ࡱ > i y q` bjbjqPqP ( : : ] %
* * * 8 * z+
Q J, ^ , " , , , A; 3< T , ߔ * ZC 2 M N 4 `Q 0 Q M V V E V ON V
ON 8 < < < P P .G ^ < < 2, !. . ":0G52, . . =KH, . . ;B0@652A:0O, . . >@>28=0, !. . /@=5=:>, . . 09=A>=, . . 8:>;052, . ". @04NH:>, . . ;0A>2, . . 0;8E>2, . . C7L, . . ;852
' / ( ! ! , ! ,% $" & #' "
Y u . A . B a r s u k o v , S . I . T k a c h e v , V . I . K n y s h , N . D . O l t a r z h e v s k a y a , M . A . K o r o v i n a , S . P . Y a r m o n e n k o , A . A . V a i n s o n , A . V . N i k o l a e v , A . T . G r a d y u s h k o , O . A . V l a s o v , A . G . M a l i k h o v , D . V . K u z m i c h e v , V . M . K u l u s h e v , D . A . O s k i r k o , V . A . A l i e v
K o m b i n e d T r e a t m e n t o f R e c t a l C a n c e r w i t h P r e o p e r a t i v e I r r a d i a t i o n a n d O n e o r T w o R a d i o m o d i f i c a t o r s
;NG52K5 A;>20: @0: ?@O9 :8H:8, :>20==>5 ;5G5=85, @048>48D8:0B>@K, ?>;8@048>48D8:0F8O
K e y w o r d s : r e c t a l c a n c e r , c o m b i n e d t r e a t m e n t , r a d i m o d u l a t o r s , p o l y r a d i o m o d i f i c a t i o n
# & 8E8=0 3. >A:20
R u s s i a n C a n c e r R e s e a r c h C e n t e r , M o s c o w
$ "
&5;L: >2KA8BL MDD5:B82=>ABL ?@54>?5@0F8>==>9 ;CG52>9 B5@0?88 =0 >A=>25 8A?>;L7>20=8O =5A:>;L:8E @048>48D8:0B>@>2 2 :>20==>< ;5G5=88 @0:0 ?@O9 :8H:8.
0B5@80; 8 4K: >A=>2C @01>BK ?>;>65= 0=0;87 @57C;LB0B>2 E8@C@38G5A:>3> 8 :>20==>3> ;5G5=8O 9 6 1 1>;L=KE, 2:;NG5==KE 2 B@8 ?@>B>:>;0 ?@>A?5:B82=KE @0=4>20==KE 8AA;54>20=89 1>;55 G54 =01;N45=8O 2 # & 8E8=0 . # 2 7 6 87 =8E ?@>2545=0 ?@54>?5@0F8>==0O ;CG520O B5@0?8O ( 5 @ 2 B5G5=85 5 4=59 4> ! 2 5 @59) , C 3 9 5 2K?>;=5=> B>;L:> >?5@0B82=>5 2. @54>?5@0F8>==0O B5@;CG520O B5@0?8O ( G0AB>B0 M;5:B@>;510=89 4 6 0 F ?@8 2=CB@8@5:B0;L=>3@520=88) ?@>2545=0 C 2 2 4 1>;L=KE. @>3@0<A?>;L7>20=85A5=A818;870B>@>2 ( ;>:0;L=>9 !'- 38?5@B@5@=>0:F5?B>@=>3> A>548=5=8O =8407>;0, 22>483> 2=CB@8@5:B0;L=>) ?@>2545=0 C 6 6 ?0F85=B>2 ( ?0B5=B >AA89A:>9 $545@0F88 ! 2 2 3 4 3 1 8 >B 2 0 0 4 3. ) .
57C;LB0BK: OB8;5B=85 @57C;LB0BK :>20==>3> 40 ;5G5=8O A 8A?>;L7>20=854=>9 ?@54>?5@0F8>==>9 ;CG52>9 B5@0?88 C;CGH5=K ( =0 1 3 . 9 % ) 70 AG5B A=865=8O G0AB>BK ;>:>@538>=0@=KE @5F8482>2 @0:0 ( A 1 9 , 8 % 2 E8@C@38G5A:>9 3@C??5 4> 8 , 7 % ?@8 :>20==>< ;5G5=88) . @8 ?@8?5@0F8>==>3> B5@;CG52>3> :>=5=B0 G0AB>B0 ;>:>@538>=0@=KE @5F8482>2 4>AB>25@=> C 4 , 7 % ?> A@02=5=8N A 1 1 , 1 % ?@8 8A?>;L7>20=88 >4=>9 ?@54>?5@0F8>==>9 ;CG52>9 B5@0?88 8 2 0 , 0 % 2 E8@C@38G5A:>9 3@C??5. @57C;LB0B5 ?>:070B5;L 157@5F8482=>9 2K68205AB8 A 8A?>;L7>20=85< B5@;CG52>3> :>=5=B0 ?>2KA8;AO 4> 6 4 , 9 % ?> A@02=5=8N A 5 5 , 0 % ?@8 >4=>9 ?@54>?5@0F8>==>9 ;CG52>9 B5@0?88 8 4 4 . 3 % 2 E8@C@38G5A:>9 3@C??5. 7 6 6 1>;L=KE, 2:;NG5==KE 2 ?@>3@0<;8@048>48D8:0F88, ?@8 B@5E;5B=5:5 =01;N45=8O =5 2KO2;5=> =8 >4=>3> @5F84820 @0:0, 8 ;8HL C >4=>3> ?0F85=B0 ( 1 , 5 % ) 4803=>AB8@>20=K 4K: >20==K9 4 A 8A?>;L7>20=85?5@0F8>==>9 ;CG52>9 B5@0?859 4>;65= 1KBL 4>@0 2 ;5G5=88 1>;L=KE @0:>< ?@O9 :8H:8. @8:0;L=>9 !'- 38?5@B5@2KH05B :>;8G5AB2> 1>;L=KE A I I I AB5?5=LN ;CG52>3> ?0B>@D>70, ?> A@02=5=8N A 8A?>;L7>20=854=>9 ?@54>?5@0F8>==>9 ;CG52>9 B5@0?859. 0;L=59H85 ?5@A?5:B82K 2 C;CGH5=88 @57C;LB0B>2 :>20==>3> 40 ;5G5=8O @0:0 ?@O9 :8H:8 A2O70=K A @50;870F859 ?@>3@0<;8@048>48D8:0F88 A 2:;NG5=85 2 AE5?5@0F8>==>9 ;CG52>9 B5@0?88 =5A:>;L:8E @07=>=0?@02;5==KE @048>48D8:0B>@>2.
A B S T R A C T
P u r p o s e : T o e n h a n c e t h e e f f i c i e n c y o f p r e o p e r a t i v e r a d i o t h e r a p y b a s e d o n a p p l i c a t i o n o f s e v e r a l r a d i o m o d i f i e r s i n c o m b i n e d t r e a t m e n t o f r e c t a l c a n c e r .
M a t e r i a l s a n d m e t h o d s : W e r e a n a l y z e d r e s ults of surgery and combined treatment of 961 patients included into 3 prospective randomized trials during more 28 years follow-up in Russian Cancer Research Center. 276 patients were treated preoperative radiotherapy (5-Gy fractions daily during 5 days up to total dose 25 Gy, with subsequent surgery for 3-5 days), and 395 was performed only surgery alone. The second protocol enrolled 224 patients (with preoperative termoradiotherapy). Since 2004 for further enhancement of preoperative radiotherapy efficiency was originated program of combined treatment included two radiosensitinogens of tumor cell hypoxic fraction local microwave hyperthermia and electronoacceptor compound of Metronidazolum /M3/, intrarectally, in the form of radiosensitizing intermixture (the patent of the Russian Federation !2 2 3 4 3 1 8 / 2 0 0 4 ) . T h e i n l e t o f M e t r o n i d a z o l u m w a s a c c o m p l i s h e d o n t h e 3 - r d , t h e 4 - t h a n d t h e 5 - t h s e s s i o n s b e f o r e i r r a d i a t i o n f o l l o w e d b y l o c a l m i c r o w a v e h y p e r t h e r m i a .
R e s u l t s : T h e 5 - y e a r o u t c o m e s o f c o m b i n e d t r e a t m e n t w i t h u s e p r e o p e r a t i v e r a d i o t h e r a p y a l o n e were improved at 13,9% due to reduction of locoregional recurrence frequency (from 19,8% in surgery group to 8,7% in combined treatment group). Application of preoperative thermoradiotherapy in patients with distal rectal cancer (middle and lower ampullar parts) reliably decreased the locoregional recurrence frequency up to 4,7% as compared with 11,1% for use preoperative radiotherapy alone and 20,0% in surgery group. As a result recurrence-free survival rate in group of thermoradiotherapy has raised up to 64,9% as compared with 55,0% in preoperative radiotherapy alone and 44,3% in surgery groups. From 66 patients included in the program of polyradiosensitivisation during 2-year follow up was revealed no cancer relapse and for one patient were diagnosed only metastases in the liver.
Conclusion: Combined treatment with use of preoperative radiotherapy should to be a method of choice in the treatment of patients with rectal cancer. Application of local microwave hyperthermia enhances amount of patients with the 3-rd grade of radiation pathomorphism as compared with application of preoperative radiotherapy alone, that leads to reduction of locoregional recurrence rate (from 11,1% to 4,7%). Further perspectives in improvement of rectal cancer combined treatment outcomes are connected with realisation of polyradiosensitizations program including several different radiomodifiers into preoperative radiotherapy scheme.
2545=85
!@548 ?@8>@8B5B=KE =0?@02;5=89 2 ;5G5=88 7;>:0G5AB25==KE >?CE>;59 @07;8G=KE ;>:0;870F89, 2 B>< G8A;5 8 @0:0 ?@O9 :8H:8, 206=59H8B:0 8 2=54@5=85 :>3@0<B40;5==KE @57C;LB0B>2 ;5G5=8O. 1>A=>20==>ABL 40==>3> ?>;>65=8O >?@545;O5BAO >BACBAB285B40;5==KE @57C;LB0B>2 E8@C@38G5A:>3> 40 ;5G5=8O 70 ?>A;54=85 45AOB8;5B8O, GB> A2O70=> A 2KA>:>9 G0AB>B>9 2>7=8:=>25=8O ;>:>@538>=0@=KE @5F8482>2 @0:0 ( >B 2 0 4> 3 5 % ) , ?>A;5 2K?>;=5=8O, :070;>AL 1K, @048:0;L=KE >?5@0B82=KE 2:0;L=K9 E0@0:B5@ @0728B8O @5F8482>2 @0:0 ?@O9 :8H:8, @5H0NICN @>;L 2 @07@01>B:5 ?@>3@0< 8E ?@>D8;0:B8:5 B2>489 B5@0?88, :>B>@0O O2;O5BAO I=K@>:0;L=>3> :>=B@>;O 70 @0A?@>AB@0=5=85?CE>;52>3> ?@>F5AA0. !@548 20@80=B>2 :>20==>3> ;5G5=8O @0:0 ?@O9 :8H:8 8A?>;L7>20=85 ?@54>?5@0F8>==>9 ;CG52>9 B5@0?88, ?> =0H5<C ;55 >1>A=>20==KB5@0?8O, 2>7459AB2CO =0 >?CE>;L, ?@54>B2@0I05B 8=B@0>?5@0F8>==CN ;83535==CN 48AA5?CE>;52KE :;5B>: 8 C=8GB>605B :;8=8G5A:8 =5 >?@545;O5<K5 <5B0AB07K 2 ;8<D0B8G5A:8E C7;0E 3> B070, =5 ?>4;560I8E C40;5=8N ?@8 2K?>;=5=88 AB0=40@B=KE >?5@0B82=KE 2;L ?>4274>H=KE A>AC4>2, 2 >1BC@0B>@=>9 O2K5 ;8<, AC<G03>20O 4>70 >1;CG5=8O 4>;6=0 1KBL =5 87>MDD5:BC ?@8 @07;8G=KE @568=8@>20=8O, 0 >1J51;CG5=8O 4>;65= 2:;NG0BL 2A5 @538>=0@=K5 ;83> B0: 8 2B>@>3> MB0?0 2>76=>3> 20=8O. "5< =5 ;L7C5?5@0F8>==>45 4>70 ;CG52>9 B5@0?88 >1;0405B O2=> =54>AB0B>G=KF84=K7459AB285A>15==> 4;O @048>@578AB5=B=KE 38?>:A8G5A:8E :;5B>: :0: ?5@28G=>9 >?CE>;8, B0: 8 2 2 @538>=0@=KE ;8<D0B8G5A:8E C7;0E. A2O78 A MB81>A=>20= ?>8A: B0:8E ?@>3@0<B>@KE ?>2KH5=85 MDD5:B82=>AB8 ;CG52>3> :>=5=B0 :>20==>3> ;5G5=8O 4>AB830;>AL 1K =5 70 AG5B ?@>AB>3> =0@0I820=8O ?>3;>I5==>9 AC<9 4>7K 87;CG5=8O, 0 >A=>2K20;>AL 1K =0 CA8;5=88 8718@0B5;L=>3> ?>2@5645=8O D@0:F88 @048>@578AB5=B=KE 38?>:A8G5A:8E >?CE>;52KE :;5B>:. 4=84>;5=88 @048>@578AB5=B=>AB8 >?CE>;52KE :;5B>: 2 ?@>F5AA5 ;CG52>9 B5@0?88 O2;O5BAO 8A?>;L7>20=85 @07;8G=KE @048>48D8:0B>@>2 ( E815A?5G820NI8E 8718@0B5;L=>5 ?>2KH5=85 8E @048>GC2AB28B5;L=>AB8. :0G5AB25 @048>48D8:0B>@>2 =081>;55 G0AB> 8A?>;L7CNBAO ;>:0;L=0O !'- 38?5@B5@=>0:F5?B>@=K5 A>548=5=8O ( =8407>; 8 53> ?@>872>4=K5) , 38?5@3;8:5B82>>?CE>;52KE ?@5?0@0B>2 ( 1 , 2 , 3 , 4 ) . 4=0:> ?@84=>3> @048>48D8:0B>@0 2 A>G5B0=88 A ;CG52>9 B5@0?859 =5 2A5340 >:07K205BAO MDD5:B82=K76=>AB8 4>AB865=8O =5>1E>483> C@>2=O @048>A5=A818;870F88. >MB>2KH5=8O MDD5:B82=>AB8 ;CG52>3> :>=5=B0 :>20==>3> 40 ;5G5=8O A;54C5B @0AA740=8O ?@>3@0<< A 2:;NG5=85< 2 AE504JN20=B=>9 ;CG52>9 B5@0?88 >4=>3> 8;8 =5A:>;L:8E @048>4C;8@CNI8E 035=B>2, B. 5. 2 @50;870F88 ?@>3@0<;8@048>48D8:0F88.
"0:81@07>4 ?>;8@048>48D8:0F859 A;54C5B ?>=84=>2@55 8;8 ?>A;54>20B5;L=>5 ?@8;L:8E @07=>=0?@02;5==KE @048>4C;8@CNI8E 035=B>2 2 ?@>F5AA5 ;CG52>9 B5@0?88 " ( 7 ) .
AE>4O 87 2KH587;>65==>3>, F5;LN 40==>3> 8AA;54>20=8O O28;>AL ?>2KH5=85 MDD5:B82=>AB8 ?@54>?5@0F8>==>9 ;CG52>9 B5@0?88 A 8A?>;L7>20=85;L:8E @048>48D8:0B>@>2 2 :>20==>< ;5G5=88 @0:0 ?@O9 :8H:8.
0B5@80;K 8 4K
>A=>2C @01>BK ?>;>65= 0=0;87 @57C;LB0B>2 E8@C@38G5A:>3> 8 :>20==>3> ;5G5=8O 9 6 1 1>;L=KE, 2:;NG5==KE 2 B@8 ?@>B>:>;0 ?@>A?5:B82=KE @0=4>20==KE 8AA;54>20=89, ?@>2545==KE 2 # & 8E8=0 1>;55 G54 =01;N45=8O.
?5@2K9 ?@>B>:>; ?@>A?5:B82=>3> @0=4>20==>3> 8AA;54>20=8O, A>740==>3> 2 # & 8E8=0 2 1 9 7 8 3. , 2:;NG5=K 6 7 1 1>;L=KE >?5@015;L=K< ?@O9 :8H:8, C :>B>@KE 87CG0;0AL MDD5:B82=>ABL ?@54>?5@0F8>==>9 ;CG52>9 B5@0?88 ( ?@>B>:>; @0=4>20==>3> 8AA;54>20=8O ! 1 - 0 3 / 7 8 ) . # 2 7 6 87 =8E ?@>2545=0 ?@54>?5@0F8>==0O ;CG520O B5@0?8O, C 3 9 5 2K?>;=5=> B>;L:> >?5@0B82=>5 2. 5>04JN20=B=0O ;CG520O B5@0?8O ?@>2>48;0AL =0 ;8=59=KE CA:>@8B5;OE M;5:B@>=>2 A M=5@3859 D>B>=>2 6 - 1 8 M, 5 @, 2 B5G5=85 ?OB8 4=59 5654=52=> 4> ! 2 5 @, A ?>A;54CNI59 >?5@0F859 2 B5G5=85 3 - 5 4=59.
B>@>9 ?@>B>:>; ?@>A?5:B82=>3> @0=4>20==>3> 8AA;54>20=8O, A>740==K9 2 # & 8E8=0 2 1 9 8 4 3. >1J548=8; 2 2 4 1>;L=KE, C :>B>@KE 2 AE5?5@0F8>==>3> >1;CG5=8O 2:;NG5=0 2=CB@8?>;>AB=0O !'- 38?5@B5@B>:>; @0=4>20==>3> 8AA;54>20=8O ! 1 - 0 3 / 8 4 ) . >:0;L=0O !'- 38?5@B5@ACI5AB2;O;0AL =0 0??0@0B0E /;8: 8 /EB0- 4 8 ?@>2>48;0AL =0 3 - 5?5@0F8>==>9 ;CG52>9 B5@0?88 A G0AB>B>9 M;5:B@>;510=89 4 6 0 F 2 B5G5=85 6 0 AB865=88 B5?CE>;8 4 3 , 5 - 4 4 , 0 !.
2 0 0 4 3. 2 # & 8E8=0 A F5;LN 40;L=59H53> ?>2KH5=8O MDD5:B82=>AB8 :>20==>3> 40 ;5G5=8O A>740=0 ?@>3@0<<0 A 2:;NG5=85< 2 AE5?5@0F8>==>3> >1;CG5=8O 42CE @048>A5=A818;870B>@>2 38?>:A8G5A:>9 D@0:F88 >?CE>;52KE :;5B>: ;>:0;L=>9 !'- 38?5@B5@=>0:F5?B>@=>3> A>548=5=8O =8407>;0 / / , 22>483> 2=CB@8@5:B0;L=>, 2 2845 @048>A5=A818;878@CNI59 AAA89A:>9 $545@0F88 ! 2 2 3 4 3 1 8 >B 2 0 0 4 3. ) ( 6 ) . 1>A=>20=85G5B0==>3> ?@8:0;L=>9 !'- 38?5@B5@=>0:F5?B>@=>3> A>548=5=8O =8407>;0 ?>A;C68;8 40==K5 > A8=5@387F5AA>2 @048>A5=A818;870F88 8 3815;8 38?>:A8G5A:8E >?CE>;52KE :;5B>: ?@8 8E A>2< ?@83> 22545=8O =8407>;0 A>B@C4=8:03@5AA ( . . ;B0@652A:0O A A>02B. ) @07@01>B0=0 B5E=>;>38O 873>B>2;5=8O @048>A5=A818;878@CNI59 A;L7>20=852>9 ;5G51=>9 D>@35;O =0 >A=>25 18>?>;8ABLN 2 , 6 3 0" A A 4>102;5=853> @0AB2>@0 ! ( C=825@A0;L=K9 B@0=A?>@B5@) . ! F5;LN >?@545;5=8O 4>7K 2 @048>A5=A818;878@CNI59 A:07K20NI89 @048>A5=A818;878@CNI89 MDD5:B =0 >?CE>;L ( :>=F5=B@0F8O 2 >?CE>;8 4>;6=0 1KBL =5 <5=55 1 5 0 2545=> :>;8G5AB25==>5 87CG5=85 A>45@60=8O =8407>;0 2 >1@07F0E B:0=59 >?CE>;8 ?@O9 :8H:8 A CG5B>78F88 @048>A5=A818;878@CNI59 A<5A8 2 ?@O9 :8H:5 ( 3 - 4 8 5 - 6 G0A>2) 8 :>=F5=B@0F88 2 =59 =8407>;0 2 7028A8AB8 >B ?;>I048 ?>25@E=>AB8 B5;0 8 4>7K =8407>;0 2 A<5A8 ( 6 , 8 8 1 0 3/ 48:0 70:;NG0;0AL 2 A;54CNI5A;5 22545=8O @048>A5=A818;878@CNI59 A<5A8 2 ?@OA;54=OO G5@57 3 - 4 8;8 5 - 6 G0A>2 C40;O;8, BI0B5;L=> >BB >AB0B:>2 . 0B5?CE>;L @07@570;8 8 87 3;C18=K 1@0;8 ?OBL :CA>G:>2 B:0=59 ( B@8 87 F5=B@0;L=>9 G0AB8 8 420 A ?5@8D5@88) . !?5:B@>D>B><5B@8G5A:8< 4>?@545;O;8 :>;8G5AB25==>5 A>45@60=85 =8407>;0 2 B:0=8 >?CE>;8. > 40==>9 AE52545=> 87CG5=85 1 6 5 >1@07F>2 B:0=59 >?CE>;8 C 3 7 1>;L=KE @0:>< ?@O9 :8H:8, ?>425@3=CBKE @07;8G=K< 2840?5@0F89. >;CG5==K5 @57C;LB0BK ?@54AB02;5=K
2 6 8 : N R T V X Z n r t v x z
h\ 5aJ( h\ 5aJ( mHsHh4Gj h\ 5aJ( mHsH h\ 5NH \aJ( mHsH h\ 5\aJ( mHsHM
d f ,
.
0
B D F H J L $Tdh `Ta$ Tdh `T
$dh a$gd4Gj dh gd4Gj $dh a$ $Tdh `Ta$ " 2 6 8 : L P R T V X b f
0
N
D H J L \ d j zpzh\ CJ NH aJ( h\ CJ aJ( h\ 5>*CJ aJ( h4Gj 5CJ aJ( h\ 5CJ aJ( mH sH h\ 5CJ aJ( h\ aJ( mHsH
h\ aJ( h\ 6\]aJ( h\ 6NH \]aJ( mHsHh\ 6\]aJ( mHsHh\ 5NH aJ( h\ 5aJ( mHsH
h\ 5aJ( ,L \ d" f" h" j" l" n" " # L) - / / / / / / $
Tdh `Ta$ $Tdh `Ta$ Tdh `T
! Tdh `T $Tdh `Ta$ " $ : *CJ mH sH h\ 5CJ aJ( mH sH h4Gj 5CJ aJ( h\ CJ aJ( mH sH h\ CJ NH aJ( h\ CJ aJ( h\ 5CJ aJ( h\ 5>*CJ aJ( :$ $ $ $ % % & & L) \) a* b* &+ '+ + + , , - - - (- <. =. a/ b/ / / / 0 0 0 0 2 2 3 3 4 4 L5 N5 5 5 6 6 H7 J7 7 7 F9 H9 9 9 : : ; ; < > @? B? ? ? ǾǶh\ CJ NH aJ( h\ CJ aJ( h! 5CJ aJ( h\ 5CJ aJ( h\ 5CJ aJ( mH sH h\ 5>*CJ mH sH h\ CJ mH sH h\ CJ NH mH sH D/ 0 H dJ L :L 45@60=8O =8407>;0 2 >?CE>;8 ( B 53> :>=F5=B@0F88
2 @048>A5=A818;878@CNI59 A<5A8 8 2@59 M:A?>78F88
!>45@60=85 =8407>;0 2 @048>A5=A818;878@CNI59 A25@E=>AB8 B5;0 @578F88 3 - 4 G0A0 5 - 6 G0A>2 6 3/ <2 1 3 9 , 5 1 7 , 1 <:3/ 3 1 0 0 , 4 2 0 , 5 <:3/ 3 8 3/ <2 1 8 6 , 7 2 1 , 7 <:3/ 3 1 2 2 , 4 2 4 , 8 <:3/ 3 1 0 3/ <2 2 0 4 , 4 4 5 , 1 <:3/ 3 1 9 6 , 3 2 7 , 6 =F5=B@0F88 =8407>;0, A>AB02;ONI59 8 3/ <2 8 1 0 3/ 25@E=>AB8 B5;0 2 @048>A5=A818;878@CNI59 A M:A?>78F88 2 ?@O9 :8H:5 2 B5G5=85 3 - 4 G0A0, 4>AB8305BAO =5>1E>48A5=A818;878@CNI0O :>=F5=B@0F8O 2 >?CE>;8. 4=0:> 2 40;L=59H5=F5=B@0F8O =8407>;0 2 @048>A5=A818;878@CNI59 A<5A8 1 0 3/ 25@E=>AB8 B5;0 >15A?5G8205B =5>1E>48A5=A818;878@CNICN :>=F5=B@0F8N 53> 2 >?CE>;8.
AE>4O 87 2KH587;>65==>3>, 1K;0 ?@54;>65=0 48:0 :>20==>3> ;5G5=8O @0:0 ?@O9 :8H:8 A 8A?>;L7>20=8548D8:0B>@>2 - M;5:B@>=>0:F5?B>@=>3> A>548=5=8O =8407>;0 8 2=CB@8@5:B0;L=>9 ;>:0;L=>9 !'- 38?5@B5@48:0 70:;NG0;0AL 2 42C:@0B=>A5=A818;878@CNI59 A9 B5@0?88) , A>45@60I59 =8407>;0 1 0 3/ 25@E=>AB8 B5;0 ( 2 A@54=5B 1 8 4> 2 2 3 2 @048>A5=A818;878@CNI59 A78F859 55 2 ?@O9 :8H:5 2 B5G5=85 H5AB8 G0A>2 A ?>A;54CNI82545=859 B5@0?88 8 2=CB@8@5:B0;L=>9 ;>:0;L=>9 !'- 38?5@B5@: 1 .
S H A P E \ * M E R G E F O R M A T
4=>2@5 A 2=CB@8@5:B0;L=K< 22545=85A5=A818;878@CNI59 A?@>2>48B5;L=0O B5@0?8O, :>B>@0O 70:;NG0;0AL 2> 2=CB@825==>2 4> 2 ;8B@>2 684:>AB59 ( @0AB2>@>2 3;N:>7K, D878>;>38G5A:8E @0AB2>@>2, G53>==KE) A F5;LN C=F5=B@0F88 =8407>;0 2 :@>28 1>;L=>3>, ?@54>B2@0I0O B5< A0<K76=>ABL @0728B8O B>:A8G5A:8E 8 =59@>B>:A8G5A:8E ?@>O2;5=89.
0A?@545;5=85 ?0F85=B>2 2 G5BK@5E 3@C??0E ?> AB048O;520=8O ?@54AB02;5=> 2 B01;. 2 .
"01;8F0 2
0A?@545;5=85 1>;L=KE 2 7028A8AB8 >B AB0488 >?CE>;52>3> ?@>F5AA0
84 ;5G5=8O !B048O >?CE>;52>3> ?@>F5AA0 A53> T 2 N 0 M 0
T 3 N 0 M 0
T ;N10O N ( 1 - 2 ) M 0
%8@C@38G5A:>5 9 6 ( 2 4 , 3 % ) 1 8 4 ( 4 6 , 6 % ) 1 1 5 ( 2 9 , 1 % ) 3 9 5 B+ >?5@0F8O 5 4 ( 1 9 , 6 % ) 1 3 1 ( 4 7 , 5 % ) 9 1 ( 3 3 , 0 % ) 2 7 6 "+ !'+
>?5@0F8O 4 6 ( 2 0 , 5 % ) 1 0 1 ( 4 5 , 1 % ) 7 7 ( 3 4 , 4 % ) 2 2 4 + "+ !'+
>?5@0F8O 1 4 ( 2 1 . 2 % ) 2 8 ( 4 2 . 4 % ) 2 4 ( 3 6 . 3 % ) 6 6 A53> 2 1 0 ( 2 1 . 9 % ) 4 4 4 ( 4 6 . 2 % ) 3 0 7 ( 3 1 . 9 % ) 9 6 1
0: 284=> 87 ?@54AB02;5==>9 B01;8FK =5 2KO2;5=> @07;8G89 <564C 87CG5==K<8 3@C??0;L=KE ?> B0:><C 206=59H53=>AB8G5A:>3> D0:B>@C :0: AB048O >?CE>;52>3> ?@>F5AA0. 8AB>;>38G5A:0O D>@;L=KE 1K;0 ?@54AB02;5=0 045=>:0@F8=>9.
57C;LB0BK 8 >1AC645=85
57C;LB0BK :>20==>3> 8 E8@C@38G5A:>3> 40 ;5G5=8O ( ?@>B>:>; ! 1 ) ?@54AB02;5=K =0 @8A. 2 .
8AC=>: 2 . 57@5F8482=0O 2K68205ABL ?@8 E8@C@38G5A:>20==> AB0B8AB8G5A:8 7=0G8:070B5;59 157@5F8482=>9 2K68205AB8 :0: ?@8 ?OB8;5B=5< ( =0 1 3 , 9 % ) , B0: 8 45AOB8;5B=5:5 =01;N45=8O ( =0 1 2 , 7 % ) . "0:>5 C;CGH5=85 >B40;5==KE @57C;LB0B>2 :>20==>3> 40 ;5G5=8O 4>AB8305BAO 70 AG5B A=865=8O G0AB>BK ;>:>@538>=0@=KE @5F8482>2 @0:0 A 1 9 , 8 % ?@8 E8@C@38G5A:> 8 , 7 % ?@8 :>20==>B0 >B40;5==KE 2 4>AB>25@=> =5 @07;8G0;0AL 1 5 , 2 % ?@8 E8@C@38G5A:>20==>?5@0F8>==>9 B5@;CG52>9 B5@0?88 ( ?@>B>:>; ! 2 ) ?@54AB02;5=K =0 @8A. 3 .
8AC=>: 3
E M B E D M S G r a p h . C h a r t . 8 \ s
* - L o g - t a n k t e s t ( "+ >?5@0F8O) P = 0 , 0 2
* * - L o g - r a n k t e s t ( "+ "+ >?5@0F8O) P = 0 , 0 0 1
@8 D>@20=88 40==>3> ?@>B>:>;0 2 ?>A;54=89 2:;NG0;8AL ;8HL ?0F85=BK A ;>:0;870F859 >?CE>;8 2 A@54=5 - 8 =86=50B45;0E ?@O9 :8H:8 ( ?@>AB=K9 >B45; ?@O9 :8H:8) , GB> >1CA;>2;5=> B5E=8G5A:876=>ABO9 0=B5==K) ?@8 ?@>2545=88 2=CB@8?>;>AB=>9 ;>:0;L=>9 !'- 38?5@B5@ 87 ?@54AB02;5==>9 4803@0<;L7>20=88 B5@;CG52>3> :>=5=B0 2 ?@>3@0<20==>3> ;5G5=8O ?>;CG5=> 40;L=59H55 ?>2KH5=85 ?>:070B5;59 157@5F8482=>9 2K68205AB8 ( =0 9 , 9 % ) ?> A@02=5=8N A >4=>9 ;CG52>9 B5@0?859, 70 AG5B A=865=8O G0AB>BK ;>:>@538>=0@=KE @5F8482>2 @0:0. "0:, ?@8 8A?>;L7>20=88 ?@54>?5@0F8>==>3> B5@;CG52>3> :>=5=B0 G0AB>B0 ;>:>@538>=0@=KE @5F8482>2 A>AB028;0 4 , 7 % ?> A@02=5=8N A 1 1 , 1 % ?@8 8A?>;L7>20=88 >4=>9 ?@54>?5@0F8>==>9 ;CG52>9 B5@0?88 8 2 0 , 0 % 2 E8@C@38G5A:>9 3@C??5. 1 CA8;5=88 ?>2@5640NI53> 2>7459AB28O ;CG52>9 B5@0?88 =0 >?CE>;L A 8A?>;L7>20=85:0;L=>9 !'- 38?5@B5@:070B5;8 ;CG52>3> ?0B>@D>70 ( @8A. 4 ) .
8AC=>: 4
CG52>9 ?0B>@D>7 ?@8 8A?>;L7>20=88 ?@54>?5@0F8>==>9 ;CG52>9 8 B5@;CG52>9 B5@0?88
E M B E D M S G r a p h . C h a r t . 8 \ s
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
>20==>5 ;5G5=85 A 2:;NG5=85< 2 AE5?5@0F8>==>9 ;CG52>9 B5@0?88 42CE @048>4C;8@CNI8E 035=B>2 ( ;>:0;L=>9 !'- 38?5@B5@=>0:F5?B>@=>3> A>548=5=8O =8407>;0) ?@>2545=> 6 6 ?0F85=B0ABL 40==>9 ?@>3@0<F5=5=0 ?> G0AB>B5 ?@>O2;5=8O =59@>B>:A8G=>AB8, ?>:070B5;O3> ?0B>@D>70, G0AB>B5 2>7=8:=>25=8O @5F8482>2 8 2 2 B5G5=85 "@5E;5B=53> A@>:0 =01;N45=8O 8 157@5F8482=>9 2K68205AB8 1>;L=KE. 7CG5=85 ?5@5=>A8AB8 =8407>;0 ?@8 2=CB@8@5:B0;L=>A5=A818;878@CNI59 A72>;8;> CAB0=>28BL, GB> 2 @57C;LB0B5 2>7=8:H59 =59@>B>:A8G=>AB8 ( B>H=>B0, @2>B0) , =5AB@O =0 ?@>2545=85 A>?@>2>48B5;L=>9 B5@0?88, C 1 1 ( 1 6 , 6 % ) 87 6 6 1>;L=KE ?@8 ;8HL >4=>:@0B=>5 2=CB@8@5:B0;L=>5 22545=85 @048>A5=A818;878@CNI59 AAB0;L=KE 5 5 ( 8 3 . 3 % ) ?0F85=B>2 8A?>;L7>20=85 A>?@>2>48B5;L=>9 B5@0?88 ?>72>;8;> 871560BL =59@>B>:A8G=>AB8 8 >15A?5G8BL 42C:@0B=>5 2=CB@8@5:B0;L=>5 22545=85 @048>A5=A818;878@CNI59 A;L7>20=85 42CE @048>4C;OB>@>2 ?>72>;8;> C25;8G8BL ?>:070B5;8 G0AB>BK ?>O2;5=8O I I I AB5?5=8 ;CG52>3> ?0B>@D>70 4> 3 8 , 4 % ( @8A. 5 ) .
8AC=>: 5
I I I AB5?5=L ;CG52>3> ?0B>@D>70
?@8 @07;8G=KE 20@80=B0E :>20==>3> ;5G5=8O
E M B E D M S G r a p h . C h a r t . 8 \ s
7 6 6 1>;L=KE, 2:;NG5==KE 2 ?@>3@0<;8@048>48D8:0F88, ?@8 B@5E;5B=5:5 =01;N45=8O =5 2KO2;5=> =8 >4=>3> @5F84820 @0:0, 8 ;8HL C >4=>3> ?0F85=B0 ( 1 , 5 % ) 4803=>AB8@>20=K : 6
>:070B5;8 >?CE>;52>3> ?@>F5AA0 ?>A;5 E8@C@38G5A:>3> 8 @07;8G=KE 284>2 :>20==>3> ;5G5=8O @0:0 ?@O9 :8H:8
! 8A?>;L7>20=853@0<;8@048>48D8:0F88 C40;>AL ?>2KA8BL ?>:070B5;L B@5E;5B=59 157@5F8482=>9 2K68205AB8 4> 9 7 , 3 % , ?> A@02=5=8N A ?@54>?5@0F8>==>9 B5@;CG52>9 B5@0?859 8 7 , 3 % , 8 >4=>9 ;CG52>9 B5@0?859 7 6 , 3 % . >:070B5;L 157@5F8482=>9 2K68205AB8 ?@8 >4=>< 2AB028; 6 4 , 8 % ( @8A. 7 ) .
8AC=>: 7
>:070B5;8 ?@>3@5AA8@>20=8O >?CE>;52>3> ?@>F5AA0 ?>A;5 E8@C@38G5A:>3>
8 @07;8G=KE 284>2 :>20==>3> ;5G5=8O @0:0 ?@O9 :8H:8
"0:81@07>;CG5==K5 B@5E;5B=85 @57C;LB0BK 8A?>;L7>20=8O ?@>3@0<;8@048>48D8:0F88 ?>72>;ONB =045OBLAO, GB> 40;L=59H0O @50;870F8O A>740==>9 ?@>3@0<20==>3> ;5G5=8O A 2:;NG5=85< 2 AE504JN20=B=>9 ;CG52>9 B5@0?88 42CE @048>48D8:0B>@>2 ?>72>;8B A=878BL G0AB>BC ;>:>@538>=0@=KE @5F8482>2 8 2 @0:0 8 C;CGH8BL >B40;5==K5 @57C;LB0BK ;5G5=8O.
K2>4K.
1 . >20==K9 4 A 8A?>;L7>20=8504JN20=B=>9 ;CG52>9 B5@0?859 4>;65= 1KBL 4>@0 2 ;5G5=88 1>;L=KE @0:>< ?@O9 :8H:8.
2 . #AB0=>2;5=0 7028A8ABL G0AB>BK 2>7=8:=>25=8O ;>:>@538>=0@=KE @5F8482>2 @0:0 >B AB5?5=8 ;CG52>3> ?0B>@D>70 >?CE>;8. @8 I I I AB5?5=8 ;CG52>3> ?0B>@D>70 2 >?CE>;8 =5 2KO2;5=> =8 >4=>3> @5F84820 @0:0.
3 . @8:0;L=>9 !'- 38?5@B5@2KH05B :>;8G5AB2> 1>;L=KE A I I I AB5?5=LN ;CG52>3> ?0B>@D>70, ?> A@02=5=8N A 8A?>;L7>20=854=>9 ?@54>?5@0F8>==>9 ;CG52>9 B5@0?859 8 A?>A>1AB2C5B A=865=8N G0AB>BK 2>7=8:=>25=8O ;>:>@538>=0@=KE @5F8482>2 8 >B40;5==KE 2.
4 . 0;L=59H85 ?5@A?5:B82K C;CGH5=8O @57C;LB0B>2 :>20==>3> 40 ;5G5=8O @0:0 ?@O9 :8H:8 A2O70=K A @50;870F859 ?@>3@0<;8@048>48D8:0F88 A 2:;NG5=85 2 AE5?5@0F8>==>9 ;CG52>9 B5@0?88 =5A:>;L:8E @07=>=0?@02;5==KE @048>48D8:0B>@>2. @8 B@5E;5B=545 =01;N45=8O A 8A?>;L7>20=853@0<;8@048>48D8:0F88 =5 2KO2;5=> =8 >4=>3> ;>:>@538>=0@=>3> @5F84820, 0 2>7=8:=>25=85 >B40;5==KE 2 CAB0=>2;5=> ;8HL C 1 , 5 % ?0F85=B>2.
!?8A>: ;8B5@0BC@K
1 . ;5:A0=4@>2 . . , !02G5=:> . . , $@04:8= !. . , 02@84 -. . @8<5=5=85 38?5@B5@<88 8 38?5@3;8:5:0G5AB25==KE >?CE>;59. 548F8=0, . , 1 9 8 0 , !. 2 5 6
2 . 5@4>2 . . , C@?5H52 . . , 0@4K=A:89 .. !. ;8O=85 38?5@B5@<88 8 38?5@3;8:5ABL ;CG52>9 B5@0?88 >=:>;>38G5A:8E 1>;L=KE. / / >A. >=:>;. 6C@=. , 1 9 9 9 , ! 1 , !. 1 2 1 6
3 . >9:> . . , 0@LO;>20 !. . , @>H=520 . . , !84>@>2 . . 048>48D8:0F8O ;5:0@AB25==K<8 ?@5?0@0B0:0G5AB25==KE =>2>>1@07>20=89 B5@3> >B45;0 B>;AB>9 :8H:8. / / "57. 4>:;. A5@>A. :>=D. 048>18>;>38G5A:85 >A=>2K ;CG52>9 B5@0?88. . , 2 0 0 5 , !. 1 6 .
4 . 8A5;520 . !. , 0@LO;>20 !. . -;5:B@>=>0:F5?B>@=K5 A>548=5=8O :0: @048>A5=A818;870B>@K 38?>:A8G5A:8E :;5B>: >?CE>;59 G5;>25:0. / / 54. @048>;>38O, 1 9 8 4 , ". 2 9 , ! 9 , !. 7 4 8 2
5 . >=>?;O=8:>2 . . , #A?5=A:89 . . A?>;L7>20=85 M;5:B@>=>0:F5?B>@=KE A>548=5=89 2 AE53> 8 ;5:0@AB25==>3> ;5G5=8O 1>;L=KE A> 7;>:0G5AB25==K2>>1@07>20=8O>E@0=5=85. !5@8O. =:>;>38O. 17>@=0O 8=D>@A>1 ;5G5=85 @0:0 ?@O9 :8H:8. 0B5=B =0 87>1@5B5=85 ! 2 2 3 4 3 1 8 . 0@538AB@8@>20= 2 >AC40@AB25==>1@5B5=89 $ 2 0 . 0 8 . 2 0 0 4 3. ( 02B. 0@AC:>2 .. . , ;B0@652A:0O . , ":0G52 !. . 8 4@. ) .
7 . /@=5=:> !. . >;8@048>48D8:0F8O :0: =>2K9 ?>4E>4 : ?>2KH5=8N MDD5:B82=>AB8 ;CG52>9 B5@0?88 >?CE>;59. / / :=. 048>48D8:0B>@K 2 ;CG52>9 B5@0?88 >?CE>;59 , 1=8=A:, 1 9 8 2 , !. 1 2 6 1 2 7 .
P A G E
P A G E 8
5 @
5 @
E M B E D M S G r a p h . C h a r t . 8 \ s
E M B E D M S G r a p h . C h a r t . 8 \ s
! - 2 5 @ ( 4 0 87>@)
5B>48:0 :>20==>3> ;5G5=8O
A 8A?>;L7>20=8548D8:0B>@>2
!'
!'
!'!' "
5 @
5 @
5 @
| ^} `} } ~ (~ *~ ,~ >~ N } kd $$If l 4 0
&
t 0 &6 4 4
l al f4 $T$If `Ta$gd3% $If gd3% $Tdh `Ta$gd4Gj Tdh `Tgd4Gj ^} } } (~ *~ R~ T~ `~ b~ ~ ~ ~ ~ ~ j l n 2 @ D T Z r Ȁ r t Ȃ ʂ @ B h j R T Z \ ͺͺͺͺ "j h4Gj CJ UaJ( mH nH u j h4Gj CJ UaJ( h\ CJ H*aJ( h\ CJ NH aJ( h\ CJ aJ( h4Gj aJ( mHsH h4Gj CJ H*aJ(
h4Gj aJ( h4Gj CJ NH aJ( h4Gj CJ aJ( 8>~ R~ T~ d~ ~ ~ _ S $$If a$gd3% kd $$If l 4 F
&
t 0 &6 4 4
l al f4 $T$If `Ta$gd3% ~ ~ ~ ~ ~ r b V b $$If a$gd3% $T$If `Ta$gd3% kdx $$If l ^F
&
t 0 &6 4 4
l al ~ H j r b b b $T$If `Ta$gd3% kd4 $$If l F
&
t 0 &6 4 4
l al j l n V D Z Ƌ o ` M M M M M M $ Tdh ^ `Ta$gd4Gj $Tdh `Ta$gd4Gj kd $$If l F
&
t 0 &6 4 4
l al J L ċ Ƌ @ | b d n p v x z | ~ č . 0 Կ܉܉܃wwwwwwwww܃܃ h4Gj CJ aJ( mH sH
h4Gj aJ( h4Gj CJ NH aJ( h4Gj 5CJ \aJ( h4Gj 6CJ ]aJ( h4Gj h4Gj CJ aJ h4Gj h\ CJ aJ h4Gj h4Gj CJ aJ( h\
soflens comfort
5003.17 ()
kiev apartaments service
mobil cut
dolmar
cad
wow
5440.14 ()
sky link
macintosh
cad
spartherm
outlook
407
summer
kiev apartaments rent
summer
2110
danfoss
-
bella italia
o2 optix
stihl
2112
snr
-
5440.15 ()
thuraya sg 2510
ardo
mobil pegasus
mobihel
omega
2111
protherm
ielts
ipsec
.
vps vds
nokia 6021
danfoss
isdn