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The relationship between lung cancer histology and the clinicopathological characteristics of bone metastases
Lung Cancer 96 (2016) 19–24
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The relationship between lung cancer histology and the clinicopathological characteristics of bone metastases Marcelo Braganc¸a dos Reis Oliveira a,∗ , Fernanda Carvalho de Queiroz Mello b,c , Marcos Eduardo Machado Paschoal c a
Trauma-Orthopaedics Service, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil c Thoracic Diseases Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil b
a r t i c l e
i n f o
Article history: Received 1 December 2015 Received in revised form 3 February 2016 Accepted 25 March 2016 Keywords: Lung cancer Bone metastasis SRE Histology
a b s t r a c t Objectives: Lung cancer is the leading cause of death due to cancer, and bone is one of the most frequent sites of metastasis. However, there is no published evidence regarding an association between lung cancer histology and skeletal complications. Therefore, we evaluated the influence of lung cancer histology on the frequency of bone metastases (BMs), skeletal-related events (SREs), and survival after BM. Material and methods: This retrospective study evaluated medical records from 413 patients who were diagnosed with lung cancer between 2003 and 2012. The prevalences of BMs and SREs were calculated, and their associations with the histological subtypes were evaluated using the chi-square test, odds ratios (OR), and 95% confidence intervals (CI). Overall survivals and associations with the histological subtypes were evaluated using the Kaplan-Meier method and the log-rank test. Results: The prevalences of BM, synchronous BM, and SREs were 28.2%, 70.4%, and 68.7%, respectively. Adenocarcinoma was the most common histological subtype (46.7%), and was significantly more frequent among patients with BM (58.3% vs. 42.1%; p = 0.003; OR: 1.92; 95% CI: 1.29–2.97). Squamous cell was significantly less frequent among patients with BM (13.0% vs. 29.8%; p = 0.0004; OR: 0.35; 95% CI: 0.19–0.64). The median survival time after the first BM diagnosis was 4 months, and there was no significant difference in the survival periods for the various histological subtypes. Conclusion: Adenocarcinoma and squamous cell were significantly associated with higher and lower risks of developing BM, respectively. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer-related deaths, and metastatic carcinoma is the most frequent malignant bone tumor, which occurs in approximately 15–40% of patients with lung cancer [1,2]. Furthermore, bone is one of the most frequent sites of metastasis, which results in a high morbidity and a reduced quality of life among these patients [3–5]. In this context, osteoclast
Abbreviations: BTA, bone target agent; BM, bone metastasis; SRE, skeletalrelated event; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; LC, large cell carcinoma; NOS, not otherwise specified; Adeno, adenocarcinoma. ∗ Corresponding authors at: Servic¸o de Traumato-Ortopedia do Hospital Universitário Clementino Fraga Filho da Universidade Federal do Rio de Janeiro. Rua Rodolpho Paulo Rocco, 255, Cidade Universitária − Ilha do Fundão, Rio de Janeiro. RJ, CEP: 21941-913 Brasil. E-mail addresses: [email protected], [email protected] (M.B.d.R. Oliveira). http://dx.doi.org/10.1016/j.lungcan.2016.03.014 0169-5002/© 2016 Elsevier Ireland Ltd. All rights reserved.
inhibition using bone target agents (BTAs), such as bisphosphonates and denosumab, is currently a topic of increasing debate in lung cancer [4–6]. However, there are few studies regarding the influence of lung cancer histology on the frequency and characteristics of bone metastasis (BM). Recent studies have demonstrated that BTAs are associated with a reduction in the risk of, and time to, skeletal related events (SREs) among patient with non-small cell lung cancer (NSCLC) [7–11] and possibly with an increased survival [12]. However, their routine use in patients with BM from lung cancer remains relatively low [5,6]. Approximately 40% of patients with NSCLC develop BM, and adenocarcinoma is the most frequent histological subtype [2,13–17]. Although no studies have specifically compared the prevalence of BM according to the histological subtypes among patients with NSCLC or small cell lung cancers (SCLC), several studies have assessed the frequency of BM and the histological subtypes of lung cancer using various approaches. Nevertheless, to our best knowledge, there is no published evidence regarding an association
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413 pts Lung cancer 6 pts were excluded 407 pts Histologic criteria
170 pts / 41,8% Localized or regional disease*
237 pts / 58,2% Distant disease*
115 pts / 28,2% Bone metastases
34 pts / 29,6% Metachronous bone metastases
81 pts / 70,4% Synchronous bone metastases
79 pts / 68,7% SREs
* Stage at cancer diagnosis Fig. 1. Cohort diagram—Lung cancer patients according to the stage at cancer diagnosis, the presence of bone metastases at diagnosis or throughout follow-up, and skeletalrelated events (SREs).
between histology and skeletal complications. Thus, we designed this study to assess whether lung cancer histology influenced the occurrence of BM and SREs, as well as the overall survival of patients with BM, in a cohort of patients who had not been routinely treated using BTAs. This information may be useful for guiding early surveillance for BM detection or interventions in high-risk groups that can improve patients’ quality of life and survival. 2. Material and methods 2.1. Study population This retrospective study’s design was approved by our institutional ethics review board. We retrospectively evaluated medical records from 413 patients who were diagnosed with malignant primary lung tumors at our institution between January 2003 and January 2012. The inclusion criteria were pathological confirmation of NSCLC or SCLC and complete tumor staging data. To accurately evaluate the association with survival, we excluded patients who were diagnosed with a second malignant primary tumor or had an unknown date of death. Lung carcinoma was classified according
to histological subtype, using the World Health Organization classifications: adenocarcinoma, squamous cell, large cell (LC), NSCLC not otherwise specified (NOS), and SCLC [18]. The events of interest were the occurrence of BM, SREs, and death. BMs were diagnosed via histopathologic examination of bone biopsy samples or via Tc99− bone scintigraphy with two additional imaging modalities (X-ray radiography, computed tomography, or magnetic resonance imaging). SREs were defined as the need for radiotherapy, pathological fracture, spinal cord compression, the need for surgery due to BM, or hypercalcemia. BMs were classified as synchronous or metachronous according to the times of diagnosis for the first BM and the lung cancer. The minimum follow-up period after a diagnosis of BM was 24 months (excluding cases of death before 24 months). 2.2. Statistical analysis The chi-square test was used to compare the proportions of histological subtypes among patients who did and did not develop BM, synchronous BM, SREs, or pathological fracture. The relationship between histological subtype and the occurrence of BMs was
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Table 1 Characteristics of lung cancer patients overall and by the presence of bone metastasis at lung cancer diagnosis or throughout follow-up. Characteristic
Lung cancer patients cohort overall
Lung cancer patients without bone metastasis
Lung cancer patients with bone metastasis
N = 407
N = 292
N = 115
N Mean age (range) Gender Male Female Smoking Never smoked <40 packs/year ≥40 packs/year Histology Adeno Squamous LC NOS/NSCLC SCLC Initial stage Localized Regional Distant
%
N
63.4 years (32–87)
%
65.7 years (42–84)
N
%
62.6 years (32–87)
250 157
61.4 38.6
175 117
59.3 40.7
75 40
65.2 34.8
55 96 256
13.5 23.6 62.9
30 63 199
10.3 21.6 68.1
25 33 57
21.7 28.7 49.6
190 102 11 56 48
46.7 25.1 2.7 13.7 11.8
123 87 9 40 33
42.1 29.8 3.1 13.7 11.3
67 15 2 16 15
58.3 13.0 1.8 13.9 13.0
39 131 237
9.6 32.2 58.2
37 115 140
12.7 39.4 47.9
2 16 97
1.7 14.0 84.3
Adeno: adenocarcinoma; LC: large cell; NOS: not otherwise specified; NSCLC: non-small cell lung cancer, SCLC: small cell lung cancer; SRE: skeletal-related event.
Table 2 The prevalences of bone metastases and skeletal-related events according to histology. Event
Bone metastasis Synchronous metastasis SREs Radiotherapy Pathological fracture Spinal cord compression Orthopedic surgery Hypercalcemia
Histology (%) Adeno Squamous LC
NOS/NSCLC SCLC All
35.3 68.7 73.1 61.2 23.9 10.4 9.0 5.9
28.6 81.3 68.8 93.7 12.5 18.6 0 6.3
14.7 73.3 66.7 53.3 6.7 0 0 6.7
18.1 100 50 50 50 0 50 0
31.2 60.0 53.3 46.7 13.3 6.7 6.7 6.7
28.2 70.4 68.7 64.3 19.1 9.6 7.0 6.1
Adeno: adenocarcinoma; LC: large cell; NOS: not otherwise specified; NSCLC: nonsmall cell lung cancer, SCLC: small cell lung cancer; SRE: skeletal-related event.
also evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs). The overall survivals and associations with the histological subtypes were evaluated using the Kaplan-Meier method, and the difference between patients with adenocarcinoma and non-adenocarcinoma were evaluated using the log-rank test. All analyses were performed using SPSS software (version 10.0; SPSS Inc., Chicago, IL), and a p-value < 0.05 was considered statistically significant. 3. Results 3.1. Demographics Among the 413 patients, 407 were eligible for analysis based on the inclusion criteria. A cohort diagram is shown in Fig. 1 and the patients’ demographic characteristics are shown in Table 1. The mean age was 63.4 years, 61.4% of the patients were men and 86.5% were current or ex-smokers. At initial diagnosis, 58,2% had distant disease. The distribution of the histologic subtypes was adenocarcinoma (n = 190; 46.7%), squamous cell (n = 102; 25.1%), LC (n = 11; 2.7%) NOS/NSCLC (n = 56; 13.7%), and SCLC (n = 48; 11.8%), (Table 1). One hundred and fifteen patients had bone BM, and the demographic data of patients with (n = 115) and without BM (n = 292) are shown in Table 1.
3.2. BMs and SREs Among the entire cohort, the overall prevalence of BM was 28.2% (n = 115). The prevalences according to histology are presented in Table 2. Bone involvement was more prevalent among patients with adenocarcinoma (n = 67; 35.3%). Bone involvement was also observed in patients with squamous cell (n = 15; 14.7%), LC (n = 2; 18.1%), NOS/NSCLC (n = 16; 28.6%), and SCLC (n = 15; 31.2%). Synchronous metastases were significantly more frequent than metachronous metastases (n = 81, 70.4% vs. n = 34, 29.6%; p = 0.0021). The prevalences of synchronous metastases were 68.7% (n = 46) for adenocarcinoma, 73.3% (n = 11) for squamous cell, 100% (n = 2) for LC, 81.3% (n = 13) for NOS/NSCLC, and 60% (n = 9) for SCLC (Table 2). A total of 79 patients had experienced 122 SREs, with an overall prevalence of 68.7% among the patients with BM. The need for radiotherapy was the most frequent event (n = 74; 64.3%), which was followed by pathological fracture (n = 22; 19.1%), spinal cord compression (n = 11; 9.6%), surgical treatment for BM (n = 8; 7.0%), and hypercalcemia (n = 7; 6.1%) (Table 2). 3.3. Number and location of BMs Among the 115 patients with bone involvement, we observed 305 BMs (2.65 metastases per patient). The most frequently sites were the spine (98 metastases; 32.1%), pelvic girdle (53 metastases; 17.4%), proximal femur and humerus (52 metastases; 17.1%), and the chest wall (46 metastases; 15.1%). There was no correlation between location and histology. 3.4. Histology and the occurrence of BMs or SREs Table 3 presents the proportions of histological subtype among patients who did and did not develop BM, synchronous BM, SREs, or pathological fracture. Adenocarcinoma was the most frequent histological subtype in the entire cohort. The frequency of adenocarcinoma was significantly higher among the patients who developed BM (n = 67; 58.3%), compared to the patients who did not develop BM (n = 123; 42.1%) (p = 0.003). Squamous cell was significantly less frequent among patients who developed BM (n = 15,
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Table 3 Comparison of histological subtypes proportions among patients who did and did not develop bone metastases, synchronous metastasis, SREs, or pathological fractures. Histology
Adeno Squamous LC NOS/NSCLC SCLC
Bone metastasis
Synchronous metastasis
SREs
Yes
No
Yes
No
Yes
No
Yes
No
N(%)
N(%)
N(%)
N(%)
N(%)
N(%)
N(%)
N(%)
67(58.3) p-valor = 0.003 15(13.0) p-valor = 0.0004 2(1.7) p-valor = 0.451 16(13.9) p-valor = 0.954 15(13.0) p-valor = 0.623
123 (42.1)
46(56.8) p-valor = 0.621 10(12.3) p-valor = 0.731 2(2.5) p-valor = 0.355 14(17.3) p-valor = 0.106 9(11.1) p-valor = 0.342
21(61.8)
49(62.0) p-valor = 0.646 10(12.7) p-valor = 0.979 1(1.3) p-valor = 0.607 11(13.9) p-valor = 0.869 8(10.1) p-valor = 0.229
18(50.0)
16(72.7) p-valor = 0.125 1(4.5) p-valor = 0.188 1(4.5) p-valor = 0.262 2(9.1) p-valor = 0.467 2(9.1) p-valor = 0.54
51(54.8)
87(29.8) 9(3.1) 40(13.7) 33(11.3)
5(14.7) 0(0) 2(5.9) 6(17.6)
Pathological fracture
5(13.9) 1(2.8) 5(13.9) 7(19.4)
14(15.1) 1(1.1) 14(15.1) 13(14.0)
Adeno: adenocarcinoma; LC: large cell; NOS not otherwise specified; NSCLC: non-small cell lung cancer, SCLC: small cell lung cancer; SRE: skeletal-related event.
Table 4 The risk of bone metastasis according to histology. Histology
Odds ratio
Adeno Squamous LC NOS/NSCLC SCLC
1.92 0.35 0.55 1.01 1.17
95% confidence interval 1.29–2.97 0.19–0.64 0.12–2.61 0.54–1.90 0.61–2.26
Adeno: adenocarcinoma; LC: large cell; NOS not otherwise specified; NSCLC: nonsmall cell lung cancer, SCLC: small cell lung cancer.
13.0% vs. n = 87, 29.8%; p = 0.0004). However, there were no other statistically significant differences between the other histological subtypes. We used ORs and 95% CIs to evaluate the associations between histological subtype and the occurrence of BM (Table 4). The ORs were 1.92 (95% CI: 1.29–2.97) for adenocarcinoma, 0.35 (95% CI: 0.19–0.64) for squamous cell, 0.55 (95% CI: 0.12–2.61) for LC, 1.01 (95% CI: 0.54–1.90) for NOS/NSCLC, and 1.17 (95% CI: 0.61–2.26) for SCLC. 3.5. Survival The survival outcomes were calculated after excluding 20 patients, due to the diagnosis of a second malignant primary tumor (n = 12) or an unknown date of death (n = 8). One patient with BM was alive at the end of the follow-up. The median survival time after the diagnosis of BM was 4 months (Table 5). The median survival times for adenocarcinoma, squamous cell, LC, NOS/NSCLC and SCLC were 3.0 months, 4.5 months, 9.0 months, 2.5 months, and 4.5 months, respectively. There was no significant difference in the survival time for patients with adenocarcinoma and nonadenocarcinoma. 4. Discussion In the present cohort of patients with lung cancer who were treated at a single academic general hospital, we observed a BM prevalence of 28,2%. This result is similar to those in previous reports, and confirms that bone is one of the most frequent metastatic sites [2,13–17]. Although studies from the 1990s used bone scintigraphy to determine that the incidence of BM was <20% [19–21], we believe that the detection method influences the results, because more recent studies have used positron emission tomography and reported higher frequencies (20–40%) [13,22,23]. However, Sugiura et al. used bone scintigraphy and x-ray radiography, and reported a lower prevalence (10.4%) [2]. In contrast, Tsuya et al. identified 70 (30.4%) patients with BM from lung cancer using bone scintigraphy, radiography, and magnetic resonance
imaging [14]. Their detection methods and metastasis frequencies were similar to those from the present study, although we studied a larger sample, due to the intentional inclusion of SCLC. The results of the present study confirm that adenocarcinoma is the most prevalent histological subtype, regardless of BM development, which agrees with previous epidemiological reports that have demonstrated that adenocarcinoma accounts for >45% of lung carcinomas [24,25]. However, the prevalence of BM in this study varied according to the histologic subtype, and we found relatively high prevalence for adenocarcinoma (35.3%) and SCLC (31.2%), and a relatively low prevalence for squamous cell (14.7%). These results indicate that the likelihood of bone dissemination can vary according to the lung cancer’s subtype. Therefore, we compared the frequencies of the histological subtypes among patients with and without BM to test this hypothesis. The occurrence of BM was significantly and positively associated with a diagnosis of adenocarcinoma (58.3% vs. 42.1%, p = 0.003, OR: 1.92, 95% CI: 1.29–2.97), and was significantly and negatively associated with a diagnosis of squamous cell (13.0% vs. 29.8%, p = 0.0004, OR: 0.35, 95% CI: 0.19–0.64). Although some studies have also reported a relatively high frequency of adenocarcinoma, they did not directly evaluate the possible association between lung cancer histology and bone dissemination. Nevertheless, Sugiura et al. identified adenocarcinoma as the most frequent histological subtype (70%) among 118 patients with BM from NSCLC [2], and Kagohashi et al. reported that 67% of patients with BM had adenocarcinoma [17]. Furthermore, a recent cohort study evaluated the entire population of Denmark, and reported a higher frequency of adenocarcinoma among patients with BM (50.3%), compared to all patients with lung cancer (37.9%), and a lower frequency of squamous cell among patients with BM (13.0%), compared to all patients with lung cancer (24.6%) [15]. Those studies did not directly evaluate the association between histology and the frequency of metastasis. The prevalence of adenocarcinoma among patients with BM in the present study was slightly lower (35%) than those in the previous reports. However, we observed significantly higher and lower risks from adenocarcinoma and squamous cell, respectively. Moreover, the majority of studies regarding bone involvement in lung cancer have not included SCLC, which was the second most prevalent subtype in the present cohort. Therefore, it remains unclear whether the frequency and characteristics of BM for this histological subtype differ from those of NSCLC. However, the relatively high frequency that we found is compatible with the more aggressive nature of SCLC [26]. The population-based studies by Cetin et al. and Sathiakumar et al. reported that the rates of bone dissemination were higher for NSCLC [15,27], and these are some of the few studies that have included SCLC, which was diagnosed in 16.7% and 13% of the patients with BM. These findings are similar to the 13% that we observed. In contrast, the we observed that the prevalence of
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Table 5 Survival data according to histology. Histology
N
Survival, months
Survival, % (95% confidence interval)
p-value
Mean
Median
At 6 months
At 12 months
At 24 months
32.7 (20.3–45.1) 30 (1.6–58.4) 100 (0–100) 26.7 (4.3–49.0) 30.8 (5.7–55.8) 32.7 (20.3–45.1) 32.5 (18.0–47.0)
14.5 (5.2–23.9) 0
7.2 (0.4–14.1) 0
0
0
13.3 (0–30.5) 23.1 (0.2–46.0) 14.5 (5.2–23.9) 12.5 (2.2–22.7)
0
Adeno
55
7.2
3.0
Squamous
10
4.5
4.5
LC
2
9.0
9.0
NOS/NSCLC
15
5.5
2.5
SCLC
13
6.5
4.5
Adeno
55
7.2
3.0
Non-adeno
40
5.7
4.3
0 7.2 (0.4–14.1) 0
0.33
Adeno: adenocarcinoma; LC: large cell; NOS not otherwise specified; NSCLC: non-small cell lung cancer, SCLC: small cell lung cancer; SRE: skeletal-related event.
BM was 31.2% among patients with SCLC, compared to the 5.8% prevalence that was observed by Cetin et al. and the 23.3% prevalence that was observed by Sathiakumar et al. [15,27]. These results indicate that additional studies are needed, and that these studies should carefully evaluate the characteristics of BM in this group of patients. The majority of patients with BM exhibited bone involvement at the time of the lung cancer diagnosis (70.4%). However, we did not find an association between synchronous BM and histology, which was likely due to the low number of individuals in our stratified groups. Other series have also reported high frequencies of synchronous bone involvement, which ranged from 46% to 66% [2,14,23]. However, our frequency may also have been overestimated, due to possible selection bias, as our institution became a referral center for patients with bone tumors in 2010, which resulted in a significant increase in the number of patients with BM from initially unknown primary sites. The survival rate after a diagnosis of BM was very low in the present cohort predominantly treated with platinum-based chemotherapy. Epidermal growth factor receptor inhibitor, such as gefitinib, that have prolonged the median survival time, especially in patients with adenocarcinoma, was not available for use at our institution during the study period. This finding reflects the survival rate in our country, where lung cancer is usually diagnosed in a late stage and is associated with a high frequency of SREs, which we observed in the present cohort. Hansen et al. have reported the effect of BM on survival in various types of carcinomas, and found that patients with BM from lung cancer had a mean survival of 3 months [28]. In the series of Sathiakumar et al., patients who developed BM experienced a 2.4-fold greater risk of death (95% CI: 2.4–2.5) [23]. Furthermore, Sugiura et al. reported that the median survival time after a diagnosis of BM was 7.2 months [2]. The median survival time in the present study (4 months) was lower than that in the majority of the previous studies, and may be related to a relatively high frequency of patients who were initially diagnosed with stage 4 cancer [2,13,14,29,30]. Our results are closer to the results from a retrospective French study, which estimated a median survival time of 5.8 months [29]. Unfortunately, our study’s design did not allow for a comparison of survival after the cancer diagnosis for patients with and without BM, because our aim was only to compare survival according to histological subtype after BM. In addition, we did not observe any statistically significant difference in survival according to the histological subtypes. Regarding the frequency of SREs, our results are also similar to those that were published by Kuchuk et al. [5,6]. In the present study, 68.7% of the patients with BM had experienced SREs, such as the need for radiotherapy (64.3%), pathological fracture
(19.1%), orthopedic surgery (7.0%), spinal cord compression (9.6%), and hypercalcemia (6.1%). Interestingly, studies in the American population have reported SREs in 51–55% of patients with bone involvement from lung cancer [27]. Similar to our findings, the previous studies also reported that radiotherapy and pathological fracture were frequent events [5,6,13,14,27]. Although we did not find any significant difference in the frequency of SREs according to histology, there do not appear to be any other studies that have performed a similar analysis. The higher frequency of SREs in the present cohort could be related to the limited use of bisphosphonates for treating BM from lung cancer at our institution, as these drugs were only used for hypercalcemia treatment before 2015. Furthermore, BTA therapy has been more common among patients with BM from breast and prostate cancer, compared to patients with BM from lung cancer [5,6]. Despite the recent favorable results due to the use of BTAs in patients with BM from NSCLC, our findings are similar to other retrospective observational data, where the rates of bisphosphonate use were 6–50% [5,6]. The limited use of BTAs may be due to the reduced patient survival among patients with BM from lung cancer, as our previous institutional understanding was that lung cancer metastases resulted in a poor prognosis that would not allow sufficient time for the treatment to promote bone remodeling. Furthermore, many patients have coexisting visceral metastases and there may also be concerns regarding nephrotoxicity. Despite their relatively infrequent use, the benefits of BTAs for treating BM from lung cancer are reduced frequencies and incidences of SREs, reduced treatment costs, and improved quality of life [7–12]. As patients may live longer due to improving systemic therapies (such as targeted agents and immunotherapy), the role of preventing and treating SREs will become more important. Furthermore, we agree with Langer and Hirsh that the early detection and treatment could delay the occurrence of potentially debilitating SREs, despite the fact that BM are usually not diagnosed until they become symptomatic [4]. Therefore, the histology-specific risks of BM from the present study may help justify better surveillance of patients with high-risk histological subtypes, such as adenocarcinoma. The advantages of this study are the inclusion of SCLC and the association that we observed between BM and lung cancer histology. However, our findings point to the need for additional studies that compare the clinicopathological characteristics according to histology. The main limitation is a possible selection bias, as our institution became a referral hospital for bone tumors in 2010, which increased the frequency of patients with synchronous metastasis after that time.
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In conclusion, to our best knowledge, this is the first study to report that adenocarcinoma was associated with a higher risk of BM, and that squamous cell was associated with a lower risk of BM. These data support the new perspectives that patients with adenocarcinoma may benefit from more vigilant surveillance that aims for early detection of BM and starting treatment using BTAs that may help improve the patient’s quality of life and survival. Conflicts of interest None. Acknowledgement We thank Editage (www.editage.com.br) for English language editing. References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2015, CA. Cancer J. Clin. 65 (2015) 5–29. [2] H. Sugiura, K. Yamada, T. Sugiura, T. Hida, T. Mitsudomi, Predictors of survival in patients with bone metastasis of lung cancer, Clin. Orthop. Relat. Res. 466 (2008) 729–736. [3] H. Katagiri, M. Takahashi, K. Wakai, H. Sugiura, T. Kataoka, K. Nakanishi, Prognostic factors and a scoring system for patients with skeletal metastasis, J. Bone Joint Surg. Br. 87 (2005) 698–703. [4] C. Langer, V. Hirsh, Skeletal morbidity in lung cancer patients with bone metastases: demonstrating the need for early diagnosis and treatment with bisphosphonates, Lung Cancer 67 (2010) 4–11. [5] M. Kuchuk, C.L. Addison, M. Clemons, I. Kuchuk, P. Wheatley-Price, Incidence and consequences of bone metastases in lung cancer patients, J. Bone Oncol. 2 (2013) 22–29. [6] M. Kuchuk, I. Kuchuk, E. Sabri, B. Hutton, M. Clemons, P. Wheatley-Price, The incidence and clinical impact of bone metastases in non-small cell lung cancer, Lung Cancer 89 (2) (2015) 197–202. [7] L.S. Rosen, D. Gordon, S. Tchekmedyian, et al., Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group, J. Clin Oncol. 21 (2003) 3150–3157. [8] L.S. Rosen, D. Gordon, N.S. Tchekmedyian, et al., Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial, Cancer 100 (2004) 2613–2621. [9] V. Hirsh, N.S. Tchekmedyian, L.S. Rosen, M. Zheng, Y.J. Hei, Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications, Clin. Lung Cancer 6 (2004) 170–174. [10] V. Hirsh, P.P. Major, A. Lipton, et al., Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity, J. Thorac. Oncol. 3 (2008) 228–236. [11] D.H. Henry, L. Costa, F. Goldwasser, et al., Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma, J. Clin. Oncol. 29 (2011) 1125–1132.
[12] G.V. Scagliotti, V. Hirsh, S. Siena, et al., Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study, J. Thorac. Oncol. 7 (2012) 1823–1829. [13] J.M. Sun, J.S. Ahn, S. Lee, J.A. Kim, J. Lee, Y.H. Park, et al., Predictors of skeletal-related events in non-small cell lung cancer patients with bone metastases, Lung Cancer 71 (2011) 89–93. [14] A. Tsuya, T. Kurata, K. Tamura, M. Fukuoka, Skeletal metastases in non-small cell lung cancer: a retrospective study, Lung Cancer 57 (2007) 229–232. [15] K. Cetin, C.F. Christiansen, J.B. Jacobsen, M. Nørgaard, H.T. Sørensen, Bone metastasis, skeletal-related events, and mortality in lung cancer patients: a Danish population-based cohort study, Lung Cancer 86 (2014) 247–254. [16] V. Lorusso, I. Duran, C. Garzon-Rodriguez, D. Lüftner, A. Bahl, J. Ashcroft, et al., Health resource utilisation associated with skeletal-related events in European patients with lung cancer: alpha subgroup analysis from a prospective multinational study, Mol. Clin. Oncol. 2 (2014) 701–708. [17] K. Kagohashi, H. Satoh, H. Ishikawa, M. Ohtsuka, K. Sekizawa, Bone metastasis as the first manifestation of lung cancer, Int. J. Clin. Pract. 57 (2003) 184–186. [18] W.D. Travis, E. Brambilla, M. Noguchi, A.G. Nicholson, K.R. Geisinger, Y. Yatabe, et al., International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma, J. Thorac. Oncol. 6 (2011) 244–285. [19] L.E. Quint, S. Tummala, L.J. Brisson, I.R. Francis, A.S. Krupnick, E.A. Kazerooni, et al., Distribution of distant metastases from newly diagnosed non-small cell lung cancer, Ann. Thorac. Surg. 62 (1996) 246–250. [20] F. Michel, M. Solèr, E. Imhof, A.P. Perruchoud, Initial staging of non-small cell lung cancer: value of routine radioisotope bone scanning, Thorax 46 (1991) 469–473. [21] K. Tornyos, O. Garcia, B. Karr, R. LeBeaud, A correlation study of bone scanning with clinical and laboratory findings in the staging of nonsmall-cell lung cancer, Clin. Nucl. Med. 16 (1991) 107–109. [22] J. Kosteva, C. Langer, Incidence and distribution of skeletal metastases in NSCLC in the era of PET, Lung Cancer 46 (Suppl 1) (2004) S45 (abstract). [23] I. Sekine, H. Nokihara, N. Yamamoto, H. Kunitoh, Y. Ohe, T. Tamura, Risk factors for skeletal-related events in patients with non-small cell lung cancer treated by chemotherapy, Lung Cancer 65 (2009) 219–222. [24] M.L. Janssen-Heijnen, J.W. Coebergh, The changing epidemiology of lung cancer in Europe, Lung Cancer 41 (2003) 245–258. [25] A. Charloux, E. Quoix, N. Wolkove, D. Small, G. Pauli, H. Kreisman, The increasing incidence of lung adenocarcinoma: reality or artefact: a review of the epidemiology of lung adenocarcinoma, Int. J. Epidemiol. 26 (1997) 14–23. [26] F. Heidemann, A. Schildt, K. Schmid, O.T. Bruns, K. Riecken, C. Jung, et al., Selectins mediate small cell lung cancer systemic metastasis, PLoS One 9 (2014) e92327. [27] N. Sathiakumar, E. Delzell, M.A. Morrisey, C. Falkson, M. Yong, V. Chia, et al., Mortality following bone metastasis and skeletal-related events among patients 65 years and above with lung cancer: a population-based analysis of U.S. Medicare beneficiaries, 1999–2006, Lung India 30 (2013) 20–26. [28] B.H. Hansen, J. Keller, M. Laitinen, P. Berg, S. Skjeldal, C. Trovik, et al., The Scandinavian Sarcoma Group Skeletal Metastasis Register: survival after surgery for bone metastases in the pelvis and extremities, Acta Orthop. Scand. Suppl. 75 (2004) 11–15. [29] C. Decroisette, I. Monnet, H. Berard, G. Quere, H. Le Caer, S. Bota, et al., Epidemiology and treatment costs of bone metastases from lung cancer: a French prospective, observational, multicenter study (GFPC 0601), J. Thorac. Oncol. 6 (2011) 576–582. [30] H.M. Bae, S.H. Lee, T.M. Kim, D.W. Kim, S.C. Yang, H.G. Wu, et al., Prognostic factors for non-small cell lung cancer with bone metastasis at the time of diagnosis, Lung Cancer 77 (2012) 572–577.
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
The relationship between lung cancer histology and the clinicopathological characteristics of bone metastases Marcelo Braganc¸a dos Reis Oliveira a,∗ , Fernanda Carvalho de Queiroz Mello b,c , Marcos Eduardo Machado Paschoal c a
Trauma-Orthopaedics Service, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil c Thoracic Diseases Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil b
a r t i c l e
i n f o
Article history: Received 1 December 2015 Received in revised form 3 February 2016 Accepted 25 March 2016 Keywords: Lung cancer Bone metastasis SRE Histology
a b s t r a c t Objectives: Lung cancer is the leading cause of death due to cancer, and bone is one of the most frequent sites of metastasis. However, there is no published evidence regarding an association between lung cancer histology and skeletal complications. Therefore, we evaluated the influence of lung cancer histology on the frequency of bone metastases (BMs), skeletal-related events (SREs), and survival after BM. Material and methods: This retrospective study evaluated medical records from 413 patients who were diagnosed with lung cancer between 2003 and 2012. The prevalences of BMs and SREs were calculated, and their associations with the histological subtypes were evaluated using the chi-square test, odds ratios (OR), and 95% confidence intervals (CI). Overall survivals and associations with the histological subtypes were evaluated using the Kaplan-Meier method and the log-rank test. Results: The prevalences of BM, synchronous BM, and SREs were 28.2%, 70.4%, and 68.7%, respectively. Adenocarcinoma was the most common histological subtype (46.7%), and was significantly more frequent among patients with BM (58.3% vs. 42.1%; p = 0.003; OR: 1.92; 95% CI: 1.29–2.97). Squamous cell was significantly less frequent among patients with BM (13.0% vs. 29.8%; p = 0.0004; OR: 0.35; 95% CI: 0.19–0.64). The median survival time after the first BM diagnosis was 4 months, and there was no significant difference in the survival periods for the various histological subtypes. Conclusion: Adenocarcinoma and squamous cell were significantly associated with higher and lower risks of developing BM, respectively. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer-related deaths, and metastatic carcinoma is the most frequent malignant bone tumor, which occurs in approximately 15–40% of patients with lung cancer [1,2]. Furthermore, bone is one of the most frequent sites of metastasis, which results in a high morbidity and a reduced quality of life among these patients [3–5]. In this context, osteoclast
Abbreviations: BTA, bone target agent; BM, bone metastasis; SRE, skeletalrelated event; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; LC, large cell carcinoma; NOS, not otherwise specified; Adeno, adenocarcinoma. ∗ Corresponding authors at: Servic¸o de Traumato-Ortopedia do Hospital Universitário Clementino Fraga Filho da Universidade Federal do Rio de Janeiro. Rua Rodolpho Paulo Rocco, 255, Cidade Universitária − Ilha do Fundão, Rio de Janeiro. RJ, CEP: 21941-913 Brasil. E-mail addresses: [email protected], [email protected] (M.B.d.R. Oliveira). http://dx.doi.org/10.1016/j.lungcan.2016.03.014 0169-5002/© 2016 Elsevier Ireland Ltd. All rights reserved.
inhibition using bone target agents (BTAs), such as bisphosphonates and denosumab, is currently a topic of increasing debate in lung cancer [4–6]. However, there are few studies regarding the influence of lung cancer histology on the frequency and characteristics of bone metastasis (BM). Recent studies have demonstrated that BTAs are associated with a reduction in the risk of, and time to, skeletal related events (SREs) among patient with non-small cell lung cancer (NSCLC) [7–11] and possibly with an increased survival [12]. However, their routine use in patients with BM from lung cancer remains relatively low [5,6]. Approximately 40% of patients with NSCLC develop BM, and adenocarcinoma is the most frequent histological subtype [2,13–17]. Although no studies have specifically compared the prevalence of BM according to the histological subtypes among patients with NSCLC or small cell lung cancers (SCLC), several studies have assessed the frequency of BM and the histological subtypes of lung cancer using various approaches. Nevertheless, to our best knowledge, there is no published evidence regarding an association
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413 pts Lung cancer 6 pts were excluded 407 pts Histologic criteria
170 pts / 41,8% Localized or regional disease*
237 pts / 58,2% Distant disease*
115 pts / 28,2% Bone metastases
34 pts / 29,6% Metachronous bone metastases
81 pts / 70,4% Synchronous bone metastases
79 pts / 68,7% SREs
* Stage at cancer diagnosis Fig. 1. Cohort diagram—Lung cancer patients according to the stage at cancer diagnosis, the presence of bone metastases at diagnosis or throughout follow-up, and skeletalrelated events (SREs).
between histology and skeletal complications. Thus, we designed this study to assess whether lung cancer histology influenced the occurrence of BM and SREs, as well as the overall survival of patients with BM, in a cohort of patients who had not been routinely treated using BTAs. This information may be useful for guiding early surveillance for BM detection or interventions in high-risk groups that can improve patients’ quality of life and survival. 2. Material and methods 2.1. Study population This retrospective study’s design was approved by our institutional ethics review board. We retrospectively evaluated medical records from 413 patients who were diagnosed with malignant primary lung tumors at our institution between January 2003 and January 2012. The inclusion criteria were pathological confirmation of NSCLC or SCLC and complete tumor staging data. To accurately evaluate the association with survival, we excluded patients who were diagnosed with a second malignant primary tumor or had an unknown date of death. Lung carcinoma was classified according
to histological subtype, using the World Health Organization classifications: adenocarcinoma, squamous cell, large cell (LC), NSCLC not otherwise specified (NOS), and SCLC [18]. The events of interest were the occurrence of BM, SREs, and death. BMs were diagnosed via histopathologic examination of bone biopsy samples or via Tc99− bone scintigraphy with two additional imaging modalities (X-ray radiography, computed tomography, or magnetic resonance imaging). SREs were defined as the need for radiotherapy, pathological fracture, spinal cord compression, the need for surgery due to BM, or hypercalcemia. BMs were classified as synchronous or metachronous according to the times of diagnosis for the first BM and the lung cancer. The minimum follow-up period after a diagnosis of BM was 24 months (excluding cases of death before 24 months). 2.2. Statistical analysis The chi-square test was used to compare the proportions of histological subtypes among patients who did and did not develop BM, synchronous BM, SREs, or pathological fracture. The relationship between histological subtype and the occurrence of BMs was
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21
Table 1 Characteristics of lung cancer patients overall and by the presence of bone metastasis at lung cancer diagnosis or throughout follow-up. Characteristic
Lung cancer patients cohort overall
Lung cancer patients without bone metastasis
Lung cancer patients with bone metastasis
N = 407
N = 292
N = 115
N Mean age (range) Gender Male Female Smoking Never smoked <40 packs/year ≥40 packs/year Histology Adeno Squamous LC NOS/NSCLC SCLC Initial stage Localized Regional Distant
%
N
63.4 years (32–87)
%
65.7 years (42–84)
N
%
62.6 years (32–87)
250 157
61.4 38.6
175 117
59.3 40.7
75 40
65.2 34.8
55 96 256
13.5 23.6 62.9
30 63 199
10.3 21.6 68.1
25 33 57
21.7 28.7 49.6
190 102 11 56 48
46.7 25.1 2.7 13.7 11.8
123 87 9 40 33
42.1 29.8 3.1 13.7 11.3
67 15 2 16 15
58.3 13.0 1.8 13.9 13.0
39 131 237
9.6 32.2 58.2
37 115 140
12.7 39.4 47.9
2 16 97
1.7 14.0 84.3
Adeno: adenocarcinoma; LC: large cell; NOS: not otherwise specified; NSCLC: non-small cell lung cancer, SCLC: small cell lung cancer; SRE: skeletal-related event.
Table 2 The prevalences of bone metastases and skeletal-related events according to histology. Event
Bone metastasis Synchronous metastasis SREs Radiotherapy Pathological fracture Spinal cord compression Orthopedic surgery Hypercalcemia
Histology (%) Adeno Squamous LC
NOS/NSCLC SCLC All
35.3 68.7 73.1 61.2 23.9 10.4 9.0 5.9
28.6 81.3 68.8 93.7 12.5 18.6 0 6.3
14.7 73.3 66.7 53.3 6.7 0 0 6.7
18.1 100 50 50 50 0 50 0
31.2 60.0 53.3 46.7 13.3 6.7 6.7 6.7
28.2 70.4 68.7 64.3 19.1 9.6 7.0 6.1
Adeno: adenocarcinoma; LC: large cell; NOS: not otherwise specified; NSCLC: nonsmall cell lung cancer, SCLC: small cell lung cancer; SRE: skeletal-related event.
also evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs). The overall survivals and associations with the histological subtypes were evaluated using the Kaplan-Meier method, and the difference between patients with adenocarcinoma and non-adenocarcinoma were evaluated using the log-rank test. All analyses were performed using SPSS software (version 10.0; SPSS Inc., Chicago, IL), and a p-value < 0.05 was considered statistically significant. 3. Results 3.1. Demographics Among the 413 patients, 407 were eligible for analysis based on the inclusion criteria. A cohort diagram is shown in Fig. 1 and the patients’ demographic characteristics are shown in Table 1. The mean age was 63.4 years, 61.4% of the patients were men and 86.5% were current or ex-smokers. At initial diagnosis, 58,2% had distant disease. The distribution of the histologic subtypes was adenocarcinoma (n = 190; 46.7%), squamous cell (n = 102; 25.1%), LC (n = 11; 2.7%) NOS/NSCLC (n = 56; 13.7%), and SCLC (n = 48; 11.8%), (Table 1). One hundred and fifteen patients had bone BM, and the demographic data of patients with (n = 115) and without BM (n = 292) are shown in Table 1.
3.2. BMs and SREs Among the entire cohort, the overall prevalence of BM was 28.2% (n = 115). The prevalences according to histology are presented in Table 2. Bone involvement was more prevalent among patients with adenocarcinoma (n = 67; 35.3%). Bone involvement was also observed in patients with squamous cell (n = 15; 14.7%), LC (n = 2; 18.1%), NOS/NSCLC (n = 16; 28.6%), and SCLC (n = 15; 31.2%). Synchronous metastases were significantly more frequent than metachronous metastases (n = 81, 70.4% vs. n = 34, 29.6%; p = 0.0021). The prevalences of synchronous metastases were 68.7% (n = 46) for adenocarcinoma, 73.3% (n = 11) for squamous cell, 100% (n = 2) for LC, 81.3% (n = 13) for NOS/NSCLC, and 60% (n = 9) for SCLC (Table 2). A total of 79 patients had experienced 122 SREs, with an overall prevalence of 68.7% among the patients with BM. The need for radiotherapy was the most frequent event (n = 74; 64.3%), which was followed by pathological fracture (n = 22; 19.1%), spinal cord compression (n = 11; 9.6%), surgical treatment for BM (n = 8; 7.0%), and hypercalcemia (n = 7; 6.1%) (Table 2). 3.3. Number and location of BMs Among the 115 patients with bone involvement, we observed 305 BMs (2.65 metastases per patient). The most frequently sites were the spine (98 metastases; 32.1%), pelvic girdle (53 metastases; 17.4%), proximal femur and humerus (52 metastases; 17.1%), and the chest wall (46 metastases; 15.1%). There was no correlation between location and histology. 3.4. Histology and the occurrence of BMs or SREs Table 3 presents the proportions of histological subtype among patients who did and did not develop BM, synchronous BM, SREs, or pathological fracture. Adenocarcinoma was the most frequent histological subtype in the entire cohort. The frequency of adenocarcinoma was significantly higher among the patients who developed BM (n = 67; 58.3%), compared to the patients who did not develop BM (n = 123; 42.1%) (p = 0.003). Squamous cell was significantly less frequent among patients who developed BM (n = 15,
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Table 3 Comparison of histological subtypes proportions among patients who did and did not develop bone metastases, synchronous metastasis, SREs, or pathological fractures. Histology
Adeno Squamous LC NOS/NSCLC SCLC
Bone metastasis
Synchronous metastasis
SREs
Yes
No
Yes
No
Yes
No
Yes
No
N(%)
N(%)
N(%)
N(%)
N(%)
N(%)
N(%)
N(%)
67(58.3) p-valor = 0.003 15(13.0) p-valor = 0.0004 2(1.7) p-valor = 0.451 16(13.9) p-valor = 0.954 15(13.0) p-valor = 0.623
123 (42.1)
46(56.8) p-valor = 0.621 10(12.3) p-valor = 0.731 2(2.5) p-valor = 0.355 14(17.3) p-valor = 0.106 9(11.1) p-valor = 0.342
21(61.8)
49(62.0) p-valor = 0.646 10(12.7) p-valor = 0.979 1(1.3) p-valor = 0.607 11(13.9) p-valor = 0.869 8(10.1) p-valor = 0.229
18(50.0)
16(72.7) p-valor = 0.125 1(4.5) p-valor = 0.188 1(4.5) p-valor = 0.262 2(9.1) p-valor = 0.467 2(9.1) p-valor = 0.54
51(54.8)
87(29.8) 9(3.1) 40(13.7) 33(11.3)
5(14.7) 0(0) 2(5.9) 6(17.6)
Pathological fracture
5(13.9) 1(2.8) 5(13.9) 7(19.4)
14(15.1) 1(1.1) 14(15.1) 13(14.0)
Adeno: adenocarcinoma; LC: large cell; NOS not otherwise specified; NSCLC: non-small cell lung cancer, SCLC: small cell lung cancer; SRE: skeletal-related event.
Table 4 The risk of bone metastasis according to histology. Histology
Odds ratio
Adeno Squamous LC NOS/NSCLC SCLC
1.92 0.35 0.55 1.01 1.17
95% confidence interval 1.29–2.97 0.19–0.64 0.12–2.61 0.54–1.90 0.61–2.26
Adeno: adenocarcinoma; LC: large cell; NOS not otherwise specified; NSCLC: nonsmall cell lung cancer, SCLC: small cell lung cancer.
13.0% vs. n = 87, 29.8%; p = 0.0004). However, there were no other statistically significant differences between the other histological subtypes. We used ORs and 95% CIs to evaluate the associations between histological subtype and the occurrence of BM (Table 4). The ORs were 1.92 (95% CI: 1.29–2.97) for adenocarcinoma, 0.35 (95% CI: 0.19–0.64) for squamous cell, 0.55 (95% CI: 0.12–2.61) for LC, 1.01 (95% CI: 0.54–1.90) for NOS/NSCLC, and 1.17 (95% CI: 0.61–2.26) for SCLC. 3.5. Survival The survival outcomes were calculated after excluding 20 patients, due to the diagnosis of a second malignant primary tumor (n = 12) or an unknown date of death (n = 8). One patient with BM was alive at the end of the follow-up. The median survival time after the diagnosis of BM was 4 months (Table 5). The median survival times for adenocarcinoma, squamous cell, LC, NOS/NSCLC and SCLC were 3.0 months, 4.5 months, 9.0 months, 2.5 months, and 4.5 months, respectively. There was no significant difference in the survival time for patients with adenocarcinoma and nonadenocarcinoma. 4. Discussion In the present cohort of patients with lung cancer who were treated at a single academic general hospital, we observed a BM prevalence of 28,2%. This result is similar to those in previous reports, and confirms that bone is one of the most frequent metastatic sites [2,13–17]. Although studies from the 1990s used bone scintigraphy to determine that the incidence of BM was <20% [19–21], we believe that the detection method influences the results, because more recent studies have used positron emission tomography and reported higher frequencies (20–40%) [13,22,23]. However, Sugiura et al. used bone scintigraphy and x-ray radiography, and reported a lower prevalence (10.4%) [2]. In contrast, Tsuya et al. identified 70 (30.4%) patients with BM from lung cancer using bone scintigraphy, radiography, and magnetic resonance
imaging [14]. Their detection methods and metastasis frequencies were similar to those from the present study, although we studied a larger sample, due to the intentional inclusion of SCLC. The results of the present study confirm that adenocarcinoma is the most prevalent histological subtype, regardless of BM development, which agrees with previous epidemiological reports that have demonstrated that adenocarcinoma accounts for >45% of lung carcinomas [24,25]. However, the prevalence of BM in this study varied according to the histologic subtype, and we found relatively high prevalence for adenocarcinoma (35.3%) and SCLC (31.2%), and a relatively low prevalence for squamous cell (14.7%). These results indicate that the likelihood of bone dissemination can vary according to the lung cancer’s subtype. Therefore, we compared the frequencies of the histological subtypes among patients with and without BM to test this hypothesis. The occurrence of BM was significantly and positively associated with a diagnosis of adenocarcinoma (58.3% vs. 42.1%, p = 0.003, OR: 1.92, 95% CI: 1.29–2.97), and was significantly and negatively associated with a diagnosis of squamous cell (13.0% vs. 29.8%, p = 0.0004, OR: 0.35, 95% CI: 0.19–0.64). Although some studies have also reported a relatively high frequency of adenocarcinoma, they did not directly evaluate the possible association between lung cancer histology and bone dissemination. Nevertheless, Sugiura et al. identified adenocarcinoma as the most frequent histological subtype (70%) among 118 patients with BM from NSCLC [2], and Kagohashi et al. reported that 67% of patients with BM had adenocarcinoma [17]. Furthermore, a recent cohort study evaluated the entire population of Denmark, and reported a higher frequency of adenocarcinoma among patients with BM (50.3%), compared to all patients with lung cancer (37.9%), and a lower frequency of squamous cell among patients with BM (13.0%), compared to all patients with lung cancer (24.6%) [15]. Those studies did not directly evaluate the association between histology and the frequency of metastasis. The prevalence of adenocarcinoma among patients with BM in the present study was slightly lower (35%) than those in the previous reports. However, we observed significantly higher and lower risks from adenocarcinoma and squamous cell, respectively. Moreover, the majority of studies regarding bone involvement in lung cancer have not included SCLC, which was the second most prevalent subtype in the present cohort. Therefore, it remains unclear whether the frequency and characteristics of BM for this histological subtype differ from those of NSCLC. However, the relatively high frequency that we found is compatible with the more aggressive nature of SCLC [26]. The population-based studies by Cetin et al. and Sathiakumar et al. reported that the rates of bone dissemination were higher for NSCLC [15,27], and these are some of the few studies that have included SCLC, which was diagnosed in 16.7% and 13% of the patients with BM. These findings are similar to the 13% that we observed. In contrast, the we observed that the prevalence of
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23
Table 5 Survival data according to histology. Histology
N
Survival, months
Survival, % (95% confidence interval)
p-value
Mean
Median
At 6 months
At 12 months
At 24 months
32.7 (20.3–45.1) 30 (1.6–58.4) 100 (0–100) 26.7 (4.3–49.0) 30.8 (5.7–55.8) 32.7 (20.3–45.1) 32.5 (18.0–47.0)
14.5 (5.2–23.9) 0
7.2 (0.4–14.1) 0
0
0
13.3 (0–30.5) 23.1 (0.2–46.0) 14.5 (5.2–23.9) 12.5 (2.2–22.7)
0
Adeno
55
7.2
3.0
Squamous
10
4.5
4.5
LC
2
9.0
9.0
NOS/NSCLC
15
5.5
2.5
SCLC
13
6.5
4.5
Adeno
55
7.2
3.0
Non-adeno
40
5.7
4.3
0 7.2 (0.4–14.1) 0
0.33
Adeno: adenocarcinoma; LC: large cell; NOS not otherwise specified; NSCLC: non-small cell lung cancer, SCLC: small cell lung cancer; SRE: skeletal-related event.
BM was 31.2% among patients with SCLC, compared to the 5.8% prevalence that was observed by Cetin et al. and the 23.3% prevalence that was observed by Sathiakumar et al. [15,27]. These results indicate that additional studies are needed, and that these studies should carefully evaluate the characteristics of BM in this group of patients. The majority of patients with BM exhibited bone involvement at the time of the lung cancer diagnosis (70.4%). However, we did not find an association between synchronous BM and histology, which was likely due to the low number of individuals in our stratified groups. Other series have also reported high frequencies of synchronous bone involvement, which ranged from 46% to 66% [2,14,23]. However, our frequency may also have been overestimated, due to possible selection bias, as our institution became a referral center for patients with bone tumors in 2010, which resulted in a significant increase in the number of patients with BM from initially unknown primary sites. The survival rate after a diagnosis of BM was very low in the present cohort predominantly treated with platinum-based chemotherapy. Epidermal growth factor receptor inhibitor, such as gefitinib, that have prolonged the median survival time, especially in patients with adenocarcinoma, was not available for use at our institution during the study period. This finding reflects the survival rate in our country, where lung cancer is usually diagnosed in a late stage and is associated with a high frequency of SREs, which we observed in the present cohort. Hansen et al. have reported the effect of BM on survival in various types of carcinomas, and found that patients with BM from lung cancer had a mean survival of 3 months [28]. In the series of Sathiakumar et al., patients who developed BM experienced a 2.4-fold greater risk of death (95% CI: 2.4–2.5) [23]. Furthermore, Sugiura et al. reported that the median survival time after a diagnosis of BM was 7.2 months [2]. The median survival time in the present study (4 months) was lower than that in the majority of the previous studies, and may be related to a relatively high frequency of patients who were initially diagnosed with stage 4 cancer [2,13,14,29,30]. Our results are closer to the results from a retrospective French study, which estimated a median survival time of 5.8 months [29]. Unfortunately, our study’s design did not allow for a comparison of survival after the cancer diagnosis for patients with and without BM, because our aim was only to compare survival according to histological subtype after BM. In addition, we did not observe any statistically significant difference in survival according to the histological subtypes. Regarding the frequency of SREs, our results are also similar to those that were published by Kuchuk et al. [5,6]. In the present study, 68.7% of the patients with BM had experienced SREs, such as the need for radiotherapy (64.3%), pathological fracture
(19.1%), orthopedic surgery (7.0%), spinal cord compression (9.6%), and hypercalcemia (6.1%). Interestingly, studies in the American population have reported SREs in 51–55% of patients with bone involvement from lung cancer [27]. Similar to our findings, the previous studies also reported that radiotherapy and pathological fracture were frequent events [5,6,13,14,27]. Although we did not find any significant difference in the frequency of SREs according to histology, there do not appear to be any other studies that have performed a similar analysis. The higher frequency of SREs in the present cohort could be related to the limited use of bisphosphonates for treating BM from lung cancer at our institution, as these drugs were only used for hypercalcemia treatment before 2015. Furthermore, BTA therapy has been more common among patients with BM from breast and prostate cancer, compared to patients with BM from lung cancer [5,6]. Despite the recent favorable results due to the use of BTAs in patients with BM from NSCLC, our findings are similar to other retrospective observational data, where the rates of bisphosphonate use were 6–50% [5,6]. The limited use of BTAs may be due to the reduced patient survival among patients with BM from lung cancer, as our previous institutional understanding was that lung cancer metastases resulted in a poor prognosis that would not allow sufficient time for the treatment to promote bone remodeling. Furthermore, many patients have coexisting visceral metastases and there may also be concerns regarding nephrotoxicity. Despite their relatively infrequent use, the benefits of BTAs for treating BM from lung cancer are reduced frequencies and incidences of SREs, reduced treatment costs, and improved quality of life [7–12]. As patients may live longer due to improving systemic therapies (such as targeted agents and immunotherapy), the role of preventing and treating SREs will become more important. Furthermore, we agree with Langer and Hirsh that the early detection and treatment could delay the occurrence of potentially debilitating SREs, despite the fact that BM are usually not diagnosed until they become symptomatic [4]. Therefore, the histology-specific risks of BM from the present study may help justify better surveillance of patients with high-risk histological subtypes, such as adenocarcinoma. The advantages of this study are the inclusion of SCLC and the association that we observed between BM and lung cancer histology. However, our findings point to the need for additional studies that compare the clinicopathological characteristics according to histology. The main limitation is a possible selection bias, as our institution became a referral hospital for bone tumors in 2010, which increased the frequency of patients with synchronous metastasis after that time.
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In conclusion, to our best knowledge, this is the first study to report that adenocarcinoma was associated with a higher risk of BM, and that squamous cell was associated with a lower risk of BM. These data support the new perspectives that patients with adenocarcinoma may benefit from more vigilant surveillance that aims for early detection of BM and starting treatment using BTAs that may help improve the patient’s quality of life and survival. Conflicts of interest None. Acknowledgement We thank Editage (www.editage.com.br) for English language editing. References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2015, CA. Cancer J. Clin. 65 (2015) 5–29. [2] H. Sugiura, K. Yamada, T. Sugiura, T. Hida, T. Mitsudomi, Predictors of survival in patients with bone metastasis of lung cancer, Clin. Orthop. Relat. Res. 466 (2008) 729–736. [3] H. Katagiri, M. Takahashi, K. Wakai, H. Sugiura, T. Kataoka, K. Nakanishi, Prognostic factors and a scoring system for patients with skeletal metastasis, J. Bone Joint Surg. Br. 87 (2005) 698–703. [4] C. Langer, V. Hirsh, Skeletal morbidity in lung cancer patients with bone metastases: demonstrating the need for early diagnosis and treatment with bisphosphonates, Lung Cancer 67 (2010) 4–11. [5] M. Kuchuk, C.L. Addison, M. Clemons, I. Kuchuk, P. Wheatley-Price, Incidence and consequences of bone metastases in lung cancer patients, J. Bone Oncol. 2 (2013) 22–29. [6] M. Kuchuk, I. Kuchuk, E. Sabri, B. Hutton, M. Clemons, P. Wheatley-Price, The incidence and clinical impact of bone metastases in non-small cell lung cancer, Lung Cancer 89 (2) (2015) 197–202. [7] L.S. Rosen, D. Gordon, S. Tchekmedyian, et al., Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group, J. Clin Oncol. 21 (2003) 3150–3157. [8] L.S. Rosen, D. Gordon, N.S. Tchekmedyian, et al., Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial, Cancer 100 (2004) 2613–2621. [9] V. Hirsh, N.S. Tchekmedyian, L.S. Rosen, M. Zheng, Y.J. Hei, Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications, Clin. Lung Cancer 6 (2004) 170–174. [10] V. Hirsh, P.P. Major, A. Lipton, et al., Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity, J. Thorac. Oncol. 3 (2008) 228–236. [11] D.H. Henry, L. Costa, F. Goldwasser, et al., Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma, J. Clin. Oncol. 29 (2011) 1125–1132.
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