Chemotherapy of hepato-biliary and pancreatic tumours

1. Chemotherapy of hepato-biliary and pancreatic tumours

2. Dox – toxic death rate > RRDox – toxic death rate > RR

3. Advanced Hepatocellular CarcinomaSorafenib vs. Placebo Raf-Kinase over-expressed Raf / MEK / ERK implicatated Sorafenib multi-targeted TKI against RAF family, VEGF, PDGFb, cKIT

4. Toxicity

5. Phase III SHARP TrialTime to progression (Independent central review)

6. Phase III SHARP TrialOverall survival (Intention-to-treat)

7. Biliary Tract CancersPeri-operative therapies There is no evidence that peri-operative oncological therapies improve outcomes in resectable biliary tract cancers In the Espac-3 trial patients who had undergone a Whipple’s resection for distal bile duct cancers were randomised between observation, gemcitabine and 5FU-leucovorin. This part of the trial has not yet reported its results Within the UK patients are currently being recruited to the BilCap trial of adjuvant capecitabine chemotherapy versus observation

8. Photodynamic therapy (PDT) PDT has been used in the management of inoperable biliary tract cancers Case series report positive effects on biliary patency and small trials suggest survival benefit. Larger confirmatory trials are awaited. Main side effect is photosensitivity Depth of activity about 1cm PhotofrinDepth of activity about 1cm Photofrin

9. Advanced biliary tract cancers: no standard of care Disease-related factors Uncommon cancers Unwell, elderly population with sepsis and obstruction Histologically and cytologically confirmation difficult Lack of evidence Disease often not measurable (unreliable response assessment) Few phase III chemotherapy studies (underpowered) Database primarily small phase II studies, mostly fluoropyrimidine, platinum or gemcitabine-based Lack of multi-centre collaboration Mixed populations of HPB malignancy

10. ABC-02 - schema

11. ABC-02: study design Prospective, national, multicentre, phase III study Inclusion criteria: Histologically / cytologically verified, non-resectable or recurrent / metastatic cholangiocarcinoma, GB or ampullary carcinoma Adequate biliary drainage, no uncontrolled infection ECOG PS 0-2 LFTs: bilirubin ? 1.5 x ULN, ALT/ AST/ alk phos ? 3 x ULN (? 5 if liver metastases) No prior systemic treatment* Consenting informed-patients

12. ABC-02

15. Duration of treatment

16. Second-line treatment

17. Haematological toxicity

18. Non-haematological toxicity

19. ABC-02 - Overall Survival Stratified sub-group analysis

20. ABC-02 conclusions Cisplatin and gemcitabine for ABC significantly improved overall survival (by 3.6m) Reduced risk of death by 36% (HR 0.64, p<0.001) Significantly improved progression-free survival and tumour control First demonstration of survival benefit in ABC Benefit gained with no clinically significant added toxicity or decrease in QoL Large, collaborative, randomised studies in patients with BTC are feasible CisGem is recommended as a worldwide standard of care and the backbone for future studies

21. Pancreatic cancer - rationale for adjuvant therapies Surgical failure is common, with 80% of patients developing progressive disease within 12 months of surgery Disease progression occurs both locally and at distant sites

22. Adjuvant post-op chemoradiation Kalser et al (1985) Arch Surg (GITSG trial) N=43 randomised between chemo-XRT (4000 rads, split course 5FU d1-3) or observation. Chemo continued for 2 years 24% of patients couldn’t start Rx ‘till after wk10 The GITSG trial was the first prospective randomized trial suggesting survival advantage with postoperative chemo-radiotherapy using bolus 5-FU (median survival: 20 months vs. 11 months; 5-year survival: 18% vs. 8%) [3]. However, this study was criticized for poor patient accrual, early termination, and small patient numbers, and some maintained that the radiotherapy dose was suboptimal (some authors advocate 50 Gy as a total effective dose).The GITSG trial was the first prospective randomized trial suggesting survival advantage with postoperative chemo-radiotherapy using bolus 5-FU (median survival: 20 months vs. 11 months; 5-year survival: 18% vs. 8%) [3]. However, this study was criticized for poor patient accrual, early termination, and small patient numbers, and some maintained that the radiotherapy dose was suboptimal (some authors advocate 50 Gy as a total effective dose).

23. Klinkenbijl et al (1999) Ann Surg (EORTC trial) N=218, pancreatic (55%) and peri-ampullary cancers. 20% received no treatment due to post-op complications or patient refusal. Split course 40 Gy XRT. 5FU infusion 25mg/kg/d d1-5 XRT course 1 and up to d5 course 2 In patients with pancreatic cancer: The European Organization of Research and Treatment of Cancer (EORTC) compared 5-FU with concurrent radiotherapy using a split course with observation only in patients with resected pancreatic and periampullary cancer [4]. The subgroup analysis looking only at pancreatic cancer patients showed a trend toward benefit in median survival (17.1 months vs. 12.6 months; P=0.099) [4]. This study too was criticized for suboptimal dose of radiotherapy and split courses.The European Organization of Research and Treatment of Cancer (EORTC) compared 5-FU with concurrent radiotherapy using a split course with observation only in patients with resected pancreatic and periampullary cancer [4]. The subgroup analysis looking only at pancreatic cancer patients showed a trend toward benefit in median survival (17.1 months vs. 12.6 months; P=0.099) [4]. This study too was criticized for suboptimal dose of radiotherapy and split courses.

24. Espac-1 study Neoptolomos (2001+2004) 541 patients randomised 2x2 design between surgery +/- chemoradiation (40Gy (although clinicians were allowed to administer higher radiation doses) + 5FU d1-3) +/- chemotherapy (5FU/FA – ‘Mayo clinic’ regimen) 2x2 design –means that 1/2 of ‘no chemo’ and of ‘chemo’ patients received chemoradiation 50 patients did not receive assigned therapy Only 285 patients randomised in 2x2 design 1/3 of ‘no chemotherapy’ patients received chemoradiation, as did 1/3 of chemo patients. No QA 1/3 of ‘no chemotherapy’ patients received chemoradiation, as did 1/3 of chemo patients. No QA

25. Espac-1 study 1/3 of ‘no chemotherapy’ patients received chemoradiation, as did 1/3 of chemo patients. Only 2/3 of patients completed chemo following chemoradiation and 17% didn’t even start it 1/3 of ‘no chemotherapy’ patients received chemoradiation, as did 1/3 of chemo patients. Only 2/3 of patients completed chemo following chemoradiation and 17% didn’t even start it

26. ESPAC-1Chemoradiotherapy v no chemoradiotherapy Espac-1 Survival by CRT vs no CRTEspac-1 Survival by CRT vs no CRT

27. ESPAC-1 Chemotherapy v no chemotherapy Espac-1 Survival by CRT vs no CRTEspac-1 Survival by CRT vs no CRT

28. Adjuvant treatment in resected Pancreatic CancerCONKO-001 Trial Design

30. Conko-001 Disease-free survival (months)

31. Conko-001 Overall survival (months) Good data on DFS ns for overall survivalGood data on DFS ns for overall survival

32. US Intergroup Adjuvant: RTOG 97-04

33. US Intergroup Adjuvant: RTOG 97-04 Analysis of patients with pancreatic head cancer only demonstrated a non-significant benefit to the gemcitabine alone arm Hazard ratio 0.82 (0.65 – 1.03) No significant diff if body and tail tumours were includedNo significant diff if body and tail tumours were included

35. Espac-3 10% didn’t start post-op chemo. Only 55-60% of patients completed it. Safety, compliance, dose intensity and SAEs better with gemcitabine 10% didn’t start post-op chemo. Only 55-60% of patients completed it. Safety, compliance, dose intensity and SAEs better with gemcitabine

36. Ongoing trial of adjuvant treatment Espac-4 Gemcitabine versus gemcitabine-capecitabine

37. What is optimal therapy in resectable pancreatic cancer? No evidence of benefit to pre-op treatment Many patients take too long to recover from surgery for post-op treatment No randomised evidence for benefit of post-op radiotherapy and median survival in intergroup study worse than that in Espac-3 Survival benefit for post-op chemo, but the optimal regimen remains to be determined

38. Management of Advanced disease Burris (1997) 126 patients randomised between weekly bolus 5FU and gemcitabine Endpoint ‘clinical benefit response’

39. Clinical benefit response

40. Chemotherapy for advanced disease Bramall – gem + MMPI = gem Moore – gem vs MMPI – 2.9 month survival advantage to gemBramall – gem + MMPI = gem Moore – gem vs MMPI – 2.9 month survival advantage to gem

41. Locally advanced/metastatic pancreatic cancer - NCIC CTG PA.3 Overexpression of epidermal growth factor (EGFR) pathway is commonly seen in pancreatic cancer; associated with more aggressive disease and poorer outcome Erlotinib (Tarceva): small molecule tyrosine kinase inhibitor of EGFR Preclinical synergy observed between gemcitabine + erlotinib in xenograft models (Ng Mol Cancer Ther 2002) Activating k-ras mutations occur in > 90% of patients with pancreatic adenocarcinomaActivating k-ras mutations occur in > 90% of patients with pancreatic adenocarcinoma

42. Locally advanced/metastatic pancreatic cancerNCIC CTG PA.3 – Overall Survival

44. Locally advanced/metastatic pancreatic cancerNCIC CTG PA.3 – Rash and Survival

45. Unrelated to EGFR expression by IHCUnrelated to EGFR expression by IHC

47. Locally advanced/metastatic pancreatic cancerGEM-CAP toxicity

50. Five meta-analysis comparing gemcitabine monotherapy with gemcitabine plus a second drug (chemotherapy or targeted drugs) in the treatment of advanced pancreatic cancer, have been recently published. All but one of these meta-analysis have found a modest but statistically significant improvement in OS when a doublet was used. Five meta-analysis comparing gemcitabine monotherapy with gemcitabine plus a second drug (chemotherapy or targeted drugs) in the treatment of advanced pancreatic cancer, have been recently published. All but one of these meta-analysis have found a modest but statistically significant improvement in OS when a doublet was used.

51. Combination Chemotherapy Chemo combinations can increase response rates wrt gemcitabine alone, but don’t increase survival Meta-analysis suggests marginal survival benefit for combination therapies Subgroup analyses of some trials suggest that gemcitabine doublets or triplets may be of benefit in patients of PS 0 or 1

52. Chemotherapy Trials in Pancreatic Cancer Pointers in pancreatic cancer Reponses can be hard to measure due to local fibrotic reaction, so radiological responses may be less helpful than with other tumour types Phase II trials often have large proportions of patient with locally advanced disease, which has a significantly better prognosis than metastatic disease Only well-validated endpoint is survival. CA19-9 measurement is not a validated endpoint Watch out for trials of liposomal paclitaxel

53. Immunotherapy – Telovac ASCO last year – phase III of TV1001 showed no benefit – trial therefore prematurely terminatedASCO last year – phase III of TV1001 showed no benefit – trial therefore prematurely terminated

54. 2nd line therapy? - Conko-03 PD on gemcitabine, KPS =70% FF - FA 200mg/m2 + 5FU 2g/m2 over 24 hrs d 1,8,15,22 q 42/7 OFF – FF + oxaliplatin 85mg/m2 d 8 and 22 Characteristics n= 168. Randomised on average 2/52 after PD (range 0-6) =2/3 patients metastatic disease 40% KPS 90-100 Median 23/52 on gem, 20% gem refractory In their practice 30-50% patients receive 2nd line therapy. Median in this trial 34/52 on gem.In their practice 30-50% patients receive 2nd line therapy. Median in this trial 34/52 on gem.

55. Conko-03

56. About 20% of pancreatic cancer patients get clinical evidence of thromboembolic diseaseAbout 20% of pancreatic cancer patients get clinical evidence of thromboembolic disease

57. Thromboembolic disease and pancreatic cancer Fragem and conko-4 trials. Final results awaited.Fragem and conko-4 trials. Final results awaited.

58. Chemotherapy of pancreatic and hepato-biliary tumours