1. Adjuvant chemotherapy in NSCLC
종양혈액내과
이재진

2. 우리나라 암발생률
보 건 복 지 부

3. 암 발생 통계 연도 남자 여자 계
1999년
57,687
43,202
100,889
2000년
57,417
43,050
100,467
2001년
61,927
47,432
109,359
177,031
133,684
301,715
연평균발생건수
59,010
44,561
103,571

4. 성별 암종별 발생분율 남자 여자 2 5

5. Incidence and Survival of Lung Cancer
2002년 한국중앙암등록본부
2002년, 발생율 †
2002년, 사망분율 ‡

6. Screening test for early detection of Lung caner
Low dose chest CT
Sputum cytology
Chest X-ray

7. Disease stage at diagnosis of Lung caner Disease stage at diagnosis
5-year survival

8. To improve the survival of lung cancer,
Minimize the relapse of lung cancer
at curative setting

9. Rationale for adjuvant chemotherapy - Disease recurrence
Stage
Chest
Distant
Stage I
T1N0
10 %
15 %
T2N0
30 %
Stage II
T1-2N1
12 %
40 %
Stage IIIA N2
60 %
5YS
55-65 %
40-55 %
20-25 %
Feld 1984; Pairolero 1984; Mqrtini 1980; Thomas 1990

10. Rationale for adjuvant chemotherapy - Theoretical premises
An inverse relationship between cell number and curability
Skipper HE et al. Cancer Chemother Res 1964;35:1
Larger fractional kill in smaller tumors that have larger growth fraction
Norton LA. Cancer Res 1988;48:7067
Drug resistant cells emerge as tumor burden increases
Goldie JH et al. Cancer Treat Rep 1979;63:1727

11. Rationale for adjuvant chemotherapy - Theoretical premises
Cancer medicine 6th edition

12. Rationale for adjuvant chemotherapy - Theoretical premises
Systemic therapy
will be
more effective
in the setting of
minimal residual tumor

13. Survival benefit of adjuvant chemotherapy in other solid tumors
Early breast cancer
3.2% at 5Y, 6.3% at 10Y
Early ovarian cancer
8% at 5Y
Duke’s class C colon cancer
5% at 3Y
Limited stage SCLC (by RT & PCI)
5.4% at 3Y

14. Evidence-based medicine Level and Grade of evidence for recommendations

15. Clinical trial of Adjuvant chemotherapy
0. A British Medical Research Council, NSCLC Collaborative Group
Meta-analysis, N=4457, 17 trials (BMJ 1995;311: )
Nonsignificant 5 percent absolute increase (stage I,II,III) (p=0.08)
The International Adjuvant Lung Cancer Trial (IALT)
The Adjuvant Lung Project Italy-EORTC (ALPI)
The Adjuvant Navelbine International Trialist Association (ANITA)
The Big Lung Trial (BLT)
National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) JBR.10 trial
Lung Adjuvant Cisplatin Evaluation (LACE)
Meta-analysis, N=4584, 5 trials (2006 ASCO Annual Meeting)
CALGB protocol 9633 trial/ CALGB protocol 9633 trial
The Japanese Lung Cancer Research Group

16. Concern in adjuvant setting
Elderly patients
Surgery type, i.e., pneumonectomy
Adjuvant RT
What regimen
Compliance, i.e., planned dose

17. The International Adjuvant Lung Cancer Trial (IALT)
The effect of cisplatin-based adjuvant CTx on survival ?
3 or 4 cycles of cisplatin-based CTx vs. observation
Etoposide, vinorelbine, vinblastine, vindesine
1867 pts: 932 pts (CTx) vs.935 pts (Obs)
Stage I, stage II, stage III
1995/ /12/31
European
Early termination (N=3,300 pts) d/t slow enrollment ← neoadjuvant CTx
NEJM 2004;350:351-60

18. The International Adjuvant Lung Cancer Trial (IALT)
NEJM 2004;350:351-60

19. The International Adjuvant Lung Cancer Trial (IALT)
Median F/U: 56 months
5Y OS: 44.5% vs. 40.4%
5Y DFS: 39.4% vs. 34.3%
Overall survival
HR 0.86
(95% CI, , p<0.03)
Disease free survival
HR 0.83
(95% CI, , p<0.003)
Survival Benefit (+)
NEJM 2004;350:351-60

20. The International Adjuvant Lung Cancer Trial (IALT)
Compliance
Planned dose: 73.8% of pts
The chief reasons for incomplete treatment
Adverse effects: 51.5%
Pts or physician’s refusal: 24.3%
PD: 5.1%
Adjuvant RT; 31% of pts
Planned therapy: 70.4% in chemotherapy vs. 84.2% in control group
Acute adverse effects
Treatment-related death: 0.8% (7pts)
BM aplasia, renal failure, hyponatremia
Any grade 4 toxicity: 22.6% of the patients
NEJM 2004;350:351-60

21. The Adjuvant Lung Project Italy-EORTC (ALPI)
The effect of cisplatin-based adjuvant CTx on survival ?
3 cycles of cisplatin-based CTx vs. observation
mitomycin, vindesine, cisplatin (MVP regimen)
1209 pts: 606 pts (CTx) vs. 603 pts (Obs)
Stage I, II, IIIA
1994/1-1999/1
European
J Natl Cancer Inst 2003;95:

22. The Adjuvant Lung Project Italy-EORTC (ALPI)
J Natl Cancer Inst 2003;95:

23. The Adjuvant Lung Project Italy-EORTC (ALPI)
Median F/U: 64.5 months
5Y survival benefit: 1%
Median; 55.2m vs. 48m
5Y DFS benefit: 4%
Median; 36.5m vs. 28.9m
Overall survival
HR 0.96
(95% CI, , p=0.589)
Disease free survival
HR 0.89
(95% CI, , p=0.128)
Survival Benefit (-)
J Natl Cancer Inst 2003;95:

24. The Adjuvant Lung Project Italy-EORTC (ALPI)
Compliance
Planned dose: 69% of pts
The chief reasons for incomplete treatment, 110 pts (22%)
Adverse effects: 60%
Pts refusal: 40%
Adjuvant RT; 43% of pts
65% in chemotherapy vs. 82% in control group
Acute adverse effects
Treatment-related death: 0.5% (3pts)
Grade 3/4 neutropenia: 16%/12% of the patients
Grade 3/4 N/V: 13%/4% of the patients
J Natl Cancer Inst 2003;95:

25. ANITA Trial The effect of cisplatin-based adjuvant CTx on survival ?
4 cycles of vinorelbine plus cisplatin vs. observation
840 pts: 407 pts (CTx) vs. 433 pts (Obs)
Stage IB, stage II, stage IIIA
1995/ /12/31
European
Lancet Oncol 2006;7:719-27

26. ANITA Trial
Lancet Oncol 2006;7:719-27

27. ANITA Trial Median F/U: 76 months 5Y OS: 8.6% benefit
5Y DFS: 8.7% benefit
(M)
Overall survival
HR 0.80
(p=0.017)
Disease free survival
HR 0.76
(p=0.002)
Survival Benefit (+)
Lancet Oncol 2006;7:719-27

28. ANITA Trial Compliance Acute adverse effects Planned dose: 50% of pts
Dose intensity; vinorelbine (59%), cisplatin (89%)
3 or more cycles: 61% of pts
Adjuvant RT; 28% of pts
Acute adverse effects
Treatment-related death: 2% (7pts)
G3/4 toxicity: fatigue (28%), nausea (27%), FN (9%), neuropathy (3%)
Lancet Oncol 2006;7:719-27

29. Big Lung Trial (BLT)
The effect of cisplatin-based adjuvant CTx on survival ?
3 cycles of cisplatin-containing regimen vs. observation
Vindesine, mitomycin & ifosfamide, mitomycin & vinblastine, vinorelbine
381 pts: 192 pts (CTx) vs pts (Obs)
Stage IB, stage II, stage III, stage IV
Adjuvant setting, 97% (neoadjuvant setting 3%)
1995/ /11 UK
Early closure d/t slow accrual & ceased funding
Eur J Cardiothorac Surg 2004;26:173-82

30. Big Lung Trial (BLT) Complete resection
Extra information;
R0, 15 pts
R1, 21 pts
R2, 8 pts
True complete resection rate: 95%
Median duration to start of CTx: 7 wks
Eur J Cardiothorac Surg 2004;26:173-82

31. Big Lung Trial (BLT) Median F/U: 34.6 months 2Y OS: 58% vs. 60%
Median, 33.9m vs. 32.6m
2Y DFS: 53% vs. 51%
Median, 27m vs. 24.7m
(Mo)
(Mo)
Overall survival
HR 1.02
(p=0.90)
Disease free survival
HR 0.97
(p=0.81)
Survival Benefit (-)
Eur J Cardiothorac Surg 2004;26:173-82

32. Big Lung Trial (BLT) Compliance Acute adverse effects
Planned dose: 64% of pts
21% of pts: early termination
Cause: pts’ and physician decision (49%), toxicity (34%), death, PD
13% of pts: no chemotherapy
Cause: death, refusal, poor condition
Adjuvant RT; 14% of pts
Acute adverse effects
Treatment-related death: 3.1% (6pts)
Any G3/4 toxicity: 30%, hematologic, N/V, FN
Eur J Cardiothorac Surg 2004;26:173-82

33. NCIC CTG JBR. 10 trial
The effect of adjuvant vinorelbine plus cisplatin on survival ?
4 cycles of vinorelbine plus cisplatin vs. observation
482 pts: 242 pts (CTx) vs. 240 pts (Obs)
Stage IB, stage II (except, T3N0)
1994/ /4
CALGB, SWOG, ECOG joined in 1998
Canadian and American
NEJM 2005;352:

34. NCIC CTG JBR. 10 trial
NEJM 2005;352:

35. NCIC CTG JBR. 10 trial Median F/U: 63 months 5Y OS: 69% vs. 54%
5Y DFS: 61% vs. 49%
Overall survival
HR 0.69
(p=0.009)
Disease free survival
HR 0.60
(p<0.001)
Survival Benefit (+)
NEJM 2005;352:

36. NCIC CTG JBR. 10 trial
7% benefit
20% benefit
NEJM 2005;352:

37. NCIC CTG JBR. 10 trial Compliance Planned dose: 48% of pts
Median cycle: 3
3 or more cycles: 58% of pts
32% of patients required hospitalization
7% for chemotherapy
6% for unrelated treatment
19% for medical problem related to toxicity
Adjuvant RT (-)
Acute adverse effects
Treatment-related death: 0.8% (2pts)
G3/4 toxicity: fatigue (15%), nausea (10%), FN (7%)
G3/4 neurotoxicity: hearing loss (2%), sensory & motor (5%)
NEJM 2005;352:

38. Lung Adjuvant Cisplatin Evaluation (LACE)
Meta-analysis
5 Randomized Trials
4,584 patients
Inclusion
Sample size >300
Cisplatin-based chemotherapy
Median F/U; 5.1 years ( )
2006 ASCO Annual Meeting

39. Lung Adjuvant Cisplatin Evaluation (LACE)
Overall survival
HR 0.89 (p=0.004)
Survival Benefit (+)
2006 ASCO Annual Meeting

40. Lung Adjuvant Cisplatin Evaluation (LACE)
3.9%
5.3%
Overall survival
Survival Benefit (+)
2006 ASCO Annual Meeting

41. Lung Adjuvant Cisplatin Evaluation (LACE)
Cisplatin-based chemotherapy is effective for stages II & III
2006 ASCO Annual Meeting

42. Lung Adjuvant Cisplatin Evaluation (LACE)
The effect of cisplatin + vinorelbine was marginally better than that of other drug combination (p=0.04, post-hoc analysis)
2006 ASCO Annual Meeting

43. CALGB protocol 9633 trial
The effect of adjuvant paclitaxel plus carboplatin on survival ?
4 cycles of paclitaxel plus carboplatin vs. observation
344 pts: 173 pts (CTx) vs. 171 pts (Obs)
Stage IB
1996/ /11
American
Early closure d/t slow accrual & ceased funding
JCO 2004;22:14S, ASCO abstract
JCO 2006;24:18S, ASCO abstract

44. CALGB protocol 9633 trial Patients’ characteristics Age; 61 yr (34-81)
M;F=64%;36%
Surgery
Lobectomy; 89%
JCO 2004;22:14S, ASCO abstract
JCO 2006;24:18S, ASCO abstract

45. CALGB protocol 9633 trial Median F/U: 34 months Median F/U: 54 months
3Y OS: 79% vs. 71%
5Y OS: 59% vs. 57%
Overall survival
HR 0.62
(p=0.028)
Overall survival
HR 0.80
(p=0.32)
Disease free survival
HR 0.69
(p=0.035)
Disease free survival
HR 0.74
(p=0.027)
Survival Benefit (+)
Survival Benefit (-)
JCO 2004;22:14S, ASCO abstract
JCO 2006;24:18S, ASCO abstract

46. CALGB protocol 9633 trial 3Y OS: 79% vs. 71% 5Y OS: 59% vs. 57%
Survival Benefit (+)
Survival Benefit (-)
JCO 2004;22:14S, ASCO abstract
JCO 2006;24:18S, ASCO abstract

47. CALGB protocol 9633 trial Survival Benefit (+) DFS Benefit (+)
JCO 2004;22:14S, ASCO abstract
JCO 2006;24:18S, ASCO abstract

48. CALGB protocol 9633 trial Compliance Planned cycle: 84% of pts
33% of patients required dose modification
Acute adverse effects
Treatment-related death: 0%
G3/4 neutropenia; 36% of pts
JCO 2004;22:14S, ASCO abstract
JCO 2006;24:18S, ASCO abstract

49. The Japanese Lung Cancer Research Group
The effect of Uracil-tegafur adjuvant CTx on survival ?
oral uracil-tegafur for 2 years vs. observation
979 pts: 491 pts (CTx) vs.488 pts (Obs)
pT1N0, pT2N0 (stage I)
Adenocarcinoma
1994/ /3
NEJM 2004;350:

50. The Japanese Lung Cancer Research Group
NEJM 2004;350:

51. The Japanese Lung Cancer Research Group
Median F/U: 73 months
5Y OS: 88% vs. 85%
5Y OS: 85% vs. 74%
Overall survival
HR 0.71
(p=0.04)
Overall survival with T2 disease
HR 0.48
(p=0.005)
Survival Benefit (+)
NEJM 2004;350:

52. The Japanese Lung Cancer Research Group
Compliance
Planned dose: 74% of pts at 1Y, 61% at 2Y
The chief reasons for incomplete treatment
Adverse effects: 123 pts
Patient’s refusal: 52 pts
Physician’s decision: 34 pts
Acute adverse effects
Any grade 3 toxicity: 2% of the patients
Anorexia, nausea, diarrhea, increase of ALT
NEJM 2004;350:

53. Phase III trial Trial IALT ALPI ANITA BLT JBR.10 CALGB Japan When N
Regimen RT
Stage
5YS (+)
P-value
Nation
TRD
Subgroup analysis
IALT 95
1867 P+
VNR,VBL,VDS,VP-16
31%
I,II,III
4.1%
<0.03
Europe
0.8% -
ALPI 94
1209
MMC+VDS
43% 1%
0.589
0.5%
ANITA
840
VNR
28%
IB,II,IIIA
8.6%
0.017 2%
N1,N2 (+)
BLT
381
VDS,MI,
MV,VNR
14%
IB,II,III
2Y,
-2%
0.90 UK
3.1%
JBR.10
482
IB,II
15%
0.009
Canada
USA
Stage II(+)
CALGB 96
344
CbTx IB
3Y,8%
5Y,2%
0.028
0.32 0%
T>4cm(+)
Japan
979
Tegafur
I,adenoca 3%
0.04
T2(+)

54. Survival benefit Worldwide 한국 75세 미만; 900,000/yr, Lung cancer Dx
 80% NSCLC; 720,000
 1/3 resectable; 240,000
 75% adjuvant chemotherapy Ix: 180,000
 4% survival benefit; 7000/yr safe 한국
75세 미만; 11,000/yr, Lung cancer Dx
 80% NSCLC; 9,000
 1/3 resectable;3,000
 75% adjuvant chemotherapy Ix: 2,500
 4% survival benefit; 100/yr safe

55. Standard therapy of resectable NSCLC
Harrison, 16th Edition:
Surgical resection for stage IA, IB, IIA, IIB, some IIIA
Surgical resection with complete-mediastinal LN dissection
Discussion of risks/benefits of adjuvant Ctx within individual patients
Recommend Cisplatin-based adjuvant chemotherapy for stage II & III NSCLC.
Consider cisplatin-based adjuvant chemotherapy for stage IB.
- size, age, surgery type etc.

56. Limitation Compliance QoL A large proportion of patients with cancer
Age, pneumonectomy
QoL
Fatigue, N/V
A large proportion of patients with cancer
without any benefit
Toxic effects of treatment
TRD: below 1.0 %

57. Major issue of adjuvant chemotherapy
Poor compliance
LCSG 772: cumulative dose: 58% of the scheduled dose
LCSG 791: only 51% of pts as scheduled dose
NCIC CTG BR.10: only 50% of pts as scheduled dose
Lung Cancer 2005;47:385-94

58. Compliance of adjuvant chemotherapy
Lung Cancer 2005;47:385-94

59. 평균수명까지 생존 시 암에 걸릴 확률은 ? 평균수명 (2000년) 72.8세 80.1세 암에 걸릴 확률 74세까지 누적위험
29.0%
80세까지
20.2%
약 3명 중 1명
약 5명 중 1명

60. Major issue of adjuvant chemotherapy
Adjuvant chemotherapy in elderly patients, NCIC-CTG JBR.10
West
>65 years: more than 50%
>70 years: 30-40%
Korea
>65 years: 54.7%
>70 years: 34.0%
JCO 2007;25:

61. Adjuvant chemotherapy in elderly patients
JCO 2007;25:

62. Adjuvant chemotherapy in elderly patients
Overall survival, age> 65 years
JCO 2007;25:

63. Impact of adjuvant chemotherapy in Elderly patients
Adjuvant CTx improves survival in patients older than 65 years with acceptable toxicity
Adjuvant CTx should not be with held from elderly patients

64. QoL of adjuvant chemotherapy
NCIC CTG BR.10 with EORTC QLQ-C30
Observation arm: improvement in QoL by 3 months
Chemotherapy arm: Rapidly resolved within 3 months after completion of CTx
BLT with EORTC QLQ-C30
No evidence to suggest a detrimental effect on QoL from the use of CTx
LCSG 801, 853 with FLIC (functional living index-C)
Baseline (post-op)

65. Impact of adjuvant chemotherapy on QoL
No significant impact of a short course of chemotherapy on QoL
If any side effect, rapidly resolved

66. Conclusion Recommend adjuvant chemotherapy for stage II and III
Consider adjuvant chemotherapy for stage IB
Especially, T>4cm
Elderly patients are no contraindication for adjuvant chemotherapy
QoL may be rapidly resolved by 3 months after adjuvant therapy