항암약물치료 Recent Clinical Data Review -Gastric Cancer (Anticancer Systemic Treatment) Do-Youn Oh, MD., PhD. Medical Oncology, Seoul National University Hospital Cancer Research Institute, Seoul National University College of Medicine 85 th Board Review, 23 Oct 2015
Case 1 56세여자 3개월전부터시작된어지럼증 2개월전부터시작된식후더부룩함 최근 3개월간 4 kg 의체중감소 Hgb: 7.5g/dL
Case 1 위내시경 Eso; Free Sto; Body lesser curvature 전체를 involve 하는 10cm 크기의 ulcerofungating mass 가 GE junction 을 invasion 하고있음. Duo; Free Imp) AGC Borrmann type II. Bx: Poorly differentiated carcinoma (Adenoca, PD)
Case 1 내시경초음파 Body lesser curvature 에 subserosal invasion 을동반하는 wall thickening 이관찰되며, max. diameter 1.7cm 크기의 multiple celiac lymphadenopathy 를동반하고있음. Imp) AGC with subserosal invasion. T3N2.
Case 1. Stomach CT Extensive ulceroinfiltrative wall thickening and mass, lesser curvature side of gastric cardia to angle. -with perigastric fat infiltration. - with several enlarged LNs. -with intravascular tumor thrombi within perigastric vein and main portal vein
Case 1 이환자의치료로추천할방법은? 1) 수술 보조항암치료 (Adjuvant chemotherapy) 2) 선행보조항암치료 (Neoadjuvant chemotherapy) 수술 3) 수술전보조항암치료 (Preop chemotherapy)-> 수술 -> 수술후보조항암치료 (Postop chemotherapy) 4) 수술 보조항암방사선치료 (Adjuvant chemoradiotherapy) 5) 선행보조항암방사선치료 (Neoadjuvant chemoradiotherapy) 수술
Surgical Procedure : NCCN guideline Resectable tumors Gastric resection should include the regional lymphaticsperigastric lymph nodes (D1) and those along the named vessels of the celiac axis (D2), with a goal of examining at least 15 or greater lymph nodes.
Adjuvant Therapy for GC 4 different modalities in 4 different regions
Pivotal positive trials in 2000 s Study Country Strategy Chemo -agents SWOG90 08/INT01 16 US Postop. CCRT Vs. S alone FL Cancer Stage N Surgery Survival GC:80% GEJ:20% Eso:0% IB-IVM0 559 (227:282) D2: 10% D1: 36% D0:54% 5YSR 43% vs 27% HR 0.669 MAGIC UK, etc Periop. Chemo Vs S alone ECF GC:74% GEJ:11% Eso:15% II-IVM0 503 (250:253) D2:42% D1:17% Esophage ctomy 26.5% 5YSR 36% vs 23% HR 0.75 ACTS- GC Japan Postop. Chemo Vs S alone S-1 GC:100 % Eso:0% II, IIIA, IIIB (Japanes e) 1059 (529:530) D2:94% D3:6% D1:0% 5YSR 71% vs 61% HR 0.669 CLASSIC East Asia Postop. Chemo Vs S alone XELOX GC:100 % Eso:0% II, IIIA, IIIB 1035 (520:515) D2:100% 5YSR 78% vs 69% HR 0.66
Pivotal positive trials in 2000 s Difference in survival outcome across trials 5Y-OS Rate 90% 80% 70% 60% 50% 40% 0.669 0.75 0.669 0.66 HR Surgery alone Adjuvant treatment 30% 20% 10% 0% INT0116 MAGIC ACTS-GC CLASSIC
Case 1 이환자는 Total gastrectomy with D2 LN dissection 을시행받았다. 이환자의수술후병리결과는다음과같다. Adenocarcinoma, Poorly differentiated, diffuse type pt4a :invades serosa (visceral peritoneum) pn2 : 3/43 LN (+) Resection margin (-) Stage IIIB (AJCC 7th ed.) 수술 5 주차에환자의 performance status 는 ECOG 1 이다.
Case 1 이후의치료로추천할방법은? 1) TS-1 for 6 months 2) Capecitabine+Oxaliplatin for 6 months 3) 5-FU+Leucovorin for 6 months 4) Etoposide+Cisplatin+5-FU for 6 months 5) TS-1+Oxaliplatin for 6 months
ACTS-GC Stage II or III GC After D2 resection N=1059 R A N D O M I Z A T I O N 1:1 N=529 S-1 for 12 months Observation: No adjuvant therapy N=530 Primary endpoint: Overall survival Secondary endpoints: RFS, Safety
CLASSIC Surgically (D2) resected Stage II, IIIA, or IIIB* GC, 6 weeks prior to randomization No prior chemotherapy or radiotherapy n=1035 R A N D O M I Z A T I O N 1:1 n=520 Capecitabine: 1,000mg/m 2 bid, d1 14, q3w Oxaliplatin: 130mg/m 2, d1, q3w n=515 8 cycles of XELOX (6 months) Observation: No adjuvant therapy Primary endpoint: 3-year DFS Secondary endpoints: overall survival and safety profile *Sixth edition of the AJCC/UICC cancer staging manual (2003-2010) Stratified by stage and country with age, sex, and nodal status as covariates GASTRIC project: 3-year DFS and 5-year overall survival are strongly associated, Burzykowski et al. ASCO 2009
Case 2 57 세여자 4개월전부터시작된허리통증 1개월전부터시작된명치부위통증 한달반사이에 66kg->60kg 으로체중감소
Case 2 위내시경 조직검사 Eso; Free Sto; High body ant.wall 에서 lesser curvature 에걸쳐광범위한 infiltrative mass 가관찰됨. Duo; Free Adenocarcinoma, poorly differentiated with signet ring cell component Imp) Infiltrative mass on high body ant.wall to lesser curvature. R/O AGC Borrmann type III.
Case 1. Abdomen CT
Case 1. PETCT
Case 2 이환자의 Systemic treatment 를결정하기위해 tumor tissue 에서확인해야할것은? 1) EGFR Immunohistochemistry 2) HER2 Immunohistochemistry 3) VEGF Immunohistochemistry 4) KRAS mutation 5) EGFR mutation
Targeting HER2 in GC ToGA: Phase III, randomised, open-label, international, multicentre study 3,807 patients screened 1 810 HER2- positive Primary endpoint: OS HER2- positive advanced GC (n=584 * ) HER2-positive : IHC 3+ or HER2 FISH (+) Secondary endpoints: PFS, TTP, ORR, clinical benefit rate, DoR, QoL, safety, pain intensity, analgesic consumption, weight change, pharmacokinetics R XP or FP (n=290) XP or FP + trastuzumab (n=294) * 594 patients randomised, 10 patients never received treatment Chosen at investigator s discretion: 87.5% of patients received capecitabine ITT population R = randomisation Bang, et al. Lancet 2010
Targeting HER2 in GC No. at risk Probability of survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 F/X + C + Trastuzumab F/X + C 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 294 290 277 266 246 223 209 185 173 143 Overall Survival 11.1 13.8 147 117 113 90 90 64 71 47 56 32 Events 43 24 167 182 30 16 21 14 Median OS 13.8 11.1 13 7 12 6 HR 0.74 6 5 4 0 95% CI 0.60, 0.91 Months 1 0 0 0 p value 0.0046 F, 5-FU; X, Xeloda ; C, cisplatin
Case 2 Tumor tissue 에서시행한 HER2 Immunohistochemistry 의결과는다음과같다. IHC equivocal (2+) :Weak to moderate complete or basolateral membrane staining in >10% of cells
Case 2 이후치료를위한결정은? 1) HER2 IHC 2+ 로양성소견이므로, Trastuzumab/Capecitabine/Cisplatin 치료를한다. 2) HER2 IHC 2+ 로음성소견이므로, Capecitabine/Cisplatin 치료를한다. 3) HER2 FISH 검사를시행한다. 4) VEGF Immunohistochemistry 를시행한다. 5) EGFR Immunohistochemistry 를시행한다.
Targeting HER2 in GC HER2 positivity IHC 0 IHC 1+ IHC 2+ IHC 3+ HER2 Amplification(-) HER2 Amplification(+) ToGA: IHC 3+ or HER2 FISH (+, HER2/CEP17 ratio>2) US FDA: IHC 3+ or HER2 FISH (+) EMA: IHC3+ or IHC2+/FISH+
Probability of survival Targeting HER2 in GC OS in HER2 IHC 2+/FISH+ or IHC 3+ (exploratory analysis) 1.0 0.8 0.6 0.4 XP/FP + T Median Events OS HR 95% CI XP/FP 136 11.8 120 16.0 0.65 0.51, 0.83 D 4.2 0.2 11.8 16.0 0.0 0 6 12 18 24 30 36 Time (months) No. at Risk XP/FP + T XP/FP 228 218 196 170 142 122 100 84 65 51 39 28 20 12 11 5 4 1 0 218 198 170 141 112 96 75 53 39 28 20 13 11 4 3 3 0 0 0
Case 2 시행한 HER2 FISH 검사에서양성소견을보였다. 환자는 work-up 중에, 허리통증등에대해증상조절을하여서, 현재 ECOG 1 의 Performance status 를보이고있다. 이에 Trastuzumab/Capecitabine/Cisplatin 치료를계획중, 추가적으로확인해야할것은? 1) Brain MRI 2) 안과검진 3) PFT 4) ECHOCG 5) Urine analysis
Case 2 2 주기의 Trastuzumab/Capecitabine/Cisplatin 치료후시행한반응평가는다음과같다.
Case 2 2 주기의 Trastuzumab/Capecitabine/Cisplatin 치료후시행한반응평가는다음과같다.
Case 2 반응평가는? 1) CR 2) PR 3) SD 4) PD 5) Not evaluable
Case 2 치료를진행하는중, 환자는다시허리통증을호소하였다.
Case 2 치료를진행하는중, 환자는다시허리통증을호소하였다.
Case 2 이환자의 Performance status 는 ECOG 1 을유지하고있다. 치료에대해환자와상의할점은? 1) 2 차항암치료는효과가입증되어있지않으므로, 보존적치료를추천한다. 2) 2 차치료로는효과가입증되어있는약제가없으므로신약임상연구를추천한다. 3) 보존적치료만하는것보다 2 차항암치료를하는것이생명연장에도움이된다. 4) 보존적치료만하는것보다 VEGF 에대한표적치료제가생명연장에도움이된다. 5) 2 차항암치료제단독보다 VEGF 에대한표적치료제를추가하여치료하면생명연장에도움이된다.
2 nd -line chemotherapy Second-line chemotherapy vs. BSC, Korea GC Failure to previous chemotherapy (n = 193) R 2:1 Docetaxel 60 mg/m 2 q3wks or Irinotecan 150 mg/m 2 q2wks BSC alone Strict QC measures for BSC Standard BSC regimen a priori defined BSC patients could exit BSC at any time All patients treated & followed up in same way Kang JH et al. J Clin Oncol 2012
Probability of Survival 2nd-line chemotherapy Second-line chemotherapy vs. BSC, Korea 1.0 0.8 0.6 Median f/u (95% CI): 17 mo (16-18 mo) Median 95% CI SLC + BSC 5.1 mo 4.0-6.2 BSC alone 3.8 mo 3.0-4.6 Log-rank P=0.009 0.4 0.2 0.0 0 6 12 18 Months Kang JH et al. J Clin Oncol 2012
Targeting VEGFR2 in GC Ramucirumab: Fully humanized IgG1 monoclonal antibody with high affinity and specificity to VEGFR2 VEGF-C VEGF-D VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2 VEGF-A VEGFR2 Ramucirumab Endothelial cell membrane VEGFR2 VEGF-A VEGF-C VEGF-D Ramucirumab binds to VEGFR2, blocks VEGF ligand binding Ligand binding activates VEGFR2 and p44/p42 MAP kinases Angiogenesis Tumor growth No signaling Inhibit new blood vessel formation and tumor growth
REGARD-2 nd -line Phase III, 119 centers, 29 countries Gastric or GEJ ca Failure to 1 st -line chemotherapy ECOG 0,1 (N=355) R 2:1 Ramucirumab + BSC (N=238) Placebo + BSC (N=117) Stratification: geographic region, weight loss, location of primary tumor Primary objective: To compare the OS Secondary objectives: To evaluate PFS, PF at week 12,RR, DoR, Safety, PD and immunogenicity profile
REGARD-2 nd -line OS PFS -Ram 5.2 m -Placebo 3.8 m -Ram 2.1 m -Placebo 1.3 m Charles S Fuchs, et al. Lancet 2014
REGARD-2 nd -line Time to deterioration in ECOG PS to a score of 2 or worse Charles S Fuchs, et al. Lancet 2014
RAINBOW-2 nd -line Phase III, 170 centers, 27 countries Gastric or GEJ ca Failure to 1 st -line chemotherapy ECOG 0,1 (N=665) R 1:1 Paclitaxel + Ramucirumab Paclitaxel+ Placebo Stratification: geographic region, measurable vs non-measurable, time to progression on 1 st -line therapy (<6m vs >6m) Primary objective: To compare the OS (H0:7.0m, H1: 9.3m, HR 0.75, 90% power) Secondary objectives: To evaluate PFS, TTP, Overall response,
RAINBOW-2 nd -line All efficacy parameters are improved with Ram OS PFS RR DCR Paclitaxel + Ram(N=330) 9.63 m 4.40 m 28% 80% Paclitaxel+ Plac(N=335) 7.36 m 2.86 m 16% 64% HR 0.807 (0.67-0.96) P=0.0169 HR 0.635 (0.53-0.75) P<0.0001 P=0.0001 P<0.0001 Absolute difference 2.3 m 1.5m 12% 16% Wilke H, et al. Lancet Oncol 2014
Summary 항암약물치료는암에대한전신적 control 을위해시행된다. 종류는 cytotoxic chemotherapy, targeted agents (-nib, -mab, etc), hormonal agent, immune-acting agent (CTLA4 inhibitor, PD1/PDL1 inhibitor, vaccine, etc) 등을모두포함한다. Localized cancer 의경우는 definitive treatment modality 에보조적으로시행되어, cure 의확률을올린다. Advanced cancer 의경우는, 생존기간의향상과삶의질을향상시킨다. 환자의전반신체수행능력이특정약제를사용하기에적절한경우에고려한다. 암종류에따라, personalized treatment 를위한진단검사, 치료의가이드라인을따른다.