?????????????S T???????S

1
?????????????S T???????S

• ?? ?. ???st?d?????
• ?a??????? ?????????
• ??. ?/?t?? ? ??????????? ????????
• ??s???µe?? Metropolitan

2
??t??a???????? Te?ape?e?

• ?e?????????
• ??t??o?e?ape?a
• ??µ????e?ape?a
• ??µe???e?ape?a
• ???s??e?ape?a
• St??e?µ??e? Te?ape?e? ?
• ?????????? Te?ape?e?

3
?e????????? ????????a (1)
4
?e????????? ????????a (2)

• ??a??es? p??t?pa???? est?a?
• (?????? ?e?ape?a)
• ??a??es? µetast?se??
• (?????? ?e?ape?a pa??????t???)

5
??t????e?ape?t??? ????????a

• ???te???? ??t???ß???a
• (??ß??t??, ??aµµ???? ep?ta???t??)
• ??a???e?ape?a
• (e?d??????t??? p.?. µ?t?a, ???p??, ß??????,
  ??s?f???? ? e?d??st??? p.?. ???ssa, ?e????,
  p??st?t??)
• ?e ?ad??f??µa?a
• ( I131 st?? ????e?d?, st???t??/ ?????/ saµ????
  st?? ?st???? µetast?se??, ??d?? se
  ?e???e?d?????e?? ??????)

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??µ????e?ape?a (1)

• ?a?????? t?? µast??
• ?a?????? t?? p??st?t?
• ?a?????? t?? e?d?µ?t????

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??µ????e?ape?a (2)

• ?a?????? t?? µast??
• LHRH-a????st??
• ???e?t???? t?op?p?p???t?? ??µ?????? ?p?d?????
  (SERMS) p.?. taµ???f???, f???ßest???t?
• ??ast??e?? ?a? ad?a??p???t?? a??µat?s?? p.?.
  a?ast?a????, ?et??????, e?eµest???
• ???a (p???este????e?d?, a?d?????a)

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??µ????e?ape?a (3)

• ?a?????? t?? p??st?t?
• LHRH-a????st??
• ??t?a?d?????a
• ?????? d?se?? ??st???????

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??µ????e?ape?a (3)

• ?a?????? t?? e?d?µ?t????
• ????este????e?d?
• ??ast??e??-ad?a??p???t?? a??µat?s??
• ?aµ???f???

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??µe???e?ape?a (1)

• ??tta??stat???
• ?? e?d??? t?? ?????? f??µa?a
• ?????????te? pa?????te? (?????f?sfaµ?d?,
  ?f?sfaµ?d?, µe?fa???? ?.?.p)
• ??t?ß??t??? (a???a??????e?, µ?t?µ????? ?.?.p)
• ??d??? t?? ?????? f??µa?a
• F?se?? G1 (????µa, L-aspa?a????s?)
• F?se?? S (a?t?µetaß???te? p.?. 5F4,
  µe??t?e??t?, ?apes?taµp???, ?eµs?taµp???)
• F?se?? G2 (µp?e?µ?????, et?p?s?d?)
• F?se?? ? (a??a??e?d? vinca,ta???e?, pa?????a
  p?at??a? ?.?.p.)

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??µe???e?ape?a (2)

• ??????t?ta
• ??e??t?????t?ta
• ?a?d??t?????t?ta
• ?ef??t?????t?ta
• Gast?e?te???? t?????t?ta
• ?pat?t?????t?ta
• ?e?µat??? t?????t?ta
• ??e?µ????? t?????t?ta
• ??t?d??se?? ?pe?e?a?s??s?a?

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??µe???e?ape?a (3)

• S?µp????µat??? (adjuvant)
• ???e??e???t??? (neo-adjuvant)
• Te?ape?a ??a µetastat??? ??s? (p??t??, de?te???
  ?.?.p. ??aµµ??)

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??µe???e?ape?a (4)

• ?p?st????t???? pa?????te?
• ??t?eµet??? f??µa?a
• (a?ta????st?? S-HT3, a?ta????st?? ?p?d?????
  ??-1)
• ??µ?p???t???? a???t???? pa?????te?
• (GCSF, e?????p???t???)
• ?e?t??sa? se s?µa?t??? ßa?µ? t?? p???t?ta ????
  t?? as?e???, p?? ?p?ß?????ta? se ??µe???e?ape?a

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???s??e?ape?a (1)

• ??tta?????e? (??te?fe????, ??te??e?????)
• µe????µa, Ca ?ef???
• ??????????? a?t?s?µata
• Ca µast??, Ca p?e?µ??a, Ca e?t????, Ca ?ef???
• ?µß???a

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???s??e?ape?a (2)

• ?µß???a
• ???????a ????ta ?a??????? ??tta?a
• (a?t????a, ete?????a)
• Ge?et??? t??p?p???µ??a ?a??????? ??tta?a
• (? ????d?a?? µetaf??? ???eta? µ?s? ???,
  p?asµ?d?a??? ? ??µ??? DNA, ??p?s?µ?t??,
  de?d??t???? ??tt????)

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???s??e?ape?a (3)

• ???? ta ?a??????? eµß???a ?a? ????
• ta a?t?-???? eµß???a p.?. ??a?t? HBV ? HPV

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St??e?µ??e? ? ?????????? ?e?ape?e? (1)

• ??d? µ?????
• ??????????? a?t?s?µata
• ????? µ???a, a?ast??e?? t???s?????? ???as??
• ???a

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St??e?µ??e? ? ?????????? ?e?ape?e? (2)

• ??????????? ?a? st???? t???
• HER2/neu ? cerbB2 Trastuzumab (Herceptin)
• Ca µast??
• EGFR Cetuximab (Erbitux)
• Ca e?t????, p?a??de? Ca ?efa???-t?a????? (p???
  ????f?????a)
• VEGF Bevacizumab (Avastin)
• Ca e?t????, Ca µast??, NSCLC, Ca ?ef???,
• G????µata (), HKK ()

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St??e?µ??e? ? ?????????? ?e?ape?e? (3)

• ??ast??e?? ????s?????? ????s?? ?a? st???? t???
• EGFR Erlotinib (Tarceva)
• NSCLC
• EGFR Gefitinib (Iressa)
• NSCLC
• VEGFR1, VEGFR2, PDGFR Sunitinib
  (Sulent)
• Ca ?ef???, GIST
• VEGFR1, VEGFR2, PDGFR Sorafenib (Nexavar)
  
• Ca ?ef???, ???, ?a????e? µe????µa ()
• C kit, PDGFR Imatinib (Glivec)
• GIST, ???

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St??e?µ??e? ? ?????????? ?e?ape?e? (4)

• ???a µ???a ?a? st???? t???
• ??ast??e?? p??teas?µat??
• (Bortezomib, p???ap?? µ????µa)
• ??ast??e?? farnesyl transferase
• ??ast??e?? µeta???p??te??as??
• ??ast??e?? p??te?????? ???as??

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??????????? ?e??te?

• ?e??te? se pe??aµat???a
• (p??sd????sµ?? LD10)
• ?e??te? se ??tta????? se????
• (p??sd????sµ?? IC50, µe??t? ?d??t?t?? t??
  fa?µ???? p.?. ep?d?as? st? DNA, st?? ??tta????
  ?????, st?? ap?pt?s? ?.?.p.)

22
???????? ?e??te?

• F?se?? ?
• F?se?? ??
• F?se?? ???

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???????? ?e??te? F?se?? ?

• ?s?e?e?? µe d??f??e? ?a????e?e?
• S?????? a??et? p???e?ape?µ????
• ?????eta? stad?a?? ? d?s? (?µ?de? t?? 3 as?e???)
• S??p?? (1) ?a p??sd????ste? ? µ???st? a?e?t? d?s?
  (MTD) ?a? ?a p??ta?e? d?s? ??a f?se?? ?? µe??te?
• S??p?? (2) ?a p??sd????ste? ? d?s?pe?????st???
  t?????t?ta (DLT) a??? ?a? ?? ?p????pe?
  t?????t?te? t?? fa?µ????

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???????? ?e??te? F?se?? ??

• ?s?e?e?? µe µ?a s???e???µ??? ?a????e?a
• S?????? p???e?ape?µ????
• S??p?? (1) ?a p??sd????ste? ? a?tap????s? t??
  ????? st? s???e???µ??? f??µa??
• S??p?? (2) ?a µe?et??e? ?a??te?a ? t?????t?ta

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???????? ?e??te? F?se?? ???

• ?s?e?e?? µ? p???e?ape?µ???? ? ???o
  p???e?ape?µ????
• S??????eta? ? ??a ?e?ape?a µe t?? ?a??e??µ???
• S??p?? ?a p??sd????ste? ? ep?ß??s? ? t? e?e??e??
  ??s?? d??st?µa
• S?????? p???????ta? µe??te? f?se?? ??? st??
  µetastat??? ??s? ?a? a???????? st?? p???µ?

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?????s? ???? fa?µ???? ? ??a? ?e?ape?a? ap? FDA
?a? ????

• ?atat??eta? ? f??e??? t?? fa?µ???? µe ta
  ap?te??sµata ???? t?? ???????? ?a? p??????????
  µe?et?? p?? ????? d?e?a??e? ?a? ????? a?a??????e?
  se ?G???? ???S???????? S??????? ?a? ?G????
  ???S???????? ?????????.
• ?pa?te?ta? t??????st?? µ?a µe??t? f?se?? ???, p??
  de???e? ße?t??s? t?? ep?ß??s?? ? t?? e?e??e???
  ??s?? d?ast?µat??.

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?????s? ???? fa?µ???? ? ??a? ?e?ape?a? ap? FDA
?a? ????

• ???fa??? ??? ?aµß????ta? ?p???? ?? s??e?te??e??
  t?? e?e???t?? se ???, ??te ?? ?????e?
  a?tap????se?? s?ßa??? d?µ?s?????f??.
• ???fa??? ??? ?aµß????ta? ?p???? ?? ap??e?? t??
  bloggers ? ?? a?af???? st? d?ad??t?? pe??
  ?a?µat?????? fa?µ????.

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• ?G????G??? S????????

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Colorectal cancer Treatment of metastatic
disease

• 1960s 1990s 5-FU-based chemotherapy most
  commonly used
• Multiple biomodulation and dosing
• strategies explored
• No clear best way to give 5-FU was established
• 5-FU5-fluorouracil

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Newer agents in CRC

• Irinotecan (CPT-11, Campto)
• Oxaliplatin (Eloxatin)
• Capecitabine (Xeloda)
• Cetuximab (225, Erbitux)
• Bevacizumab (Avastin)

31
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32
(No Transcript)
33
(No Transcript)
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Bevacizumab Recombinant Humanised monoclonal
antibody to VEGF-A
35
Avastin mechanism of action

• Avastin may act against tumours in three ways
• regression of existing microvasculature
• normalisation of mature vasculature
• inhibition of production of new vasculature

36
Phase III trial of IFL Avastin (AVF2107g)
survival
Median survivalIFL placebo 15.6 (95 CI
14.317.0) vs IFL Avastin 20.3 (95 CI
18.524.2) HR0.66 (95 CI 0.540.81) plt0.001
1.0 0.8 0.6 0.4 0.2 0
IFL Avastin IFL placebo
Probability of survival
15.6
20.3
0 10 20 30 40
Time (months)
Hurwitz H, et al. N Engl J Med 2004350233542
CI confidence interval HR hazard ratio
37
Phase III trial of Avastin plus FOLFOX in second
line (E3200) overall survival
1.0 0.8 0.6 0.4 0.2 0
HR0.76 A vs B p0.0018 B vs C p0.95
Probability of survival
10.8
10.2
12.9
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
Alive
Dead
Median
Total
A FOLFOX4 Avastin
289
246
43
12.9
B FOLFOX4
290
257
33
10.8
C Avastin
243
216
27
10.2
Giantonio BJ, et al. J Clin Oncol 200523(June 1
Suppl.)1s (Abstract 2)
38
ERBITUX
39
BOND study ERBITUX irinotecan is active in mCRC
Cunningham et al. N Engl J Med 2004 351337-345
40
Advances in CRC treatment
1980 1985 1990
1995 2002 2006
Best supportive care
5-FU
41
First-line therapy response rate
Response rate ()
ERBITUXFOLFOX41
ERBITUX FUFOX2
ERBITUXAIO IRI/5-FU3
ERBITUXFOLFIRI4
FOLFIRI5
FOLFOX5
AIO IRI/5-FU6
1Cervantes A, et al. ECCO (2005) 2Data on file
3Folprecht G, et al. Ann Oncol (2005) 4Rougier
P, et al. ECCO (2005) 5Tournigand, et al. J
Clin Oncol (2004) 6Köhne C-H, et al. EORTC-Study
40986 (2005)
42
First-line therapy resectability rate
Objective response Resectability
OR and resectability rate ()
ERBITUXFOLFOX41
ERBITUXAIO IRI2
ERBITUXFOLFIRI3
FOLFIRI4
AIO IRI5
FOLFOX4

• ERBITUX leads to high resection rates ? potential
  for cure
• or long-term survival

1Cervantes A, et al. ECCO (2005) 2Folprecht G,
et al. Ann Oncol (2005) 3Rougier P, et al. ECCO
(2005) 4Tournigand, et al. J Clin Oncol (2004)
5Köhne C-H, et al. EORTC-Study 40986 (2005)