Adjuvant chemotherapy in NSCLC 종양혈액내과 이재진

우리나라 암발생률 1999-2001 보 건 복 지 부 2005. 4. 27

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

성별 암종별 발생분율 남자 여자 2 5

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

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

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

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

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

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

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

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

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

Evidence-based medicine Level and Grade of evidence for recommendations

Clinical trial of Adjuvant chemotherapy 0. A British Medical Research Council, NSCLC Collaborative Group Meta-analysis, N=4457, 17 trials (BMJ 1995;311:899-909) 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

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

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 1995/2 - 2000/12/31 European Early termination (N=3,300 pts) d/t slow enrollment ← neoadjuvant CTx NEJM 2004;350:351-60

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

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, 0.76-0.98, p<0.03) Disease free survival HR 0.83 (95% CI, 0.74-0.94, p<0.003) Survival Benefit (+) NEJM 2004;350:351-60

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

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;95:1453-61

The Adjuvant Lung Project Italy-EORTC (ALPI) J Natl Cancer Inst 2003;95:1453-61

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, 0.81-1.13, p=0.589) Disease free survival HR 0.89 (95% CI, 0.76-1.03, p=0.128) Survival Benefit (-) J Natl Cancer Inst 2003;95:1453-61

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;95:1453-61

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 1995/2 - 2000/12/31 European Lancet Oncol 2006;7:719-27

ANITA Trial Lancet Oncol 2006;7:719-27

ANITA Trial Median F/U: 76 months 5Y OS: 8.6% benefit 5Y DFS: 8.7% benefit 0 20 40 60 80 100 (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

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

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. 1893 pts (Obs) Stage IB, stage II, stage III, stage IV Adjuvant setting, 97% (neoadjuvant setting 3%) 1995/11 - 2001/11 UK Early closure d/t slow accrual & ceased funding Eur J Cardiothorac Surg 2004;26:173-82

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

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

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

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 - 2001/4 CALGB, SWOG, ECOG joined in 1998 Canadian and American NEJM 2005;352:2589-97

NCIC CTG JBR. 10 trial NEJM 2005;352:2589-97

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;352:2589-97

NCIC CTG JBR. 10 trial 7% benefit 20% benefit NEJM 2005;352:2589-97

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;352:2589-97

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 (3.1-5.9) 2006 ASCO Annual Meeting

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

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

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

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

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 1996/9 - 2003/11 American Early closure d/t slow accrual & ceased funding JCO 2004;22:14S, ASCO abstract JCO 2006;24:18S, ASCO abstract

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

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

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

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

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

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 1994/1 - 1997/3 NEJM 2004;350:1713-21

The Japanese Lung Cancer Research Group NEJM 2004;350:1713-21

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;350:1713-21

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;350:1713-21

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(+)

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

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.

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 %

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

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

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

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;25:1553-61

Adjuvant chemotherapy in elderly patients JCO 2007;25:1553-61

Adjuvant chemotherapy in elderly patients Overall survival, age> 65 years JCO 2007;25:1553-61

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

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)

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

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