Upper Gastrointestinal Cancers in the Elderly. Choo Su Pin Senior Consultant Medical Oncology National Cancer Centre Singapore

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1 Upper Gastrointestinal Cancers in the Elderly Choo Su Pin Senior Consultant Medical Oncology National Cancer Centre Singapore

2 Gastric Cancer --High Global Burden Global Cancer Deaths % of all cancer (2008) deaths Lung Cancer 1,400, % Stomach Cancer 740, % Liver Cancer 700, % Colorectal Cancer 610, % Breast Cancer 460, % Jemal et al. CA Cancer J Clin 2011;61:69 90

3 OesophagealCancers Among top 10 causes of cancer deaths worldwide More common in males Affects developing countries more esp Africa and East Asia Squamous cell carcinoma predominant in these countries In Singapore 80% are squamous cell carcinoma, the rest mostly adenocarcinoma GLOBOCAN 2008

4 Gastro-oesophagealCancer is a disease of the elderly 60.9% of oesophagealand 64.6% of gastric cancers occur in those aged 65years

5 Curative Surgery is mainstay of care in Gastric Cancer (GC) D2 Gastrectomy is a standard of care here European studies have not shown better outcomes with D2 vs D1 dissection and have higher postop mortality: Dutch postop mortality 4% vs Japanese postop mortality 0.8% D2 dissection includes removal of: 7, left gastric artery; 8, common hepatic artery; 9, celiac artery; 10, splenic hilus; 11, splenic artery Sasako 2008, Hatgrink 2004

6 Are surgical outcomes in elderly the same for GC? (Takeshita 2013) N=1193 gastrectomiesfor GC, of which n=104 aged 80 years and above Postopmortality 1.9% in 80yrs vs 0.7% in younger But no differences in disease-specific survival between those 80yrs vs those < 80yrs even when D2 gastrectomy done

7 More postop complications in the elderly Hayashi 2012

8 E-PASS score predicts for postop N=414 pts who had gastrectomies + LND for GC: 38.4% 75yrs 61.6% < 75yrs Comprehensive Risk Score ( CRS) predicted for survival outcome after surgery and death from comorbid disease CRS calculated from Pre-op Risk Score ( Age, severity of IHD and lung disease, DM, ECOG and ASA physiological status) and Surgical Stress Score ( blood loss/weight; operation time; extent of skin incision) complications Ariake2014

9 ROLE of ADJUVANT THERAPY in GASTRIC CANCER Practice differs between regions: Gastric Cancer amenable to surgery Should we be offering adjuvant therapy to elderly patients? Is this benefit worth the potential side Curative Surgery followed by Adjuvant Chemotherapy +/-RT Prevent Relapse Cure Prolong Survival effects? Absolute benefit of Adjuvant Therapy after curative surgery is about 10-15%

10 Adjuvant Chemotherapy in GC our practice Options are: 1) Oral TS-1 x 1 year ACTS-GC trial (Sakuramoto 2007) N=1059 Aged 20-80yrs, all had D2 gastrectomy 2) Oral Xeloda+ iv Oxaliplatin( XELOX) x 6 months CLASSIC trial ( Bang 2012, 2013) N=1035, D2 gastrectomy, R0 68% HR for death=0.68; p= y DFS 53% P< S1 post-op Surgery XELOX post-op Surgery 3-year OS 80.1% 70.1% 3-year RFS 72.2% 59.6% 5-year DFS 68% 53% 5-year OS 78% 69%

11 Adjuvant TS-1 in resectedgc ( ACTS-GC trial) Patients aged > 80yrs were not included in this trial NEJM 2007; 357:

12 Classic study Subgroups and toxicity Bang Lancet 2012 G3/4 AE XELOX (%) Neutropenia 22 PLT 8 Nausea 8 Vomiting 7 Neuropathy 2 DFS benefit appears to be less in N0. Stat sig in N1 and N2. However only 10% of pt N0. 12

13 MAGIC trial N= 503 from Centers from UK, Holland, Germany, Brazil, Singapore, NZ About 20% were 70 yrs and above 14% lower oes 11% EGJ Cunningham 2006

14 Adjuvant Chemo in Elderly with D2 Gastrectomy Retrospective series, n=360 GC patients aged >65years All had D2 gastrectomy 34.7% received adjuvant chemotherapy Findings: Adjuvant chemotherapy increased OS, HR0.60, p0.003 Stage 3 GC benefited from chemo, not Stage I & II Benefit was seen with fluropyrimidine chemotherapy Jin 2013

15 Adjuvant Therapy in Elderly with ResectedGC Most of the trials included elderly patients Benefit of adjuvant therapy shown across all age groups Whether or not adjuvant therapy should be given should be discussed with each patient: Balance benefit with potential toxicities

16 Curative Approaches to Oesophageal Cancers-our practice Surgery alone Definitive ChemoRT(cervical oesophageal) Pre-operative ChemoRTfollowed by surgery

17 Surgical Approaches for Oesophageal Ca

18 Outcomes of oesophagealresection in elderly-retrospective series

19 Definitive ChemoRT for oesophageal cancer: RTOG T3N0-1 thoracic eso SCF LN allowed 90% SqCC, 10% adeno N=123 R CF cisplatin75mg/m2 D1 and 5-FU 1000mg/m2 for 4 days on D1 and D29 with RT 50Gy/25# > 2 cycles CF q3wk RT 64Gy CRT RT Median OS 14.1m 9.3m 5yr OS 27% 0% Local failure 47% 66% P<0.001 More than 20% in each arm were aged 70y and above CRT is toxic 64% G3/4 toxicity > 50% myelosuppresion, 8% N&V No toxicity analysis in relation to age Herskovic A et al. NEJM 1992 Al-SaraffM et al. JCO 1997

20 Definitive ChemoRT in Elderly with OC Study Patients Treatment Outcomes Toxicities Tougeron 2008 Single institution series Anderson 2007 Single institution series Servagi Vemat 2009 Phase II N=109, 70y and above with OC (70.6% SCC) N=25, Pts > 65y with stage II or III OC N=22 aged 75y stage II & III ( 68% SCC) Concurrent RT with Cisplatin + 5FU ( 89.9%) or Irinotecan + Cisplatin (9.2%) Concurrent RT with5fu + Mitomycin-C Concurrent RT with cisplatin Median OS 15.2m DFS 8.3m 5Y 0S 12.8% Median OS 35m 2y OS 64% 56.9% grade 2 AE 36% grade 3-4 haem toxicity 1y OS 62.4% Only grade 2 vomiting 53.2% had dose reductions No differences in outcomes between Charlson comorbid score 2 or >2.

21 Neoadjuvant Chemo RT followed by surgery: CROSS trial Thoracic oeso+ GOJ (<2cm invasion stomach) adenoca, SqCC, large cell T1N1 or T2/3 N0-1 No M1a/b ds N=366 Pts aged 36-79yrs 75% adenoca; 23% SCC 80% T3; 65% N1 80% lower oeso (58%) / GEJ (22%) 5x Weekly carboauc2 5x Weekly taxol 50mg/m2 RT 41.4Gy in 25# + Surgery Surgery CRT-- Surgery Surgery Median OS 49.4m 24m R0 resection 92% 69% Local recurrence 14% 34% Peritoneal mets 4% 14% Less than 13% grade 3 toxicities No analysis on relationship between age and outcomes or toxicities Van Hagen et al. NEJM 2012

22 Palliative chemotherapy in the Elderly with Gastro-oesophageal cancers

23 Management of Advanced Gastric Cancer; Chemotherapy improves OS compared to BSC Survival with best supportive care (BSC) alone: 3 months Chemotherapy improves OS compared to BSC: Benefit about 6 months Quality of life isalso improved. (HR 0.39, 95% Cl , p< ) Wagner et al., JCO 2006

24 Is combination chemo better than single agent? Combination chemo superior to single agent [HR 0.83, 95%CI , p=0.001] Wagner A D et al. JCO 2006;24:

25 Which combination is better? New generation regimen since 2000 Study Treatment No.Pt RR (%) TTP (month) OS (month) p - value Van Cutsem (V325) Dank (V306) Cunningham (REAL-2) Kang Boku (JCOG9912) Narahara (SPIRITS) Ajani (FLAGS) CDDP+5FU Doce+CDDP+5FU CDDP+5FU Irinotecan+5FU/LV ECF EOF ECX EOX CDDP+5FU CDDP+capecitabine FU CDDP+irinotecan S S CDDP+S CDDP+5-FU CDDP+S NS 0.02 NS NS

26 Studies on chemotherapy in Elderly GC Catalona 2012 No. of pts Regimen Response PFS OS Gd3 Toxicities 43 mfolfox 1 st line Liu mfolfox 1 st line Kim Frail or elderly; Kim aged 70yrs Tsushima aged 70yrs mfolfiri salvage 77% received doublet or triplet chemo S-1+ cisplatin (n=21) vs S-1 (n=37) 34.9% 6.8m 10.5m <10% 52.5% 6.5m 10m <8% 12.5% 2m 5.4m 20% 26% m 19.7% - 5m vs 5.2m 14.4m vs 10.9m Haem toxicities 57% vs 35%

27 Trastuzumabimproves survival when added onto Chemo for HER2 + GC: ToGAtrial Phase III, randomised, open-label, international, multicentre study 3807 patients screened 1,2 810 HER2-positive* Primary endpoint: OS Stratification factors HER2-positive advanced GC (n=584) advanced vs metastatic GC vs GEJ measurable vs non-measurable ECOG PS 0-1 vs 2 capecitabine vs 5-FU R 5-FU or capecitabine + cisplatin (n=290) 5-FU or capecitabine + cisplatin + trastuzumab (n=294) *as defined in the protocol (IHC 3+ and/or FISH+) Chosen at investigator s discretion 1. Bang et al. ASCO 2009; Abstract Chung et al. ECCO-ESMO 2009; Abstract

28 Efficacy: OS subgroup analysis Category Subgroup N HR 95% CI All All , 0.91 Primary site GEJ , 1.08 Stomach , 0.96 ECOG PS , , 1.79 Fluoropyrimidine 5-FU , 1.23 Capecitabine , 0.95 Age group < , 1.14 > , 0.88 Region Asia , 1.11 C/S America Europe , , 0.89 Other , 3.08 GC type Diffuse Intestinal , , 0.88 Mixed , 1.46 Prior gastrectomy No 451 Yes , , 1.34 No. metastatic sites , 1.26 > , Favours T Risk ratio Favours no T

29 ToGatrial:Safety: cardiac AEs Cardiac event, n (%) F+C n=290 F+C + trastuzumab n=294 All Grade 3/4 All Grade 3/4 Cardiac AEs, total 18 (6) 9 (3) 17 (6) 4 (1) Cardiac failure 2 (<1) 2 (<1) 1 (<1) 1 (<1) LVEF drops* <50% 2 (1.1) 14 (5.9) <50% and by 10% 2 (1.1) 11 (4.6) Cardiac AEs leading to death 2 (<1) Cardiac arrest; cardio-respiratory arrest 2 (<1) Acute MI; cardiac failure Would recommend careful systolic dysfunction monitoring in elderly *Measured at baseline and every 12 weeks; MI, myocardial infarction

30 Palliative Chemotherapy in Elderly Multiple clinical trials have shown that there are a variety of effective chemotherapy options for GOC Current data shows that chemotherapy in elderly is as effective However, toxicities can be more common We have to tailor treatment to particular needs of each elderly patient

31 Concluding thoughts There is underrepresentation of elderly patients in clinical trials partly due to strict selection criteria Thus applying what we know as best treatment to elderly patients has to be balanced against known risks of the treatment itself Regardless, chronological age should not be a limiting factor in determining best treatment but the biological age and fitness of the patient should be considered first Any treatment decisions in the elderly must take into consideration ECOG, nutritional status, comorbidity and future QOL Several tools exist ( geriatric assessment scores etc) to help us make these decisions. While running elderly specific trials may be difficult, more such trials are needed in order to answer our questions. In meantime, other trials should be designed to incorporate age in relation to outcomes

32 Thank you