Prospective study on incidence of bone metastasis(BM) and skeletal related events (SREs) inpatients(pts) with stage IIIB and IV lung cancer(CSP-HOR13)
Haruko Daga1, Nobuyuki Katakami2, Keisuke Tomii3, Hiroshi Kunikane4,Kenji Eguchi5, Koichi Takayama6, Toshiyuki Sawa7, Hiroshi Saito8,
Masao Harada9, Souichiro Yokota10, Kiyoshi Ando11, Yasuo Ohashi12
1: Department of Clinical Oncology, Osaka City General Hospital, 2: Institute of Biomedical
Research and Innovation Hospital, 3: Kobe City Medical Center General Hospital , 4:
Yokohama Municipal Citizen's Hospital, 5: Teikyo University School of Medicine, 6: Universityof Kyushu School of Medicine, 7: Gifu Municipal Hospital, 8: Aichi Cancer Center-Aichi , 9:
Hokkaido Cancer Center, 10: Toneyama National Hospital, 11: Tokai University; 12:
University of Tokyo
1

発表者・研究責任者の利益相反開示事項
研究費の財源その他（ 支援事業）

発表者氏名

駄賀 晴子
該当なし

企業の職員・法人の代表



企業等の顧問職



株式など



講演料など



原稿料など



寄付金



委受託研究（治験等）



専門的助言・証言

その他



試験責任者氏名

江口 研二
該当なし

企業の職員・法人の代表



企業等の顧問職



株式など



講演料など



原稿料など



寄付金



委受託研究（治験等）



専門的助言・証言

その他



財源の供給元
所属／身分

財団法人 パブリックヘルスリサーチセンター

大阪市立総合医療センター臨床腫瘍科／副部長

該当有りの場合：企業名等

所属／身分

臨床腫瘍科帝京大学医学部付属病院内科/／教授

該当有りの場合：企業名等

1

BACKGROUND• Although the overall incidence of BM is not known, BM area frequent complication in patients with advanced lungcancer.
• BM can be associated with SREs, which include pathologic
fracture, need for surgery or radiation to bone, spinal cord
compression, and hypercalcemia of malignancy.
• As patients’ quality of life deteriorates tremendously once
SREs develop, it is important for investigators to treat
patients with BM with an appropriate treatments as early as
possible.
3PURPOSE
The aim of this study is to investigate prospectively
the following items in patients with advanced lungcancer.
1) Incidence of BM and time interval ofdeveloping BM2) Time interval between BM and developingof SREs, and incidence and types of SREs
3) Predictive factors of BM and SREs
42

METHODS
Definition of SRE• Pathologic fracture• Radiation to bone lesion• Surgery to bone
• Spinal cord compression• Hypercalcemia of malignancy
Staging of lung cancer• Chest and upper abdomen CT scan,bone scan or PET scan, brain CT or
MRI scan were required.
5METHODS
During the follow up period• Chest CT scan: every 3 months• Brain CT or MRI scan: every 6 months• Bone scan or PET scan : every 6 months• QOL questionnaire was carried out at enrollment,
3 months and 12 months• Treatment for lung cancer and use of zoledronate
were at the discretion of the investigator
63

Eligibility Criteria
Inclusion criteria
1. newly diagnosed SCLC in all stages and NSCLC instage IIIB or stage IV
2. age > 20 years old
3. enable to reply QOL questionnaire
4. written informed consent
5. treatment for lung cancer and use of zoledronate
were at the discretion of the investigator
Exclusion criteria
1. patient who is judged to be inappropriate to enrollment
by the investigator
7

Schedule of examination
Visit

０

１

４

５

６

７

８

9－12

Enrollment

1month2months 3months

4months

5months

6months

9months

12months

24months

±2wks

±2wks

±2wks

±2wks

±2wks

±6wks

±6wks

±6wks

Allowance≤1monthBone scintigram or PET○X-ray（DV・L-spine）○○(chest andChest CTTumor marker
Bone marker（blood・urine）○

Bone metastasis

SRE

○
○
○
○
○
○

QOL・ADL○heightweightBlood biochemistry

Metastasis extra-bone
Bisphosphonate
Bone Pain
Analgesic use

３±2wks★
☆

abdomen)

○
○
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○
○

Patient background
P.S.

２☆

☆

☆

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○Outcome☆：±4wks ★：±6wks☆

○4 wks after SRE（±２wks）

Repeatbetween
７and ８○On demand

84

RESULTS
Total Enrollment : 277 pts••••

Entry period：April 2007 to December 2009
Participating institution : 12
Follow-up：until December 2011
Exclusion：delayed registration 2
not eligible(stage IIIA NSCLC) 1

Analysis： 274 pts• SCLC• NSCLC: 77: 197 (Stage IIIB/IV : 73/124)

9RESULTS• Analysis： 274 pts
 Termination
2yr completion
deathchanging hospitalpatient refusalothers

249
64
112
65
35

 Under follow-up

25•

Follow-up duration(median): 12.7 months [range 0-27.4]•Analysis for time data：

272 pts

2 patients were excluded due to missing data.
105

Patients characteristics at enrollment
NSCLC

SCLC

Total

124

77

274

57/16

79/45

57 /20193/ 8169.0〔35-86〕

67.0〔41-89〕69.0〔45-82〕68.0〔35-89〕022 ( 30.1)

31 ( 25.0)

23 ( 29.9)

76 ( 27.7)

143 ( 58.9)

82 ( 66.1)

46 ( 59.7)

171 ( 62.4)

27 ( 9.6)

8 ( 6.5)

8 ( 10.4)

23 ( 8.4)≥3

1 ( 1.4)

3 ( 2.4)0 ( 0)

4 ( 1.5)-73 (100.0)

65 ( 52.4)

58 ( 75.3)

196 ( 71.5)+059 ( 47.6)

19 ( 24.7)

78 ( 28.5)-73 (100.0)

104 ( 83.9)

73 ( 94.8)

250( 91.2)+0

20 ( 16.1)

4 ( 5.2)

24 ( 8.8)

Stage IIIB

Stage IVn73

Gender （Male/Female）
Age（Median ）〔Range〕

PS (ECOG)

Bone metastasis
SRE

11

Tree Diagram of enrolled patients
Enrollment (n=274)

BM(+)at enrollment (n=78)

SRE(+)
24SRE(-)
54

SRE(+)

over followup time

11SRE(-)
over followup time
43BM(-)at enrollment (n=196)

BM(+)
34

SRE(+)
over followup time
15BM(-)
162

SRE(-)
over followup time
19126

Incidence and type of SRE (n=274)
New SREs
during followup

SREs atenrollment

Total

n％

n％

n％

24

8.8

26

9.5

50

18.2

Pathologic fracture

93.3

4

1.5

13

4.7

Radiation to bone lesion

228

21

7.7

43

15.7

Surgery to bone

000000Spinal cord compression

20.7

1

0.4

3

1.1

Hypercalcemia of malignancy

10.4

5

1.8

6

2.2

Any SRE13probability of bone metastasis

Time to bone metastasis fromdiagnosis of lung cancer
0.8

N=271

0.7
0.6
0.5
0.4
0.3
0.2
0.1
000.5

11.5

22.5

Duration of follow-up (year)
Day 0 : diagnosis date of lung cancer

7

Time to SRE from diagnosis oflung cancer
0.8

probability of SRE

0.7
0.6

N=247

0.5
0.4
0.3
0.2
0.1
000.5

1

1.5

22.5

Duration of follow-up (year)
Day 0 : diagnosis date of lung cancer

Time to SRE from bone metastasis
0.8

N=107

probability of SRE

0.7
0.6
0.5
0.4
0.30.2
0.1
00

0.5

11.5

22.5

Duration of follow-up (year)
Day 0 : diagnosis date of BM8

Analyses for subgroups by age
0.8

probability

0.7<64 years （n=172）

0.6

BM

0.5>65 years（n=99）

0.4<64 years （n=159）

0.3

SRE

0.2>65 years（n=88）

0.1
0.0

0.0

0.5

1

1.5

22.5

Duration of follow-up (year)17

Cox regression for BM incidence<multivariable analysis>

FactorHR(95% CI)

p value

Stage III NSCLC/SCLC

0.31(0.15-0.66)

0.002

Stage IV NSCLC/SCLC

2.23(1.38-3.60)<.0001

Gender (female/male)

1.03(0.67-1.57)

0.895

Age (>65 / <64)0.74

(0.49-1.11)

0.146

PS (>1 / 0)

1.70

(1.03-2.80)

0.037

LDH [1000 U]

2.72(1.23-6.02)

0.014

Alb [g/dL]

0.76(0.51-1.13)

0.175

Ca [mg/dL]

0.91(0.69-1.19)

0.486

PTHrP [pmol/L]

0.90(0.74-1.10)

0.308

BALP [100U/L]

1.94(1.13-3.33)

0.016

NTx [1000nmolBCE/mmolCRE]

0.82(0.31-2.14)

0.688

189

Cox regression for SRE incidence<multivariable analysis>Factor

HR(95% CI)

p value

Stage III NSCLC/SCLC

0.63(0.22-1.81)

0.391Stage IV NSCLC/SCLC

2.82(1.34-5.97)

0.001

Gender (female/male)

0.82(0.42-1.58)

0.545

Age (>65 / <64)

0.44(0.24-0.78)

0.005

PS (>1 / 0)1.23

(0.60-2.52)

0.576

LDH [1000 U]

1.57(0.46-5.32)

0.469

Alb [g/dL]

0.64(0.38-1.09)

0.101

Ca [mg/dL]

0.88(0.61-1.27)

0.500

PTHrP [pmol/L]

0.96(0.75-1.23)

0.742

BALP [100U/L]

1.17(1.89-1.54)

0.248

NTx [1000nmolBCE/mmolCRE]

0.79(0.23-2.71)

0.703
19

Summary of Results (1) Two hundred and seventy four pts were enrolled into thestudy between Apr. 2007 and Dec. 2009 from 12institutions.
 Seventy eight of 124 pts with stage IV NSCLC (48%)
already had BM at the time of enrollment .
 Twenty four of 78 pts with known BM (31%) had some kindof SREs concomitantly. Additional 11 pts developed SREs
during follow up time and the total incidence of SREs was45%.
 Thirty four of 196 pts without initial BM (17%) developedbone metastases, and 15 of these 34 pts developed SREs
during the follow up period.
2010Summary of Results (2) The type of SREs was radiation to bone 15.7%, pathologic
fracture 4.7%, hypercalcemia 2.2% and spinal cord
compression 1.1%.
 Multivariate analysis by Cox regression model showed thatfactors predicting subsequent BM at enrollment were
NSCLC, stage IV, PS >1, LDH and BALP.
 Multivariate analysis by Cox regression model showed thatfactors predicting subsequent SREs at enrollment wereNSCLC, stage IV and age < 64.
21

CONCLUSIONS The incidence of BM at initial diagnosis was 48% in patientswith stage IV NSCLC and was higher than initially expected.
 Various SREs developed in 18% of all the patients during thefollow up time.
 Forty percent of patients enrolled into the study had BM andhalf of the patients who had developed BM had SREs during
the follow up time.
 Multivariate analysis revealed that factors predicting BM wereNSCLC, stage IV, PS >1, LDH and BALP, and factors
predicting SREs were NSCLC, stage IV and age < 64.
 Quality of life assessment and other therapeutic factors
affecting BM and SREs will be reported next year.
2211参加施設・研究者一覧＊：研究代表者（実行委員長）＃：実行委員·愛知県がんセンター愛知病院

齋藤博、山本麻衣子·

独立行政法人国立病院機構 刀根山病院

横田総一郎、上野智子·

東海大学医学部附属病院

安藤潔、稙田いずみ·

財団法人先端医療振興財団 先端医療センター

片上信之#、笹木美幸·

独立行政法人国立病院機構 北海道がんセンター

原田眞雄、内藤義博·

九州大学病院

高山浩一、平田麿梨·

岐阜市民病院 呼吸器・腫瘍内科

澤祥幸、水井貴詞·

浜松医科大学医学部附属病院

千田金吾、木村路子·

神戸市立医療センター中央市民病院

富井啓介、桜川圭子·

大阪市立総合医療センター

武田晃司、服部美千代·

横浜市立市民病院

国兼浩嗣# 、吉田牧子·

帝京大学医学部附属病院

江口研二*、宮野千恵·

独立行政法人国立病院機構 四国がんセンター

江口久恵#·

静岡県立静岡がんセンター

齊藤裕子#

財団法人パブリックヘルスリサーチセンター支援研究2312