1、替吉奥治疗胃癌的进展替吉奥治疗胃癌的进展 徐建明徐建明 军事医学科学院军事医学科学院307307医院肿瘤中心医院肿瘤中心 试验背景替吉奥胶囊p 替吉奥胶囊（S-1），是日本大鹏药品工业株式会社研制的一种口服氟脲嘧啶类衍生物。1999年在日本上市，在日本已取得胃癌、结直肠癌、头颈癌、肺癌、胰腺癌、乳腺癌、胆管癌等7个适应症。p 2005年，S-1获得SFDA批准进行胃癌、结直肠癌、头颈癌临床试验，其中胃癌临床试验已完成，将于近日获得进口批准。结直肠癌于2006年2007年完成I期临床试验，目前将进一步进行II期探索更佳治疗方案，为III期报批试验做准备。p S-1治疗晚期结直肠癌的疗效： 199
2、4-2001年，单药一线治疗：ORR 16.7%37.4%，提示S-1单药治疗不亚于奥沙利铂及CPT-11等药（单药疗效7.833.3%） 2004-2007年，S-1/LV I/II期临床试验(日本)一线治疗：ORR 57.1%，TTP 203天，疗效良好，值得进一步探索。l S-1是一种口服氟尿嘧啶类衍生物，组成：替加氟是一种口服氟尿嘧啶类衍生物，组成：替加氟 (FT; 5-FU前体药物前体药物)： 吉美嘧啶吉美嘧啶(CDHP) ：奥替拉西钾：奥替拉西钾(Oxo) =1：0.4：1l 口服亚叶酸钙口服亚叶酸钙(LV) 可增强可增强S-1的抗肿瘤活性。的抗肿瘤活性。 S-1 / LV 的作用
3、机制的作用机制H. Narahara1, W. Koizumi2, T. Hara3, A. Takagane4, T. Akiya5, M. Takagi6, K. Miyashita7, T. Nishizaki8, O. Kobayashi9, S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group;1Osaka Medical Center for Cancer and CV Diseases, Osaka, JAPAN, 2Kitasato University East Hospital, Kanagawa, JAPAN, 3K
4、ouseiren Takaoka Hospital, Toyama, JAPAN, 4Iwate Medical University, Iwate, JAPAN, 5Gunma Prefectural Cancer Center, Gunma, JAPAN, 6Shizuoka General Hospital, Shizuoka, JAPAN, 7National Hospital Organization Nagasaki Medical Center, Nagasaki, JAPAN, 8Matsuyama Red Cross Hospital,Ehime, JAPAN, 9Kanag
5、awa Cancer Center, Kanagawa, JAPAN.ASCO 2007: #4514ASCO 2007: #4514背景-2NSASCO 2007: #4514Boku et al. ASCO2007 abstract#: LBA4513 ASCO 2007: #4514ASCO 2007: #4514 l ASCO 2007: #4514ASCO 2007: #4514ASCO 2007: #4514ASCO 2007: #4514ASCO 2007: #4514ASCO 2007: #4514ASCO 2007: #4514ASCO 2007: #4514ASCO 200
6、7: #4514ASCO 2007: #4514ASCO 2007: #4514*TTP3) Proc ASCO 2006; Vol 24, No. 18S: LBA40181) J Clin Oncol 2006; 24: 4991 49972) Proc ASCO 2006; Vol 24, No. 18S: LBA4017ASCO 2007: #4514l S-1 中位生存 S-1+CDDP S-1+CDDP 耐受性好，无治疗相关的死亡 S-1+CDDP 方案可以当作 AGC 的一线治疗方案ASCO 2007: #4514N. Boku, S. Yamamoto, K. Shirao,
7、T. Doi, A. Sawaki, W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, A. Ohtsu Gastrointestinal Oncology Study Groupof Japan Clinical Oncology Group 5-FU 单药单药、 、CPT-11 顺铂顺铂 (CP) 、 、S-1 单药单药治治疗疗晚期晚期GC的随机的随机 III期期临临床研究床研究(JCOG9912)背背 景景l 晚期胃癌无晚期胃癌无标标准化准化疗疗方案方案.l III期期临临床研究床研究(JCOG9205)并未并未证证明，明， 5-FU+CDDP
8、 比比 5-FU 单药单药延延长长生存生存. l II 期研究表明期研究表明 S-1单药单药 和和 CPT-11+CDDP 疗疗效好、效好、 毒性反毒性反应应可以接受可以接受.(Sakata, Eur J Cancer 1998; Koizumi, Oncology 2000; Boku, J Clin Oncol 1999) (Ohtsu, J Clin Oncol 2003)Primary endpoint： ：总总生存生存Secondary endpoints： ：到治到治疗疗失失败败的的时间时间 (TTF)Non-hospitalized survival (NHS)Adverse E
9、vents (NCI-CTC ver.2)Response rate (RECIST, central review) 与与 5-FU 持持续续静滴静滴 (5-FUci)比比较较 CPT-11+CDDP的的优优效性效性 S-1的非劣效性的非劣效性研究目的研究目的Inclusion Criteria 1) 组织组织学学证实证实的不能手的不能手术术切除的或复切除的或复发发的胃腺癌的胃腺癌 2) 能口服能口服药药物物 3) Age: 20, 75 4) PS (ECOG)： ： 0, 1, 2 5) 主要主要脏脏器功能正常器功能正常 6) 未接受未接受过过放化放化疗疗 except adjuvant
10、 chemotherapy completed 6 months before 7) 不一定要有可不一定要有可测测量的病灶量的病灶 8) 无无严严重的腹膜播散重的腹膜播散 9) Written informed consentS-1 40 mg/m2, po, bid, days 1-28q 6 weeks Stratified by (minimization) Institution PS 0/1/2 Unresectable/ Recurrence with adjuvant Cx/ Recurrence without adjuvant Cx5-FUciCPT-11 + CDDPS-1
11、Randomization800 mg/m2/day, ci, days 1-5q 4 weeksCPT-11 70 mg/m2, div, days 1&15CDDP 80 mg/m2, div, day 1q 4 weeks III 期研究期研究 (JCOG9912)Continued until disease progression, unacceptable toxicities, patients refusalBSA 1.25 80 mg/body/day 1.25 BSA 1.5 100 mg/body/day 1.5 3- / +* Japanese Classificati
12、on of Gastric Carcinoma * Lauren classification, no data available in 2 pts* 1 pt with adenosquamous type includedNo. of patients6个月内个月内 Gr.3 AE (1)5.63.83.90.941.505.665.01.312.839.315.51.34.70.40.47.7009.40S-1CPT-11+CDDP5-FUci234236234Treatment related death*0.41.30LeukocytesNeutrophilsHemoglobinP
13、lateletsInfection without neutropeniaInfection with Gr.3 or 4 neutropeniaFebrile neutropenia* Judged by Data and Safety Monitoring Committee1.703.0Stomatitis5.620.56.9Nausea7.79.00.4Diarrhea12.432.912.5Anorexia5.110.31.7Fatigue4.72.64.7AST3.42.63.4ALT4.31.33.0Bilirubin0.92.10Creatinine5.222.66.5Hypo
14、natremia6个月内个月内 Gr.3 AE(2)No. of patientsS-1CPT-11+CDDP5-FUci234236234PFS和有效率和有效率Response rate- in pts with target lesion -5-FUciCPT-11+CDDPS-1CR+PR156849n175181175RR9%38%28%CR and PR were confirmedby central review0.0010.62-0.900.754.2M2340.001-0.57-0.83-95%C.I.-2.9M2340.694.8M236HRMedian nP-value1
15、224 (months)050(%)100: one-sided log-rank test (superiority)S-15-FUciCPT-11+CDDPPFS0.0010.59-0.850.714.0M234S-10.014-P-value0.67-0.98-95%C.I.-2.3M2345-FUci0.813.7M236CPT-11+CDDPHRMedian n: one-sided log-rank test (superiority)到治到治疗疗失失败败的的时间时间1224 (months)050(%)100治治疗疗失失败败的原因的原因OtherDeathRefusal not
16、related to toxicityRefusal related to toxicityToxicitiesDisease progression Continuing at final analysisNo. of patients2108142036S-123491839361430CPT-11+CDDP2366199919915-FUci234122436 (months)050(%)100Overall SurvivalP-value0.0340.055-0.68-1.010.70-1.04-95%C.I.-44.0%10.8M2345-FUci0.8347.9%11.4M234S
17、-10.8552.5%12.3M236CPT-11+CDDPHR1-yrMSTn: one-sided log-rank test (superiority)non-inferiority 0.001: multiplicity adjusted by Holms methodSignificancelevel0.050.0250.0250.0030.62-0.920.769.2M234S-10.027-0.68-1.00-95%C.I.-7.2M2345-FUci0.829.5M236CPT-11+CDDPHRMedian nP-value: one-sided log-rank test
18、(superiority)Non-hospitalized Survival122436 (months)050(%)100= overall survival time hospitalized days* type unknown were excluded from the analysis生存期的生存期的亚组亚组分析分析- Hazard Ratio to 5-FUci and 95% Confidence Interval -Hazard ratioAge 65 (n=332)PS 0 (n=454)1,2 (n=250)Unresectable (n=567)Recurrent (n
19、=137)Intestinal (n=323)*Diffuse (n=379)(-) (n=173)Target lesion (+) (n=531)No. of met sites 0,1 (n=305)2 (n=399)Peritoneal mets (-) (n=472)(+) (n=232)All randomized (n=704)CPT-11+CDDPS-1生存期的亚组分析P-valueS-15-FUci122436(months)050(%)1000.0701750.015-175181nP-value10.5M9.0M12.1MMST 3.8M2.2M4.8MPFS- Targ
20、et Lesion (+) - Target Lesion (-) -0.1818.1M590.54-13.5M5914.4M55MST n: one-sided log-rank test (superiority)S-15-FUciCPT-11+CDDPCPT-11+CDDP050(%)100122436(months)结结 论论 S-1 的生存期明的生存期明显显不劣于不劣于 5-FUci ，毒性，毒性较较低低 RR, TTF, NHS and PFS 更好更好 各个各个亚组亚组的生存期都比的生存期都比5-FUci 组长组长 CPT-11+CDDP 生存期并不生存期并不优优于于 5-FUc
21、i ，且毒性大，且毒性大导导致更多致更多 的治的治疗疗失失败败 但但 RR, TTF, NHS and PFS 更好更好 在在TL (+)亚组亚组的生存比的生存比 5-FUci 长长 在在TL (-) 和腹膜和腹膜转转移移 (+)者的生存更短者的生存更短 S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer.Abstract No. #4533; Poster No. #21背 景 40% 初次诊断的胃癌患者是晚期, 4060 术后复发. AGC 无标
22、准治疗方案. S-1治疗 GC有效. 无论是单药还是 SP 在日本广泛用于AGC 治疗*. S-1 在中国无经验, 中国是GC发病率最高的国家之一.*:S-1 is manufactured and supplied by Taiho Pharmaceutical Co., Ltd. Tokyo, Japan研究目标 Primary endpoint: Response Rate (RR)#1 Secondary endpoint: Time to Treatment Failure (TTF) Overall Survival (OS) Toxicity/safety#2#1: RECIST
23、 guideline, used IRC evaluation results.#2: NCCN CTCAE version 3.0研究设计不可切除的晚期或转移性 GCCentral randomization( dynamic balance) Stratification： Performance Status; Number of metastatic sites; Gastrectomy S-15-FU/CDDPS-1/CDDP60 patients60 patients60 patientsIf failed, can switch to S-1治疗方案 Arm A (S-1): S
24、-1, 42 days/cycleS-1 40 mg/m2, Bid, oralRest 14 daysd1d28 (4 weeks)d29d42 (2 weeks) Arm B (SP): S-1 + CDDP, 35 days/cycleS-1 40 mg/m2, Bid, oralRest 14 daysd1d21 (3 weeks)d22d35 (2 weeks)CDDP, 60mg/m2, d8, infusion3hrs Arm C (FP) : 5-FU + CDDP, 28 days/cycle (4 weeks)5-FU+CDDPRest 23 daysd1d5d6d28CD
25、DP, 20mg/m2, infusion0.5hr5-FU, 600mg/m2, infusion24hrs入组标准l组织学证实的胃腺癌l不可切除, 晚期或转移性病灶l对转移灶既往未放化疗. 辅助和/或新辅助结束6个月以上者可以入选lAge 18 or abovelECOG performance status 0 to 2lAdequate hematological, renal and liver function患者分配230 pts randomized(Jul.2005Oct.2006)S-1 n=80SP n=76FP n=74FAS n=77FAS n=74FAS n=73W
26、ithout target lesion, n=1Inclusion criteria violationn=1Without target lesionn=1Without target lesionn=3一般状况 （FAS=224）Patient CharacteristicsS-1(n=77)SP(n=74)FP(n=73)P-valueSex Male Female5621551961120.241Age Mean Median Minmax56.257.032.082.056.156.524.080.055.758.033.077.00.951BSA(m2) Mean Median
27、Minmax1.61.61.21.91.61.61.32.11.61.61.31.90.157PS 0 1 2125312145281350100.922No. of metastastic sites 1 1 1958116316570.308Gastrectomy status Present Absent3938344037360.802Pre-treated Yes Not2849205426470.404There is no significant difference between the three arms in FAS.RR 比较 (FAS)TreatmentnRespo
28、nseP-valueaDiff. of RR (%)bCRPRSDPDNERR(%)95%CIS-1771181525824.7(19/77)d15.6-35.80.06213.2SP741273110537.8(28/74)c,d26.8-49.9FP7301428181319.2(14/73)c10.9-30.10.02118.7 nCRPRSDRR41151114.6(6/41）41 of 73 pts switched to S-1 monotherapy after failed in FPOS*Until January 15, 2007, 224 patients were fo
29、llowed up, 94 died(42%),115 alive,15 lost follow-up.*: Logrank testTreatmentnDeathMST (day)95%CIP-value*S-177412672023230.001SP7422433365FP73313092380.038* FPs survival include 41 pts contribution who switched to S-1Hazard: S-1 vs. SP=2.262(95%CI1.327-3.856)FP vs. SP=1.908(95%CI1.089-3.341)TTFTreatm
30、entnFailureMedian-TTF (day)95%CIP-value*S-17762126921520.008SP7444159146220FP735585661060.001Hazard: S-1 vs. SP=1.709(95%CI1.145-2.552)FP vs. SP=2.673(95%CI1.755-4.071)*: Logrank test.药物主要的副作用AE TermS-1SPFPn=80n=76n=74G3+G4 n(%)G3+G4 n(%)G3+G4 n(%)Anemia2(2.5)4(5.3)4(5.4)Leucopenia1(1.3)10(13.2)7(9.
31、5)HGB decreased5(6.3)8(10.5)3(4.1)Lymphocyte decreased7(8.8)4(5.3)5(6.8)Neutropenia3(3.8)13(17.1)12(16.2)PLT decreased05(6.6)9(12.2)Nausea02(2.6)4(5.4)Vomitting1(1.3)5(6.6)9(12.2)Diarrhea3(3.8)5(6.6)0Anorexia001(1.4)Decreased appetite2(2.5)01(1.4)Constipation001(1.4)小 结 从从 2005.7月月 2006.10月，月， 80 pt
32、s in S-1, 76 pts in SP and 74 pts in FP 入入组组.三三组组患者的一般状况无患者的一般状况无显显著差异著差异.独立独立评评估委估委员员会会评评估的估的结结果果, RR 24.7% in S-1, 37.8% in SP and 19.2% in FP. SP 有效率有效率优优于于FP (CMH p=0.021).FP 组组41例患者交替到例患者交替到 S-1组组 后的后的RR 14.6%, 说说明明 S-1 2nd-line 治治疗疗有效有效.SP 组组的生存明的生存明显长显长于于FP 组组(Log-rank p=0.038) 和和 S-1组组 (Log-
33、rank p0.001).S-1/SP/FP 最常最常见见的的 3/4 毒性反毒性反应应(%) : 贫贫血血, 2.5/5.3/5.4; 白白细细胞下降胞下降, 1.3/13.2/9.5; 中性粒减少中性粒减少, 3.8/17.1/16.2; PLT 减少减少, 0/6.6/12.2; 恶恶心心, 0/2.6/5.4; 呕吐呕吐, 1.3/6.6/12.2; 腹泻腹泻, 3.8/6.6/0. S-1 和和 SP 组组均能很好耐均能很好耐受受.结结 论论 S-1 和 SP 均有效、耐受性好. SP 有可能成为晚期中国胃癌患者的标准治疗方案.q Primary endpoint: Superior
34、ity in OSq N = 1000 non-Asian AGC for 1st line palliative chemotherapyFLAGS Trial: S-1 + CDDP vs 5-FU + CDDP5-FU 1,000 mg/m2/d CIV D1-5Cisplatin 100 mg/m2 iv D1, every 4 weeksS-1 25 mg/m2 po bid D1-21Cisplatin 75 mg/m2 iv D1, every 4 weeksRAjani, et al. ASCO GI 2009FLAGS: OSAjani, et al. ASCO GI 200
35、9% 存活率存活率1009080706050403020100随机后时间（月）0246810 12 14 16 18 20 22 24 26 28 30 32 34Log-rank Test: p=0.1983相对危险度相对危险度: 0.92 (95% CI: 0.80, 1.05)中位总生存时间中位总生存时间:CS: 8.6 monthsCF: 7.9 monthsCS（顺铂（顺铂/S1）CF（顺铂（顺铂/5-Fu）N at riskS-1:5-FU:521 479 402 341 276 212172 1249069483624146400508 452 385 326 250 19915
36、6 1167956352619128310FLAGS: PFSAjani, et al. ASCO GI 2009% 无进展生存率无进展生存率1009080706050403020100Log-rank Test: p=0.9158相对危险度相对危险度: 0.99 (95% CI: 0.86, 1.14)CS: 4.8 monthsCF: 5.5 monthsCS （顺铂（顺铂/S1）CF （顺铂（顺铂/5-Fu）024681012 1416182022 242628521365237152914124171298510508335235149753622161164N at riskS-1:
37、5-FU:随机后时间（月）FLAGS: 3/4 度血液学毒性 Ajani, et al. ASCO GI 2009患者比例患者比例 (%)706050403020100贫血中性粒细胞减少血小板减少白细胞减少中性粒细胞减少性发热*CSCF*P1.5 x ULN肌酐清除率肌酐清除率 1.5 x ULN肝相关不良事件肝相关不良事件(所有分级所有分级)肝功能损害肝功能损害肾毒性肾毒性肝毒性肝毒性*CSCF*P0.05*P0.01*FLAGS: 结论与与顺铂顺铂/5-Fu相比，相比，顺铂顺铂/S1并不提高并不提高OS次要次要终终点指点指标标：有效性：有效性：顺铂顺铂/S1与与顺铂顺铂/5-Fu 无差异无
38、差异顺铂顺铂/S1 在安全性上比在安全性上比顺铂顺铂/5-Fu更好更好. 然而，然而，顺铂顺铂/S1 方案中方案中顺铂剂顺铂剂量量是是顺铂顺铂/5-Fu方案方案 的的75% ，且，且S-1 剂剂量也低于日本研究的量也低于日本研究的剂剂量量Ajani, et al. ASCO GI 2009Sakuramoto et al. N Engl J Med 2007; 357:1810-20研究目标 探讨II/III 胃癌D2 术后，S-1 单药辅助治疗的有效性 Primary endpoint Overall survival Secondary endpoints Relapse-free sur
39、vival Safety of S-1Sakuramoto et al. N Engl J Med 2007; 357:1810-20入组标准 组织学证实的胃癌 D2 术后 术后分期II/III (Japanese classification) R0 resection (curability A or B) Negative peritoneal cytology Age 20-80 years 既往未做辅助治疗 Adequate organ function Written informed consentSakuramoto et al. N Engl J Med 2007; 357:
40、1810-20研究设计Curative gastrectomy (D2)Central Randomization (dynamic balancing)Adjustment factors : stage*(II, IIIA, IIIB), Institutionwithin 6 weeks after surgeryS-1 80-120 mg/day* 4 wks administration with 2wks off in each course for 12 monthsSurgery alone(No further therapy)*Japanese Classification
41、 of Gastric Carcinoma, 13th ed,1999* Body surface area (m2) 1.25 80mg/day1.25 - = 1.5120mg/daySakuramoto et al. N Engl J Med 2007; 357:1810-20统计学考虑 5-year OS for surgery alone = 70% Improvement by S-1 at a hazard ratio of 0.7 (5y OS:77.9%) Follow up: 5 years Two-sided = 0.05, statistical power = 80%
42、 485 patients in each group *Calculated by the method of FreedmannTwo interim analyses1 and 3 years after completion of the enrollmentAlpha spending function: OBrien & Fleming typeSakuramoto et al. N Engl J Med 2007; 357:1810-20Accrual Opened: October 2001 Closed : December 2004 Randomized : 1059 pt
43、s (S-1: 529, Surgery alone: 530) Eligible: 1034 pts (S-1: 515, Surgery alone: 519) Institutions : 109 Japanese institutionsSakuramoto et al. N Engl J Med 2007; 357:1810-20一般状况 (1)(All randomized)S-1(n=529)Surgery Only(n=530)Sex no. (%)Male367 (69.4)369 (69.6)Female162 (30.6)161 (30.4)Age no. (%)6019
44、9 (37.6)195 (36.8)60-69193 (36.5)215 (40.6)70-80137 (25.9)120 (22.6)Median (Range):yr63 (27-80)63 (33-80)Sakuramoto et al. N Engl J Med 2007; 357:1810-20一般状况 (2)(All randomized)S-1(n=529)Surgery Only(n=530)T no. (%)T11 (0.2)0T2289 (54.6)286 (54.0)T3225 (42.5)232 (43.8)T414 (2.6)12 (2.3)N, Japanese c
45、lassification no. (%)N051 (9.6)64 (12.1)N1296 (56.0)281 (53.0)N2182 (34.4)185 (34.9)N300No. of lymph-node metastasis no. (%)051 (9.6)64 (12.1)1-6331 (62.6)325 (61.3)7-15117 (22.1)113 (21.3)1630 (5.7)28 (5.3)Sakuramoto et al. N Engl J Med 2007; 357:1810-20一般状况 (3)(All randomized)S-1(n=529)Surgery Onl
46、y(n=530)Stage, Japanese classification no. (%)II236 (44.6)238 (44.9)IIIA202 (38.2)207 (39.1)IIIB90 (17.0)85 (16.0)IV1 (0.2)0Stage, TNM classification no. (%)IB1 (0.2)0II264 (49.9)282 (53.2)IIIA170 (32.1)157 (29.6)IIIB54 (10.2)56 (10.6)IV40 (7.6)35 (6.6)Sakuramoto et al. N Engl J Med 2007; 357:1810-2
47、0一般状况 (4)(All randomized)S-1(n=529)Surgery Only(n=530)Type of lymph-node dissection no. (%)D101 (0.2)D2501 (94.7)497 (93.8)D328 (5.3)32 (6.0)Type of gastrectomy no. (%)Total220 (41.6)201 (37.9)Distal301 (56.9)316 (59.6)Proximal4 (0.8)11 (2.1)Others4 (0.8)2 (0.4)Sakuramoto et al. N Engl J Med 2007; 3
48、57:1810-20依从性 : S-1PeriodCompliance (n=517)3 months87.4%6 months77.9%9 months70.8%12 months65.8%Reasons for discontinuation by 12 monthsPatients withdrawal (adverse events etc.)71 ptsDoctors decision (adverse events or complications) 72 ptsRelapse or second cancer27 ptsSakuramoto et al. N Engl J Med
49、 2007; 357:1810-20不良事件 (1)S-1(n=517)Surgery Only(n=526)Grade 3Grade 4Grade 3Grade 4Luekopenia6 (1.2%)02 (0.4%)0Anemia6 (1.2%)03 (0.6%)1 (0.2%)Thrombocytopenia1 (0.2%)02 (0.4%)0AST9 (1.7%)017 (3.2%)1 (0.2%)ALT6 (1.2%)016 (3.0%)1 (0.2%)Total bilirubin7 (1.4%)1 (0.2%)5 (1.0%)1 (0.2%)Creatinine001 (0.2%
50、)1 (0.2%)*NCI-CTC (Ver.2.0)Sakuramoto et al. N Engl J Med 2007; 357:1810-20不良事件 (2)S-1(n=517)Surgery Only(n=526)Grade 3Grade 4Grade 3Grade 4Stomatitis1 (0.2%)000Anorexia30 (5.8%)1 (0.2%)8 (1.5%)3 (0.6%)Nausea19 (3.7%)-6 (1.1%)-Vomiting6 (1.2%)07 (1.3%)3 (0.6%)Diarrhea16 (3.1%)01 (0.2%)0Rash5 (1.0%)0
