Conservative treatment of liver metastasis Alvydas Cesas MD, head of chemotherapy department Klaipeda Hospital

Frequency of Liver Metastases of Colorectal Cancer  30 - 40% of colorectal primaries Frequency of liver metastases of colon cancer are approximatly 30-40% for all cases. Steele Jr G et al., Ann Surg, 1989

In this slide you can see treatment modalities in cases liver metastases and probabilitty of survival. We shoud to choose one or more treatment modalities.

Survival benefit 30% at 5 years COLORECTAL CANCER LIVER METASTASES Resectable 10-20% Non resectable 80-90% IV Chemo IA Chemo Others Until recently, the treatment of hepatic metastases from colorectal cancer had a dismal prognosis, with a median survival of 6 months.Only 10-20% liver metastases are resectable. Other 80-90% of patients should receive some types of concervative treatment. Intra venous, intra arterial chemotherapy and other minimal invasion procedures. Survival benefit 30% at 5 years

Goal of chemotherapy for colorectal cancer liver metastases Management palliation and control symptoms Control tumor growth Attempts to lengthen progression-free and overall survival Extreme care (chemotherapy) must be taken to adequately assess each individual’s potential for both benefit and harm from chemotherapy In this slide you can see goal of chemotherapy for colorectal cancer of liver metastases.

Goal of chemotherapy for colorectal cancer liver metastases Quality-of-life issues must be frankly and objectively discussed with patients about expectations can be within a realistic framework Keep in mind that virtually all of the clinical trials involving patients with metastatic disease were restricted by design to patients who were in good overall general condition. (The same.)

Unresectable liver metastasis before treatment after 6 months treatment Chemotherapy produce good response and unresectable liver metastases reduce to resectable. It’s prime aim of multimodality treatment.

The effects of chemotherapy for MCRC Objective response rates Time to disease progression Overall survival Quality of life What is main effects of chemotherapy for metastatic colorectal cancer? Objective response rate, Time to disease progresion, overall survival and of course quality of life.

Chemotherapy Plus BSC Versus BSC Alone: Meta-analysis Risk ratio 1-year mortality 0.1 0.2 0.5 1 2 5 10 Relative risk (95% CI) 1.0 (0.41–2.45) 0.64 (0.46–0.92) 0.72 (0.54–0.95) 0.64 (0.44–0.93) 0.58 (0.34–0.99) 0.75 (0.53–1.06) 0.78 (0.40–1.53) 0.69 (0.60–0.81) Hine Rougier NGTATG Scheithauer Hafstrom Allen-Mersh Glimelius Pooled But chemotherapy produced more adverse events and reduse quality of life. In this slide you can see meta-analysis from randomized trials, where chemotherapy is favours then best supporitive care. Favours chemotherapy Favours control Jonker W et al. Br Med J 2000;82:1789–94

Chemotherapy in MCRC Median survival Action taken (month) 4-5 Supportive care 5-7 Supportive care, trial patients 10-12 5-Fu/LV, trial patients 12-14 5-Fu/LV, good PS trial patients 14-15 5-Fu/LV + new drug, good PS trial patients 15-17 5-Fu/LV+new drug, second line treatment 18-20 5-Fu/LV + new drug, sequential treatments, local methods Until 25 5-Fu/LV + new drug + target therapy, sequential treatments, local methods Median survival without chemotherapy is 4-5 month in non trial population and 5-7 month in trial patients.

Results of chemotherapy effects Until the very end of the 1980s there was no firm evidence that treatment had any meaningful influence on the well-being of many patients In 1989, two large randomised trials comparing 5-Fu alone and 5-Fu with biochemically modulated, reported slightly prolonged survival (median about 3 months) and QoL by the combined regimen. NGTATG J Clin Oncol 1989,7:1437-1446; Poon MA et all J Clin Oncol 1989,7:1407-1418 Borner MM et al Ann Oncol 1998,9:535-541 Shmoll HJ et al Proc Am Soc Clin Oncol 2000,19:Abstr935 Tekstas.

5-Fu regimes and leucovorin doses No firm evidence showing that any of the modulated 5-Fu regimens is superior to the others¹ Low leucovorin dose is to be preferred for routine use since regimens using higher leucovorin doses are not superior² ¹Glimelius EJC Vol I;2003,6:173-180 ²Sobrero AF et al J Clin Oncol 1997,15:808-815 Chemotherapy with 5-Fu is standart treatment of metastatic colorectal cancer. No firm evidence showing that any of the modulated 5-Fu regimens is superior to others. Low leucovorin dose is to be preferred for routine use since regimens using higher leucovorin doses are not superior.

Meta-analysis: What is impact of 5-FU modulation with LV? Response rate odds ratio (95% CI) Overall survival odds ratio (95% CI) Trial GITSG NCOG GOIRC GISCAD Genova Toronto City of Hope RPCI Bologna Overall In this slide you can see meta-analysis trials, where 5-Fu was used with or without leucovorin. This analysis showed advantages in biomodulators group in response rate and overall survival. 0.45 (0.34–0.60) 0.97 (0.86–1.09) 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 5-FU + LV better/5-FU + LV worse 5-FU + LV better/5-FU + LV worse Advanced CRC Meta-Analysis Project. J Clin Oncol 1992;12:960–9

Chemotherapy in MCRC Median survival Action taken (month) 4-5 Supportive care 5-7 Supportive care, trial patients 10-12 5-Fu/LV or Capecitabine trial patients 12-14 5-Fu/LV, good PS trial patients 14-15 5-Fu/LV + new drug, good PS trial patients 15-17 5-Fu/LV+new drug, second line treatment 18-20 5-Fu/LV + new drug, sequential treatments, local methods Until 25 5-Fu/LV + new drug + target therapy, sequential treatments, local methods 5-Fu + leucovorin or capecitabin prolong survival until 10-12 months in trial patients and 12-14 month in trial patients with good performance status.

5-Fu bolus vs. infusional High-dose infused regimens with modulated 5-Fu are likely superior to conventional bolus regimens, since they result in more tumour regressions, longer times to disease progression, less toxicity and/or longer overall survival. Schmoll et al Proc Am Soc Clin Oncol 2000, 19:abst 935 de Gramont A et al J Clin Oncol 1997, 15: 808-815 Aranda E Ann Oncol 1998, 9:727-731 Weh HJ Oncologie 1998,21 403-407 More discussions was inspired about 5-Fu administrations regimes. Europe likes infusional, north America likes bolus regimes. In this slide you can see conclusion.

Safety of infused 5-FU/LV superior to bolus? de Gramont regimen superior in terms of grade 3/4 diarrhoea: 3 vs 7% severe stomatitis: 2 vs 13% grade 3/4 neutropenia: 2 vs 7% But, similar incidence of all-grades principal 5-FU toxicities AIO regimen similar incidence of neutropenia and stomatitis, but more severe diarrhoea (22 vs 9%) dose reductions (34 vs 20%) withdrawals for toxicity (11 vs 4%) Safety profile is better then bolus regimes.. 1de Gramont A et al. J Clin Oncol 1997;15:808–15 2Köhne CH et al. J Clin Oncol 2003;21:3721–28

How different are the 5-FU regimens? RR TTP Mayo Clinic 14% 5.0 mo de Gramont 33% 6.3 mo RR TTP Mayo Clinic 12% 4.1 mo AIO 9% 4.4 mo AIO/LV 21% 6.4 mo 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 EORTC AIO Mayo Clinic de Gramont Mayo Clinic Estimated probability You can see main 5-Fu administration regimes and effects. Response rate and time to progresion. Infusional regimes are better than standart Mayo bolus regime. 12.5 13.0 14.2 12.0 13.2 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40 Time (months) Time (months)

Pooled data of two identical phase III trials in first-line MCRC Capecitabine (n=603) Endpoints ORR PFS overall survival tolerability pharmacoeconomics First-line MCRC Prior adjuvant >6 months ago Two international, open-label, randomised, phase III trials have compared oral Xeloda with i.v. bolus 5-FU/LV (Mayo Clinic regimen). One trial was conducted in the Americas [1] and the other was performed in Europe, the Middle East and Australasia [2]. The two trials were identical in design, selection criteria, conduct and monitoring and it was predefined to pool the data from both to obtain information on a large patient population. Therefore, a prospectively designed, integrated analysis of data from the two studies was performed [3]: The primary objective of the studies was to demonstrate that as first-line therapy for metastatic CRC oral Xeloda achieves a response rate at least equivalent to that achieved with i.v. 5-FU/LV. Secondary objectives included comparison of efficacy profiles, including time to disease progression (TTP) and overall survival, safety profiles and medical resource use. All patients had metastatic and/or advanced CRC not previously treated with cytotoxic chemotherapy, except (neo)adjuvant therapy conducted at least 6 months prior to enrolment. Patients were randomised to receive either oral Xeloda (1 250mg/m2, twice daily, days 1–14 every 21 days) or Mayo Clinic regimen (LV 20mg/m2 followed by bolus i.v. 5-FU 425mg/m2, days 1–5 every 28 days). In total, the trials enrolled 1 207 patients. The baseline characteristics of patients in the two treatment groups were well balanced: median age was 64 years in the Xeloda group and 63 years in the 5-FU/LV group both groups had a median Karnofsky Performance Status (KPS) of 90 predominant metastatic site was the liver in approximately three-quarters of patients in both treatment arms and the lungs in 12% and 14% of each group, respectively approximately one-quarter of patients in both treatment groups had received prior adjuvant treatment.   1. Hoff PM et al. J Clin Oncol 2001;19:2282–92. 2. Van Cutsem E et al. J Clin Oncol 2001;19:4097–106. 3. Twelves C et al. Eur J Cancer 2002;38(Suppl. 2):S15–S20. Bolus 5-FU/LV (n=604) Twelves C. Eur J Cancer 2002;38(Suppl. 2):S15–S20

Capecitabine in first-line MCRC: Pooled data of two phase III trials Endpoints ORR + PFS = overall survival = tolerability + pharmacoeconomics + First-line MCRC Prior adjuvant >6 months ago Two international, open-label, randomised, phase III trials have compared oral Xeloda with i.v. bolus 5-FU/LV (Mayo Clinic regimen). One trial was conducted in the Americas [1] and the other was performed in Europe, the Middle East and Australasia [2]. The two trials were identical in design, selection criteria, conduct and monitoring and it was predefined to pool the data from both to obtain information on a large patient population. Therefore, a prospectively designed, integrated analysis of data from the two studies was performed [3]: The primary objective of the studies was to demonstrate that as first-line therapy for metastatic CRC oral Xeloda achieves a response rate at least equivalent to that achieved with i.v. 5-FU/LV. Secondary objectives included comparison of efficacy profiles, including time to disease progression (TTP) and overall survival, safety profiles and medical resource use. All patients had metastatic and/or advanced CRC not previously treated with cytotoxic chemotherapy, except (neo)adjuvant therapy conducted at least 6 months prior to enrolment. Patients were randomised to receive either oral Xeloda (1 250mg/m2, twice daily, days 1–14 every 21 days) or Mayo Clinic regimen (LV 20mg/m2 followed by bolus i.v. 5-FU 425mg/m2, days 1–5 every 28 days). In total, the trials enrolled 1 207 patients. The baseline characteristics of patients in the two treatment groups were well balanced: median age was 64 years in the Xeloda group and 63 years in the 5-FU/LV group both groups had a median Karnofsky Performance Status (KPS) of 90 predominant metastatic site was the liver in approximately three-quarters of patients in both treatment arms and the lungs in 12% and 14% of each group, respectively approximately one-quarter of patients in both treatment groups had received prior adjuvant treatment.   1. Hoff PM et al. J Clin Oncol 2001;19:2282–92. 2. Van Cutsem E et al. J Clin Oncol 2001;19:4097–106. 3. Twelves C et al. Eur J Cancer 2002;38(Suppl. 2):S15–S20. Bolus 5-FU/LV (n=604) Twelves C. Eur J Cancer 2002;38(Suppl. 2):S15–S20

Chemotherapy in MCRC Median survival Action taken (month) 4-5 Supportive care 5-7 Supportive care, trial patients 10-12 5-Fu/LV, trial patients 12-14 5-Fu/LV, good PS trial patients 14-15 5-Fu/LV + new drug, good PS trial patients 15-17 5-Fu/LV+new drug, second line treatment 18-20 5-Fu/LV + new drug, sequential treatments, local methods Until 25 5-Fu/LV + new drug + target therapy, sequential treatments, local methods With the use of new agents such as Irinotecan or Oxaliplatin in combination with 5-FU/LV, the median survival has increased to 14-20 months

Combination Therapy Irinotecan improves RR, TTP and survival in first line (with 5-FU/LV)1,2 in second line polychemotherapy1 and monotherapy3 Oxaliplatin with 5-FU/LV improves RR and TTP in first line4,5 is effective in 5-FU resistant disease in second line6 Irinotecan improves response rate, time to progresion and survival in first and second line treatment of Metastatic colorectal cancer. Oxaliplatin with 5-Fu and leucovorin improves response rate and time to progresion in first line and effective in not 5-FU resistant disease but after irinotecan 5-Fu/LV combination ( de Gramont ) 1Douillard JY et al. Lancet 2000; 2Saltz LB et al. N Engl J Med 2000 3Rougier P et al. Lancet 1998; 4de Gramont A et al. J Clin Oncol 2000 5Giacchetti S et al. J Clin Oncol 2000; 6André T et al. Ann Oncol 1999

Combination Therapy Irinotecan/5-FU/FA is more active than 5-FU/FA in metastatic CRC, offering improved tumour control and prolonged survival with a manageable adverse event profile and can therefore be considered as a standard treatment Bolus & Infusional regimens of 5-FU/FA/irinotecan are safe and have a manageable toxicity pattern. Infusional regimens may have a better risk/benefit ratio than bolus 5-FU/FA/irinotecan regimens Irinotecan 5-FU/FA or leucovorin is more active than 5-Fu/FA in metastatic CRC, offering improved tumour control and prolonged survival with manageable adverse event profile and can therefore be considered as a standard treatment. Bolus and infusional regimes of 5-Fu/FA/Irinotecan are safe and have a manageble toxicity pattern. Infusional regimens may have a better risk/benefit ratio than bolus 5-Fu/FA/irinotecan regimens.

Combination Therapy Addition of oxaliplatin to 5-FU/LV improves all efficacy outcomes in first line (1-3) is effective in irinotecan-pretreated patients in second line (4,6) Addition of irinotecan to 5-FU/LV improves efficacy in first line (6,7) Combinations with infused 5-FU favoured in Europe while bolus preferred in USA Tekstas 1de Gramont A et al. J Clin Oncol 2000;18:2938–47; 2Giacchetti S et al. J Clin Oncol 2000;18:136–47 3Goldberg R et al. Proc Am Soc Clin Oncol 2003;22:252 (Abst 1009) 4Rothenberg ML et al. J Clin Oncol 2003;21:2059–69 5Rothenberg ML et al. Proc Am Soc Clin Oncol 2003;22:252 (Abst 1011) 6Douillard JY et al. Lancet 2000;355:1041–7; 7Saltz LB et al. N Engl J Med 2000;343:905–14

1st line 5-FU/LV +/– irinotecan Response PFS Median survival rate (%) (months) (months) Regimen Bolus Irinotecan/5-FU/LV 39* 7.0* 14.8* (USA) 1 5-FU/LV 21 4.3 12.6 Irinotecan 18 4.2 12.0 Infused Irinotecan/5-FU/LV 35* 6.7* 17.4* (Europe) 2 In this slide you can see analysis of 1-st line 5-Fu/LV/Irinotecan trials where comparison bolus and infusional regimes. You can see that combinatios are better than 5-FU + LV while Response rate, progresion free survival and median survival are closely. 5-FU/LV 22 4.4 14.1 Combined Irinotecan/5-FU/LV 37* 6.9* 15.9* data 3 5-FU/LV 21 4.3 13.3 *p<0.05 (vs 5-FU/LV) 1Saltz LB et al. N Engl J Med 2000;343:905–14 2Douillard JY et al. Lancet 2000;355:1041–7 3Saltz LB et al. Proc Am Soc Clin Oncol 2000;19:242a (Abst 938)

Addition of oxaliplatin later shown also to prolong survival 1st line Two yers ago Prof. Goldberg was published data about superiority OPxaliplatin regime FOLFOX up Irinotecan/5-FU/LV bolus regime in survival and statisticaly significant. But not statisticaly significant between FOLFOX and IROX. Goldberg RM, et al. Proc Am Soc Clin Oncol 2003;22:252 (abst 1009)

XELOX compares favourably with FOLFOX (n=96) 1 (n=267) 2 (n=210) 3 PR + CR (%) 55 45 50 PFS (months) 7.6 8.7 8.2 XELOX achieved a high response rate of 55%, with an additional 32% of patients having stable disease for at least 3 months [1]. The response rate, median progression-free survival (7.7 months) and median overall survival (19.5 months) with XELOX compare favourably with the results from a randomized study of infused 5-FU/LV with or without oxaliplatin (FOLFOX4), which demonstrated significant improvements for the combination compared with 5‑FU/LV alone [2,3]. These data provide a high level of confidence that XELOX will be at least as effective as FOLFOX4 in a randomised comparison.   1. Sawada N et al. Eur J Cancer 2003;1(Suppl. 5):S93 (Abst 303). 2. Goldberg R et al. Proc Am Soc Clin Oncol 2003;22:252 (Abst 1009). 3. de Gramont A et al. J Clin Oncol 2000;18:2938–47. OS (months) 19.5 19.5 16.2 1Van Cutsem E et al. Proc Am Soc Clin Oncol 2003;22 (Abst 1023) 2Goldberg R et al. Proc Am Soc Clin Oncol 2003;22:252 (Abst 1009) 3de Gramont A et al. J Clin Oncol 2000;18:2938–47

Chemotherapy in MCRC Median survival Action taken (month) 4-5 Supportive care 5-7 Supportive care, trial patients 10-12 5-Fu/LV, trial patients 12-14 5-Fu/LV, good PS trial patients 14-15 5-Fu/LV + new drug, good PS trial patients 15-17 5-Fu/LV+new drug, second line treatment 18-20 5-Fu/LV + new drug, sequential treatments, local methods Until 25 5-Fu/LV + new drug + target therapy, sequential treatments, local methods New biotechnologies drug improve survival until 25 months, but only with chemotherapy.

1st line Irinotecan/5FU/LV ± bevacizumab IFL + Placebo (N = 412) No Bevacizumab Past Disease Progression Previously Untreated Metastatic CRC IFL + BV (N = 403) May Receive Bevacizumab Past Disease Progression 5-FU/LV + BV (N = 110) May Receive Bevacizumab Past Disease Progression Cuple months ago doctor Hurwitz was published in New England Journal of Medicine new data. VEsels Epidermal factor receptors inhibitor (bevacizumab) and Irinotecan/5-Fu/LV combination was compared with standard chemotherapy of metastatic colorectal cancer. 925 patients were randomaized in 3 arms. You can see all arms and regimes. IFL: bolus 5-FU 500 mg/m2 leucovorin 20 mg/m2 irinotecan 125 mg/m2 5-FU/LV: bolus 5-FU 500 mg/m2 leucovorin 500 mg/m2 BV: 5 mg/kg Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Effect on overall survival of adding bevacizumab to 1st line IFL 1.0 0.8 0.6 0.4 0.2 Median survival (months) IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs IFL + Avastin: 20.3 (95% CI: 18.5–24.2) HR=0.66 (95% CI: 0.54–0.81) p<0.001 Probability of survival This slide emphasises the highly significant improvement in overall survival, which was the primary endpoint of the study, with separation between the two groups from very early on in the study. IFL + placebo IFL + bevacizumab 0 10 20 30 40 Survival (months) Kaplan-Meier curve Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Progression-free survival (months) Phase III trial of IFL ± Avastin in metastatic CRC (AVF2107g): progression-free survival Median progression-free survival (months) IFL + placebo: 6.2 (95% CI: 5.6–7.7) IFL + Avastin: 10.6 (95% CI: 9.0–11.0) HR=0.54 (95% CI: 0.45–0.66) p<0.001 1.0 0.8 0.6 0.4 0.2 Probability of being progression-free IFL + Avastin IFL + placebo Trial AVF2107g was a blinded, randomised, placebo-controlled phase III trial of IFL with or without Avastin 5mg/kg every 2 weeks as first-line treatment of metastatic CRC. Progression-free survival was also significantly increased by 71% in the IFL plus Avastin arm (10.6 [95% CI 9.0–11.0] vs 6.2 [95% CI 5.6–7.7] months, p<0.001).1 The stratified HR for disease progression or death during first‑line therapy in the IFL plus Avastin arm relative to the IFL plus placebo arm was 0.54 (95% CI 0.45–0.66). It is interesting to note that the difference in overall and progression-free survival between the two treatment arms is relatively constant at 4.7 and 4.4 months. Together with the study design, in which the treatment arms differed only with the addition of Avastin to IFL, this suggests that the increase in survival is due to the addition of Avastin. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. 6.2 10.6 0 10 20 30 Progression-free survival (months) Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Improvements in the RR of MCRC to 1st line infusional 5-FU based chemotherapy Slide 27 RR (%) RRs of ~10%, 10%, 1215% and 1732% have been reported in randomized phase III trials for bolus 5-FU, infusional 5-FU, bolus 5-FU/FA (Mayo Clinic regimen) and for the intermittent infusional 5-FU/FA (AIO, de Gramont) regimens respectively. The addition of irinotecan to bolus 5-FU/FA or intermittent infusional 5-FU/FA regimens resulted in randomized phase III trials in RRs of 31-39% and 41-56%, respectively. Combinations of Cituximab™ + infusional 5-FU/FA + irinotecan produced RRs of 58% and 74% with very high response rate particulary liver metastasis. After decades of stagnation the options for mCRC are finally expanding. The combination of 5-FU/FA + irinotecan or oxaliplatin has improved the survival of patients. Further improvements are likely by incorporating biologically-targeted therapies. ‘The prospects for further substantial advances in the management of colorectal cancer are brighter than they have ever been,’ Holen KD, Saltz LB. Lancet Oncol 2001; 2:290–297. 5-FU 5-FU/FA FOLFIRI, FOLFOX (inf), Bevacizumab + IFL Cituximab + IRI / 5-FU/FA (inf)

Overall survival: first-line fluoropyrimidine combination regimens 5-FU/LV (Saltz) 5-FU/LV (Douillard) 5-FU/LV (de Gramont) IFL (Goldberg) IFL (Saltz) FOLFIRI (Douillard) Fluoropyrimidine-based regimens are still the mainstay of CRC treatment. During the last 5 years we have seen new regimens incorporating new agents significantly improve outcomes in the first-line treatment of metastatic CRC. This slide shows the development of fluoropyrimidine-based treatment and the improvements in survival provided by first-line treatment with combination regimens incorporating irinotecan and oxaliplatin [1–5]. Overall survival is improved with irinotecan/5-FU/LV combination therapy compared with 5-FU/LV [1, 2]. European data show that FOLFOX is superior to infused 5-FU/LV [3]. Recent data from the NCCTG intergroup trial show that overall survival with FOLFOX is improved compared with IFL [4]. Overall survival is improved with IFL + Avastin, but as the NCCTG intergroup trial suggests, IFL is not the optimal fluoroupyrimidine-based regimen [5]. 1. Saltz LB et al. N Engl J Med 2000;343:905–14. 2. Douillard JY et al. Lancet 2000;355:1041–7. 3. de Gramont A et al. J Clin Oncol 2000;18:2938–47. 4. Updated from Goldberg RM et al. Proc Am Soc Clin Oncol 2002;20:128a (Abst 511). 5. Hurwitz H et al. Proc Am Soc Clin Oncol 2003 (Abst 3646). FOLFOX (de Gramont) FOLFOX (Goldberg) IFL+ Avastin 0 5 10 15 20 25 Median OS (months)

FOLFOX4 after failure of irinotecan/5-FU/LV (IFL) 2nd line 1.0 0.8 0.6 0.4 0.2 RR TTP OS FOLFOX4 9.6% 5.6 mo 9.8 mo LV5FU2 0.7% 2.6 mo 8.7 mo Eloxatin® 1.5% 1.9 mo 8.1 mo 5.6 2.6 Probability In second line chemotherapy metastatic colorectal cancer we can use very good regime ( FOLFOX) if in 1-th line was used iRinotecan containing regime with good response rate, time to progression and overall survival. 1.9 FOLFOX4 Eloxatin® LV5FU2 0 5 10 15 20 Months Rothenberg M, et al. Proc Am Soc Clin Oncol 2003;22:252 (abst 1011)

Cetuximab +/- irinotecan 2nd line after irinotecan failure Mono Combo 1 No. 111 218 Response Rate (%) 11 23 P < 0.05 0.8 Survival (months) 6.9 8.6 P = NS 0.6 Proportion HR (95% CI): 0.54 (0.42; 0.71) log rank p-value < 0.0001 0.4 Cetuximab is New monoclonal antibody that binds selectively to the epidermal growth factor receptor (EGRF). Combine chemotherapy with Irinotecan 5-FU/FA + cituximab vs cituximab alone irinitecan refractory colorectal cancer was showed time to tumor progresion favored the combination as well (4.0 vs 1.6 month). Survival on the two arms was not significantly different. 0.2 2 4 6 8 10 12 Time to progression (months) Cunningham, Van Cutsem et al 2003 Proc Am Soc Clin Oncol 22: Abstract 1012

Cituximab as single agent in 2nd line treatment of irinotecan-refractory mCRC Slide 19 Pts RR Dis Con mTTP mS Saltz 2002 57 11% 34% 1.4 mths 6.4 mths Cunningham 2003* 111 1.5 mths 6.9 mths Single-agent Erbitux™ is active in EGFR-expressing mCRC resistant to irinotecan-based chemotherapy. Single agent Erbitux™ has been used at an initial dose of 400 mg/m2 followed by 250 mg/m2 iv weekly in a non-randomized and a randomized phase II study. The non-randomized phase II study investigated Erbitux™ in 57 patients and showed a response in 6/57 patients (11%) with stable disease in 13/57 patients (23%), giving a tumor growth control rate of 34%. The median TTP was 1.4 mths and median survival (mS) 6.4 mths [1]. Erbitux™ monotherapy was also studied in a pivotal randomized phase II trial in which ~40% of the patients received the investigational treatment as a 3rd or higher line treatment [2]. In 111 evaluated patients the RR was 11%, median TTP was 1.5 mths and the median survival was 6.9 mths. Saltz L, Meropol NJ, Loehrer PJ, et al. Proc Am Soc Clin Oncol 2002; 21: Abstract 504, updated data presented at meeting. Cunningham D, Humblet Y, Siena S, et al. Proc Am Soc Clin Oncol 2003; 22: Abstract 1012, updated data presented at meeting. * ~ 40% of pts received cituximab as a 3rd or higher line treatment

Cituximab plus irinotecan is active 2nd line in irinotecan-refractory mCRC Slide 20 Efficacy results PR 27 / 120 (23%) Disease control 36 / 120 (30%) Median duration of response (MDR) 6.2 mths The combination of Erbitux™ plus irinotecan has been investigated in a phase II trial in 120 patients with EGFR-expressing mCRC resistant to irinotecan-based chemotherapy [1]. Erbitux™ was administered at an initial 400 mg/m2 dose followed by 250 mg/m2 weekly. Irinotecan was given at the same dose schedule on which patients had previously progressed [1]. A partial response was seen in 27/120 patients (23%) and 9 patients (8%) showed stabilization of their disease, giving a tumor growth control rate of 30%. The maximum duration of response (MDR) was was 6.2 mths [1]. The efficacy of Erbitux™ + irinotecan in terms of RR was independent of the level of EGFR expression with similar RRs for tumor expression levels 1 to 3 [2]. Saltz L, Rubin M, Hochster H, et al. Proc Am Soc Clin Oncol 2001; 20: Abstract 7, updated data presented at meeting. O’Dwyer PJ, Benson AB. Semin Oncol 2002; 29 Suppl 14:10–17. Saltz et al 2001 Proc Am Soc Clin Oncol 20: Abstract 7

HAI and systemic chemotherapy in randomized studies Response rate 2-years survival No. pts. HAI SYS p HAI SYS p MSKCC 162 53 21 .001 17 12 - NCI 64 62 17 .003 47 13 - French 163 49 14 NS 22 10 .02 German 168 43 20 - 12,7 17,6 - CALGB 135 48 25 .009 22,7 19,8 .027 The original HAI trials were performed with percutaneously placed hepatic arterial lines. A number of randomized studies have now been conducted to answer the question of whether HAI therapy is more effective treatment for metastatic colorectal cancer. In French trials was showed HAI superiority up only systemic chemotherapy with the same drug. CALGB trial with good randomization and patients stratification was showed significantly better Response rate 48% vs 25% and median survival 22.7 vs 19 .8 respectively.

Drugs for HAI Drug Half-life (min) Estimated Increased Exposure bay HAI 5-Fluoruracil 10 5-10 fold Floxuridine <10 100-400 fold Carmustine < 5 6-7 fold Mitomycin C <10 6-8 fold Cisplatin 20-30 4-7 fold Adriamycin 60 2 fold Vincent T. De Vita Cancer principles and practice of oncology 2005 7-th The use of drugs that are largery extracted by the liver during the first pass rezults in high local concetrations of drug with minimal systemic toxicity. Floxuridine FUDR is the best drug to use for regional therapy because 94% to 99% of FUDR is extracted during the first pass, compared to 19% to 55% of 5-FU.

Survival after Adjuvant Therapy Subsequent to liver resection with HAI and systemic therapy versus systemic therapy alone Survival rate HAI+SYS Comparison (n=74) SYS (n=82) P value 2-Y survival 85% 69% .02 2-Y hepatic DFS 89% 57% .00001 2-Y DFS 57% 41% .07 Approximately 75% of patients who undergo hepatic resection experience recurrent metastases within 2 years, and approximately one-half recur in liver. Memorial Sloan Kettering Cancer center trial treated patients after liver resections: arm A HAI + Systemic chemotherapy and Arm B with systemic chemotherapy alone. Results from randomized trial you can see on this slide. 2 years survival and hepatic disease free survival were statisticaly significant better then systemic treatment alone. Kemeny MM et al N Engl J Med 1999:341-2039

Time from Second Progression to Death MST from 2nd line 9-10 months TTP 2nd line 3- 4 months Time from 2nd P to death 6 months From Cunningham and Rougier 1999 MST folfiri folfox 21 months TTP 1st + 2nd line 14 months Time from 2nd P to death 7 months From Tournigand ASCO 2001 WHY NOT THIRD LINE CT ?

Where are we now? In the metastatic setting……. Addition of bevacuzimab to bolus 5-FU/irinotecan prolongs survival as 1st line therapy After irinotecan failure, addition of cetuximab is an alternative to FOLFOX as 2nd line treatment But Unclear yet if both agents also effective with 5-FU alone, Xeloda alone or oxaliplatin combinations Optimal sequence not known Don’t know how to tailor treatments to specific patients

Patient selection: Trials and the real world Trials patients Young and fit Normal liver and renal function Limited other medication Treated at specialist units Specific tumour and drug free! Treatment patients with liver metastasis are very important and difficult think. Patients selection in clinical trials are very precision. (>>>>>>>)

Patient selection: Trials and the real world Trials patients Young and fit Normal liver and renal function Limited other medication Treated at specialist units Specific tumour and drug free! Clinic patients Older and less fit Liver/renal function often abnormal Many of them on other drugs Treated by general oncologists Variety of tumours? and drug costs money Or in clinical practice is different (>>>>>>>>>>>).

Potential Prognostic Subgroups Older patients (>65 years old) Poor performance status (>0) >1 metastatic site Prior adjuvant therapy with 5-FU/LV Elevated LDH, alkaline phosphatase, WBC

Prognostic Factors for Advanced CRC ECOG performance status >1 0–1 WBC No. of sites >10K <10K >1 1 No. of sites AP >1 1 >300 <300 MST = 6 months MST = 10 months MST = 15 months We need separate patients with different conditions. You can see on this slide patients selections (From KOEHNE) on to three median survival groups. Performance status, Number of sites metastases, alcaline phosphatase, and white blood cell counts are very important prognostic criterias. AP = alkaline phosphatase From Koehne, Ann. Oncol 2001

Conclusion Active drugs have had a dramatic impact on the treatment of colorectal cancer metastases: Capecitabin (tolerability), Cetuximab (time to progression), Irinotecan, oxaliplatin, bevacuzimab (survival) HAI + Systemic chemotherapy improved survival and hepatic DFS Future improvements are probable using a multididciplinary approach, together with a hope that new treatments, based upon recent tumor-biological knovledge, will eventualy yield clinically meaningful effects. The results of chemotherapy have improved substantialy during the past 15 years. Median survival has been prolonged from less than 6 month to above 20-25 months. Earlier detection of metastasic disease, , detecting smaller lesions than possible before, is responsible for some of the much longer survival presently seen. Active drugs have had a dramatic impact on the treatment of colorectal cancer liver metastases. Capecitabin improve tolerability, ………………………………………………………………………..