| Japanese Journal of Clinical Oncology | Pages |
Clinical Characteristics of Patients with Metastatic Breast Cancer with Complete Remission Following Systemic Treatment
Introduction
Patients and Methods
Results
Discussion
Acknowledgments
References
Clinical Characteristics of Patients with Metastatic Breast Cancer with Complete Remission Following Systemic Treatment
Methods: We analyzed 315 consecutive MBC patients treated with several types of systemic treatments at the National Cancer Center Hospital between January 1988 and December 1993.
Results: The median survival time (MST) and median progression-free survival were 28.0 and 17.1 months, respectively. Forty patients were defined as `first-CR' following initial or second-line systemic treatment and the majority of them had a good performance status, low number of metastatic sites and low incidence of liver involvement. Nine of 40 patients with first-CR continued progression-free 5 years after beginning systemic treatments. The major sites of metastasis were the lung and bone and there were no cases with liver metastasis. Five patients received standard doxorubicin-containing combination chemotherapy with or without tamoxifen. Two of these nine patients remain progression free in first-CR. Three of them remained in first-CR after 5 years and died of progressive breast cancer and two others died of unrelated causes. Two patients relapsed after obtaining a first-CR for at least 5 years and remain alive with active metastatic disease. The MST and median progression-free survival of nine patients were 10.6 and 9.0 years, respectively. These nine patients represented 22.5% of all first-CR patients and 3.2% of the total patients.
Conclusions: Although MBC is commonly recognized to be an incurable disease, a small percentage of patients clearly are alive and progression free for prolonged periods after initiation of systemic treatments.
INTRODUCTION
Breast cancer is the second most frequently diagnosed cancer after gastric cancer among Japanese women, with approximately 27 000 cases and 7800 deaths in 1995. Although these figures are much lower compared with Western countries, the incidence of breast cancer in Japan is increasing and the number of newly diagnosed cases in the year 2015 is predicted to exceed 40 000 (1).
Combination chemotherapy is the most effective modality of treatment for the majority of patients with metastatic breast cancer (MBC). Overall response rates of 45-80% have been reported consistently over the last few years and the duration of survival after chemotherapy has ranged from 18 to 24 months (2). However, MBC is commonly recognized to be an incurable disease and even though systemic treatments such as chemotherapy and endocrinetherapy can induce impressive responses, their use in treating metastatic disease is usually limited to palliative rather than curative purposes. Thus, even though long-term survivors exist, their extended survival is thought to be attributed to the indolent nature of their disease rather than the treatments (3-8). On the other hand, MBC patients who achieve complete remission have a longer duration of remission and longer survival and a fraction of them are potentially curable (9-11). A careful study of the quality and length of complete remissions in MBC is essential in order to estimate the overall impact of systemic treatment on the survival of MBC patients.
We have analyzed our experience with consecutive MBC patients treated at the National Cancer Center Hospital in recent years. The purpose of our retrospective analysis was to describe the clinical characteristics of patients who had complete remissions (CR) to the treatment of systemic chemotherapy with or without endocrinetherapy.
PATIENTS AND METHODS
Between January 1988 and December 1993, 315 consecutive MBC patients were treated with several types of systemic treatments at the National Cancer Center Hospital. Thirty-six patients were excluded owing to inappropriate data with respect to medical records and 11 patients had insufficient data to determine response status but were assumed not to have achieved complete remission. Therefore, the data for the remaining 279 (89%) MBC patients were used for further analysis.
Responses were evaluated after the first two or three cycles (or 2-3 months) of systemic treatments. Standard International Union Against Cancer (UICC) criteria were used to determine responses to treatment (12). A complete remission (CR) was defined as the disappearance of all clinical evidence of an active tumor for a minimum period of 4 weeks. In the case of bone metastases, CR was determined by clear evidence of complete bone recalcification with attainment of near-normal bone architecture or a normal bone scan. Partial remission (PR) was defined as a 50% or greater decrease in the sum of products of the largest perpendicular diameters of measurable lesions, provided that no lesions increased in size and no new lesions appeared for a minimum of 4 weeks. No change (NC) was defined as no change in tumor dimensions for a minimum of 4 weeks. Progressive disease (PD) was defined as an unequivocal 25% increase in the size of any measurable lesions or the appearance of new lesions. In this analysis, both patients who achieved CR after initial systemic treatment and those who failed initial treatment but achieved CR on second-line treatment, were defined as `first-complete remission' (first-CR).
Figure 1. Progression-free and overall survival curves of the total MBC patients. The extent of metastatic involvement was determined by physical examination, biochemical analyses and routine imaging procedures before systemic treatment began. Bone involvement was determined by lytic or blastic lesions shown on radiographs. Bone scans alone were not considered diagnostic. Abnormalities shown on bone scans had to be confirmed by radiography. Liver involvement was determined by computed tomography or ultrasound consistent with the location of the metastases. Pleural or peritoneal involvement was determined by positive cytology for tumor cells in the effusion fluid and by appropriate imaging studies. Lymph node involvement was classified into two categories; regional and distant lymph node metastases based on the UICC criteria. Regional lymph node metastasis included ipsilateral axillary, interpectoral, supraclavicular and internal mammary lymph node involvement, while any other lymph node involvement was classified as distant lymph node metastasis, including cervical and contralateral internal mammary lymph node involvement. Figure 2. Flow chart describing the clinical course of 40 MBC patients who achieved first-CR on initial or second-line systemic treatments. NED; no evidence of disease. The following parameters were analyzed: age, menopausal status, estrogen (ER) receptor status, progesterone (PgR) receptor status, ECOG performance status (PS), number of metastatic sites, dominant metastatic sites, documented metastatic sites, types of adjuvant treatments, types of initial (first-line) systemic treatments, responses to initial systemic treatment and disease-free interval (DFI) from the time of initial diagnosis. Calculation of the number of metastatic sites did not distinguish between single and multiple metastasis in a given organ in patients with the metastatic disease; for example, a multiple bone metastasis, multiple pulmonary metastasis or multiple skin metastasis was counted as one site. Estimates of progression-free and overall survival were based on the Kaplan-Meier method (13). All deaths were considered as events regardless of their cause. Each patient was considered to be alive at the time of her last evaluation unless death had been documented and censored data were taken into account (14). The differences between pairs of curves were tested for statistical significance by a stratified log-rank test. Differences with a P value <0.05 were considered significant. All P values were two-sided. All analyses were performed using SPSS Ver. 6.1 statistical software.
Table 1.
| Patient characteristics | CR patients | Others | ||
| No. | % | No. | % | |
| No. of patients | 33 | 12 | 246 | 88 |
| Median age (range) (years) | 48 (35-72) | 51 (28-83) | ||
| Median disease-free interval (months) | 37.1 | 24.8 | ||
| Menopausal status | ||||
| Premenopausal | 19 | 58 | 121 | 49 |
| Postmenopausal | 13 | 39 | 110 | 45 |
| Unknown | 1 | 3 | 15 | 6 |
| Estrogen receptor status | ||||
| Negative | 11 | 33 | 75 | 30 |
| Positive | 7 | 21 | 57 | 23 |
| Unknown | 15 | 45 | 114 | 46 |
| Progesterone receptor status | ||||
| Negative | 9 | 27 | 66 | 27 |
| Positive | 7 | 21 | 44 | 18 |
| Unknown | 17 | 52 | 136 | 55 |
| Performance status | ||||
| 0 | 18 | 58 | 64 | 30 |
| 1 | 12 | 39 | 123 | 57 |
| 2 | 1 | 3 | 18 | 8 |
| 3 | 0 | 0 | 4 | 2 |
| 4 | 0 | 0 | 5 | 2 |
| Number of metastatic sites | ||||
| 1 | 20 | 61 | 130 | 53 |
| 2 | 12 | 36 | 64 | 26 |
| 3 | 1 | 3 | 28 | 11 |
| 4 | 0 | 0 | 13 | 5 |
| 5 | 0 | 0 | 9 | 4 |
| 6 | 0 | 0 | 0 | 0 |
| 7 | 0 | 0 | 2 | 0 |
| Dominant disease site | ||||
| Bone | 4 | 12 | 76 | 31 |
| Soft tissue | 11 | 33 | 54 | 22 |
| Visceral | 18 | 55 | 116 | 47 |
| Documented disease site | ||||
| Bone | 6 | 18 | 131 | 53 |
| Regional lymph nodes | 10 | 30 | 67 | 27 |
| Distant lymph nodes | 6 | 18 | 30 | 12 |
| Lung | 13 | 39 | 63 | 26 |
| Skin | 7 | 21 | 58 | 24 |
| Liver | 1 | 3 | 52 | 21 |
| Pleura | 5 | 15 | 24 | 10 |
| Pericardium | 0 | 0 | 6 | 2 |
| Brain | 0 | 0 | 9 | 4 |
| Adjuvant treatment | ||||
| None | 8 | 24 | 69 | 28 |
| Chemotherapy (CT) alone | 12 | 36 | 57 | 23 |
| Radiotherapy (RT) alone | 1 | 3 | 9 | 4 |
| Endocrinetherapy (ET) alone | 4 | 12 | 27 | 11 |
| CT + RT | 1 | 3 | 12 | 5 |
| RT + ET | 0 | 0 | 4 | 2 |
| CT + ET | 7 | 21 | 51 | 21 |
| CT + ET + RT | 0 | 0 | 17 | 7 |
Table 2.
| Types of initial treatment | CR patients | Others | ||
| No. | % | No. | % | |
| Anthracycline-containing regimen | 23 | 70 | 149 | 61 |
| Non-anthracycline-containing regimen | 1 | 3 | 25 | 10 |
| Oral 5-FU alone | 0 | 0 | 9 | 4 |
| Oral CPA alone | 2 | 6 | 19 | 8 |
| Investigational new agent* | 3 | 9 | 12 | 5 |
| Endocrinetherapy alone | 4 | 12 | 32 | 13 |
| Total | 33 | 100 | 246 | 100 |
RESULTS
Figure 1 shows progression-free and overall survival curves of the total MBC patients. The estimated median progression-free survival was 17.1 months [95% confidence interval (CI) = 15.0-19.2 months]. The median survival time (MST) was 28.0 months (95% CI = 22.9-33.0 months) and the 2, 5 and 10 year survival rates were 54.8, 22.5 and 5.3%, respectively.
Figure 2 shows a flow chart describing the clinical course of 40 MBC patients who were defined as `first-CR' on initial or second-line systemic treatments (33 patients achieved CR on initial treatment and seven patients, who failed initial treatment, achieved CR on second-line treatment). Thirty-one of 40 patients developed a progressive disease during the first 5 years; 29 died of metastatic breast cancer, one remains alive with metastasis and another remains in unmaintained second CR after retreatment. Nine patients who achieved a first-CR continued progression-free 5 years after beginning systemic treatments. Two of these nine patients remain progression-free in first-CR at this time. Three of them who remained in first-CR at 5 years died of progressive breast cancer and two others died of unrelated causes (infection and myocardial infarction). In addition, two patients who relapsed after obtaining a first-CR for at least 5 years remain alive with an active metastatic disease. At the time of this analysis, these nine patients who remained in first-CR for more than 5 years represented 22.5% of all first-CR patients and 3.2% of the total patient population.
Table 1 lists the clinical characteristics of patients who achieved CR on initial systemic treatment compared with all the other patients. Several factors were more frequently present in patients with CR compared with the others. For example, although 58% of CR patients were PS 0, 30% of the others were in this category. On the other hand, although only 3% of CRs had liver metastases, 21% of the others had liver metastases. The number of different metastatic sites was lower for CR patients than for the others.
Table 2 lists the profile of initial systemic treatment for the MBC patients. The majority of patients received standard anthracycline-containing chemotherapy with or without endocrinetherapy and 23 (70%) of CR patients received it. On the other hand, 56 (20%) of the total patients received a non-anthracycline-containing regimen, oral fluorouracil (5-FU) or cyclophosphamide alone. However, only three (5%) patients achieved CR and no CR was observed in patients who received oral 5-FU alone.
At the time of this analysis, 33 (12%) MBC patients achieved CR while receiving initial systemic treatments (described earlier). Seventy-two patients (27%) achieved PR, 112 (42%) had no change in their tumor dimensions and 51 developed PD (19%). The overall response rate was 39% (95% CI = 33.4-45.0%).
The progression-free survival curves of the total patients, according to the maximum response status achieved following initial systemic treatment, are shown in Fig. 3. Eleven patients whose response status was not determined were excluded from Figs 3 and 4 (described below). The estimated median progression-free survival of the patients with CR, PR, NC and PD were 31.8, 19.1, 16.6 and 5.5 months, respectively. The overall survival curves of the total patients, according to the maximum response status achieved following initial systemic treatment, are shown in Fig. 4. MSTs of the patients with CR, PR, NC and PD were 41.9, 33.9, 28.0 and 9.6 months, respectively.
Figure 3. Progression-free survival curves of the total patients following initial systemic treatment according to the maximum response status. Table 3 shows the individual characteristics of the nine patients who remained in first-CR for more than 5 years. All of these patients had good PS and the majority of them had received adjuvant chemotherapy with a longer DFI. The major sites of metastasis were the lung and bone and there were no cases with liver metastasis. Five patients received standard doxorubicin-containing combination chemotherapy with or without tamoxifen (ACT or AC). Median progression-free survival of these cases and MST were 9.1 (range 5.6-11.9) and 10.6 (range 6.7-15.6) years, respectively. Although three patients were died of MBC, two patients remain progression-free in first-CR at the time of this analysis. Most patients with breast cancer are diagnosed at an early stage, when potentially curative treatment strategies are possible. However, 20-85% of these patients, depending on the initial stage and the treatment strategy followed, will develop distant metastases within 5 years of their initial diagnosis (2). It is commonly recognized that the great majority of MBC patients will eventually die of their disease, usually within a few years of relapse. On the other hand, it is less recognized that a small fraction of patients treated with systemic treatment will remain alive and progression-free for prolonged periods after initiation of systemic treatment (15). Figure 4. Overall survival curves of the total patients following initial systemic treatment according to the maximum response status. Greenberg et al. (16) reported that a small fraction (3.1%) of MBC patients remained alive and in CR for more than 5 years and more than half of these patients were alive and disease-free within a minimum 10 years follow-up. Between January 1988 and December 1993, 315 consecutive MBC patients were treated at the National Cancer Center Hospital, generally with standard anthracycline-containing combination chemotherapy with or without endocrinetherapy. Among these patients, nine of 40 patients, who achieved first-CR, remain disease-free for more than 5 years following systemic treatment. These nine patients represented 3.2% of the total patients and the results were similar to those reported by Greenberg et al. (16). In other words, we confirmed that a small fraction of Japanese MBC patients also remain alive and progression-free for prolonged periods with CR following systemic treatment. However, it was difficult to determine from our data whether long-term CRs result from the treatment strategy or the underlying indolent nature of MBC in some patients. Achieving CR is more likely for patients with a low tumor burden and good performance status (17,18). CRs were also more common among patients with pulmonary and regional lymph node metastases and less common in patients with bone metastases in our study (shown in Table 1). This discrepancy may be partially caused by differences in the tumor burden and also differences in the ability to detect metastases in different organ sites and by monitoring changes. Additionally, assessment of the responses in bone metastases is based on indirect measurements, a factor that is probably responsible for the difficulty of evaluating the response to therapy in these sites of the disease. In most studies, visceral involvement, especially liver involvement, was a poor prognostic factor (19,20). Our data also showed that patients with liver involvement had a poorer prognosis than those without liver involvement (MST; 11.1 vs 33.1 months, p < 0.0001 by log-rank test) and only one (3%) of the patients with liver involvement achieved CR. Table 3. 
DISCUSSION
No.
Stage*
ER*
PgR*
Adj.
treat.DFI
(yr)Age[dagger]
(yr)PS[dagger]
Menopausal
status[dagger]Site of
metastatis1st-line
treat.PFS
(yr)OS
(os)Present status
1
II
UN
UN
CT
9.0
50
1
Pre.
Lung, bone
TAM
9.8
10.6
Dead with NED
2
I
UN
UN
None
7.1
48
1
Post.
Lung, DLNs
ACT
8.2
11.5
Alive with metastasis
3
IIIa
UN
UN
CT+RT
5.8
50
1
Pre.
Lung
CPA
11.1
13.1
Dead with metastasis
4
II
UN
UN
CT
3.5
52
0
Post.
Skin
CPA+TAM
11.9
15.6
Alive with metastasis
5
II
+
+
CT
3.2
62
1
Post.
Bone
TAM
10.6
10.6
Dead with NED
6
UN
UN
UN
CT
6.1
40
1
Pre.
Pleura
ACT
9.1
9.1
Still in first-CR
7
IIIb
UN
UN
CT+ET
2.5
57
1
Post.
Skin
AC
6.3
6.7
Dead with metastasis
8
IV
-
-
None
0
49
1
Pre.
Lung, bone, pleura
ACT
5.6
7.3
Dead with metastasis
9
I
UN
UN
CT
2.1
38
0
Pre.
Lung
ACT
8.5
8.5
Still in first-CR
The factor that appears to be most important is the initial achievement of a CR. Only five (6.9%) of 72 patients with PR and 14 (12.5%) of 112 patients with NC remained progression-free beyond 5 years because the response rate to salvage chemotherapy regimens, once hormonal and first-line chemotherapy have been exhausted, is extremely poor and short-lived (21). Although combined chemotherapy and endocrinetherapy might result in longer CRs, there is no evidence that the long-term disease-free survival percentage is increased by this strategy. There is also no evidence to suggest that the addition of radiotherapy increases the fraction of long-term disease-free survivors. Our data failed to show the significant differences between patients who received anthracycline-containing chemotherapy and those who did not receive it with respect to not only overall survival but also progression-free survival (data not shown). One of the possible reasons is the insufficient impact of today's combination chemotherapy and the outcome for MBC patients may be strongly influenced by the indolent nature of their disease. To break down the current status, it is necessary to develop new and better treatment strategies. One possible strategy is high-dose chemotherapy with hematopoietic stem cell support. When high-dose chemotherapy is used for response consolidation, CR rates ranging from 47 to 80% have been reported, with some lasting longer than 2 years (22,23).
In conclusion, a small percentage of MBC patients clearly are alive and disease-free more than 5 years after initial relapse. The fraction may be small, but it might expand to the majority of MBC patients by some treatment strategy completely different from today's combination chemotherapy.
Acknowledgments
We thank Misses Momoko Kitahara and Hiromi Orita for secretarial assistance.
References
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Last modification: 24 Jul 1998
Copyright©Japanese Journal of Clinical Oncology, 1998.
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