Neo- and adjuvant treatment for gastric cancer: The role of chemotherapy

Transcription

1 Anna Dorothea Wagner, PD & MER Department of Oncology University of Lausanne Neo- and adjuvant treatment for gastric cancer: The role of chemotherapy

2 Structure 1. Background and overview 2. Adjuvant chemotherapy: ACTS-GC/ «CLASSIC»/ ITACA-S-trials 3. Neoadjuvant/perioperative chemotherapy MAGIC/ FFCD/ FLOT-4 4. Who benefits by how much? 5. Perspectives: integration of targeted therapies

3 1. Background: ESMO Guidelines

4 1. Background: Evolution of chemotherapy Author/Jahr Regimen ORR % Med. OS (Months) Cunningham 2008 ECF vs. EOX 41 vs. 48 % 9.9 vs 11.2 Dank 2006 CF vs. IF 27 vs. 32 % 8.7 vs 9.0 Ajani 2006 CF vs. DCF 25 vs. 37 % 8.6 vs 9.2 Al-Batran 2006 FLP vs. FLO 25 vs. 35 % 8.8 vs 10.7 Kang 2008 FP vs. XP 29 vs. 41 % 9.3 vs 10.5 Al-Batran 2010 FLO vs. FLO-T 27 vs. 49 % 14.4 vs 17.3 Bang 2010 XP-T (in HER-2+ pts) 47 % 13.8

5 1. Background: the role of docetaxel in advanced gastric cancer Substitutive comparisons Additive comparisons Primary endpoint: overall survival Wagner, ASCO GI 2015

6 Structure 1. Background and overview 2. Adjuvant chemotherapy: landmark studies 3. Neoadjuvant chemotherapy 4. Perioperative chemotherapy 5. Who benefits by how much? 6. Perspectives: integration of targeted therapies

7 HR for OS for adjuvant CTX 0.82, 95% CI y OS 49.6 vs % Paoletti, JAMA 2010

8 ACTS-GC trial N= stage II or III gastric cancer after D2-resection Primary endpoint: overall survival Secondary endpoints: relapse-free survival and safety Sakuramoto NEJM 2007, update: Sasako, J Clin Oncol 2011

9 ACTS-GC trial S mg/day for 4 weeks every 6 weeks cycle for one year within 6 weeks after surgery R Observation Sakuramoto NEJM 2007, update: Sasako, J Clin Oncol 2011

10 ACT-GC trial One year of adjuvant chemotherapy with S-1 significantly improves survival in patients with stage II or III GC Update: Sasako, J Clin Oncol 2011

11 ACT-GC trial update: Sasako, J Clin Oncol 2011

12 However Macdonald, J Clin Oncol 2014

13 «CLASSIC trial» trial N= 1035 pts, median age 56, stage II-IIIB enrolment in South Korea, China and Taiwan randomization 6 months adjuvant capecitabine/oxaliplatin versus observation D 2-resection: 100 % Bang, Lancet 2012/ update: Noh, Lancet Oncol 2014

14 «CLASSIC» trial» trial Noh, Lancet Oncol 2014

15 «CLASSIC» trial Updated analysis of disease-free survival HR 0.58 (95% CI ; p< ) Noh, Lancet Oncol 2014

16 «CLASSIC» trial Overall survival: HR 0.66 (95% CI , p= ) Estimated 5-year overall survival 78% (95% CI 74-82) for patients treated with CapOx versus 69% (95% CI 64-73) Noh, Lancet Oncol 2014

17 Classic trial - subgroup analysis for overall survival Noh, Lancet Oncol 2014

18 ITACA-S: FOLFIRI DCversus 5-FU Does the intensification of adjuvant chemotherapy improve results? N= 1106, phase III FOLFIRI q d 14 x 4, followed by docetaxel/ cisplatin (75mg/m2 on d1 q d 21) x 6 cycles of XP (capecitabine 2000mg/m 2 d1-14+ CDDP 60 mg/m 2 q d 21 x 3 R Single-agent 5-FU Bajetta, Ann Oncol 2014

19 ITACA-S: FOLFIRI DC versus 5-FU N= Overall survival Bajetta, Ann Oncol 2014

20 ITACA-S: FOLFIRI DC versus 5-FU Conclusion: Intensification of adjuvant chemotherapy by sequential use of two non-crossresistant doublet chemotherapy regimens (FOLFIRI/docetaxel/cisplatin) does not improve the efficaccy as compared to single-agent 5-FU Bajetta, Ann Oncol 2014

21 Structure 1. Background and overview 2. Adjuvant chemotherapy: landmark studies 3. Neoadjuvant/ Perioperative chemotherapy 5. Who benefits by how much? 6. Perspectives: Integration of targeted therapies

22 «MAGIC» study - clinical stage II or greater adenocarcinoma - 74% stomach N=250 R N=253 86% completed preop. ECF ECF x 3 S U R G E R Y 92% S U R G E R Y 42% completed postop. ECF ECF x 3 98% Cunningham, NEJM 2006

23 «MAGIC» study HR 0.75 (95% CI ) p=.009 in favor of perioperative chemotherapy 5-y survival 23 vs 36 % Cunningham, NEJM 2006

24 «MAGIC» study perioperative chemotherapy with ECF improves survival surgnificantly postoperative chemotherapy is feasible in less than 50% of patients in Europe value of postoperative part of perioperative chemotherapy unclear Cunningham, NEJM 2006

25 «MAGIC» study: critical points limited preoperative staging D2-resection less than 45% survival in surgery alone arm insufficient Cunningham, NEJM 2006

26 FFCD-trial: design Resectable adenocarcinoma of GE-junction (64%) or stomach N=113 R N=110 CF x 3 S U R G E R Y S U R G E R Y 47% recieved postop. CF ECF x 3 Cunningham, NEJM 2006

27 FFCD-trial study HR O.69 (95% CI ) in favor of perioperative Chemotherapy 5 year OS: 38 vs 24% Ychou 2011

28 Comparison MAGIC N= 503 chemotherapy: ECF 25 % GEJ D2-resection 40% FFCD N= 224 chemotherapy CF 64% GEJ R0-resection 87 vs. 74%

29 EORTC-trial:design Resectable adenocarcinoma of GE-junction or stomach - Staging included EUS and laparoscopy R - No adjuvant part - N= 144 CF x 3 months S U R G E R Y S U R G E R Y Cunningham, NEJM 2006

30 EORTC-trial:results PFS Overall Logrank test: p=0.200 HR 0.76 (0.49,1.16) (years) O N Number of patients at risk : Treatment S CS Overall Logrank test: p=0.466 OS HR 0.84 (0.52,1.35) (years) O N Number of patients at risk : Treatment S CS No significant advantage in disease-free or overall survival But: underpowered study Schumacher, J Clin Oncol 2011

31 Comparison FLOT- 4 study: background Pooled analysis: Impact on pathological response on prognosis Lorenzen, Ann Oncol 2013

32 FLOT- 4 study Pauligk et al, ESMO 2015

33 FLOT- 4 4 Primary endpoint phase II (n=300): rate of complete pathological remission (pcr) Primary endpoint for phase III (n=714): OS, HR 0.76, power 80%, two sided p<0.05 Pauligk et al, ESMO 2015

34 FLOT- 4 Pathological Remission (ITT FLOT- 4 group) Pauligk et al, ESMO 2015

35 FLOT - 4 FLOT is associated with significantly higher rates of pcr than ECF(X) However: path. response as endpoint not prospectively validated Enrolment of the phase III trial is completed. Survival results are expected in 2016/2017.

36 Conclusions neoadjuvant/perioperative Comparison chemotherapy Advantages + Chemotherapy is administered earlier in the disease independent of surgical complications Feasibility better before than after surgery

37 Conclusions neoadjuant/perioperative Comparison chemotherapy Disadvantages - Preoperative staging is unreliable, pathological tumor stage is unavailable. Indication for preoperative chemo is dependent on (unreliable) clinical staging Risk of disease progression during chemotherapy

38 Structure 1. Background and overview 2. Adjuvant chemotherapy: landmark studies 3. Neoadjuvant chemotherapy 4. Perioperative chemotherapy 5. Who benefits by how much? 6. Perspectives: integration of targeted therapies

39 5. Who benefits by how much? 3 subgroups need to be considered : - Gastric versus GE-Junction tumors (RT?) - Signet-cell cancers - HER-2 positive disease

40 Gastric- and GE-junction adenocarcinoma need to be distinguished Meta-analysis of neoadjuvant/perioperative chemotherapy versus surgery alone Outcome: overall survival Ronellenfitsch et al, European J Cancer 2013

41 5. Do patients with signet-cell cancers benefit from perioperative chemotherapy? Ann Surgery 2011

42 Pathological response rates with FLOT vs. ECF according to LAUREN % paaents with pcr % paaents with pcr FLOT 30 23, ,9 0,0 0 intesanal (N=52) diffuse (N=34) FLOT 23,1 2,9 0,0 intesanal (N=52) diffuse (N=34) Lauren Classificaaon ECF % paaents with pcr 25 18,75 14,3 12,5 6,25 2,6 0 intesanal (N=60) mixed (N=7) diffuse (N=39) Lauren Classificaaon Lauren Classificaaon

43 BMC 2013

44

45 Background: HER-2 positive breast cancer n=235 pts HER-2+, locally advanced/inflammatory BC, treated with CTX with versus without Trastuzumab Primary endpoint: 3-year event-free-survival 71 vs. 56 %, HR 0.59 ( ) p=0.013 Gianni Lancet 2010

46 CLEOPATRA-TRIAL: Pertuzumab in metastatic breast cancer CLEOPATRA-TRIAL: Pertuzumab in metastatic breast cancer NEJM

47 EORTC 1203

48 Conclusions Adjuvant chemotherapy is the standard of care in Asia Perioperative chemotherapy has demonstrated significant survival benefits in 2 European phase III studies Perioperative treatment with FLOT improved pathological responses as compared to ECF in a randomized phase II-trial. Phase III results are pending

49 Thank you for your attention «One size fits all» is NOT Thank the adequate you approach! in modern oncology