Departments of 1 Nuclear Medicine, 2 Breast Surgery and 3 Internal Medicine, Cancer Institute Hospital, Tokyo, Japan
Received 4 November 2002; revised 22 April 2003; accepted 22 April 2003
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Abstract |
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Breast cancer has been the subject of many recent studies because it is a significant cause of death in women. This study was performed to clarify whether solitary skeletal metastasis has clinical significance compared with multiple skeletal metastasis.
Patients and methods:
Seven hundred and three patients who developed metastatic bone lesions up to September 2002 after beginning treatment for breast cancer from 1988 to 1998 were included. The lesions were classified first as solitary or multiple based on bone scan results and then according to anatomical distribution. Next, solitary-to-multiple conversion was investigated in patients with solitary skeletal metastasis. Then factors related to solitary or multiple skeletal metastasis were analyzed. The prognosis of skeletal metastasis was compared between patients with solitary or multiple metastatic bone lesions. A Cox proportional hazards model was used to test whether solitary skeletal metastasis compared with multiple skeletal metastasis was an independent factor of survival.
Results:
Two hundred and eighty-nine patients (41%) had solitary skeletal metastasis and 414 patients (59%) showed multiple skeletal metastasis. The sternum was a frequent site for solitary skeletal metastasis (98 of 289, 34%), while other skeletal sites were more frequent in patients with multiple metastatic bone lesions (P <0.001). Solitary sternal metastatic lesions remained solitary longer than solitary metastatic bone lesions to places other than the sternum (P <0.001), but did not lengthen patient survival times (P = 0.871). The factors related to solitary skeletal metastasis are TNM stage (tumornodemetastasis) and histology. The patients with earlier stage and favorable histology tend to have solitary skeletal metastasis. The patients with solitary skeletal metastasis lived longer than those with multiple metastatic bone lesions (P <0.001). Multivariate analysis revealed that a solitary metastatic bone lesion (P = 0.002) is an independent favorable prognostic factor in patients with skeletal metastasis.
Conclusions:
Solitary skeletal metastasis has a different anatomical distribution and is an independent prognostic factor in patients with skeletal metastasis.
Key words: breast cancer, skeletal metastasis, solitary and multiple, sternum
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Introduction |
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An analysis of metastatic bone lesions in patients with breast cancer was performed to determine whether solitary lesions have distinctive characteristics compared with multiple lesions. Solitary and multiple skeletal metastases were compared with their anatomical distribution and related risk factors. Then, the difference between solitary and multiple skeletal metastasis was analyzed to determine whether it might be an independent prognostic factor.
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Patients and methods |
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Skeletal metastasis was surveyed by bone scan and confirmed by other imaging methods. Bone scan was performed 2.54.0 h after injection of 740 MBq of hydroxymethylene diphosphonate or methylene diphosphonate Tc 99m. Scanning was performed using the whole-body moving camera technique (anterior and posterior) and the static image technique (anterior skull, anterior chest oblique and additional views at the physicians requests). However, due to its low specificity, if a bone scan was positive or equivocal for skeletal metastasis, other imaging techniques including X-ray, computed tomography (CT) and magnetic resonance imaging (MRI) scans were used to confirm the diagnosis [9]. When other imaging modalities could not determine skeletal metastasis, the diagnosis was made by follow-up studies or biopsy. All 703 patients included in this study had clinically confirmed skeletal metastasis, as determined by the agreement of at least two different imaging or diagnostic techniques.
Data from the 703 patients with skeletal metastasis were analyzed as follows: (i) Skeletal metastasis was first classified as solitary or multiple at the initial diagnosis of skeletal metastasis. The anatomical distribution of skeletal metastasis was determined. (ii) The time of conversion from solitary metastatic bone lesions to multiple lesions was measured (time from the solitary date to the first multiple date in bone scan). (iii) Relationships to skeletal metastatic state (solitary and multiple) among patient demographic data (age, menstrual status), tumor characteristics (tumor size, nodal status, histology and hormone receptor status), other site metastasis and time to skeletal metastasis were analyzed. (iv) Survival analysis after skeletal metastasis development was performed. Cause-specific death was used as an end point.
TNM (tumornodemetastasis) classification was performed according to International Union Against Cancer criteria [10] as stages I, II, III and IV. Histological classification was done according to Japanese Breast Cancer Society criteria [11, 12] as papillotubular cancer, solid tubular cancer, scirrhous cancer, invasive lobular cancer and other cancer. If the estrogen receptor (ER) concentration and progesterone receptor (PgR) concentration were 10 fmol/mg total protein, the results were regarded as positive. Other site metastasis is divided as follows: (i) first recurrence is restricted to bone, (ii) first recurrence is not only bone but also another site, and (iii) first recurrence is another site.
Statistical analyses are carried out using an unpaired t-test and Fishers exact test. A KaplanMeier estimate with a log-rank test was used to evaluate conversion to multiple metastatic bone lesions and comparison of survival between solitary and multiple osseous metastasis. A logistic regression analysis was used to analyze the factors that related to solitary and multiple skeletal metastasis. A Cox proportional hazards analysis was used in the evaluation of prognostic factors. All P values were two-tailed. P <0.05 was taken to be significant, and the 95% confidence interval (CI) for such results was calculated.
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Results |
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Anatomical distribution of skeletal metastasis.
The whole-body distribution of metastatic bone lesions is shown in Table 1. Distribution of solitary metastatic bone lesions is different from that of multiple metastatic bone lesions. Metastasis to sternum occurred most frequently (34%, P <0.001, Fishers exact test) in patients with a solitary metastatic bone lesion, while metastasis to other skeletal sites occurred more frequently in patients with multiple metastatic bone lesions.
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Conversion of solitary-to-multiple metastatic bone lesions
Patients with solitary bone metastasis were studied to determine incidence of multiple conversion (solitary-to-multiple metastatic bone lesion development). Of 289 patients with a solitary metastatic bone lesion, 161 developed multiple metastatic bone lesions. Patients with a solitary sternal lesion showed a lower conversion that those with a solitary bone lesion at other sites (Figure 1; Table 2), (P <0.001, KaplanMeier with log-rank test).
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Discussion |
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Data collected in this study show that solitary metastatic bone lesions account for 41% of initially diagnosed metastatic bone lesions. This is a higher incidence rate than previously reported [6]. Boxer et al. [6] reported that solitary lesions constituted 21% of metastatic bone lesions from breast cancer initial diagnosis and also stated that their figure was higher than previously reported. Our data show a higher figure than that of Boxer et al. The difference may be due to the frequent follow-up used in the present study, which may be more frequent than current clinical procedure in breast cancer. Our follow-up plan of bone scans after initial breast cancer treatment is principally once a year. Another possibility for the high detection incidence of solitary metastatic bone lesions in this study is the use of improved gamma camera techniques, both improved equipment and scanning techniques, and the use of other imaging techniques, including MRI, to confirm diagnosis. These technical improvements may have contributed to both the early detection of skeletal metastasis and the high incidence of solitary metastatic bone lesions detected in this study.
The incidence of sternal metastasis founded in this study was 34% (98 of 289) of all solitary metastatic bone lesions. This figure is also more frequent than previously reported [5, 6]. The bone scanning procedure using an anterior oblique view of the thorax may have contributed to this difference. Indeed, many metastatic sternal lesions, normally difficult to diagnose from an anterior-only bone scan image, were readily detected by the anterior oblique view of the thorax used in this study. Additionally, CT, MRI or both techniques confirmed all sternal lesions in this study. As the prognosis of patients with solitary metastatic bone lesions is better than that of patients with multiple metastatic bone lesions, and the incidence of solitary sternal metastatic bone lesions is high, the anterior oblique bone scan view should be a standard measurement taken in assessing breast cancer patients.
Data were analyzed using the hypothesis that prognosis of patients with solitary sternal lesions might be different from that of solitary metastatic bone lesions at sites other than the sternum. This is because breast cancer patients often develop isolated sternal lesions, many of which are caused by local tumor invasion from adjacent parasternal lymph nodes metastasis [5]. Analysis revealed that earlier TNM stage and favorable histology were significantly predictable factors for development of solitary metastatic bone lesions. Additionally, although the multiple conversion rate was lower in patients with solitary sternal metastasis than in patients with a solitary bone lesion at other sites, there was no difference in survival time between the two groups. Patients with a solitary metastatic bone lesion, regardless of the site, had better prognosis compared with patients with multiple metastatic bone lesions at initial appearance of skeletal metastasis. This may result from a leading effect (early diagnosis effect). However, time from initial diagnosis to development of skeletal metastasis was longer in patients with a solitary metastatic bone lesion. Furthermore, a solitary metastatic bone lesion often resolves during treatment, and complete remission is not unusual. The reason for these differences may be due to biological difference; that is, patients who develop solitary skeletal metastasis have favorable biological factors compared with those who develop multiple skeletal metastasis at initial osseous metastatic events. The patients who developed solitary osseous metastasis received chemotherapy, hormone therapy, radiotherapy, or the combination of these therapies in the present study. The early commencement of therapy may contribute the prolonged survival of the patients with solitary bone lesion.
Coleman et al. [8] reported that important prognostic factors for survival after the development of osseous metastasis in breast cancer were the histopathological grade of the primary tumor, ER status, presence of skeletal metastasis at initial breast cancer diagnosis, disease-free interval and age. In the present study, multivariable Cox proportional hazards analysis showed that ER status, PgR status, disease-free interval (bone metastasis-free interval) first metastasis organs and the type of bone lesions (solitary versus multiple) were independent prognostic factors. Patients with a solitary metastatic bone lesion, who had longer disease-free interval and who had positive hormone receptor status had a better prognosis. Age, TNM stage and histology did not affect survival after the development of skeletal metastasis. Consequently, diagnosing solitary metastatic bone lesions and starting treatment early increases the survival of breast cancer patients.
Summary
Skeletal metastasis was analyzed in a cohort of breast cancer patients treated at the Cancer Institute Hospital, in Tokyo, Japan. Seven hundred and three patients undergoing treatment of breast cancer developed metastatic bone lesions. Solitary metastatic bone lesions were found in 289 patients (41%) and multiple metastatic bone lesions in 414 (59%). Metastasis to the sternum was more frequent in patients with a solitary metastatic bone lesion compared with those with multiple metastatic bone lesions. The prognosis of patients with a solitary metastatic bone lesion was better than that of patients with multiple metastatic bone lesions. Although patients with sternal metastasis remained with a solitary lesion longer than patients with solitary metastatic lesions at other sites, no significant difference in survival was detectable between patients with solitary sternal metastasis and patients with a solitary metastatic bone lesion at sites other than the sternum. Multivariate analysis revealed that a solitary metastatic bone lesion is an independent prognostic factor in patients who developed skeletal metastasis.
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Acknowledgements |
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Footnotes |
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