進行・再発非小細胞肺癌初回治療終了後患者の観察研究（SAPPHIRE研究），初回報告
森清志1，笠井尚1，葉清隆2，内藤陽一3，後藤悌4，大橋靖雄5，國頭英夫6
栃木県立がんセンター 呼吸器内科1 ; 国立がん研究センター東病院 呼吸器内科2 ;国立がん研究センター東病院 乳腺科・血液化学療法科3 ; 東京大学大学院医学系研究科 呼吸器内科学4 ;東京大学大学院医学系研究科 公共健康医学専攻 生物統計学分野5 ; 三井記念病院 呼吸器内科6Abstract【Abstract】

Result通常診療において進行・再発非小細胞肺癌（NSCLC）の初回化学療法終了後患者の二次化学療法の実施率を検討

 Data cutoff at April 2012; updated from abstract submission
 Data of 866 patients were assessable for patientcharacteristics and details of 1st line treatment; 788 for
response; 620 for maintenance chemotherapy; 547 for 2ndline chemotherapy; 479 for analysis of factors which hinders
patients from receiving 2nd- line chemotherapy

◆目的
◆対象

進行・もしくは術後再発NSCLCの診断で ，施設において連続した症例であり，初回化学療法としてプラチナ製剤＋第三世代抗癌剤の併用が開始された症例◆方法

2010/4 以降の症例を観察研究として登録した。主として初回化
学療法の種類，臨床効果（Non-PD，PD），維持化学療法の有無，及び二次化学療法実施の有無と不可能であった症例の理由について調査検討した。またこの研究はパブリックヘルスリサーチセンター
がん臨床研究支援により実施◆結果

登録症例は 2010/10 から 2011/9 までに全国 30 施設より 866 例の登録があった。全体の背景因子として性別（男/女；628/238），年齢分布（24－80，中間値 65），組織型（腺癌/扁平上皮癌/その他；603/174/89）。治療6ヶ月経過症例 592 例（2012年3月末）についての初回中間集計では，初回化学療法の効果 SD以上の比率は 68.9%，維持化学療法の実施の有/無の比率（初回化学療法 PD 症例は除く）29/71%，二次化学療法実施（6ヶ月経過時点）の有/無の症例数は 264/135，その中で増悪が認められない 42 例以外で二次化学療法非実施例の主な理由は PS
低下 55，患者拒否 20，死亡 5 であった。

Patient characteristics
Age (median, years) (range)
Gender male/female
PS (ECOG) 0/1/2/3-4
Comorbidities none/anyHistology
adenocarcinoma
squamous cell carcinoma
large cell carcinoma
other
EGFR mutation (＋)
exon21 L858R/exon19 delEGFR mutation (－)
ALK translocation (＋)/(－)/unknown
Smoking history
never/experienced/current
Body mass index (median) (range)【Objectives】
Objectives
 To investigate the proportion of patients with NSCLC who
received 2nd-line chemotherapy after platinum-based 1st-linechemotherapy.
 To elucidate the reasons and factors which hinder patientsfrom receiving 2nd-line chemotherapy.

Response to 1st line chemotherapy
CR/PR/SD/PD/NE
Maintenance therapy
none
PEM/PEM+BV
BV
Erlotinib
S-1/S-1+BV
Other
2nd-line chemotherapy
none
DOC
PEM
Erlotinib/Gefitinib
S-1
otherFactor
malefemaleage Patients with advanced or recurrent NSCLC Platinum-based 1st-line chemotherapy between April 2010 andSeptember 2011 from 30 institutions in Japan
 Platinum-naïve Without history of other malignancy

PSData Collection

BMI

 Patient characteristics including age, gender, performancestatus (ECOG), smoking status, comorbidities (diabetes mellitus,
cardiac disease, interstitial lung disease), body mass index,
histological subtype, EGFR mutation, ALK translocation,
CBC/chemistry at registration
 Details of 1st-, 2nd-, 3rd-line, and maintenance chemotherapy;
including regimen, response Reason for administration or omitting 2nd-line chemotherapy
 Survival

20.1/50.2/29.1

Number of patients(N=866)332
152/10
51
21
47/20
5501
125/2830
173/8934
168%
38.3
17.6/1.2
5.9
2.4
5.4/2.3
0.6
57.9
14.4/3.2
3.5
20.0/10.3
3.9
19.4

Number of patients
%
788
100
4/266/295/161/62 0.5/33.8/37.4/20.4/7.9
620
100
429
69.2
62/21
10.0/3.4
67
10.8
30.5
13/11
2.1/1.8
12
1.9
547
100
179
32.7
149
27.2
6912.627/16
4.9/2.918
3.38916.3Result(cont.)【Res】

 Cohort study

Patient Inclusion

174/435/252
22.1 (13-39.6)

 179 patients did not receive 2nd-line chemotherapy at thetime of data cutoff; the reasons were as follows: without
disease progression, 50 (27.9%); declined PS, 75 (41.9%);
patient refusal, 28 (15.6%); death of any cause, 6 (3.4%).

Study Design Proportion of patients who received 2nd-line chemotherapy
after platinum-based 1st-line chemotherapy

69.6
20.1
1.0
9.2
10.2
4.8/4.2
59.4
1.3/4.8/93.9

CDDP-based
CDDP+PEM/CDDP+PEM+BV
CDDP+GEM
CDDP+VNR
CDDP+DOC/CDDP+DOC+BV
CDDP+S-1
CBDCA-based
CBDCA+PEM/CBDCA+PEM+BV
CBDCA+GEM
CBDCA+PTX/CBDCA+PTX+BV
CBDCA+S-1
BV containing regimen

Methods【Methods】
Primary Endpoint

603
174
980
88
42/36
514
11/42/813

1st line Treatment delivery【Background】
Background Second-line chemotherapy comprises the standard of care fornon-small-cell lung cancer (NSCLC)1-3.
 However, not all patients could receive appropriate 2nd-linechemotherapy.
 Recent studies demonstrated that maintenance chemotherapy
prolongs survival in patients with NSCLC4-7.
 Subgroup of patients who are benefited by maintenancechemotherapy is still to be determined.
 The proportion of patients who could not receive 2nd-line
chemotherapy and the reason for undertreatment is not fully
investigated.

Number of patients%(N=866)65 (24 – 86)
628/238
72.5/27.5
343/450/65/7
39.6/52.0/7.5/0.8
654/21275.5/24.5

Smoking
Comorbidity※

EGFR

<65
≧65
0
1‐4
neverexp/current
none
any
<20
≧20
mutation (＋)
mutation (－)

2nd line therapy (N=479)
Number of patients (%)
No (n=125)
Yes (n=354)
98 (78.4)
254 (71.8)
27 (21.6)
100 (28.2)
43 (34.4)
168 (47.5)
82 (65.6)
186 (52.5)
31 (24.8)
170 (48.0)
94 (75.2)
184 (52.0)
15 (12.0)
76 (21.5)
110 (88.0)
278 (78.5)
84 (67.2)
271 (76.6)
41 (32.8)
83 (23.4)
46 (36.8)
87 (24.6)
79 (63.2)
267 (75.4)
5 (3.9)30 (8.2)
79 (61.2)
219 (59.5)

Univariate
P value*p = 0.1587
0.0120<0.0001
0.02370.04400.0106
0.2598*Fisher’s test, ※DM, cardiac disease, ILDFactorOdds ratio

95% CIAge (≧65 vs <65)
PS (1-4 vs 0)
Smoking (ex/current vs never)Comorbidities (any vs no)
BMI (≧20 vs <20)

0.648
0.395
0.500
0.649
1.565

0.416 – 1.011
0.247 – 0.631
0.270 – 0.923
0.405 – 1.040
0.989 – 2.477

Multivariate
P value**
0.05580.00010.02680.07220.0558**Logistic regression model

Summary and Conclusion
 This is the largest cohort study exploring the proportion of patients with NSCLC and reasons for omitting 2nd-line chemotherapies.
 Maintenance therapy (either switch or continuation) was administered in approximately 30% of patients.
 Although data were immature, approximately 30% of patients did not receive appropriate 2nd-line chemotherapy.
 Declined PS was the most common reason for hindering 2nd-line chemotherapy.
 Advanced age, declined PS, smoking history, comorbidity, low BMI were correlated with hindrance to 2nd-line therapy in univariate analysis;
however EGFR mutation was not significantly correlated.
 In multivariate analysis, declined PS and smoking history were associated with hindrance to 2nd-line chemotherapy.
 Further investigation to establish predictive model is currently underway.

References

1) Tassinari D, et al. Chest.
2009;135:1596-609.
2) Azzoli CG, et al. J Clin Oncol.
2011;29:3825-31.
3) NCCN Clinical Practice Guidelines inOncology (NCCN Guidelines®).
Non-Small Cell Lung Cancer. version
3.2012. available fromhttp://www.nccn.org/
4) Paz-Ares LG, et al. J Clin Oncol.
2011;29(Suppl 18):Abstract CRA7510.
5) Pérol M, et al. J Clin Oncol. 2012 Sep 4.
[Epub ahead of print].
6) Cappuzzo F, et al. Lancet Oncol.
2010;11:521-9.
7) Ciuleanu T, et al. Lancet.
2009;374:1432-40.

Acknowledgement• This study was funded by Comprehensive Support Project for Oncology Research (CSPOR) of Public HealthResearch Foundation.
• The research institutes are Mitsui Memorial Hospital, Toranomon Hospital, University of Tokyo ,andNational Cancer Center Hospital East.
• We would like to thank patients, their families, and following institutions; Hokkaido University Hospital,
KKR Sapporo Medical Center, Iwate Prefectural Central Hospital, Tohoku University Hospital, University ofTsukuba, Ibaraki Prefectural Central Hospital, Tochigi Cancer Center, Gunma Prefectural Cancer Center,Saitama Medical University International Medical Center, Saitama Cancer Center, Tokyo Metropolitan
Cancer and Infectious Diseases Center Komagome Hospital, The Cancer Institute Hospital Of JFCR, Japanese
Red Cross Medical Center, Kitasato University Hospital, Kanagawa Cardiovascular and Respiratory Center,Fujisawa City Hospital, Shinshu University Hospital, Nagoya University Graduate School Of Medicine,
Okayama University Hospital, Hiroshima Prefectural Hospital, Kurume University School of Medicine,
Nagasaki University Hospital, Mitsui Memorial Hospital, University of Tokyo Hospital, National Cancer
Center Hospital East, Toranomon Hospital, Nishigunma National Hospital, NTT Medical Center Tokyo,
Teikyo University School of Medicine, National Center for Global Health and Medicine

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