1
Basic Concept of Radiation Therapy Combined with Chemotherapy
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!" # $ % &'( )!*" * " $+ " # ,--.!*/ & 01 !* + " #'0 % & ! ! - +/, 2 ' , & % ,--.!*$ $ $ 3 %,--. (cell cycle ) " " '5 $ " # !* , " * '- $ *" # !*% 6 2 " 2 '7 8 / ! &'( + ! $ !* !* ! !'7! !*/ !*- &'( 809 $ / % 2 &'( 8%9 " +%*+ / ! " (medical inoperable) '5 !*% 6 ! " 8 - : - 2/$+ '5 // !*" -/ % 2 !*'; 8)1 !/ (local control) +-!'; + ! %) (distant metastasis) !*0<!+-!- !*'-& !* ) $ " -" '5 / &'( 6 $ -'5 ,21 !/ (local failure) = 8)1 !/ ( local control ) + (combined-modality therapy ) /$ 1 +-! '? .<. 1905 $ !**-%) $ Benzene 1 '- /</ 1950 $ 5FU 1 - 2 Bleomycin, Mitomycin C Doxorubicin Antimetabotite Methotrexate 'E$ ! $ +-! # $ +-! Cisplatin Nigro // 8+ $ < %(1) +-! 5FU Mitomycin C 0!) $ (2,3) +-! !*/ (, # '5 F ) 2 2 "'& < !*$ : % $ !*' !*- !*! !'7! !* 2- !*-) & +-! !*'-& '5
2 (Single Modality ) !" ? 1. %! & '()* ! (Inaccessibility) ,--.!* %# ,--.!*" $ !*% 6 ,--./ %, (hypoxic cell) , !2 %0! -/ "'-2 ,--.0 2 * '0 / %# "" $1 - : 2 (fractionated radiation therapy) $ !* 8 +-! %# )"% 2 (fibrosis ) , /-"'-2 0- " ' " 9!%, ( hypoxia) $ (neoadjuvant radiochemotherapy ) / $ +-!%# ,--.!*" $ #'5 Systemic treatment $ Clonogenic tumor cell , & !+- & ! $ ' /$ -+ ! ) +-!$ $ $ 2 (adjuvant treatment ) $ !* 2. , )-./0/ (Insensitivity ) $ $ - 2 $ +-!$ ,--.!*"% 2 1 "+ : - / !,--.!*'0 +-!- ! !- (short treatment time) ) (concurrent radiochemotherapy) + - (sequential radiochematherapy) $ $ % 2 ) 1 ! ,--.!*/ + * 3. !/)* % 2"30 !*! !'5 1 !/ (locally advanced disease) ! !*6 ! " +-!'5 9!/ ! tumor emboli "'& !*! !+ ! 1 2 / ! !*" 2" +- #!* 8 " ( residual tumor) !*/ - 2 !+ * (doubling time 2 -) !+-!, 2 / 8 !*/ ) * 2 $/ / $ 1 + - 2 (accelerated fractionation) $ 4. , )5'!/ 6 21 !*/ % 6 + & ! - % (radical treatment) 1 0 +-!$'0/ & / !9!+/, 2 ' "& -9!+/, 2 + / . '5 ! ! ! 1 (treament break) /!*+ $ 2 (repopulation) / !$ 3 / -% "' $ $ ,--.!*/ 6 ) ! / 81 2 $ #$ -'0/2/ ! !* (total tumor dose) $ !*- !*/ 5. 8!9: 05%* 5 ;/< ) &'( !* 8 )'! ) & +- /" #" */ &'( -8 2+ / . !+'!'! (palliative treatment) "* 2+ / .#$ &'( -8 2 " $01 % -*- 1 '0 (low-dose infusion) , ! & &'+- (alternating) + - (sequential) *"
8 5)9)= (%/ 6> 1. clone (Resistant clone) 9?/ (4) <-./0/ Goldie +-! Coldman 2 F ,--.!* !2 %0! / ,--.+ clone : - 8. (mutation ) -- $ resistant clone " #$ '; 2 " +-! # resistant clone "*/ * '; -- "/ 2 "* cross-resistance ! 1 +-! * " $ non-cross-resistant regimens - &'+ $ $ & $ '5 '5 non-cross-resistant agents / +/ 2 - < /- 2//'5 systemic non-cross resistant regimen $ / '-&# "%!& ) +-! 1 / (total body irradiation) !*/)- / -8 )!* 2-/ 8 ++-!2 (refractory diffuse aggressive Non-Hodgkin/s Lymphoma) (5,6) 2. 0 '()* 2 5"0 0 (Spatial Cooperation) - 2< ) // ,--.!*1 !/ (local therapy) +-! // ,--.!*0 (0/ " "1 ) , Spatial Cooperation 2" - # 'E ! 1 +-! (drug and radiation reaction) % spatial cooperation $ !**-% * $ systemic + $ ,--.!* $ Goserelin '5 G.) 4 !* -&+-!$'5 1 !/ -& % $2* # spatial cooperation + " 'E" -%G.) !* -&) 3. ;< / 6/ %/ '()* (Enhance tumor response) (enhancement effect) #+ '5 3 $ supraadditivity, additivity +-! subadditivity , % !* 2 ' 2
/ -% (6) +-! ) < 0(7) -% Isobologram Analysis &'/ 1 Median Effect Principle Analysis , !" - -! / 2 + '5 subadditive enhancement effect * !'!) $ . *" $ - !*/ 3+ +-! !*$ '5 2+ +-! '5 4+ , '5 subadditive * additive effect ! " - / 5+ +-! suppra-additive effect $ " - 7+ '5 "*2 - % !* 'E - 6Diminution7 4. (Biologic Mechanisms of Interaction) ! "#$% % & 4.1 #$ " *
4.1.1 % DNA " + ,%-.% DNA /0 0 * % DNA "% % alkabile site % single strand break + double strand break % * + 1 2 2 % % * & 0 % DNA 13% ++ % 2 4&3#
4.1.2 ,%-. & 2 + 2 (sublethal + potential lethal damage repair ) Cisplatin, Hydroxyurea + Nitrosourea 1 (8) & + /2 + + DNA / pathway 4 & DNA 7 #8 DNA Synthesis inhibitors 9 nucleoside 7 nucleotide metabolisms 7 0 % + 2 2 5 5 FU & thymidylate synthase + # ; nucleotide triphosphate (9) pool % cell cycle redistribution + + DNA 2#3 (10) % * / & 5FU 1+% 2# DNA + RNA (11 ,12) 3# fluoro-deoxyuridine 4 #8! + % + DNA # %-< Gemcitabine #8 pyrimidine analogue 4,%-." # ; deoxynucleoside triphosphate pool + +% 2# DNA 5FU (13) 9 & + DNA
4.3 #$
4.3.1 % = / (Cytokinetic Cooperation) (14 ) G2 + M #8 % 2 % * + S 7& % * 4,%-. S % 42 2 (15) % ,%-. S camptothecin
4.3.2 7 2#3 mitotic phase 4 #8 % 2 ! (cell phase distribution changes)
4.3.3 9 + vascular supply 7 /0 7 % 72# & 4& + 14 2 4& ; < /% 3 4& (re-oxygenation) % (16) !2 4&2 &/ 3 G2 7 M 72
4.3.4 9 4 / (Hypoxic cell) 2 % / #8 * (17) 4 /! ! Mitomycin C + Cisplatin ,%-.% / % / /4 / 13 7 ",%-. (18) %&+ additive + Supraadditive effect % / #8 radiosensitizer 9% (19) % / &/ Nimorazole 4 > ! +
4.3.5 # +# apoptosis Apoptosis 7 4 / 2 !7 4 2 &413 * " p53 gene Anthracycline, Paclitaxel + Cyclophosphamide 1,%-. * (20) Apoptosis 4&
4.3.6 #?+ 0 (Inhibition of tumor repopulation during fractionated radiation therapy) 6 0 4 4-7 #A / + 0 + + 2#39 * % 4& (21) 2% % " 4& (regrowth) 1- 2/ (22) growth factor % & epidermal growth factor receptor (EGFR) 1 (23) (24,25) " + DNA + & tumor angiogenesis / & * apoptosis /2 0 & EGFR 1 &" & 2 A tyrosine kinase 7 ,%-. #8 monoclonal antibody EGFR C225
4.3.7 & angiogenesis 7 / #8 " /4 (26,27) & 7 angiostatin, combetastatin + TNP-470 #8 5. 5 8686 (Multimodality treatment) 0 2"!6 &8%! > (toxicity ) /-<<2!8686 (Protection of normal tissue from irradiation damage) -'0 $ Multimodality treatment $ - -% (Toxicity ) / " '!.% / $ - 2* "$ !* * $ $ #$ -'0 +-!"% - &'( ALL / / CNS prophylasis -'0 2 " $ -'0,--.!* $ 100 '5 30 , $ # ,--.!*) $'0 - $ -'0+- 0/ 1 (irradiation field) % -*- " $ &'( Bulky mediastinal Hodgkin/s disease +- '5 consolidation 1 !0/ - & (residual tumor) - 2 $ (neoadjuvant chemotherapy) 6. 9?/ 5 0 2"0%/ '()* )"0 @ 6 (Inhibition of tumor repopulation during fractionated radiation therapy) 1 , $-'!0 4-7 '. + %,--.!*
! 1 (8)$ - + %,--.!*+-! "'& -8 !*/ % 2 $ 5FU +-! Actinomycin D 7. 0 2 5 6 / ) (Organ preservation regimens) -" : "- % $ /) " / + !" -/ / F /809 $ / % 2 $ !* ! ! + !*/ !*-" +-!!*! ! '7! '5 7 <" )62 2"! 6> 1 ) ' $'0 2 Gy 2 '.-! 5 2 /2 7 '. , '0+-! ' / /8 3-4 '. -% &% 2 2 ''- 1 ''0 $ - -% '5 / '5 $+-! - (Alternative, Sequential Radiochemotherapy) + $ " " % 2 - ! ! ''- (concurrent radiochemotherapy) (dose/fraction) ) $ ) -'0 2(28,29) -'0 (total dose) -'0 2 '5 + ! - - ) < +,--.!* -/- ./- + '5 ,--.!* 8 .-- !,--. (cellular heterogeneity) +- !,--. (Microenvironment) '5 % (pH ) --/ -2 +-!9!%, 2 '5 /- = + +-! -/ ! !*+ -!$
%!/6 %/ 2"! 6> + !'!) $ ." # -"M/N+-% + -- ) $* " ) # " 1. ,--.!*2 /2+-! " !'5 2+ mutation - 2. / - (vascular fibrosis ) / %# !*" % 2
3. -% ,--.' +-! % &'( % 2 / & -'0 '0 '5 -)/ !/- !*-- -% 2 8 + /'!) $ . $
8%/ 6> 0/-./ - Increased dose Increase drug-specific acute and late toxicity Increase acute toxicity of radiotherapy Duration of exposure Bolus Increase toxicity of proliferative tissues Infusion Decrease acute toxicities in general Possible increase radiotherapy interaction on tumors and normal tissues %/ Cell-cycle dependent Increase toxicity of proliferating tissue ( eg. Alkylating agents, 5 FU, bleomycin ) Cell-cycle independent Increase toxicity in all tissues ( eg. Anthracyclines, actinomycin D ) Limited organ interaction Vincristine- neuropathy Multiple organ interaction Doxorubicin-cardiac, gastrointestinal effects %/ Sequential Decrease side effects Concurrent ( Simultaneous ) Increase acute and possible increase late effects %/ -./ -
1 ) '- '0 2 ) 1 ! hypofractionation " ! ! -% ! !1 -
9 2. 8) ) ) (Late effects) -!/! ! -% !--O (microcirculation) +-! 2 (fibroconnective tissue ) // % ! 2 "' %0! - - ,--. Parenchyma $ %,--. (stem cell depletion) 2 -!/ ! ! -"+ "' $ Doxorubicin - - 2 (myocardium) + 1 - -- , "'& 9! --"$
8%! > 0/-./ - / /'5 / $ - -% 2 ' ) $'0 2" 1.8 Gy -01 -81 !0/ !* '5 " $ hypofractionation hyperfractionation !) -% 1 - & '5 ! '-'0+-!! !- $ infusion bolus '5 / $ - -% $ 5FU infusion 1 -% "%!& + bolus + -% !/ 2 1 0$ +-! !& - (, "%!&) -$ 5FU infusion '5 /-/ $ bolus '5 -- / -% !/ #& $ -- Doxorubicin 1 #& -" , -- Bleomycin +-! Actinomycin D 1 0 2 ' , -- Vincristine 1 0!'!/- (CNS) +-! -- $ Cisplatin 1 0" '5 "* # '5 $ - ! -'0 - '- "'$ / M/N- - + " -% ! 2 $ '- Cisplatin '5 Carboplatin : , $ - -% $ '- '5 + sequential, alternate +/ / !'5 + (concurrent radiochemotherapy ) '5 / 2 +$ %!*, +-!% $2 , $ & '7 8 )
6 9 $ '5 $ '!/9 ,--.!* % # -" M/N - -% +-!-- -% $ + / ./ !*/ # % '! 8 .$) < %&-/ $ #" - // < . 2 F /- '!) $ .&8 &'( !*+-! -% % 10 /! / 1. Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal : a preliminary report. Dis Colon Rectum 1974 May-Jun; 17(3): 354-6 2. Cummings BJ, Rider WD, Harwood AR,Keane TJ, Thomas GM, Erlichman C, Fine S. Combined radical radiation therapy and chemotherapy for primary squamous cell carcinoma of the anal canal. Cancer Treat Rep 1982 Mar; 66(3):489-92 3. Flam M, John M, Lovalvol LJ, Mills RJ, Romalho LD, Prather C, Mowry PA, Morgan DR, Lau PB. Definitive nonsurgical therapy of epithelial malignancies of the anal canal . A report of 12 cases. Cancer 1983 Apr 15; 51(8):1378-87 4. Goldie JH, Coldman AJ. A mathematic model for relating the durg sensitivity of tumor to their spontaneous mutation rate. Cancer Treat Rep 1979 Nov-Dec; 63(11-12):1727-33 5. Steel GG, Hill RP, Peckham MJ. Combined radiotherapy -chemotherapy of Lewis lung carcinoma. Int J Radiat Oncol Biol Phys 1978 Jan-Feb; 4(1-2): 49-52 6. Steel GG, Peckham MJ: Exploitable mechamisms in combined radiotherapy-chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys 1979 Jan; 5(1):85-91 7. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984;22:27-55 8. Fu KK: Interactions of chemotherapeutic agents and radiation. Front Radiat Ther Oncol 1992; 26: 16-30. 9. Miller EM, Kinsella TJ. Radiosensitization by fluorodeoxyuridine:effects of thymidylat synthase inhibition and cell synchronization .Cancer Res 1992 Apr; 52(7):1687 I1694. 10. Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology . J Clin Oncol 1988 Oct; 6(10) :1653 I1664. 11. Lawrence TS, Davis MA, Maybaum J. Dependence of 5-fluoro-uracil-mediated radiosensitization on DNA-directed effects. Int J Radiat Oncol Biol Phys 1994 Jun; 29(3):519 I523. 12. McGinn CJ, Shewach DS, Lawrence TS. Radiosensitizing nucleosides. J Natl Cancer Inst 1996 Sep; 88(17):1193 I1203. 13. Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2 0 ,2 0 -di fluorodeoxycytidine on DNA synthesis. Cancer Res 1991;51 :6110 I6117. 14. Sinclair WK, Morton RA. X-Ray sensitivity during the cell generation cycle of cultured Chinese hamster cells. Radiat Res 1966l; 29(3):450 I474. 11 15. Hennequin C, Giocanti N, Balosso J, Favaudon V. Interaction of ionizing radiation with the topoisomerase I poison camptothecin in growing V-79 and Hela cells .Cancer Res 1994 Apr; 54(7) :1720 I1728. 16. Milas L, Hunter NR, Mason KA, Milross CG, Saito Y, PetersLJ. Role of reoxygenation in induction of enhancement of tumor radioresponse by paclitaxel. Cancer Res 1995 Aug; 55(16):3564 I3568. 17. Hockel M, Schlenger K, Mitze M, et al : Hypoxia and radiation response in human tumor. Semin Radiat Oncol. 1996 Jan; 6(1):3-9. 18. Brown M, Siim BG: Hypoxia-specific cytotoxins in cancer therapy. Semin Radiat Oncol 1996 Jan; 6(1):22-36. 19. Overgaard J, Horsman MR: Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol 1996 Jan; 6(1):10-21. 20. Bresnick E: Biochemistry of cancer. In Holland JF, Frei E, Bast RC, et al, eds. Cancer Medicine rd 3 ed. Philadelphia: Lea & Febiger, 1993:121-137. 21. Trott KR, Kummermehr J. What is known about tumour proliferation rates to choose between accelerated fractionation or hyperfractionation? Radiother Oncol 1985 Jan; 3(1):1 I9. 22. Bandyopadhyay D, Mandal M, Adam L, Mendelsohn J, Kumar R: Physical interaction between epidermal growth factor receptor and DNA-dependent protein kinase in mammalian cells . J Biol Chem 1998 Jan; 273(3):1568 I1573. 23. Perrotte P, Matsumoto T, Inoue K, et al: Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 1999 Feb; 5(2):257 I265. 24. Mendelsohn J, Baselga J: The EGF receptor family as targets for cancer therapy. Oncogene 2000 Dec;19(56):6550I6565. 25. Huang SM, Harari PM: Epidermal growth factor receptor inhibition in cancer, therapy: biology, rationale and preliminary clinical results. Invest New Drugs 1999;17(3):259 I269. 26. Mauceri HJ, Hanna NN, Beckett MA,et al.: Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 1998 Jul; 394(6690):287 I291. 27. Lund EL, Bastholm L, Kristjansen PE.: Therapeutic synergy of TNP-470 and ionizing radiation:effects on tumor growth,vessel morphology,and angiogenesis in human glioblastoma multiforme xenografts. Clin Cancer Res 2000 Mar; 6(3):971I978. 12 28. Munro AJ: An overview of randomized controlled trials of adjuvant chemotherapy in head and neck cancer. Br. J Cancer 1995 Jan; 71(1): 83-91. 29. El-sayed, Nelson N: Adjuvant and adjunctive chemotherapy in the management of Squamous cell carcinoma of the head and neck region : A meta-analysis of prospective and randemized trials. J Clin Oncol 1996 Mar; 14(3):838-847.
9< 1 + Isobologram % A +-! B ) &' +'E % A +-! B + +-! &' % + 'E +" '5 ) 'E & &'+ supra-additive +-! sub-additive
13 < 2 +$ %!*, -F %$
"B 6 6 %!/ 0 . Wilm/s tumor '5 - &'( ! !/ 2-4 !* 2-$ Non-Hodgkin/s '5 - 0 &'( ! !/ 1-2 , lymphoma +-! 9 +8 +' - (intermediate grade lymphoma) !* 2-$ Hodgkin/s disease '5 - &'( !*! !/ 1A +-! 2A $ !*/ 2-% 6 ( bulky mass ) !*'$ non small cell '5 -0 " " !*'$ small cell ! ! '5 -+-!$'; + ! %!*"'/ !* ! ! ( inflammatary breast '5 - ( neoadjuvant cancer ) treatment ) +- ( # ) !* ! ! ( early stage ) '5 '; '5 ,21 !/ , '; + ! +-!0 + !*/ '5 -, 0 !* 8" !*'-& '5 -!*! ! IB # IVA !*-" Rectal cancer '5 !*! ! 2 +-! 3 , (neoadjuvant) - (adjuvant) !*-) & '5 - !*<!+-!-0 '5 - 0 " " '5 - 0 + - !*- '5 - '5 ( neoadjuvant treatment )
14
"B 6 6 %!/ 0 . Childhood Medulloblastoma '5 ) 1 - '!) $ . &'( * 8 3 '? !* !* "" !*! ! '!/ - !* 2 ( Soft tissue sarcoma ) '5 &'( , + ! (limb-sparing surgery) +-! / 9 +8 + ( high grade ) $ - -'5 ,2 1 !/ !*! !'7! '5 - 0 " " '5 /- &'( " / radical cystectomy !*! ! '5 !*! ! / " " (complete resection) !* $'5 +'!'! 0" #/ + radical " $'5 0 " ';
-'5 ,21 !/ - "B 6 6 0 !*-"6 '5 !*! !/ 3 1 0/ '5 !* " %&- 8 + $ !* $'5 &'( !*- !*$ anaplastic glioma, anaplastic oligodendroglioma +-! glioblastoma multiforme