886-2-2312-3456, ext 6696; Fax: 886-2-2371-1174; E-mail: [email protected]
Conflict of interest: none. Received Nov 20, 2007, and in revised form March 4, 2008. Accepted for publication March 10, 2008. 1456
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prognoses (such as combined chest wall and regional lymph node recurrence, and short disease-free interval), have higher incidences of distant metastasis and worse survival (1, 4). Under these circumstances, it would seem reasonable that a combination of comprehensive locoregional tumor excision, radiotherapy, and systemic therapy to improve locoregional control and to decrease systemic metastasis is warranted. It has been demonstrated that the widespread use of adjuvant systemic therapy after well locoregional treatment can increase the survival rates of primary breast cancer (15). These data suggest that postmastectomy patients with ILRR might potentially be cured by comprehensive locoregional treatment and systemic therapy. In this study, we investigated whether the most comprehensive locoregional treatment (recurrent tumor excision and entire-field (i.e., involved and/or elective field) radiotherapy and systemic therapy can improve clinical outcome of these patients. In addition, the prognostic factors of survival were analyzed. METHODS AND MATERIALS Patients and clinical characteristics Postmastectomy breast cancer patients who had not received any adjuvant radiotherapy and who were treated for ILRR without simultaneous evidence of distant metastasis were selected from the Cancer Registry of National Taiwan University Hospital for the period between 1992 and 2003. Presence of ILRR was defined as any relapse within the ipsilateral chest wall, axilla, the supra- or infraclavicular fossa, and the parasternal internal mammary region without distant disease at the time of diagnosis of recurrence. All recurrences were histologically confirmed by excision biopsy, incision biopsy, or fine-needle aspiration. Patients who had ILRR were treated by surgical excision followed by radiotherapy (comprehensive locoregional treatment) or definitive radiotherapy. In this series, 82 of 84 patients (98%) with chest wall or axillary recurrence underwent comprehensive locoregional treatment, whereas 16 of 31 patients (52%) with supra-/infraclavicular fossa or multiple site recurrence were given with definitive radiotherapy. Among the 115 patients with ILRR, 98 patients underwent comprehensive locoregional treatment (local tumor excision plus postoperative radiotherapy), and 17 received definitive radiotherapy alone. The use of systemic therapy with hormone therapy, systemic chemotherapy, or both at the time of ILRR was very much based on individual physician’s judgment and patient preference.
Radiotherapy technique A 60Co machine or 6-MV linear accelerator was used to deliver radiotherapy to the involved field, elective fields, or both. The area of involved-field radiotherapy included chest wall, supra- / infraclavicular region, axilla, or internal mammary region containing the recurrent tumor. The area of elective-field radiotherapy included the uninvolved chest wall and supra- /infraclavicular lymphatics, as well as the axillary or internal mammary lymphatics if there was gross recurrent disease shown on the imaging studies in these two regions. Because this retrospective review spans over a decade, the radiotherapy techniques varied considerably. In the early days of this protocol, involved-field radiotherapy was frequently used, although more recently entire-field radiotherapy has been used. Patients with chest wall recurrence were typically treated with either tangential photon beams or en face electron beams.
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Patients with supra-/infraclavicular or axillary recurrence were usually treated with a single anterior field or the opposed anterior– posterior/posterior–anterior fields. Choice of technique, as mentioned previously, was based on anatomic considerations and the judgment of the treating physicians. Radiation doses varied from 30 Gy in 10 fractions to 66 Gy in 33 fractions, with the most frequently used dose being at least 50 Gy.
Statistical analysis Follow-up data available as of June 30, 2006, were analyzed. The second locoregional failure was defined as any recurrence within the ipsilateral chest wall and/or regional draining lymphatics after radical treatment for initial ILRR. Distant metastasis–free survival was measured from the date of original diagnosis of ILRR to the date of distant recurrence. Invasive disease–free survival (IDFS) was measured from the date of diagnosis of ILRR to the date of ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence, death attributable to any cause, contralateral invasive breast cancer, and second primary, nonbreast invasive cancer (16). The OS was calculated from the diagnosis of ILRR to the day of death attributable to breast cancer, cause other than breast cancer, or unknown cause at the last follow-up date (16). Survival was estimated using the Kaplan-Meier product-limit method; for survival data 95% confidence intervals were given where indicated. Survival was compared between groups using the log-rank test. The Chi-square test and Fisher’s exact test were used to compare the clinicopathologic parameters between two groups. The following variables and categories were used for the univariate analyses and Cox regression analyses: tumor size, lymph nodal status, histologic grade, estrogen receptor status, and progesterone receptor status at primary diagnosis, time to ILRR, site of ILRR, target volume of radiotherapy, and use of systemic therapy after ILRR. The level of significance was chosen as 5%, and all p values were two-tailed.
RESULTS Patterns and treatment of recurrence A total of 115 patients, with a median age of 48 years (range, 24–75 years), met the criteria for inclusion in the study. The majority of recurrences occurred at the chest wall and around the mastectomy scar (69 patients, 60%). Supra- or infraclavicular lymph node recurrence represented 22% of all ILRR (25 patients), axillary failure 13% (15 patients), and multiple locoregional recurrences 5% (6 patients). Clinicopathologic features in these patients at the time of original diagnosis are listed in Table 1. At the primary diagnosis, the median number of nodes examined was 14 (range, 5–40). Of the patients, 67% had more than 10 axillary nodes excised. The median number of positive nodes was five (range, one to 28). In the patients with one to three positive nodes, the involved nodal ratio was 0.29. Among 15 patients with axillary recurrence, the medium number of nodes examined at primary diagnosis was 13 (range, seven to 25). At the time of ILRR, 14 of 15 patients with axillary recurrence received local tumor excision, including axillary clearance. Among them, the median number of nodes examined at ILRR was three (range, one to 13), and the median number of positive nodes at ILRR was one (range, one to 13). Although there is clear evidence for an impact of the postmastectomy radiotherapy (PMRT) in patients with high-risk
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Table 1. Clinicopathologic features at initial diagnosis and treatment of all postmastectomy patients with isolated locoregional recurrence (ILRR) Characteristic Patient age at diagnosis (y) Median Range Tumor size at initial diagnosis (cm) 2 >2–5 >5 No. of nodes positive at initial diagnosis 0 1–3 4 Tumor grade at initial diagnosis 1 2 3 Unknown Hormone receptor status at initial diagnosis ER and/or PR: positive ER and PR: negative Unknown Locoregional treatment of ILRR Comprehensive locoregional treatment (surgery and radiotherapy) Radiotherapy alone Systemic treatment after ILRR None Chemotherapy Hormone therapy Sequential chemotherapy and hormone therapy
No. (%) 48 24–75 28 (24) 66 (57) 21 (19) 41 (36) 30 (26) 44 (38) 24 (21) 56 (49) 28 (24) 7 (6) 73 (64) 35 (30) 7 (6) 98 (85) 17 (15) 36 (30) 26 (23) 31 (27) 22 (20)
Abbreviations: ER = estrogen receptor; PR = progesterone receptor.
factors (e.g., four or more involved nodes, a locally advanced primary tumor, lymphatic vessel invasion, possible large tumor size, and a positive margin), a substantial proportion of our highest-risk patients did not receive PMRT because of physician attitude or patient refusals, especially among patients undergoing mastectomy between 1985 and 1995. This retrospective review spans more than a decade, which may be one of the reasons why a relatively higher percentage of our postmastectomy ILRR patients with tumors greater than 5 cm and/or with more than three metastatic lymph nodes did not receive adjuvant PMRT at the time of their primary diagnosis. Among the 115 patients with ILRR, post-ILRR radiotherapy alone was given to 36. Post-ILRR radiotherapy was combined with hormonal therapy in 31 patients, with systemic chemotherapy in 26, and with both systemic modalities in 22 (Table 1). The chemotherapy in these patients was either an anthracycline-based, taxane-containing, or vinorelbinecontaining regimen. The systemic hormone regimen contained one or more of the following: tamoxifen, goserelin, letrozole, or anastrozole. Involved-field radiotherapy was given to 69 patients, whereas entire-field radiotherapy was given to 46 patients (Table 2). Among patients receiving comprehensive locoregional treatment, involved-field radiotherapy was given to 59 patients, and entire-field radiotherapy was given to 39 (Table 2). At the time of ILRR, 87
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(76%) of 115 patients received a radiation dose of 50 Gy or more, whereas 28 patients received a dose of less than 50 Gy. Among them, 6 patients received 39 Gy in 13 fractions (a biologically equivalent dose of 50 Gy in 2-Gy fractions). Clinicopathologic features and treatment variation To investigate whether patient and tumor variables could potentially result in differential outcomes in postmastectomy patients with ILRR who received radiotherapy alone, those who received surgery and involved-field radiotherapy, and those who received surgery and entire-field radiotherapy, we compared patients and tumor characteristics in these three subgroups. We found that the patients in these three subgroups were similar in terms of age, tumor size, number of positive axillary lymph nodes, tumor grade, and hormone receptor status at primary diagnosis, as well as radiation dose at ILRR, except that the patients in the radiotherapy-alone group had a significantly higher percentage of recurrence in the supra-/infraclavicular fossa (Table 2). Survival outcomes At the end of the follow-up period (median, 46.2 months; range, 32–150 months), 43 patients had died and 72 patients were alive. The median OS from initial diagnosis of breast cancer for all patients was 159 months (95% CI, 137–182); actuarial 5- and 10-year survival rates after primary treatment were 79% and 59%, respectively. The median OS after ILRR was 106 months (95% CI, 51–161), and the 5-year survival rate was 57% (Fig. 1). The median IDFS after ILRR was 52 months (95% CI, 27–77), and the 5-year IDFS rate was 46% (Fig. 1). Locoregional control and treatment variation Of the 115 patients, 20 (17%) had a second ILRR after locoregional treatment. Moreover, 48 (42%) of 115 patients subsequently developed distant metastases. Bone, liver, lung, and brain were the most common sites of distant medastasis. As shown in Table 3, the second ILRR was significantly rare in patients treated with comprehensive locoregional treatment using the entire-field design. Similarly the 5-year rate of time to freedom from second recurrence after ILRR was 97% in patients with such a comprehensive locoregional treatment (i.e., surgery and postoperative entire-field radiotherapy), as compared with 81% in patients with surgical excision followed by involved-field radiotherapy and 40% in patients with definitive radiotherapy alone (p = 0.028). The second ILRR and distant metastasis rates respectively were 6.5% and 26.1% in patients treated with entire-field radiotherapy, as compared with 24.6% and 52.2% in patients treated with involved-field radiotherapy alone, irrespective of surgical treatment (second ILRR, p = 0.012; second distant metastasis, p = 0.005). Prognostic factors analysis The influence of primary tumor characteristics, recurrence pattern after ILRR, and treatment factors after ILRR on IDFS and OS were tested by univariate analyses. The correlation of
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Table 2. Clinicopathologic features at initial diagnosis and treatment variation of all postmastectomy patients with isolated locoregional recurrence (ILRR) Characteristic No. of patients Patient age at diagnosis (y) Median Range Tumor size at initial diagnosis (cm) 2 >2–5 >5 No. of nodes positive at initial diagnosis 0 1–3 4 Tumor grade at initial diagnosis 1 2 3 Unknown Hormone receptor status at initial diagnosis ER and/or PR: positive ER and PR: negative Unknown ILRR area Chest wall and around the mastectomy scar Axillary area Supra- or infraclavicular area and multiple ILRR Radiation dose (Gy)* $50 <50
Surgery + comprehensive RT, n (%)
Surgery + involved-field RT, n (%)
RT alone, n (%)
39 (34)
59 (51)
17 (15)
10 (26) 23 (59) 6 (15)
13 (22) 37 (64) 9 (14)
5 (30) 6 (35) 6 (35)
0.200
15 (38) 10 (26) 14 (38)
21 (36) 18 (30) 20 (34)
5 (29) 2 (12) 10 (59)
0.369
10 (26) 16 (41) 11 (28) 2 (5)
11 (19) 33 (56) 12 (20) 3 (6)
3 (18) 7 (41) 5 (29) 2 (12)
0.485
28 (72) 9 (23) 2 (5)
39 (66) 17 (29) 3 (5)
6 (35) 9 (53) 2 (12)
0.123
21 (54) 9 (23) 9 (23)
48 (81) 4 (7) 7 (12)
0 (0) 2 (12) 15 (88)
<0.001
35 (90) 4 (10)
45 (76) 14 (24)
13 (77) 4 (23)
0.223
p Value
48 24–75
Abbreviations: ER = estrogen receptor; PR = progesterone receptor; RT = radiotherapy. * Biologically equivalent dose of 50 Gy in 2-Gy fractions.
5-year OS and IDFS with the various prognostic factors is listed in Table 4. Number of positive axillary lymph nodes, tumor grade, hormone receptor status at primary diagnosis, disease-free interval, and combined use of comprehensive lo-
Fig. 1. Overall survival (OS) and invasive disease–free survival (IDFS) after isolated locoregional recurrence for all postmastectomy patients.
coregional and systemic treatment were significantly associated with IDFS; in contrast, primary tumor size, site of recurrence, irradiated target volume, and systemic therapy for recurrence were not associated with IDFS. Number of positive axillary lymph nodes, tumor grade, hormone receptor status at primary diagnosis, disease-free interval, and combined use of comprehensive locoregional and systemic treatment were significantly associated with OS, whereas primary tumor size, site of recurrence, irradiated target volume, and systemic therapy for recurrence were not significantly associated with OS. In multivariate analysis, positive axillary lymph nodes, Grade II/III tumor, negative hormone receptor status at primary diagnosis, short diseasefree interval, and use of comprehensive locoregional treatment were significantly associated with OS (Table 5). In addition, positive axillary lymph nodes, Grade II/III tumor, negative hormone receptor status at primary diagnosis, short disease-free interval, and use of comprehensive locoregional treatment remained statistically significant in predicting IDFS (Table 5). As shown in Table 4, with regard to local treatment modality, patients treated with recurrent tumor excision and radiotherapy for ILRR had significantly better 5-year IDFS and OS after ILRR than those treated with definitive radiotherapy alone (IDFS rate, 51% vs. 16%, p = 0.006; OS rate,
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Table 3. Second isolated locoregional recurrence (ILRR) and locoregional treatment %3000
Entire-field RT and excision of recurrent tumor
Involved-field RT and excision of recurrent tumor
Involved- or entire-field RT alone
39 2 (5.1%)
59 12 (20.3%)
17 6 (35.3%)
0 1 1 0 97%
4 4 3 1 81%
2 2 1 1 40%
No. of patients Incidence of second ILRR* Failure site of second ILRR Chest wall (n) Axilla (n) Supra- or infraclavicular region (n) Multiple second ILRR (n) 5-Year rate of time to freedom from second ILRRy
Abbreviations: ILRR = isolated locoregional recurrence; RT = radiotherapy. * p = 0.016. y p = 0.028.
62% vs. 37%, p = 0.017). Patients treated with entire-field locoregional radiotherapy showed a trend toward better 5-year OS but nonsignificantly different IDFS rates of 63% and 60%, as compared with 54% (p = 0.064) and 39% (p =
0.278), respectively, in patients treated with involved-field radiotherapy alone (Table 4). Furthermore, patients who were given additional systemic therapy showed a nonsignificantly better 5-year OS (60%) than those who were not given
Table 4. Results of univariate analysis of primary tumor characteristics and treatment factors for survival of patients with isolated locoregional recurrence (ILRR) Characteristic Tumor size at initial diagnosis (cm) <2 2–5 >5 No. of nodes positive at initial diagnosis 0 1–3 $4 Tumor grade at initial diagnosis 1 2 3 Hormone receptor status at initial diagnosis ER and/or PR: positive ER and PR: negative Site of ILRR Chest wall Axilla Supra- or infraclavicular region or multiple sites Disease-free interval (y) <2 $2 Locoregional treatment Surgery + entire-field RT Surgery + involved-field RT RT alone Irradiated volume Involved field Entire field Systemic treatment after ILRR None Chemotherapy, hormone therapy, or both Comprehensive locoregional and systemic treatment Both Either or none
5-Year IDFS after ILRR
p Value
5-Year OS after ILRR
p Value
60% 44% 28%
0.285
76% 54% 40%
0.096
70% 36% 32%
0.007
81% 48% 44%
0.029
64% 44% 30%
0.014
74% 58% 36%
0.010
56% 26%
0.016
66% 40%
0.034
61% 52% 26%
0.080
63% 55% 45%
0.179
28% 58%
0.002
37% 70%
0.001
66% 45% 16%
0.004
69% 60% 37%
0.012
39% 60%
0.064
54% 63%
0.279
40% 48%
0.140
50% 60%
0.085
52% 39%
0.011
63% 50%
0.026
Abbreviations: ER = estrogen receptor; IDFS = invasive disease–free survival; OS = overall survival; PR = progesterone receptor; RT = radiotherapy.
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Table 5. Multivariate analysis of prognostic factors in survival after postmastectomy isolated locoregional recurrence (ILRR) Disease-free survival Factor Grade II or III vs. I Lymph node status Positive vs. negative Hormone receptor status ER () and PR () vs. ER (+) and/or PR (+) Disease-free interval (y) <2 vs. ($2 years) Comprehensive locoregional treatment received No vs. yes
Overall survival
HR
95% CI
p
HR
95% CI
p
1.90
1.07–3.37
0.029
2.31
1.22–4.36
0.010
2.76
1.39–5.48
0.004
2.75
1.22–6.21
0.015
2.37
1.31–4.30
0.004
2.42
1.23–4.77
0.010
2.07
1.19–3.61
0.010
3.03
1.59–5.78
0.001
1.77
1.02–3.07
0.042
2.04
1.06–3.90
0.032
Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; PR = progesterone receptor.
additional systemic therapy (50%; p = 0.085). Similarly, the 5-year IDFS rate for patients with additional systemic therapy was 48%, compared with 40% for patients without systemic therapy (p = 0.140). As shown in Figs. 2 and 3, patients treated with the most comprehensive locoregional treatment (i.e., a combination of recurrent tumor excision and entirefield radiotherapy) and the additional systemic therapy after ILRR had the best 5-year OS and IDFS as compared with those who received either treatment alone or neither treatment (OS rate, 63% vs. 50%, p = 0.026; IDFS rate, 52% vs. 39%, p = 0.011). Given that the suboptimal dose of radiation might be associated with decreased survival in postmastectomy patients with ILRR, we tried to elucidate whether comprehensive locoregional treatment (recurrent tumor excision and entirefield radiotherapy at optimal doses) remained an independent prognostic factor for patients receiving optimal doses of
Fig. 2. Overall survival (OS) after isolated locoregional recurrence, by treatment modalities (treatment with the most comprehensive locoregional treatment and systemic therapy combined [solid lines] vs. less comprehensive treatment [dotted lines]).
radiation (93 patients with a biologically equivalent dose of 50–60 Gy in 2-Gy fractions). Of these patients who received optimal doses of radiation, we found that patients treated with recurrent-tumor excision and radiotherapy for ILRR had a significantly better 5-year IDFS and OS after ILRR than those treated with definitive radiotherapy alone (IDFS rate, 56% vs. 20%, p = 0.012; OS rate, 64% vs. 26%, p = 0.016). Furthermore patients treated with the most comprehensive locoregional treatment (i.e., combination of recurrent-tumor excision and entire-field radiotherapy) and the additional systemic therapy after ILRR had the best 5-year OS and IDFS as compared with patients who received either treatment alone or neither treatment (OS rate, 64% vs. 46%, p = 0.031; IDFS rate, 58% vs. 39%, p = 0.035). With the analysis of this subgroup of patients using optimal doses, we emphasize the potentially favorable outcome in ILRR patients with the
Fig. 3. Invasive disease–free survival (IDFS) after isolated locoregional recurrence, by treatment modalities (treatment with the most comprehensive locoregional treatment and systemic therapy combined [solid lines] vs. less comprehensive treatment [dotted lines]).
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most comprehensive locoregional treatment, including field design and dose selection. DISCUSSION Use of PMRT) for highest-risk breast cancer patients have been established on the basis of the results of randomized trials and meta-analyses (17–19). Several treatment guidelines, such as the American Society of Clinical Oncology guidelines (20), the American Society for Therapeutic Radiology and Oncology guidelines (21), and the Canadian Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer (22), have been developed to help physicians to choose appropriate adjuvant radiotherapy for postmastectomy patients, based on patient and tumor characteristics. Given that PMRT and adjuvant systemic chemotherapy in highest-risk patients results in decreased ILRR rates and improved overall survival, the incidence of ILRR is decreasing in a recent decade. However, most postmastectomy patients with ILRR, even those with aggressive locoregional treatment but without systemic therapy, will eventually develop distant metastasis. Therefore, it is very unlikely that there will be any prospective clinical study or even good retrospective study with a large number of patients to define the role of most comprehensive locoregional treatment (recurrent tumor excision and entire-field radiotherapy) and systemic therapy in postmastectomy patients with ILRR. Our study represents one of the first moves toward this direction. In the present study, we conducted a long-term comprehensive follow-up study of 115 postmastectomy patients with ILRR and demonstrated that a substantial proportion of postmastectomy patients with ILRR had an unexpected long-term IDFS and OS after comprehensive locoregional and systemic therapy. Furthermore, we found that lymph node status, histologic grade, hormone status at primary diagnosis, the time interval to ILRR, and the use of comprehensive locoregional treatment are independent prognostic factors for clinical outcome of postmastectomy patients with ILRR. Postmastectomy patients with ILRR tend to have high incidence of morbidity and subsequent systemic dissemination (2–4). In contrast to the systemic disease control, these patients can have their locoregional disease control by complete excision of the tumor and post–operative radiotherapy. Patients receiving radiotherapy after the excision of local recurrent tumor have better local control than those without radiotherapy (23–26). Notably, our study showed that patients with chest wall recurrence had a marginally better OS and IDFS than those with recurrence at the other sites. For example, our patients with chest wall or axilla recurrence were often treated with comprehensive locoregional treatment, whereas most patients with supra-/infraclavicular fossa or multiple site recurrence were given with radiotherapy only. These findings are in line with previous studies reporting that patients with chest wall recurrence alone do better than those with supra-/infraclavicular nodal recurrence or recurrence at multiple lymphatic regions (27, 28). Hence the relatively limited number of our patients and selection bias
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may confound the interpretation. It appears that radiotherapy alone, for example, in our patients with higher percentage of recurrence in the supraclavicular/infraclavicular fossa, would independently influence their outcome. For example, a recent evaluation of importance in treating the LRR for postmastectomy patients entering into the DBCG 82b and 82c trials has shown that the combination of surgery and radiotherapy at the time of ILRR increased the persistent locoregional control; and that the supra/infraclavicular failure is still a poor prognostic factor for survival (4). Importantly, in their analyses, most patients with chest wall or axillary failures alone were offered a curative loco-regional treatment (surgery with and without radiotherapy), whereas most patients with supra/infraclavicular failure were offered systemic therapy or radiotherapy only (4). In the present study, postmastectomy patients with tumors greater than 5 cm and/or with more than three metastatic lymph nodes at their primary diagnosis may lack a sufficient adjuvant PMRT, and therefore had a poor prognosis after ILRR than patients without these risks. Indeed, in 1988, an analysis of failure patterns of postmastectomy patients has recommended that the routine use of PMRT for patients with four or more involved axillary nodes or tumors greater than 5 cm, given their relatively high risk of locoregional recurrence and distant metastases (29). However a recent retrospective analysis of a population–based cohort study of T1 to T2, node-positive breast cancer patients treated with mastectomy between 1988 and 1995, from the linked Surveillance, Epidemiology, and End Results database, showed that the use of PMRT was surprisingly low (30). In that analysis, only 26% of patients with more than three metastatic lymph nodes received PMRT, indicating that PMRT was underused in the late 1980s and in the early 1990s (30). This finding is in line with our findings that a proportion of our postmastrectomy ILRR patients with tumor greater than 5 cm and/or with more than three metastatic lymph nodes did not receive adjuvant PMRT at their primary diagnosis (between 1985 and 1995). Although our postmastectomy patients with tumors greater than 5 cm and/or with more than three metastatic lymph nodes at the time of their primary diagnosis lack a sufficient adjuvant radiation treatment (i.e., PMRT), these patients with ILRR may still have a chance of longterm survival (5-year IDFS rate, 32%; 5-year OS, 47%) after comprehensive locoregional and systemic treatment with surgery, entire-field radiotherapy, and adjuvant systemic therapy. These findings encourage the use of comprehensive locoregional treatment and systemic therapy for postmastectomy patients with ILRR. Our data indicate that patients undergoing entire-field radiotherapy sustained lower rates of second ILRR. Because the regional lymph nodes may harbor micrometastasis, it is reasonable to irradiate nodal regions, eradicate the potential micrometastasis, and thereby improve locoregional control and patient survival. Recent reports have also demonstrated that patients with ILRR at the chest wall who received additional elective radiation to the uninvolved nodal regions had significantly lower rates of second local recurrence than those
Treatment of postmastectomy isolated locoregional recurrence d S.-H. KUO et al.
who received involved-field radiation alone (10, 11, 31, 32). These results support our finding that entire-field (i.e., involved- and elective-field) radiotherapy reduced the rate of second ILRR from 26.1% to 6.5%, and further decreased the rate of distant metastasis from 52.2% to 24.6%. Several studies assessing the association between the interval to recurrence and prognosis in postmastectomy patients with ILRR have suggested that patients with late recurrence (>2 years after the original diagnosis) had much better prognoses than those with earlier recurrence (3, 9, 32, 33). In a recent study of 213 patients with ILRR after breast-conservatation surgery or mastectomy, patients with early chest wall recurrence had a worse prognosis than those with late recurrence (34). Although some of our patients were not treated with PMRT in the earlier days of our protocol, those patients with earlier ILRR as well as positive axillary lymph node findings, higher tumor grade, and negative hormone receptor status had significantly worse survival. Therefore the usefulness of PMRT for these patients with high-risk tumor characteristics demands emphasis. In addition these prognostic factors can aid physicians in clinical decision making regarding the use of adjuvant systemic chemotherapy or hormone therapy at the time of ILRR. Our postmastectomy patients had a 5-year OS rate of 63% and an IDFS rate of 54% after receiving aggressive locoregional treatment either with or without systemic therapy. These observations are similar to, or even better than, published series on ILRR with OS rates in the range of 42% to 79% (4, 30, 35, 36), as well as earlier series on postmastectomy ILRR with rates of 20% to 50% (11, 13, 31, 37). Although the impact of systemic chemotherapy or hormone therapy after curative locoregional therapy on locoregional control and prevention of distant metastasis is difficult to determine in this retrospective study, these findings may guide clinicians in the use of adjuvant systemic therapy after locoregional treatment, especially for higher-risk patients (38). The
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use of adjuvant hormone therapy is supported by a recent randomized trial that demonstrated improvement in IDFS but no impact on OS (36). Moreover, another study comparing locoregional therapy alone with locoregional therapy and chemotherapy combined found a trend toward improved IDFS and OS in postmastectomy patients with ILRR (39). The role of systemic chemotherapy in the treatment of ILRR patients is still of great relevance, however, because of the small patient numbers and heterogeneous patient populations (40, 41). A limitation of this study is that confounding factors likely were present in this series. For example, patients treated more recently tend to receive more comprehensive locoregional treatment and better screening for occult metastases than previous patients with ILRR. It is of note that our patients with ILRR who underwent the most comprehensive locoregional and systemic therapies had significantly better OS and IDFS than patients treated with either locoregional therapy or systemic therapy alone. These findings encourage the use of comprehensive locoregional treatment and systemic therapy for postmastectomy patients with ILRR. This combination therapy not only helps to achieve local disease control, but also to prevent distant metastasis and further improve clinical outcomes. The role of systemic therapy after comprehensive locoregional treatment should be underscored in future trials for postmastectomy patients after ILRR, especially in the era of new chemotherapy regimens and hormones. CONCLUSION In conclusion, treatment for isolated locoregional recurrent breast cancer after mastectomy is challenging but may potentially be curative. Postmastectomy patients with ILRR may still have a chance of long-term survival after comprehensive locoregional and systemic treatment using surgery, entirefield radiotherapy, and adjuvant systemic therapy.
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