CHEMOTHERAPY

Practical Gynecologic Oncology

Practical Gynecologic Oncology, 3rd edition: by Jonathan S., MD Berek, Neville F. acker, acker By !i""incott #illia$% & #ilkin%
P'bli%her%( )J'ne *+, ,---.
By OkDo/e0
1obert 2. 0o'ng and Ma'rie Mark$an
General Principles
3'$or Gro4th and 2he$othera"y
Dr'g% ca"able o5 the relatively %elective de%tr'ction o5 $alignant cell% are no4 '%ed ro'tinely in "atient% 4ith cancer. 6 4ide variety o5 %'ch
agent% are available, and the %election o5 dr'g% i% o5ten di55ic'lt. F'rther$ore, beca'%e $o%t antineo"la%tic agent% have a narro4er thera"e'tic
inde7 than dr'g% o5 other ty"e%, care5'l tho'ght %ho'ld be given to the 5actor% o'tlined in 3able 8.* be5ore the in%tit'tion o5 antineo"la%tic
che$othera"y.
9t i% i$"ortant to 'nder%tand clearly the nat'ral hi%tory o5 each "atient:% $alignancy. 3he '%e o5 che$othera"e'tic agent% %ho'ld be re%tricted to
"atient% 4ho%e $alignancie% have been "roven by bio"%y. 9n %o$e in%tance%, %econd o"inion% regarding de5initive hi%tologic diagno%e% %ho'ld be
obtained be5ore the in%tit'tion o5 che$othera"y. #hen do'bt e7i%t% concerning the diagno%i%, it i% "re5erable to delay initial thera"y and not '%e
re%"on%e to che$othera"y a% a diagno%tic trial.
3he deci%ion to '%e che$othera"y al%o de"end% on a thoro'gh kno4ledge o5 the e7tent o5 the "atient:% di%ea%e a% 4ell a% the rate o5 "rogre%%ion o5
that di%ea%e. !i$ited evidence o5 $eta%tatic %"read or doc'$ented %lo4 di%ea%e "rogre%%ion $ay 4arrant 4ithholding che$othera"y 5or a "eriod.
Beca'%e all che$othera"e'tic agent% "rod'ce to7icity, it i% i$"ortant that there be an eval'able t'$or %o that re%"on%e can be a%%e%%ed. 9t i%
ina""ro"riate, in general, to ad$ini%ter antineo"la%tic agent% 'nle%% bene5it to the "atient can be ob;ectively deter$ined. 3h'%, e7ce"t in rare
in%tance%, the ability to deter$ine t'$or re%"on%e to che$othera"y i% an i$"ortant 5actor in treat$ent deci%ion%.
3he "atient:% "artic'lar circ'$%tance% $ay "lay a $a;or role in deci%ion% regarding che$othera"y. 3he e7tent o5 "revio'% thera"y and the
"atient:% age, general health, and other co$"licating illne%%e% 5or$ an i$"ortant "art o5 the "hy%ician:% deci%ion and $ay %'b%tantially a55ect
tolerance to antineo"la%tic dr'g treat$ent. 9n addition, the "atient:% e$otional, %ocial, and even 5inancial %tat'% $'%t be re%"ected and eval'ated
be5ore a 5inal deci%ion i% $ade.
2he$othera"y %ho'ld not be '%ed 'nle%% 5acilitie% are available 5or care5'l $onitoring and treat$ent o5 the re%'lting to7icitie%. 95 %'ch 5acilitie%
are not available and che$othera"y clearly i% re<'ired, the "atient %ho'ld be re5erred to a "hy%ician or another 5acility that ha% that ca"ability.
3he deci%ion to '%e che$othera"y de"end% heavily on the "robability o5 achieving a '%e5'l re%"on%e. Not all cancer% re%"ond to che$othera"y in
%i$ilar <'antitative and <'alitative 4ay%. Neverthele%%, t'$or% can be gro'"ed into 5o'r categorie% by their likelihood o5 che$othera"e'tic
re%"on%e:
*. 9n the 5ir%t gro'" o5 t'$or% )e.g., ovarian ger$ cell t'$or%, choriocarcino$a., antineo"la%tic thera"y i% c'rative 5or $o%t "atient%.
Obvio'%ly, a deci%ion not to treat "atient% 4ith di%ea%e% kno4n to be c'rable 4ith che$othera"y i%, 4ith rare e7ce"tion%, ina""ro"riate.
=ven %'b%tantial to7icity i% acce"table i5 the "robability o5 c're i% high.
,. 9n the %econd gro'" )e.g., e"ithelial ovarian cancer., che$othera"y i$"rove% "atient %'rvival b't doe% not re%tore a nor$al li5e
e7"ectancy. Patient% 4ith the%e t'$or% '%'ally bene5it 5ro$ che$othera"y, and it %ho'ld be o55ered 'nle%% there are e7ce"tional
circ'$%tance%.
3. 9n the third gro'" )e.g., 'terine %arco$a., re%"on%e% to che$othera"y occ'r, b't i$"roved %'rvival ha% not yet been achieved 5or a
%igni5icant n'$ber o5 "atient%.
8. 9n the 5o'rth gro'" )e.g., $elano$a., 5e4, i5 any, re%"on%e% to che$othera"y are %een. 9n %'ch ca%e%, the '%e o5 che$othera"y %ho'ld be
re%tricted, and every e55ort %ho'ld be $ade to incl'de the%e "atient% in 4ell de%igned, "ro%"ective clinical trial% te%ting ne4 treat$ent
a""roache%.
Differential Sensitivity
For any "artic'lar antineo"la%tic agent to be e55ective, it $'%t have greater to7icity 5or the $alignant cell% than 5or the "atient:% nor$al cell%. 9n
that %en%e, all '%e5'l che$othera"e'tic agent% have greater activity again%t t'$or% than again%t nor$al ti%%'e%. 3he 4indo4 bet4een antit'$or
e55ect and nor$al ti%%'e to7icity $ay be %$all, beca'%e $o%t che$othera"e'tic agent% 4ork by di%r'"ting DN6 or 1N6 %ynthe%i%, a55ecting
cr'cial cell'lar en>y$e%, or altering "rotein %ynthe%i%.
Nor$al cell% al%o '%e the%e vital cell'lar "roce%%e% in 4ay% %i$ilar to tho%e o5 $alignant cell%, "artic'larly 5etal or regenerating ti%%'e or nor$al
cell "o"'lation% in 4hich con%tant cell "roli5eration i% re<'ired )e.g., bone $arro4, ga%trointe%tinal e"itheli'$, and hair 5ollicle%.. 6% a re%'lt, the
di55erential e55ect o5 antineo"la%tic dr'g% on t'$or% co$"ared 4ith nor$al ti%%'e% i% <'antitative rather than <'alitative, and %o$e degree o5
in;'ry to nor$al ti%%'e i% "rod'ced by every che$othera"e'tic agent. 3he nor$al ti%%'e to7icity "rod'ced by $o%t che$othera"e'tic agent%
correlate% 4ith the intrin%ic cell'lar "roli5eration o5 the target ti%%'e. 3hi% e7"lain% 4hy to7icitie%, %'ch a% blood co'nt %'""re%%ion, $'co%al
in;'ry, and alo"ecia, are co$$only %een 4ith $o%t che$othera"e'tic regi$en%.
Therapeutic Inde
For any "artic'lar che$othera"e'tic agent, the net e55ect on the "atient i% o5ten re5erred to a% the dr'g:% thera"e'tic inde7 )i.e., a ratio o5 the do%e%
at 4hich thera"e'tic e55ect and to7icity occ'r.. 2ancer che$othera"y re<'ire% a balance o5 thera"e'tic e55ect and to7icity to o"ti$i>e the
thera"e'tic inde7. Beca'%e the 4indo4 o5 to7icity i% o5ten narro4 5or available che$othera"e'tic agent%, %'cce%%5'l che$othera"y de"end% on
"har$acologic and biologic 5actor%.
Biologic Factor% 9n5l'encing 3reat$ent
2ell /inetic 2once"t%
Both nor$al and t'$oro'% ti%%'e% have a certain gro4th ca"acity and are in5l'enced and reg'lated by vario'% internal and e7ternal 5orce%. 3he
di55erential gro4th and reg'latory in5l'ence% occ'rring in both nor$al and t'$oro'% ti%%'e% 5or$ the ba%i% o5 e55ective cancer treat$ent. 3he
e7"loitation o5 the%e di55erence% 5or$% the ba%i% 5or the e55ective '%e o5 both radiation thera"y and che$othera"y in cancer $anage$ent )*..
Patterns !f "!r#al Gr!$th
6ll nor$al ti%%'e% have the ca"acity 5or cell'lar divi%ion and gro4th. o4ever, nor$al ti%%'e% gro4 in %'b%tantially di55erent "attern%. 3here are
three general ty"e% o5 nor$al ti%%'e gro4th, cla%%i5ied a% %tatic, rene4ing, and e7"anding.
*. 3he %tatic "o"'lation co$"ri%e% relatively 4ell di55erentiated cell% that, a5ter initial "roli5erative activity in the e$bryonic and neonatal
"eriod, rarely 'ndergo cell divi%ion. 3y"ical e7a$"le% are %triated $'%cle and ne'ron%.
,. 3he e7"anding "o"'lation o5 cell% i% characteri>ed by the ca"acity to "roli5erate 'nder %"ecial %ti$'li )e.g., ti%%'e in;'ry.. ?nder tho%e
circ'$%tance%, the nor$ally <'ie%cent ti%%'e )e.g., liver or kidney. 'ndergoe% a %'rge o5 "roli5eration 4ith regro4th.
3. 3he rene4ing "o"'lation o5 cell% i% con%tantly in a "roli5erative %tate. 3here i% con%tant cell divi%ion, a high degree o5 cell t'rnover, and
con%tant cell lo%%. 3hi% occ'r% in bone $arro4, e"ider$i%, and ga%trointe%tinal $'co%a.
?nder%tanding the%e "attern% o5 nor$al ti%%'e gro4th "artially e7"lain% %o$e o5 the $o%t co$$on ty"e% o5 to7icity %een 4ith cancer treat$ent%.
Nor$al ti%%'e% 4ith a %tatic "attern o5 gro4th are rarely %erio'%ly in;'red by dr'g thera"y, 4herea% rene4ing cell "o"'lation%, %'ch a% bone
$arro4, ga%trointe%tinal $'co%a, and %"er$ato>oa, are co$$only in;'red.
Cancer Cell Gr!$th
3'$or cell gro4th re"re%ent% a di%r'"tion in the nor$al cell'lar brake $echani%$% that e7i%t( con%e<'ently, contin'ed "roli5eration and event'al
death o5 the ho%t re%'lt. 6ltho'gh cell "roli5eration occ'r% contin'o'%ly in h'$an t'$or%, there i% evidence that it doe% not take "lace $ore
ra"idly in cancer% than in their nor$al@ti%%'e co'nter"art%. 9t i% not the %"eed o5 cell "roli5eration b't the 5ail're o5 the reg'lated balance bet4een
cell lo%% and cell "roli5eration that di55erentiate% t'$oro'% ti%%'e% 5ro$ nor$al ti%%'e%.
Go$"ert>ian Gro4th
3he characteri%tic% o5 cancer gro4th have been a%%e%%ed by $'lti"le %t'die% in ani$al% and $ore li$ited %t'die% in h'$an%. #hen t'$or% are
e7tre$ely %$all, gro4th 5ollo4% an e7"onential "attern, b't later %ee$% to %lo4. S'ch a gro4th "attern i% kno4n a% Go$"ert>ian gro4th. Strictly
%"eaking, thi% $ean% e7"onential gro4th 4ith e7"onential gro4th retardation over the entire d'ration o5 t'$or gro4th. More %i$"ly,
Go$"ert>ian gro4th $ean% that a% a t'$or $a%% increa%e%, the ti$e re<'ired to do'ble the t'$or:% vol'$e al%o increa%e%.
Do'bling 3i$e
3he do'bling ti$e o5 a h'$an t'$or i% the ti$e it take% 5or the $a%% to do'ble it% %i>e. 3here i% con%iderable variation in do'bling ti$e% o5
h'$an t'$or%. For e7a$"le, e$bryonal t'$or%, ly$"ho$a%, and %o$e $alignant $e%enchy$al t'$or% have relatively 5a%t do'bling ti$e% ),- to
8- day%., 4herea% adenocarcino$a% and %<'a$o'% cell carcino$a% have relatively %lo4 do'bling ti$e% )+- to *+- day%.. 9n general, $eta%ta%e%
have 5a%ter do'bling ti$e% than "ri$ary le%ion%.
95 it i% a%%'$ed that e7"onential gro4th occ'r% early in a t'$or:% hi%tory and that a t'$or %tart% 5ro$ a %ingle $alignant cell, then
*. 6 *@$$ $a%% 4ill have 'ndergone a""ro7i$ately ,- t'$or do'bling%.
,. 6 +@$$ $a%% )a %i>e that $ight be 5ir%t vi%'ali>ed on a radiogra"h. 4ill have 'ndergone ,A do'bling%.
3. 6 *@c$ $a%% 4ill have 'ndergone 3- do'bling%. #ere %'ch a le%ion di%covered clinically, the "hy%ician 4o'ld a%%'$e that the t'$or
had been detected early. 3he reality i% that it 4o'ld have already 'ndergone 3- do'bling%, or been "re%ent a""ro7i$ately B-C o5 it% li5e
%"an.
?n5ort'nately, o'r c'rrent clinical techni<'e% recogni>e t'$or% late in their gro4th, and $eta%ta%i% $ay 4ell have occ'rred long be5ore there i%
obvio'% evidence o5 the "ri$ary le%ion. 3he %econd i$"lication 5ro$ thi% kinetic in5or$ation i% that in late %tage% o5 t'$or gro4th, a very 5e4
do'bling% in t'$or $a%% have a dra$atic i$"act on the %i>e o5 the t'$or. Once a t'$or beco$e% "al"able )* c$ in dia$eter., only three $ore
do'bling% 4o'ld "rod'ce an enor$o'% t'$or $a%% )D c$ in dia$eter..
Cell Cycle
9n5or$ation on gro4th "attern% and do'bling ti$e% relate% to the gro4th o5 the t'$or $a%% a% a 4hole. 3he kinetic behavior o5 individ'al t'$or
cell% ha% been 4ell de%cribed and a cla%%ic cell cycle $odel ha% been "rod'ced )Fig. 8.*..
Fig're 8.* 3he cell cycle. 65ter cell divi%ion, a cell can either )*. die, ),. di55erentiate, or )3. enter re%ting )G-. "ha%e. 2ell% in the latter t4o
"ha%e% can reenter the cycle at G*.
*. M "ha%e )$itotic "ha%e. o5 the cell cycle i% the "ha%e o5 cell divi%ion.
,. G* "ha%e )"o%t$itotic "ha%e. i% a "eriod o5 variable d'ration 4hen cell'lar activitie% and "rotein and 1N6 %ynthe%i% contin'e. 3he%e G*
cell% can di55erentiate or contin'e in the "roli5erative cycle.
3. S "ha%e )DN6 %ynthetic "ha%e. i% the "eriod in 4hich ne4 DN6 re"lication occ'r%.
8. G, "ha%e )"o%t%ynthetic "ha%e. i% the "eriod in 4hich the cell ha% a di"loid n'$ber o5 chro$o%o$e% and t4ice the DN6 content o5 the
nor$al cell. 3he cell re$ain% in thi% "ha%e 5or a relatively %hort ti$e and then enter% the $itotic "ha%e again.
+. G- "ha%e )the re%ting "ha%e. i% the ti$e d'ring 4hich cell% do not divide. 2ell% $ay $ove in and o't o5 the G- "ha%e.
3he generation ti$e i% the d'ration o5 the cycle 5ro$ M "ha%e to M "ha%e. Eariation occ'r% in all "ha%e% o5 the cell cycle, b't the variation i%
greate%t d'ring the G* "eriod. 3he event% controlling thi% variation are not 4ell 'nder%tood.
3he%e cell cycle event% have i$"ortant i$"lication% 5or the cancer thera"i%t ),.. Di55erential %en%itivitie% to che$othera"y and radiation thera"y
are a%%ociated 4ith di55erent "roli5erative %tate%. Dividing cancer cell% that are actively traver%ing the cell cycle are very %en%itive to
che$othera"e'tic agent%. 2ell% in a re%ting %tate )G-. are relatively in%en%itive to che$othera"e'tic agent%, altho'gh they occ'"y %"ace and
contrib'te to the b'lk o5 the t'$or.
Cell %inetics
9n cell kinetic %t'die% "er5or$ed on h'$an t'$or%, the d'ration o5 the S "ha%e )DN6 %ynthe%i% "ha%e. i% relatively %i$ilar 5or $o%t h'$an
t'$or%, ranging 5ro$ a lo4 o5 *- ho'r% to a high o5 a""ro7i$ately 3* ho'r%. 3he length o5 the cell cycle in h'$an t'$or% varie% 5ro$ %lightly
$ore than -.+ day to "erha"% + day%. #ith cell cycle ti$e% in the range o5 ,8 ho'r% and do'bling ti$e% in the range o5 *- to *,--- day%, it i% clear
that only a %$all "ro"ortion o5 t'$or cell% are in active cell divi%ion at any one ti$e.
34o $a;or 5actor% that a55ect the rate at 4hich t'$or% gro4 are the gro4th 5raction and cell death. 3he gro4th 5raction i% the n'$ber o5 cell% in
the t'$or $a%% that are actively 'ndergoing cell divi%ion. 3here i% a $arked variation in the gro4th 5raction o5 t'$or% in h'$an being%, ranging
5ro$ ,+C to al$o%t F+C. 9n the "a%t, it 4a% tho'ght that h'$an t'$or% contained billion% o5 cell%, all gro4ing %lo4ly. 9n act'ality, only a %$all
5raction o5 cell% in a t'$or $a%% are ra"idly "roli5erating( the re$ainder are o't o5 the cell cycle and <'ie%cent.
3'$or gro4th $ay be altered by the 5ollo4ing:
*. 2ytoto7ic che$othera"y, 4hich alter% both the generation ti$e and the gro4th 5raction o5 t'$or%.
,. or$one%, 4hich a""ear to alter the gro4th 5raction 4itho't changing the generation ti$e.
3. 1adiation thera"y, 4hich alter% both the generation ti$e and the gro4th 5raction.
8. 6lteration% in o7ygen ten%ion and va%c'lar %'""ly, 4hich alter the gro4th 5raction 4itho't altering generation ti$e.
+. 9$$'nologic thera"ie%, 4hich %ee$ to alter both generation ti$e and gro4th 5raction.
Cell Cycle&Specific 'ersus "!nspecific Dru(s
6ntineo"la%tic agent% have co$"le7 $echani%$% o5 action and alter cell% in a 4ide variety o5 4ay%. Di55erent dr'g% have di55erent %ite% o5 action
in the cell cycle, and their e55ectivene%% i% al%o a 5'nction o5 the "roli5erative ca"acity o5 the ti%%'e involved. #ith the '%e o5 %o$e o5 the%e kinetic
conce"t%, it i% "o%%ible to cla%%i5y che$othera"e'tic agent% on the ba%i% o5 their cell cycle %"eci5icity and their %ite o5 $a7i$al dr'g action 4ithin
the cell cycle )3able 8.,..
3able 8., 2ell 2ycle@S"eci5icity o5 2he$othera"e'tic 6gent%
2ell 2ycle Non%"eci5ic 2ell cycleGnon%"eci5ic agent% kill in all "ha%e% o5 the cell cycle and are not too de"endent on "roli5erative ca"acity.
2ell 2ycle S"eci5ic 6t the other end o5 the %"ectr'$, cell cycleG%"eci5ic agent%, %'ch a% hydro7y'rea, de"end on the "roli5erative ca"acity and on
the "ha%e o5 the cell cycle 5or their action. 3he agent% kill in only one "ortion o5 the cell cycle, and cell% not in that "ha%e are not in;'red. 3hey
tend to be $o%t e55ective again%t t'$or% 4ith relatively long S "ha%e% and tho%e t'$or% in 4hich there i% a relatively high gro4th 5raction and a
ra"id rate o5 "roli5eration. Bet4een the%e t4o broad cla%%i5ication%, there i% a %"ectr'$ o5 dr'g% 4ith variable degree% o5 cell cycle and
"roli5eration de"endence.
9n addition to cell cycle and "roli5eration %en%itivity, che$othera"e'tic agent% $ay e7ert a greater e55ect in a "artic'lar "ha%e o5 the cell cycle.
3h'%, che$othera"e'tic agent% can be gro'"ed according to their %ite o5 action in the cell cycle and the e7tent o5 their de"endence on "roli5erative
activity )3able 8.3..
3able 8.3 Site o5 6ction in the 2ell 2ycle
)!( %ill Hyp!thesis
Fro$ kno4ledge o5 ba%ic cell'lar kinetic%, there have e$erged certain conce"t% o5 che$othera"y that have "roved '%e5'l in the de%ign o5
che$othera"e'tic regi$en%. 9n e7"eri$ental t'$or %y%te$% in ani$al%, the ani$al:% %'rvival i% inver%ely "ro"ortional to the n'$ber o5 cell%
i$"lanted or to the %i>e o5 the t'$or at the ti$e treat$ent i% initiated )3.. 3reat$ent i$$ediately a5ter t'$or i$"lantation or 4hen the t'$or i%
%'bclinical in %i>e re%'lt% in $ore c're% than 4hen the t'$or i% clinically obvio'% and large.
2he$othera"e'tic agent% a""ear to 4ork by 5ir%t@order kinetic%( that i%, they kill a con%tant 5raction o5 cell% rather than a con%tant n'$ber. 3hi%
conce"t ha% i$"ortant conce"t'al i$"lication% in cancer treat$ent. For in%tance, a %ingle e7"o%'re o5 t'$or cell% to an antineo"la%tic dr'g $ight
be ca"able o5 "rod'cing , to + log% o5 cell kill. #ith ty"ical body t'$or b'rden% o5 *-*, cell% )* kg., a %ingle do%e o5 che$othera"y i% 'nlikely to
be c'rative. 3hi% e7"lain% the need 5or inter$ittent co'r%e% o5 che$othera"y to achieve the $agnit'de o5 cell kill nece%%ary to "rod'ce t'$or
regre%%ion and c're. 9t al%o "rovide% a rationale 5or $'lti"le@dr'g or co$bination che$othera"y.
3he c're rate 4o'ld be %igni5icantly i$"roved i5 %$all t'$or% 4ere "re%ent, b't cell $a%%e% o5 *-* to *-8 cell% are too %$all 5or clinical
detection. 3hi% i% the ba%i% 5or '%ing ad;'vant che$othera"y in early %tage% o5 di%ea%e 4hen %'bclinical n'$ber% o5 cancer cell% are %'%"ected.
Dru( Resistance and Tu#!r Cell Heter!(eneity
3he clinical 'tility o5 a "artic'lar che$othera"e'tic agent or dr'g co$bination $ay be co$"ro$i%ed %everely 4hen dr'g re%i%tance develo"%.
2he$othera"e'tic agent% o5ten are active 4hen initially '%ed in cancer treat$ent, b't t'$or% co$$only beco$e re%i%tant d'ring che$othera"y.
ence, "atient% o5ten have an initial re$i%%ion 5ollo4ed by a rec'rrence that i% no longer re%"on%ive to the dr'g% that 4ere initially e55ective.
6 variety o5 cell'lar $echani%$% are involved in dr'g re%i%tance. 1e%i%tant t'$or cell% $ay di%"lay increa%ed deactivation or decrea%ed activation
o5 dr'g%, they $ay be a%%ociated 4ith increa%ed dr'g e55l'7, or they $ay re%i%t nor$al dr'g '"take. 9n %o$e in%tance%, altered %"eci5icity to an
inhibiting en>y$e or increa%ed "rod'ction o5 the target en>y$e occ'r% to e7"lain dr'g re%i%tance on a "har$acologic ba%i%.
G!ldie*C!ld#an Hyp!thesis
9t ha% been %'gge%ted that %"ontaneo'% $'tation to "henoty"ic dr'g re%i%tance occ'r% in ra"idly gro4ing $alignant t'$or%: the %o$atic $'tation
theory )8.. 3hi% theory %'gge%t% that $o%t $a$$alian cell% %tart 4ith intrin%ic %en%itivity to antineo"la%tic dr'g% b't develo" %"ontaneo'%
re%i%tance at variable rate%. 3hi% conce"tHthe Goldie@2old$an hy"othe%i%Hha% been a""lied to the gro4th o5 $alignant t'$or% and ha%
i$"ortant clinical i$"lication%.
Goldie and 2old$an develo"ed a $athe$atical $odel that relate% c'rability to the ti$e o5 a""earance o5 %ingly or do'bly re%i%tant cell%.
6%%'$ing a nat'ral $'tation rate, the $odel "redict% a variation in %i>e o5 the re%i%tant 5raction in t'$or% o5 the %a$e %i>e and ty"e, de"ending on
the $'tation rate and the "oint at 4hich the 5ir%t $'tation develo"%. Given %'ch a%%'$"tion%, the "ro"ortion o5 re%i%tant cell% in any 'ntreated
t'$or i% likely to be %$all, and the initial re%"on%e to treat$ent 4o'ld not be in5l'enced by the n'$ber o5 re%i%tant cell%. 9n clinical "ractice, thi%
$ean% that a co$"lete re$i%%ion co'ld be obtained even i5 a re%i%tant cell line 4ere "re%ent. 3he 5ail're to c're %'ch a "atient, ho4ever, 4o'ld be
directly de"endent on the "re%ence o5 re%i%tant cell line%.
3hi% $odel o5 %"ontaneo'% dr'g re%i%tance i$"lie% that:
*. 3'$or% are c'rable 4ith che$othera"y i5 no "er$anently re%i%tant cell line% are "re%ent and i5 che$othera"y i% beg'n be5ore re%i%tant
cell% develo".
,. 95 only one antineo"la%tic agent i% '%ed, the "robability o5 c're di$ini%he% ra"idly 4ith the develo"$ent o5 a %ingle re%i%tant line.
3. Mini$i>ing the e$ergence o5 dr'g@re%i%tant clone% re<'ire% $'lti"le e55ective dr'g% or thera"ie% and re<'ire% that they be a""lied a%
early a% "o%%ible in the co'r%e o5 the "atient:% di%ea%e.
8. 3he rate o5 %"ontaneo'% $'tation to re%i%tance occ'r% at a""ro7i$ately the nat'ral 5re<'ency o5 * in *-,--- to * in *,---,--- cell
divi%ion%.
3hi% $odel "redict% that alternating cycle% o5 treat$ent %ho'ld be %'"erior to the %e<'ential '%e o5 "artic'lar agent% beca'%e %e<'ential '%e o5
antineo"la%tic dr'g% 4o'ld allo4 5or the develo"$ent and regro4th o5 a do'bly re%i%tant line. 3he intrin%ic 5re<'ency o5 %"ontaneo'% $'tation to
dr'g re%i%tance i% al%o likely to be in5l'enced by etiologic 5actor% re%"on%ible 5or t'$or develo"$ent. !'ng or bladder cancer%, 5or in%tance, re%'lt
5ro$ e7"o%'re to $'lti"le carcinogenic che$ical% and $ay have a higher %"ontaneo'% $'tation rate than i% %een in other t'$or%. ?nder the%e
circ'$%tance%, n'$ero'% dr'g@re%i%tant clone% $ay be "re%ent even be5ore the t'$or% are clinically evident. 3hi% 4o'ld e7"lain the inability o5
antineo"la%tic thera"y to c're a n'$ber o5 the co$$on $alignancie%.
Plei!tr!pic Dru( Resistance
3he Goldie@2old$an $odel ha% 5oc'%ed attention on $echani%$% o5 dr'g re%i%tance. 95 the 5ail're o5 dr'g treat$ent de"end% on the %"ontaneo'%
a""earance o5 re%i%tant cell%, an 'nder%tanding o5 dr'g re%i%tance i% cr'cial to thera"e'tic %'cce%%. 6 4ide variety o5 $echani%$% 5or dr'g
re%i%tance have been de%cribed, altho'gh the%e $echani%$% '%'ally con5er re%i%tance to a "artic'lar dr'g or dr'g 5a$ily. 3he "heno$enon o5
"leiotro"ic dr'g re%i%tance occ'r% 4hen certain dr'g@re%i%tance $echani%$% con5er cro%%@re%i%tance to %tr'ct'rally di%%i$ilar dr'g% 4ith di55erent
$echani%$% o5 action )+..
So$e "leiotro"ic re%i%tant cell% contain a cell %'r5ace P glyco"rotein 4ith a $olec'lar 4eight o5 *A- kilodalton% )kd.. 9n general, the a""earance
o5 "leiotro"ic dr'g re%i%tance i% a%%ociated 4ith i$"aired ability o5 the cell to acc'$'late and retain antineo"la%tic dr'g%. 9t ha% been 5'rther
de$on%trated that thi% P glyco"rotein i% directly related to the e7"re%%ion o5 re%i%tance, and cell% that revert to %en%itive one% lo%e thi% $e$brane
glyco"rotein.
DN6 can be tran%5erred 5ro$ re%i%tant cell% into %en%itive cell%, "rod'cing a tran%5er o5 "leiotro"ic re%i%tance to 'ne7"o%ed cell%. 3he gene
re%"on%ible 5or thi% $'ltidr'g re%i%tance ha% been i%olated, and the "rod'ction o5 $onoclonal antibodie% o55er% a "o%%ible a""roach to rever%ing
thi% "leiotro"ic re%i%tance.
D!se Intensity
For $any year%, it ha% been ta'ght that 5'll do%e% o5 che$othera"y 4ere nece%%ary to obtain o"ti$al clinical re%'lt%. S'b%tantial laboratory and
clinical evidence no4 e7i%t% to %'""ort thi% conce"t. St'die% in h'$an %olid t'$or% in vitro 5re<'ently de$on%trate %tee" do%eGre%"on%e c'rve%,
%'gge%ting the i$"ortance o5 5'll dr'g do%age. 9n clinical trial%, higher do%e% o5 certain che$othera"e'tic agent% o5ten "rod'ce re%"on%e% a5ter
conventional do%e% have 5ailed. 9n te%tic'lar and ovarian cancer, 5or e7a$"le, t4o5old or three5old increa%e% in ci%"latin do%age "rod'ce clinical
re%"on%e% in "atient% 4ho have rela"%ed a5ter conventional do%e%.
6 %y%te$atic analy%i% o5 do%e inten%ity ha% been "er5or$ed 5or brea%t and ovarian cancer )B., and it i% no4 "o%%ible to co$"are di55erent
che$othera"e'tic regi$en% by converting the dr'g do%age in each individ'al "rogra$ to $illigra$% "er $eter %<'ared "er 4eek.
Do%e inten%ity I Dr'g )$g.JS'r5ace area )M,.J3i$e )4eek%.
#hen re%'lt% o5 che$othera"y trial% are analy>ed and co$"ared, it i% i$"ortant that do%e inten%ity be o"ti$i>ed and that dr'g inten%ity be
re"orted.
Mo%t o5 the data on the clinical i$"act o5 do%e inten%ity co$e 5ro$ retro%"ective analy%e%, b't %everal "ro%"ective trial% o5 do%e inten%ity in
ovarian cancer have "rod'ced $i7ed re%'lt%. 6 large Gynecologic Oncology Gro'" )GOG. trial o5 do%e@inten%ive ver%'% %tandard@do%e ci%"latin
and cyclo"ho%"ha$ide )2yto7an. in "atient% 4ith advanced ovarian cancer 5ailed to de$on%trate i$"roved d'ration o5 re$i%%ion or %'rvival,
altho'gh the do%e@inten%e regi$en 4a% do'ble the relative do%e inten%ity o5 the %tandard regi$en )A.. Several additional rando$i>ed trial% have
con5ir$ed the re%'lt% o5 the GOG trial )D,F and *-., altho'gh at lea%t one 4ell de%igned trial ha% %'gge%ted %o$e bene5it a%%ociated 4ith do%e
inten%ity in ovarian cancer )**.. o4ever, the c'rrent general con%en%'% o5 o"inion a$ong ovarian cancer clinical inve%tigator% i% that there i% no
clinically relevant do%e re%"on%e 5or ovarian cancer at concentration% o5 %tandard dr'g% achievable 4itho't %o$e 5or$ o5 bone $arro4 "rotection.
Other a""roache% are no4 being e7"lored to increa%e the inten%ity o5 dr'g regi$en% %o a% to increa%e re$i%%ion rate% and d'ration%. 3he%e have
incl'ded inten%i5ying che$othera"y 4ith the '%e o5 bone $arro4 or %te$ cell tran%"lantation or he$ato"oietic gro4th 5actor% to enhance $arro4
recovery.
Bone $arro4 tran%"lantation i% being '%ed on an e7"eri$ental ba%i% in advanced, "oor@"rogno%i%, and re5ractory ovarian cancer. 6ltho'gh higher
re%"on%e rate% are o5ten achieved, the to7icity o5 the%e regi$en% o5ten ha% been %evere )$ortality rate o5 +C to *-C., and no %'rvival bene5it ha%
been doc'$ented. Peri"heral %te$ cell tran%"lantation% are al%o being %t'died and o55er the advantage o5 not re<'iring $arro4 harve%t 'nder
general ane%the%ia. More recent %t'die% are atte$"ting to treat "atient% 4ho have de$on%trated an e7cellent re%"on%e to initial %tandard@do%e
che$othera"y, b't 4ho have "er%i%tent, %$all@vol'$e re%id'al di%ea%e doc'$ented at the ti$e o5 a %econd@look %'rgical "roced're )la"aroto$y
or la"aro%co"y..
6tte$"t% are al%o being $ade to red'ce do%e@li$iting $yeloto7icity by '%ing gran'locyteG$acro"hage colony@%ti$'lating 5actor )GM@2SF. or
gran'locyte colony@%ti$'lating 5actor G@2SF. 6ltho'gh the%e thera"ie% accelerate the recovery o5 gran'locyte% a5ter treat$ent and o5ten red'ce
the d'ration o5 ho%"itali>ation a5ter bone $arro4 tran%"lantation, they are e7"en%ive and have yet to be %ho4n to alter the thera"e'tic o'tco$e. 9n
addition, there i% no %t'dy that doc'$ent% any bene5it 5ro$ the ro'tine "ro"hylactic '%e o5 the%e he$ato"oietic gro4th 5actor% d'ring
conventional che$othera"y.
1eco$binant h'$an interle'kin@** ha% been de$on%trated to increa%e "latelet co'nt% and decrea%e the need 5or "latelet tran%5'%ion% )*,.. 6 role
5or thi% ne4 bone $arro4 %ti$'latory agent in the ro'tine treat$ent o5 ovarian cancer re$ain% to be de5ined.
Phar$acologic Factor% 9n5l'encing 3reat$ent
Phar$acologically, it i% '%e5'l to de%cribe e55ective che$othera"y a% concentration over ti$e o5 the active agent or it% $etabolite at the "ri$ary
%ite o5 antit'$or action. 6ltho'gh it i% not "o%%ible to deter$ine e7act "ericell'lar "har$acokinetic%, %'b%tantial in5or$ation on i$"ortant
"har$acokinetic 5actor% i% available )*3..
Dr'g e55ect I Dr'g concentration K D'ration o5 e7"o%'re I 2 K 3
Beca'%e direct $ea%'re$ent% o5ten are not "o%%ible, con%iderable 5oc'% i% given to the "la%$a concentration K ti$e )2 K 3. analy%e%. 6 n'$ber
o5 i$"ortant 5actor% in5l'ence thi% "har$acokinetic re%'lt, incl'ding ro'te o5 ad$ini%tration and dr'g ab%or"tion, tran%"ort, di%trib'tion,
biotran%5or$ation, inactivation, e7cretion, and interaction% 4ith other dr'g%.
R!ute !f Ad#inistrati!n and A+s!rpti!n
3raditionally, dr'g% have been given orally, intraveno'%ly, intra$'%c'larly, or intraarterially. More recently, con%iderable attention ha% been
given to the intra"le'ral or intra"eritoneal ad$ini%tration o5 che$othera"e'tic agent%, "artic'larly in ovarian cancer )*8.. 3he intra"eritoneal
a""roach i% ba%ed on the conce"t that the "le'ral or "eritoneal clearance o5 the agent i% %lo4er than it% "la%$a clearance and, a% a re%'lt, an
increa%ed concentration o5 the dr'g in the "le'ral or "eritoneal cavity i% $aintained 4hile "la%$a concentration% are lo4.
St'die% o5 a 4ide variety o5 che$othera"e'tic agent% have de$on%trated a di55erential concentration o5 3-@ to +--@5old, de"ending on the
$olec'lar 4eight, charge, and li"id %ol'bility o5 the "artic'lar dr'g. 2linical trial% in ovarian cancer have been "er5or$ed 4ith ci%"latin,
"aclita7el )3a7ol., and dr'g co$bination% )*8.. 2linical trial% '%ing intra"eritoneal ci%"latin have re%'lted in 3-C negative third@look
la"aroto$ie% in "atient% 4ith $ini$al re%id'al di%ea%e.
3he 5ir%t direct evidence intra"eritoneal dr'g delivery $ay i$"rove o'tco$e in ovarian cancer 4a% "rovided by the re%'lt% o5 a rando$i>ed trial
co$"aring intraveno'% ci%"latin to intra"eritoneal ci%"latin in 4o$en 4ith %$all@vol'$e re%id'al advanced ovarian cancer )*+.. 3hi% %t'dy
de$on%trated the regional dr'g treat$ent %trategy 4a% a%%ociated 4ith a %tati%tically %igni5icant i$"rove$ent in overall %'rvival. O5 note, beca'%e
thi% %t'dy 4a% initiated in *FD+, "atient% received intraveno'% cyclo"ho%"ha$ide rather than "aclita7el, in addition to ci%"latin.
6n ongoing GOG trial i% e7a$ining the role o5 both intra"eritoneal ci%"latin and "aclita7el, co$"ared 4ith intraveno'% dr'g delivery o5 the t4o
agent%. 3hi% trial 4ill likely be the de5initive %t'dy in de5ining a role 5or intra"eritoneal dr'g delivery in the $anage$ent o5 ovarian cancer
beca'%e it e7a$ine% the t4o $o%t active agent% in the di%ea%e delivered either %y%te$ically or regionally.
Dru( Distri+uti!n
6ntineo"la%tic agent% '%'ally "rod'ce their antit'$or e55ect by interacting 4ith intracell'lar target $olec'le%. 6% a re%'lt, the ability o5 a
"artic'lar dr'g or active $etabolite to arrive at the cancer cell in %'55icient concentration 5or lethal e55ect i% o5 $a;or i$"ortance. 65ter ab%or"tion,
dr'g% $ay be bo'nd to %er'$ alb'$in or other blood co$"onent%( their ability to "enetrate vario'% body co$"art$ent%, va%c'lar %"ace%, and
e7tracell'lar %ite% i% highly in5l'enced by "la%$a "rotein binding, relative ioni>ation at "hy%iologic ", $olec'lar %i>e, and li"id %ol'bility.
Sanct'ary Site% ?ni<'e circ'$%tance% $ay "rod'ce %anct'ary %ite%, 4hich are area% 4here the t'$or i% inacce%%ible to anticancer dr'g% and the
dr'g concentration over ti$e i% in%'55icient 5or cell kill. =7a$"le% o5 %'ch %anct'ary %ite% incl'de the cerebro%"inal 5l'id and area% o5 large t'$or
$a%%e% 4ith central t'$or necro%i% and lo4 o7ygen ten%ion.
2ell Penetration 6ltho'gh %o$e dr'g% enter the target cell by %i$"le di55'%ion, in %o$e in%tance% cell'lar "enetration i% an active "roce%%. 6% an
e7a$"le, $any o5 the alkylating agent% de"end on a carrier tran%"ort %y%te$ 5or cell'lar "enetration. For large $acro$olec'le%, it $ay be
nece%%ary 5or "inocyto%i% to acco$"li%h cell'lar entry.
Dr'g Metaboli%$
Many antineo"la%tic agent% are active a% intact $olec'le%, b't %o$e re<'ire $etaboli%$ to an active 5or$. Many o5 the anti$etabolite% re<'ire
"ho%"horylation 5or cell entry. 3he alkylating agent, cyclo"ho%"ha$ide, re<'ire% ab%or"tion and liver $etaboli%$ to be activated. 6ttention to
the%e 'ni<'e $etabolic re<'ire$ent% i% needed 5or a""ro"riate dr'g %election. For e7a$"le, i5 direct in%tallation o5 an alkylating agent i% re<'ired,
an agent that i% active a% an intact dr'g %ho'ld be %elected )e.g., thiote"a or nitrogen $'%tard., rather than cyclo"ho%"ha$ide, beca'%e the latter
dr'g re<'ire% he"atic biotran%5or$ation and 4o'ld not be active locally. Not only i% initial activation i$"ortant, b't the rate o5 $etabolic
degradation o5 the active dr'g or $etabolite i% i$"ortant in deter$ining antit'$or activity. 6% an e7a$"le, a $a;or $echani%$ o5 dr'g re%i%tance
in ovarian cancer i% increa%ed $etaboli%$ o5 alkylating agent% d'e to increa%ed intracell'lar en>y$e% )e.g., gl'tathione@S@tran%5era%e..
=7cretion
Mo%t che$othera"e'tic agent% are e7creted thro'gh the kidney or liver. Beca'%e overall kidney or liver 5'nction i% critical to nor$al dr'g
e7cretion, it i% nece%%ary to $odi5y the do%age o5 certain agent% 4hen either o5 the%e organ% i% 5'nctionally i$"aired. 2ertain dr'g% Le.g.,
vincri%tine, do7or'bicin )6dria$ycin.M, are e7creted "ri$arily thro'gh the liver, and other% )e.g., $ethotre7ate. are e7creted al$o%t entirely by
the kidney. Mo%t e7"eri$ental "rotocol% and coo"erative gro'" trial% contain 5or$'la% 5or do%e $odi5ication 5or %"eci5ic organ i$"air$ent% that
in5l'ence dr'g e7cretion.
Dr'g 9nteraction%
2o$$only, $'lti"le dr'g% are ad$ini%tered to "atient% d'ring a ho%"ital %tay. 3he%e incl'de che$othera"e'tic agent% a% 4ell a% nonGcancer@
related dr'g%. 2on%e<'ently, there are $'lti"le o""ort'nitie% 5or clinically i$"ortant dr'g interaction% to occ'r d'ring cancer treat$ent. 3he%e
interaction% $ay increa%e or decrea%e the antit'$or activity o5 a "artic'lar agent, or they $ay increa%e or $odi5y it% to7icity )*B.. 3y"e% o5 dr'g
interaction o5 "otential i$"ortance incl'de tho%e li%ted in 3able 8.8.
3able 8.8 Dr'g 9nteraction% in 2ancer 2he$othera"y
9$"ortant dr'g interaction% 4ith antineo"la%tic dr'g% incl'de:
*. 3he alkylating agent% are highly reactive co$"o'nd% and $ay "rod'ce direct che$ical or "hy%ical inactivation 4hen $'lti"le dr'g% are
$i7ed.
,. 9nte%tinal ab%or"tion o5 certain che$othera"e'tic agent% i% altered by antibiotic% that %'""re%% bo4el 5lora )e.g., red'ced ab%or"tion o5
oral $ethotre7ate., re%'lting in it% decrea%ed circ'lating level.
3. Dr'g% %'ch a% ci%"latin or $ethotre7ate bind to alb'$in or "la%$a "rotein% and $ay be di%"laced 5ro$ that binding by dr'g% that bind
to %i$ilar %ite%, %'ch a% a%"irin or %'l5a, thereby increa%ing the circ'lating level o5 bioavailable ci%"latin or $ethotre7ate.
8. 6lteration% in dr'g activation $ay occ'r, a% 4hen $ethotre7ate increa%e% +@5l'oro'racil activation( conver%ely, dr'g interaction $ay
antagoni>e antit'$or e55ect, a% 4hen +@5l'oro'racil i$"air% the anti5olate action o5 $ethotre7ate.
+. 3he ne"hroto7ic antibiotic% 5re<'ently alter $ethotre7ate e7cretion and $ay increa%e the renal to7icity o5 ci%"latin.
Principles !f C!#+inati!n Che#!therapy
6ntineo"la%tic agent% are no4 co$$only '%ed in co$bination% )*A.. 2o$bination che$othera"y ha% beco$e the %tandard a""roach to
$anage$ent o5 ovarian ger$ cell t'$or% a% 4ell a% $any other ad'lt %olid t'$or%, incl'ding odgkin:% di%ea%e, non@odgkin:% ly$"ho$a%,
brea%t cancer, and te%tic'lar cancer. 3he enth'%ia%$ 5or co$bination% re%'lt% 5ro$ %everal %igni5icant li$itation% inherent in %ingle@agent
che$othera"y. 9n addition, there i% a %olid theoretic ba%i% 5or co$bination che$othera"y 5ro$ a kno4ledge o5 cell'lar kinetic%, dr'g $etaboli%$,
dr'g re%i%tance, and t'$or heterogeneity.
!i$itation% o5 Single@Dr'g 3hera"y
3he $a;or li$itation% o5 %ingle@agent che$othera"y are:
*. 3o7icity li$it% the do%e and d'ration o5 dr'g ad$ini%tration and th'% re%trict% the t'$or cell kill achievable.
,. 6do"tive $echani%$% allo4 cell %'rvival and event'al regro4th o5 re%i%tant t'$or cell% in %"ite o5 lethal e55ect% "rod'ced in the b'lk o5
the t'$or.
3. S"ontaneo'% develo"$ent o5 dr'g re%i%tance.
8. M'ltidr'g or "leiotro"ic dr'g re%i%tance.
Several di55erent $echani%$% o5 re%i%tance are %een 4ith antineo"la%tic agent%, and %o$e o5 the%e are li%ted in 3able 8.+. Mo%t "roble$% inherent
in %ingle@dr'g thera"y cannot be corrected by %i$"ly altering the do%e or %ched'le o5 that %ingle dr'g. 6% a re%'lt, increa%ing '%e ha% been $ade
o5 $'ltidr'g co$bination che$othera"y.
3able 8.+ Mechani%$% o5 1e%i%tance to 6nticancer Dr'g%
C!#+inati!n Che#!therapy Mechanis#s
Di55erent che$othera"e'tic agent% $ay act in di55erent "ha%e% o5 the t'$or cell cycle. ?%e o5 $'lti"le dr'g% 4ith di55erent cell'lar kinetic
characteri%tic% red'ce% the t'$or $a%% $ore co$"letely than any individ'al che$othera"e'tic agent 4hile $ini$i>ing the i$"act o5 %ingle@dr'g
re%i%tance. For in%tance, i5 a cell cycleGnon%"eci5ic agent i% ad$ini%tered, "rod'cing a , log cell kill in a t'$or $a%% 4ith *-F cell%, and no 5'rther
thera"y i% given, a $inor t'$or re%"on%e 4ill occ'r, 5ollo4ed by t'$or regro4th and no i$"act on %'rvival. 95 a cell cycleG%"eci5ic agent
"rod'ce% a %i$ilar degree o5 cell kill, only the cell% co$ing into cell cycle 4ill be a55ected by %'ch an agent. Si$"ly by '%ing co$bination% or
%e<'ence% o5 cell cycleG%"eci5ic and non%"eci5ic agent%, log kill can be enhanced in t'$or%. #ith identi5ication o5 a""ro"riate co$bination% and
"ro"er %e<'encing, %'55icient log kill $ay be achieved to "rod'ce a c're.
Dru( Resistance
2o$bination che$othera"y can hel" to circ'$vent %"ontaneo'% $'tation% to dr'g re%i%tance. 65ter initial cell kill, the re%id'al t'$or $ay
contain dr'g@re%i%tant cell%. 3he "robability o5 the e$ergence o5 dr'g@re%i%tant cell% in any given "o"'lation i% red'ced i5 t4o or $ore agent% 4ith
di55erent $echani%$% o5 action can be '%ed in a tightly %e<'enced treat$ent %che$e.
Dru( Interacti!n
Dr'g interaction% $ay be additive, %ynergi%tic, or antagoni%tic. 2o$bination% that re%'lt in i$"roved thera"y beca'%e o5 increa%ed antit'$or
activity or decrea%ed to7icity are %aid to be %ynergi%tic. 6dditive thera"ie% "rod'ce enhanced antit'$or activity e<'ivalent to the %'$ o5 both
agent% acting %ingly. Finally, antit'$or agent% $ay act'ally antagoni>e the e55ect o5 each other, "rod'cing a le%%er thera"e'tic e55ect than 4hen
'%ed %ingly. For e7a$"le, +@5l'oro'racil "revent% the anti5olate action o5 $ethotre7ate 4hen '%ed be5ore $ethotre7ate ad$ini%tration.
Schedule Dependency
9n %o$e in%tance%, the %a$e dr'g% '%ed in di55erent %e<'ence% $ay "rod'ce a 4idely varied e55ect, %'gge%ting the i$"ortance o5 %ched'le
de"endency. 6n e7a$"le i% the red'ced cardiac to7icity de$on%trated 5or 4eekly lo4@do%e do7or'bicin co$"ared 4ith high@do%e bol'%
do7or'bicin. 6ltho'gh %ched'le de"endency ha% been an i$"ortant, 4ell doc'$ented "heno$enon in e7"eri$ental t'$or%, it% i$"ortance i% le%%
4ell de5ined 5or h'$an cancer che$othera"y.
3he general "rinci"le% that allo4ed the develo"$ent o5 %'cce%%5'l co$bination% are %ho4n in 3able 8.B. 6ltho'gh the%e cannot be '%ed in every
regi$en and %o$e overla" in to7icitie% i% co$$on, the%e conce"t% are a central 5eat're o5 $o%t o5 the regi$en% no4 being '%ed %'cce%%5'lly in
cancer treat$ent.
Re#issi!n
Once a treat$ent regi$en ha% been %elected, it i% nece%%ary to have %o$e %tandardi>ed 4ay to eval'ate the re%"on%e to dr'g treat$ent. 3he ter$%
co$"lete re$i%%ion and "artial re$i%%ion are '%ed 5re<'ently and "rovide a convenient 4ay to de%cribe re%"on%e% and co$"are vario'% "'bli%hed
regi$en%.
2o$"lete 1e$i%%ion 2o$"lete re$i%%ion i% the co$"lete di%a""earance o5 all ob;ective evidence o5 t'$or a% 4ell a% the re%ol'tion o5 all %ign%
and %y$"to$% re5erable to the t'$or. 2o$"lete regre%%ion% o5 cancer are tho%e a%%ociated in general 4ith %igni5icant "rolongation o5 %'rvival.
Partial 1e$i%%ion Partial re$i%%ion i% an at lea%t +-C red'ction in the %i>e o5 all $ea%'rable le%ion% along 4ith %o$e degree o5 %'b;ective
i$"rove$ent and the ab%ence o5 any ne4 le%ion% d'ring thera"y. Partial re$i%%ion% tran%late in general into i$"roved 4ell@being 5or the "atient
b't only occa%ionally are a%%ociated 4ith longer overall %'rvival.
Finally, vario'% ter$% indicate le%%er re%"on%e%, %'ch a% ob;ective re%"on%e or $inor re%"on%e, b't %'ch re%"on%e% rarely re%'lt in any %igni5icant
i$"rove$ent in %'rvival.
Do%e 6d;'%t$ent
Patient% vary in their tolerance to che$othera"y, and th'% %o$e $echani%$ 5or tailoring the treat$ent to a "artic'lar "atient i% nece%%ary. One
convenient $ethod involve% the '%e o5 a N%liding %cale.O 6 ty"ical %che$e 5or ad;'%ting che$othera"y ba%ed on $yelo%'""re%%ion i% "re%ented in
3able 8.A. Do%e% o5 $yelo%'""re%%ive agent% are red'ced i5 the "atient "rove% very %en%itive to the regi$en b't can be ret'rned to 5'll level% i5
tolerance i$"rove% in %'b%e<'ent co'r%e%.
Many e7"eri$ental "rotocol% "rovide 5or an e%calation o5 dr'g do%e i5 no %igni5icant to7icity i% e7"erienced 4ith initial co'r%e% o5 thera"y. 6
%liding %cale o55er% the be%t o""ort'nity to give the $a7i$'$ a$o'nt o5 thera"y "o%%ible. 3he %liding %cale "re%ented i% ba%ed only on bone
$arro4 to7icity. 95 the dr'g% '%ed in any "artic'lar co$bination have other %erio'% to7icitie%, %'ch a% renal or he"atic to7icity, then %liding %cale%
ba%ed on the other to7icitie% are '%ed to $ini$i>e to7icity b't $a7i$i>e thera"e'tic e55ect.
6% an e7a$"le, beca'%e carbo"latin i% cleared renally and occa%ional %evere $arro4 to7icity occ'r%, do%e@ad;'%t$ent %cale% ba%ed on renal
5'nction have been develo"ed. Do%e ad;'%t$ent% are ba%ed on glo$er'lar 5iltration rate )GF1. or creatinine clearance and the target %er'$
concentration $'lti"lied by the area 'nder c'rve )6?2. 5or the dr'g%: antit'$or activity )*D.. 3he 5or$'la i%:
Do%e )$g. I 3arget 6?2 K )GF1 P ,+.
3he de%ired target 6?2 i% 8 to B $gJ$! 5or "revio'%ly treated "atient% and + to A.+ $gJ$! 5or tho%e "revio'%ly 'ntreated. 3he '%e o5 the%e do%e@
ad;'%t$ent %che$e% tailored to the "artic'lar to7icity allo4% 5or %a5er ad$ini%tration o5 che$othera"e'tic agent%.
Treat#ent Evaluati!n
6 great n'$ber o5 co$bination regi$en% are in '%e in gynecologic $alignancie%. Many are e%tabli%hed a% treat$ent% o5 choice 5or "artic'lar
t'$or%, and other% are e7"eri$ental. 9n eval'ating any "artic'lar co$bination, %everal i$"ortant "oint% %ho'ld be con%idered:
*. a% the regi$en been '%ed 5or a n'$ber o5 year%, and ha% it been de$on%trated to be e55ective by $ore than one inve%tigator 5or a
"artic'lar %tage or %tage% o5 di%ea%eQ
,. a% the regi$en been "'bli%hed 4ith ade<'ate di%c'%%ion o5 the to7icitie% inherent in the treat$entQ
3. Doe% the regi$en contain 'n'%'al 5or$% o5 treat$ent that re<'ire 'ni<'e 5acilitie%Q
8. 9% the co$bination $ade '" o5 dr'g% that are available co$$erciallyQ
Dru( T!icity
6ntineo"la%tic dr'g% are a$ong the $o%t to7ic agent% '%ed in $odern $edicine. Many o5 the to7ic %ide e55ect%, "artic'larly tho%e to organ
%y%te$% 4ith a ra"idly "roli5erating cell "o"'lation, are do%e related and "redictable. ?%'ally the $echani%$ o5 to7icity i% %i$ilar to the
$echani%$ that "rod'ce% the de%ired cytocidal e55ect on t'$or%. =ven organ% 4ith li$ited cell "roli5eration can be da$aged by che$othera"e'tic
agent% in either a do%e@related or an idio%yncratic 5a%hion. 9n al$o%t all in%tance%, che$othera"e'tic agent% are '%ed in do%e% that "rod'ce %o$e
degree o5 to7icity to nor$al ti%%'e%.
Severe %y%te$ic debility, advanced age, "oor n'tritional %tat'%, or direct organ involve$ent by "ri$ary or $eta%tatic t'$or can re%'lt in
'ne7"ectedly %evere %ide e55ect% o5 che$othera"y. 9dio%yncratic dr'g reaction% al%o can have %evere and 'ne7"ected con%e<'ence%. 6% a re%'lt,
care5'l $onitoring o5 "atient% receiving cancer che$othera"y i% a $a;or re%"on%ibility o5 "hy%ician% 4ho elect to '%e thi% a""roach to cancer
$anage$ent )*F..
He#at!l!(ic T!icity
3he "roli5erating cell% o5 the erythroid, $yeloid, and $egakaryocytic %erie% o5 the bone $arro4 are highly %'%ce"tible to da$age by $any o5 the
co$$only '%ed antineo"la%tic agent%. Gran'locyto"enia and thro$bocyto"enia are "redictable %ide e55ect% o5 $o%t o5 the co$$only '%ed
antit'$or agent% and are %een 4ith all e55ective regi$en% o5 co$bination che$othera"y. 3he %everity and d'ration o5 the%e %ide e55ect% are
variable and de"end on the dr'g%, the do%e, the %ched'le, and the "atient:% "revio'% radiation or che$othera"y.
9n general, ac'te gran'locyto"enia occ'r% B to *, day% a5ter ad$ini%tration o5 $o%t $yelo%'""re%%ive che$othera"e'tic agent% and recovery
occ'r% in ,* to ,8 day%( "latelet %'""re%%ion occ'r% 8 to + day% later, 4ith recovery a5ter 4hite cell co'nt recovery. Several agent% are 'ni<'e in
"rod'cing delayed bone $arro4 %'""re%%ion, a$ong the$ $ito$ycin 2 and the nitro%o'rea%. Marro4 %'""re%%ion 5ro$ the%e dr'g% co$$only
occ'r% at ,D to 8, day%, 4ith recovery 8- to B- day% a5ter treat$ent.
Gran'locyto"enia Patient% 4ith an ab%ol'te gran'locyte co'nt o5 le%% than +--J$$3 5or + day% or longer are at high ri%k o5 ra"idly 5atal %e"%i%.
3he 4ide '%e o5 "ro"hylactic, e$"iric, broad@%"ectr'$ antibiotic% in 5ebrile gran'locyto"enic "atient% 4ith cancer ha% %igni5icantly decrea%ed the
incidence o5 li5e@threatening in5ection%. Gran'locyto"enic "atient% %ho'ld have their te$"erat're checked every 8 ho'r% and $'%t be e7a$ined
5re<'ently 5or evidence o5 in5ection. 3he availability o5 he$ato"oietic gro4th 5actor% %'ch a% G@2SF and GM@2SF ha% enabled "hy%ician% to
red'ce the d'ration o5 gran'locyto"enia in certain "atient%.
3hro$bocyto"enia Patient% 4ith %'%tained thro$bocyto"enia 4ho have "latelet co'nt% o5 le%% than ,-,---J$$3 are at ri%k o5 %"ontaneo'%
he$orrhage, "artic'larly ga%trointe%tinal or ac'te intracranial he$orrhage. 1o'tine "latelet tran%5'%ion% 5or "latelet co'nt% belo4 ,-,---J$$3
have %igni5icantly red'ced the ri%k o5 %"ontaneo'% he$orrhage. 9t i% co$$on to tran%5'%e B to *- 'nit% o5 rando$ donor "latelet% to the "atient
4ith a "latelet co'nt o5 le%% than ,-,---J$$3. 1e"eat tran%5'%ion% at interval% o5 , to 3 day% 5or the d'ration o5 the %evere thro$bocyto"enia are
indicated. 6ltho'gh "atient% 4ith "latelet co'nt% e7ceeding +-,---J$$3 do not co$$only e7"erience %evere bleeding, tran%5'%ion at thi% level i%
indicated:
*. 95 the "atient $ani5e%t% active bleeding
,. 95 the "atient ha% active "e"tic 'lcer di%ea%e
3. Be5ore and d'ring %'rgical "roced're%
6 "o%ttran%5'%ion "latelet co'nt "er5or$ed * ho'r a5ter "latelet ad$ini%tration %ho'ld %ho4 an a""ro"riate incre$ental increa%e. 95 no
"o%ttran%5'%ion "latelet increa%e occ'r%, it i% likely that there ha% been "revio'% %en%iti>ation to rando$ donor "latelet%, and the "atient re<'ire%
%ingle@donor h'$an le'kocyte antigen )!6.@$atched "latelet% 5or 5't're tran%5'%ion%.
1eco$binant interle'kin@** )rh9l@**. ha% been a""roved 5or '%e a% an agent to increa%e "latelet co'nt% and decrea%e the need 5or "latelet
tran%5'%ion% in "atient% e7"eriencing or antici"ated to have %evere thro$bocyto"enia d'e to che$othera"y )*,.. 3he dr'g i% ad$ini%tered
%'bc'taneo'%ly beginning B to ,8 ho'r% a5ter che$othera"y )+- RgJkg once daily. and contin'ed 'ntil the "latelet co'nt e7ceed% +-,---J$$3.
3reat$ent 4ith rh9l@** %ho'ld be di%contin'ed at lea%t , day% be5ore the ne7t che$othera"y.
Gastr!intestinal T!icity
3he ga%trointe%tinal tract i% a 5re<'ent %ite o5 %erio'% antineo"la%tic dr'g treat$ent to7icity. M'co%iti% ca'%ed by a direct e55ect on the ra"idly
dividing e"ithelial $'co%al cell% i% co$$on( conco$itant gran'locyto"enia allo4% the in;'red $'co%a to beco$e in5ected and %erve a% a "ortal o5
entry 5or bacteria and 5'ngi into the blood%trea$. 9$"aired cell'lar i$$'nity d'e to 'nderlying di%ea%e or cortico%teroid thera"y al%o can
contrib'te to e7ten%ive in5ection o5 the ga%trointe%tinal tract. Other %ide e55ect% related to the ga%trointe%tinal tract incl'de i$"aired inte%tinal
$otility re%'lting 5ro$ the a'tono$ic ne'ro"athic e55ect o5 vinca alkaloid% )vincri%tine and vinbla%tine. and na'%ea and vo$iting, ind'ced by
$any anticancer dr'g%.
?""er Ga%trointe%tinal 3he on%et o5 $'co%iti% i% 5re<'ently 3 to + day% earlier than that o5 $yelo%'""re%%ion. !e%ion% o5 the $o'th and "haryn7
are di55ic'lt to di%ting'i%h 5ro$ candidia%i% and her"e% %i$"le7 in5ection. =%o"hagiti% d'e to direct dr'g to7icity can be con5'%ed 4ith radiation
e%o"hagiti% or in5ection% 4ith bacteria, 5'ngi, or her"e% %i$"le7 beca'%e they all "rod'ce dy%"hagia and retro%ternal b'rning "ain. Oral
candidia%i% )thr'%h. re%"ond% to oral chlortri$a>ole, *- $g 5ive ti$e% daily. =%o"hageal or %evere oral candidia%i% '%'ally re%"ond% to a A@day
co'r%e o5 intraveno'% a$"hotericin B, -.+ $gJkgJ day. M'coc'taneo'% her"e% %i$"le7 clear% $ore ra"idly 4ith intraveno'% acyclovir, A+-
$gJ$,Jday. Sy$"to$atic $anage$ent o5 "ain5'l '""er ga%trointe%tinal in5la$$ation incl'de% 4ar$ %aline $o'th rin%e% and to"ical ane%thetic%,
%'ch a% vi%co'% lidocaine. 9ntraveno'% 5l'id% or hy"erali$entation $ay be re<'ired.
!o4er Ga%trointe%tinal M'co%iti% in the lo4er ga%trointe%tinal tract i% invariably a%%ociated 4ith diarrhea. Serio'% co$"lication% incl'de bo4el
"er5oration, he$orrhage, and necroti>ing enterocoliti%.
Necroti>ing enterocoliti% incl'de% a %"ectr'$ o5 %evere diarrheal illne%%e% that can be 5atal in a gran'locyto"enic "atient. Broad@%"ectr'$
antibiotic thera"y $ay "redi%"o%e the "atient to necroti>ing enterocoliti%. Sy$"to$% o5 necroti>ing enterocoliti% incl'de 4atery or bloody
diarrhea, abdo$inal "ain, %ore throat, na'%ea, vo$iting, and 5ever. Phy%ical e7a$ination '%'ally reveal% abdo$inal tenderne%% and di%tention.
Mo%t ca%e% o5 necroti>ing enterocoliti% are %een in "atient% 4ho are treated 4ith clinda$ycin and are ca'%ed by the anaerobic bacteria 2lo%tridi'$
di55icile. 3he treat$ent o5 choice 5or a 2. di55icile in5ection i% oral vanco$ycin, *,+ $g 5o'r ti$e% daily 5or *- to *8 day%.
9$$'no%'""re%%ion
Mo%t anticancer dr'g% are ca"able o5 "rod'cing %'""re%%ion o5 cell'lar and, to a le%%er e7tent, h'$oral i$$'nity. 3he $agnit'de and d'ration o5
the i$$'no%'""re%%ion vary 4ith the do%e and %ched'le o5 dr'g ad$ini%tration and have been inade<'ately characteri>ed 5or $o%t
che$othera"e'tic agent%. o4ever, $o%t o5 the ac'te i$$'no%'""re%%ive %ide e55ect% do not "er%i%t a5ter co$"letion o5 dr'g treat$ent.
!aboratory %t'die% %'gge%t a $arked decrea%e in ho%t de5en%e% d'ring treat$ent a%%ociated 4ith a rebo'nd to co$"lete or nearly co$"lete
re%toration , to 3 day% a5ter treat$ent i% co$"leted. 3hi% %hort@ter$ i$$'no%'""re%%ive e55ect ha% led to increa%ed '%e o5 inter$ittent
che$othera"y regi$en% to allo4 i$$'nologic recovery d'ring co'r%e% o5 treat$ent.
Der#at!l!(ic Reacti!ns
Several i$"ortant dr'g to7icitie% involve %kin reaction%. Skin necro%i% and %lo'ghing $ay re%'lt 5ro$ e7trava%ation o5 certain "artic'larly
irritating che$othera"e'tic agent%, %'ch a% do7or'bicin, actino$ycin D, $ito$ycin 2, vinbla%tine, vincri%tine, and nitrogen $'%tard. 3he e7tent
o5 necro%i% de"end% on the <'antity o5 dr'g e7trava%ated and can vary 5ro$ local erythe$a to chronic 'lcerative necro%i%. Manage$ent o5ten
incl'de% i$$ediate re$oval o5 the intraveno'% line, local in5iltration o5 cortico%teroid%, ice "ack thera"y 5o'r ti$e% a day 5or 3 day%, and
elevation o5 the a55ected li$b. !ong@ter$ $onitoring o5 the a55ected area i% re<'ired, and %'rgical debride$ent and 5'll@thickne%% %kin gra5ting are
o5ten nece%%ary 5or %evere le%ion%.
6lo"ecia i% the $o%t co$$on %ide e55ect o5 $any anticancer dr'g%. 6ltho'gh not intrin%ically in;'rio'%, it ha% $a;or e$otional con%e<'ence% 5or
"atient%. 6gent% co$$only a%%ociated 4ith %evere hair lo%% incl'de the anthracycline antibiotic%, the vinca alkaloid%, "aclita7el, and
cyclo"ho%"ha$ide, b't $o%t co$$only '%ed dr'g co$bination% "rod'ce variable degree% o5 alo"ecia. 6lo"ecia i% virt'ally al4ay% rever%ible i5
the "atient i% able to di%contin'e che$othera"y. air regro4th '%'ally begin% *- day% to %everal 4eek% a5ter treat$ent i% co$"leted. 6tte$"t% to
$ini$i>e alo"ecia by '%ing cold ca"% have been variably e55ective.
Generali>ed allergic %kin reaction% can occ'r 4ith che$othera"e'tic agent%, a% they do 4ith other dr'g%, and can %o$eti$e% be %evere. Other %kin
reaction% occa%ionally %een 4ith che$othera"e'tic agent% incl'de increa%ed %kin "ig$entation )bleo$ycin., "hoto%en%itivity reaction%, tran%ver%e
banding or nail lo%%, 5ollic'liti% )actino$ycin D, $ethotre7ate., and radiation recall reaction% )do7or'bicin..
!i"o%o$al do7or'bicin, an agent de$on%trated to be active in "latin'$@re5ractory ovarian cancer, can "rod'ce a "ain5'l der$atologic %yndro$e
characteri>ed by de%<'a$ation o5 the %kin, $o%t o5ten involving the hand% and 5eet ),-.. Bli%tering, 5ocal or di%%e$inated, can al%o be ob%erved.
Hepatic T!icity
Mode%t elevation% in a$inotran%5era%e, alkaline "ho%"hata%e, and bilir'bin level% are 5re<'ently %een 4ith $any anticancer agent%, b't they
re%olve %oon a5ter treat$ent i% co$"leted. Neverthele%%, $ore %evere reaction% do occ'r. !ong@ter$ ad$ini%tration o5 $ethotre7ate ind'ce%
he"atic 5ibro%i% that can "rogre%% to 5rank cirrho%i%. 3he cirrho%i% and dr'g@ind'ced he"atiti% %ho'ld be $anaged by 4ithdra4al o5 the to7ic agent,
4ith the %a$e %'""ortive $ea%'re% that are '%ed 5or he"atiti% or cirrho%i% o5 any ca'%e.
Pree7i%ting liver di%ea%e or e7"o%'re to other he"atoto7in% $ay increa%e the ri%k. 6nti$etabolite%, %'ch a% B@$erca"to"'rine and B@thiog'anine,
can "rod'ce rever%ible chole%tatic ;a'ndice. 3ran%ient liver en>y$e abnor$alitie% are %een 4ith cyto%ine arabino%ide )6ra@2, 2yto%ar@?., the
nitro%o'rea%, and !@a%"aragina%e. Mithra$ycin, an agent occa%ionally '%ed to control hy"ercalce$ia, 5re<'ently ca'%e% $arked elevation% in liver
en>y$e level% a%%ociated 4ith clotting di%order% and renal in%'55iciency. 9nteri$ lactate dehydrogena%e level% and "rothro$bin ti$e% %ho'ld be
5ollo4ed i5 $'lti"le co'r%e% o5 $ithra$ycin are to be '%ed.
Pul#!nary C!#plicati!ns
Patient% 4ith cancer have a 4ide variety o5 "roble$% that can $ani5e%t a% "'l$onary co$"lication%. 1e%"iratory co$"ro$i%e d'e to l'ng
$eta%ta%e%, "'l$onary e$boli, radiation "ne'$oniti%, t'$or@ind'ced ne'ro$'%c'lar dy%5'nction, and "ne'$onia all $ay be %igni5icant
co$"lication%. 9n addition, direct "'l$onary to7icity 5ro$ co$$only '%ed anticancer dr'g% %o$eti$e% i% %een.
9nter%titial Pne'$oniti% 9nter%titial "ne'$oniti% 4ith "'l$onary 5ibro%i% i% the '%'al "attern o5 l'ng da$age a%%ociated 4ith cytoto7ic dr'g%.
6gent% likely to ca'%e %'ch an e55ect are bleo$ycin, alkylating agent%, and the nitro%o'rea%. 3he "hy%ical and che%t radiologic 5inding% are not
ea%ily di%ting'i%hable 5ro$ tho%e o5 inter%titial "ne'$oniti% re%'lting 5ro$ in5ectio'% agent%, vir'%e%, or ly$"hangitic %"read o5 cancer.
Manage$ent o5 dr'g@ind'ced inter%titial "ne'$oniti% incl'de% di%contin'ation o5 the %'%"ected agent and %'""ortive care. Steroid% $ay have
%o$e bene5it in the hy"er%en%itivity to $ito$ycin 2 and "rocarba>ine. 3here i% little evidence o5 bene5it in ca%e% o5 "ne'$oniti% and 5ibro%i%
%econdary to alkylating agent%, the nitro%o'rea%, and the antit'$or antibiotic%.
Cardiac T!icity
2ardiac to7icity i% %een 4ith %everal i$"ortant cancer che$othera"e'tic agent%. 6ltho'gh the $yocardi'$ con%i%t% o5 largely nondividing cell%,
dr'g% o5 the anthracycline antibiotic cla%%, %"eci5ically do7or'bicin and da'no$ycin, can ca'%e %evere cardio$yo"athy.
3he ri%k o5 cardiac to7icity increa%e% 4ith the total c'$'lative do%e o5 do7or'bicin. For thi% rea%on, a c'$'lative do%e o5 +-- $gJ$, o5 ideal
body %'r5ace area i% no4 4idely '%ed a% the $a7i$'$ tolerable do%e o5 do7or'bicin. #ith care5'l and 5re<'ent $onitoring o5 le5t ventric'lar
5'nction by $ean% o5 e;ection 5raction %t'die%, thera"y can be contin'ed to higher do%e% i5 no %ati%5actory alternative e7i%t%. More in5re<'ently,
anthracycline% and "aclita7el can ca'%e ac'te arrhyth$ia% that '%'ally di%a""ear 4ithin a 5e4 day% o5 dr'g treat$ent. 3hey a""ear not to be
related to total dr'g do%e. 6nthracycline cardiac to7icity i% "otentiated by radiation.
3he $edical $anage$ent o5 cardio$yo"athy ind'ced by anthracycline% i% %'""ortive b't '%'ally 'n%ati%5actory. =arly detection o5 cardiac
co$"ro$i%e 4ith radion'clide cardiac %cintigra"hy be5ore the clinical $ani5e%tation% o5 conge%tive heart 5ail're a""ear i% i$"ortant.
Di%contin'ation o5 the dr'g at the 5ir%t indication o5 decrea%ing le5t ventric'lar 5'nction $ini$i>e% the ri%k o5 cardiova%c'lar deco$"en%ation.
1arely, cyclo"ho%"ha$ide ha% been re"orted to "rod'ce cardioto7icity, "artic'larly in the $a%%ive do%e% '%ed in con;'nction 4ith bone $arro4
tran%"lantation. #ith conventional do%e% o5 cyclo"ho%"ha$ide, thi% co$"lication i% 'nlikely. B'%'l5an and $ito$ycin 2 have been re"orted to
ca'%e endocardial 5ibro%i% and $yocardial 5ibro%i%, re%"ectively. 9n %o$e "atient%, +@5l'oro'racil ha% been re"orted to be a rare ca'%e o5 angina
"ectori%.
Genit!urinary T!icity
9n addition to che$othera"e'tic agent%, vario'% other cancer@related co$"lication% $ay "rod'ce chronic a>ote$ia or ac'te renal 5ail're, incl'ding
5l'id de"letion, in5ection, t'$or in5iltration o5 the kidney, 'reteral ob%tr'ction by t'$or, radiation da$age, and t'$or ly%i% %yndro$e.
Dr'g% that ca'%e kidney da$age incl'de:
*. 2i%"latin, 4hich "rod'ce% renal t'b'lar to7icity a%%ociated 4ith a>ote$ia and $agne%i'$ 4a%ting.
,. Methotre7ate, 4hich can "reci"itate in the renal t'b'le%, ca'%ing olig'ric renal 5ail're. Methotre7ate to7icity can be "revented by
$aintenance o5 a high 'rine vol'$e and alkalini>ation o5 the 'rine.
3. Nitro%o'rea%, 4hich ca'%e a chronic inter%titial ne"hriti% 4ith chronic renal 5ail're.
8. Mito$ycin 2, 4hich ca'%e% a %y%te$ic $icroangio"athic he$oly%i% and ac'te renal 5ail're.
Metabolite% o5 cyclo"ho%"ha$ide are irritant% to the bladder $'co%a and ca'%e a chronic he$orrhagic cy%titi%, "artic'larly d'ring high@do%e or
"rolonged treat$ent. Eigoro'% hydration and di're%i% can red'ce the ri%k o5 thi% co$"lication.
3reat$ent o5 dr'g@related genito'rinary to7icity re<'ire% di%contin'ation o5 the "o%%ibly ne"hroto7ic dr'g% and vol'$e e7"an%ion to increa%e
glo$er'lar 5iltration. S"eci5ic $etabolic abnor$alitie%, %'ch a% hy"er'rice$ia and hy"o$agne%e$ia, %ho'ld be corrected. 95 olig'ria develo"% or
i5 $edical $anage$ent i% 'n%'cce%%5'l in re%toring acce"table kidney 5'nction, %hort@ter$ "eritoneal dialy%i% or he$odialy%i% $ay be re<'ired.
Daily ad$ini%tration o5 3 ! o5 5l'id containing *-- to *+- $=< o5 %odi'$ bicarbonate "er liter $aintain% the 'rinary " above A. Beca'%e
$ethotre7ate i% "oorly dialy>ed, "rolonged to7ic level% can re%'lt i5 le'covorin re%c'e thera"y i% not contin'ed 'ntil the $ethotre7ate
concentration i% le%% than + K *-GD M.
N@acetylcy%teine or $e%na )%odi'$ $erca"toethane%'l5onate. ha% been '%ed in con;'nction 4ith very high do%e% o5 cyclo"ho%"ha$ide or
i5o%5a$ide )95e7. to "revent bladder to7icity by inactivating the to7ic $etabolite )acrolein.. Per%i%tent he$orrhagic cy%titi% that doe% not re%"ond
to con%ervative $anage$ent $ay be treated 4ith e@a$inoca"roic acid.
"eur!t!icity
Many antineo"la%tic dr'g% are a%%ociated 4ith %o$e central or "eri"heral ne'roto7icity. 3he%e ne'rologic %ide e55ect% '%'ally are $ild, b't
occa%ionally they can be %evere.
Einca 6lkaloid% 3he vinca alkaloid% )vincri%tine, vinbla%tine, and vinde%ine. are co$$only a%%ociated 4ith "eri"heral $otor, %en%ory, and
a'tono$ic ne'ro"athie%, 4hich are the $a;or %ide e55ect% o5 vincri%tine. 3o7icity 5ir%t a""ear% a% lo%% o5 dee" tendon re5le7e% 4ith di%tal
"are%the%ia%. 2ranial nerve% can be a55ected, and the a'tono$ic ne'ro"athy can a""ear a% adyna$ic ile'%, 'rinary bladder atony 4ith retention, or
hy"oten%ion. 6ll o5 the%e ne'rologic to7icitie% 5ro$ the vinca alkaloid% are %lo4ly rever%ible a5ter ce%%ation o5 the o55ending dr'g.
2i%"latin 2i%"latin "rod'ce% ototo7icity, "eri"heral ne'ro"athy, and, rarely, retrob'lbar ne'riti% and blindne%%. igh do%e% o5 ci%"latin, o5ten '%ed
in ovarian cancer thera"y, are "artic'larly likely to "rod'ce a "rogre%%ive and %o$e4hat delayed "eri"heral ne'ro"athy. 3hi% de5ect i%
characteri>ed by %en%ory i$"air$ent and lo%% o5 "ro"rioce"tion, 4herea% $otor %trength '%'ally i% "re%erved. Progre%%ion o5 thi% ne'ro"athy * to
, $onth% a5ter ce%%ation o5 high@do%e ci%"latin ha% been re"orted.
Paclita7el Paclita7el i% a%%ociated 4ith the develo"$ent o5 a "eri"heral %en%ory ne'ro"athy. 3he incidence and %everity o5 %y$"to$% relate to the
"eak level% o5 the agent reached in the "la%$a. 9n addition, the co$bination o5 "aclita7el and ci%"latin )or carbo"latin. ha% the "otential to be
$ore ne'roto7ic than either agent '%ed alone ),*..
Other Dr'g% 1arely, +@5l'oro'racil can be a%%ociated 4ith an ac'te cerebellar to7icity, a""arently related to it% $etaboli%$ to 5l'orocitrate, a
ne'roto7ic $etabolite o5 the "arent co$"o'nd. e7a$ethyl$ela$ine ha% been re"orted to "rod'ce "eri"heral ne'ro"athy and ence"halo"athy.
So$e i$"rove$ent in the "eri"heral ne'ro"athy ha% been re"orted 4ith ad$ini%tration o5 B vita$in %'""le$ent%, b't thera"e'tic e55ectivene%%
$ay be red'ced. igh@do%e cyto%ine arabino%ide ha% been a%%ociated 4ith %o$nolence, ata7ia, and con5'%ion.
'ascular and Hypersensitivity Reacti!ns
Occa%ionally, %evere hy"er%en%itivity reaction% in the 5or$ o5 ana"hyla7i% develo" 4ith che$othera"e'tic agent%. 9n rare ca%e% thi% ha% been
a%%ociated 4ith cyclo"ho%"ha$ide, do7or'bicin, ci%"latin, intraveno'% $el"halan, and high@do%e $ethotre7ate. Bleo$ycin ad$ini%tration $ay be
a%%ociated 4ith $arked 5ever reaction%, ana"hyla7i%, 1ayna'd:% "heno$enon, and a chronic %cleroder$a@like reaction. 3he %a$e reaction% have
been re"orted 4ith "rocarba>ine, eto"o%ide )EP@*B., and teni"o%ide )EM@,B..
y"er%en%itivity reaction% have been %een 4ith "aclita7el and are believed to be d'e to hy"er%en%itivity to the cre$o"hor vehicle. 3hey can be
a$eliorated 4ith intraveno'% in5'%ion% o5 de7a$etha%one ),- $g., di"henhydra$ine )+- $g., and ci$etidine )3-- $g. 3- $in'te% be5ore
"aclita7el i% ad$ini%tered. 2arbo"latin ha% been noted to be a%%ociated 4ith a %igni5icant ri%k 5or hy"er%en%itivity reaction% in "atient% 4ho have
been treated 4ith $ore than %i7 total co'r%e% o5 a "latin'$ agent ),,..
Sec!nd Mali(nancies
Many antineo"la%tic agent% are $'tagenic and teratogenic. 3he "otential o5 the%e agent% to ind'ce %econd $alignancie% a""ear% to vary 4ith the
cla%% o5 agent ),3.. 6lkylating agent% )e%"ecially $el"halan., "rocarba>ine, and the nitro%o'rea% %ee$ to be the $a;or o55ender%. 3he c'$'lative
A@year ri%k o5 ac'te nonly$"hocytic le'ke$ia develo"ing in "atient% treated "ri$arily 4ith oral $el"halan 5or ovarian cancer i% a% high a% F.BC
in "atient% receiving thera"y 5or $ore than * year ),8.. 6ltho'gh ci%"latin ha% al%o been %'gge%ted to be a%%ociated 4ith the develo"$ent o5 ac'te
le'ke$ia, the ri%k i% lo4er than 4ith the alkylating agent% ),+.. =vidence 5ro$ long@ter$ %t'die% o5 odgkin:% di%ea%e %'gge%t% a $a;or ri%k 4ith
co$bined che$othera"y and radiation thera"y. 9n %'ch "atient%, there i% a ri%k o5 ac'te le'ke$ia a% 4ell a% an increa%e in %olid t'$or%, %een
"artic'larly in the radiation "ort%. 6n increa%e in the 5re<'ency o5 ac'te le'ke$ia ha% been re"orted in "atient% treated 5or odgkin:% di%ea%e,
$'lti"le $yelo$a, and ovarian cancer.
3he %econd $alignancy co$$only occ'r% 8 to A year% a5ter %'cce%%5'l thera"y. =nco'ragingly, evidence %'gge%t% that a5ter ** year%, the ri%k o5
ac'te le'ke$ia in "atient% treated 5or odgkin:% di%ea%e decrea%e% to that o5 the nor$al "o"'lation. 6l%o enco'raging are the long@ter$ 5ollo4@'"
%t'die% in 4o$en c'red o5 choriocarcino$a, "ri$arily 4ith anti$etabolite thera"y. 9n %'ch "atient "o"'lation%, there i% no evidence o5 an
increa%ed ri%k o5 %econd $alignancy. 1adiation alone a""ear% to "rod'ce a relatively lo4 ri%k o5 late le'ke$ia. 2he$othera"e'tic regi$en% alone,
"artic'larly tho%e 4itho't alkylating agent% or "rocarba>ine, are al%o a%%ociated 4ith relatively little ri%k. 2o$bination che$othera"y and li$ited@
5ield radiation thera"y increa%e the ri%k only %lightly.
Partic'larly high ri%k% are a%%ociated 4ith:
*. =7ten%ive radiation thera"y "l'% co$bination che$othera"y
,. Prolonged alkylating agent thera"y )S* year.
3. Prolonged $aintenance thera"y
8. 6ge older than 8- year% at initial treat$ent
G!nadal Dysfuncti!n
Many cancer che$othera"e'tic agent% have "ro5o'nd and la%ting e55ect% on te%tic'lar and ovarian 5'nction. 2he$othera"e'tic agent%, "artic'larly
alkylating agent%, can ca'%e a>oo%"er$ia and a$enorrhea. Secondary %e7'al characteri%tic% related to hor$onal 5'nction '%'ally are le%%
di%t'rbed. Prolonged inten%ive co$bination che$othera"y co$$only "rod'ce% a>oo%"er$ia in $en, and recovery i% 'nco$$on.
3he on%et o5 a$enorrhea and ovarian 5ail're i% acco$"anied by an elevation o5 the %er'$ 5ollicle@%ti$'lating hor$one and l'teini>ing hor$one
and a decrea%e in the %er'$ e%tradiol level. Occa%ionally, thi% hor$onal "attern can be %een be5ore the on%et o5 a$enorrhea. 95 the characteri%tic
"attern i% %een, "atient% %ho'ld be advi%ed to con%ider conce"tion beca'%e the%e 5inding% "redict "re$at're ovarian 5ail're and early $eno"a'%e.
#hen %hort@ter$ inten%ive che$othera"y i% '%ed, "artic'larly 4ith anti$etabolite%, vinca alkaloid%, or antit'$or antibiotic%, in;'ry to the
re"rod'ctive %y%te$ i% le%% co$$on. For e7a$"le, $en treated 5or te%tic'lar cancer, children 4ith ac'te le'ke$ia, and 4o$en c'red o5
ge%tational tro"hobla%tic di%ea%e or ovarian ger$ cell $alignancie% '%'ally have recovered re"rod'ctive ca"acity a5ter thera"y.
2he$othera"y in Pregnancy 1i%k o5 congenital abnor$alitie% 5ro$ the%e dr'g% i% highe%t d'ring the 5ir%t tri$e%ter o5 "regnancy, e%"ecially 4hen
anti$etabolite% )e.g., cyto%ine arabino%ide or $ethotre7ate. and alkylating agent% are '%ed. 2he$othera"y ad$ini%tered d'ring the %econd or third
tri$e%ter% '%'ally i% not a%%ociated 4ith an increa%e in 5etal abnor$alitie%, altho'gh the n'$ber o5 "atient% %t'died i% relatively %$all.
Meta+!lic A+n!r#alities
9na""ro"riate 6ntidi'retic or$one Secretion 9na""ro"riate antidi'retic hor$one %ecretion i% characteri>ed by hy"onatre$ia, high 'rine
o%$olality, and high 'rinary %odi'$ val'e% and i% a%%ociated 4ith %everal $alignancie%, $o%t co$$only %$all cell carcino$a o5 the l'ng. 9t can
al%o be %een a% a co$"lication o5 vinca alkaloid che$othera"y. Sy$"to$% are "ri$arily ne'rologic and incl'de altered $ental %tat'%, con5'%ion,
lethargy, %ei>'re%, and co$a. 3he %everity o5 %y$"to$% i% related to the ra"idity o5 develo"$ent o5 hy"onatre$ia. 3he diagno%i% re%t% on:
*. 3he doc'$entation o5 hy"onatre$ia
,. 3he "re%ence o5 a 'rine that i% hy"ertonic to "la%$a
3. 3he e7cl'%ion o5 hy"othyroidi%$ or adrenal in%'55iciency
y"er'rice$ia y"er'rice$ia $ay be a co$"lication o5 e55ective cancer che$othera"y in certain t'$or%, "artic'larly he$atologic $alignancie%
4here ra"id t'$or ly%i% i% %een in re%"on%e to initial treat$ent. 1a"id t'$or ly%i% "rod'ce% relea%e o5 "redo$inant intracell'lar ion% and 'ric acid
and can re%'lt in li5e@threatening hy"erkale$ia, hy"er"ho%"hate$ia, hy"ocalce$ia, and hy"er'rice$ia. 1enal 5ail're a%%ociated 4ith
hy"er'rice$ia can be %evere. Prevention o5 the t'$or ly%i% %yndro$e re<'ire% $aintenance o5 a high 'rinary o't"'t, $aintenance o5 high 'rinary
" )above A.-., and "ro"hylactic '%e o5 the 7anthine o7ida%e inhibitor, allo"'rinol, a% di%c'%%ed in 2ha"ter *A.
A"TI"EOP)ASTIC DR,GS
Al-ylatin( A(ents
3hi% cla%% o5 antineo"la%tic agent act% "ri$arily by che$ically interacting 4ith DN6. 3he%e dr'g% 5or$ e7tre$ely 'n%table alkyl gro'"% that react
4ith n'cleo"hilic )electron@rich. %ite% on $any i$"ortant organic co$"o'nd%, %'ch a% n'cleic acid%, "rotein%, and a$ino acid%. 3he%e interaction%
"rod'ce the "ri$ary cytoto7ic e55ect%.
Mechani%$
6lkylating agent% co$$only bind to the N@A "o%ition o5 g'anine and to other key DN6 %ite%. 9n doing %o, they inter5ere 4ith acc'rate ba%e
"airing, cro%%@link DN6, and "rod'ce %ingle@ and do'ble@%tranded break%. 3hi% re%'lt% in the inhibition o5 DN6, 1N6, and "rotein %ynthe%i%.
Beca'%e %o$e e55ect% o5 alkylating agent% are %i$ilar to tho%e o5 irradiation, the%e dr'g% are o5ten called radio$i$etic. Mo%t o5 the e55ective
alkylating agent% are bi5'nctional or "oly5'nctional and have t4o or $ore "otentially 'n%table alkyl gro'"% "er $olec'le. 3he%e bi5'nctional
alkylating agent% allo4 cro%%@linkage o5 DN6 that re%'lt% in cell'lar di%r'"tion.
Beca'%e all alkylating agent% have %i$ilar $echani%$% o5 action, there tend% to be cro%%@re%i%tance to other agent% o5 the %a$e cla%%.
Dr'g%
6ltho'gh %everal h'ndred alkylating agent% e7i%t, tho%e $o%t co$$only in '%e incl'de nitrogen $'%tard )M'%targen., cyclo"ho%"ha$ide
)2yto7an., $el"halan )6lkeran., thiote"a, chlora$b'cil )!e'keran., b'%'l5an )Myleran., and i5o%5a$ide )95e7..
9n addition to the $ore co$$on alkylating agent%, %everal antineo"la%tic agent% o5 di55erent ty"e% are '%'ally cla%%i5ied a% alkylating@like agent%,
altho'gh their "reci%e $echani%$ o5 action i% le%% 4ell 'nder%tood and i% "robably not e7cl'%ively alkylation. 3he%e incl'de the nitro%o'rea%,
B2N? )car$'%tine., $ethyl@22N? )%e$'%tine., 22N? )lo$'%tine., D392 )dacarba>ine., and the "latin'$ analog%, ci%"latin and carbo"latin.
3he characteri%tic% o5 the co$$only '%ed alkylating agent% are li%ted in 3able 8.D and the alkylating@like agent% are li%ted in 3able 8.F.
Antitu#!r Anti+i!tics
3he antit'$or antibiotic% are antineo"la%tic dr'g% that, in general, have been i%olated a% nat'ral "rod'ct% 5ro$ 5'ngi 5o'nd in the %oil ),-.. 3he%e
nat'ral "rod'ct% '%'ally have e7tre$ely co$"le7 and di55erent che$ical %tr'ct're%, altho'gh they 5'nction in general by 5or$ing co$"le7e% 4ith
DN6.
Mechani%$
3he interaction bet4een the%e dr'g% and DN6 o5ten involve% intercalation, in 4hich the co$"o'nd i% in%erted bet4een DN6 ba%e "air%. 6 %econd
$echani%$ tho'ght to be i$"ortant in their antit'$or action i% the 5or$ation o5 5ree radical% ca"able o5 da$aging DN6, 1N6, and vital "rotein%.
Other e55ect% incl'de $etal ion chelation and alteration o5 t'$or cell $e$brane%. 3hi% cla%% o5 antineo"la%tic agent% i% tho'ght to be cell cycleG
non%"eci5ic.
Dr'g%
Ma;or dr'g% in thi% 5a$ily incl'de the anthracycline antibiotic% do7or'bicin )6dria$ycin., li"o%o$al do7or'bicin )Do7il., and da'nor'bicin
)Da'no$ycin. a% 4ell a% actino$ycin D )Dactino$ycin., bleo$ycin )Bleno7ane., $ito$ycin 2 )M'ta$ycin., and $ithra$ycin.
6nthracycline% 3he anthracycline% are antibiotic% i%olated 5ro$ the 5'ngi, Stre"to$yce%. 3he%e "ig$ented co$"o'nd% have an anthra<'inone
n'cle'% attached to an a$ino %'gar and have $'lti"le $echani%$% o5 action. Beca'%e o5 the "lanar %tr'ct're o5 the anthra<'inone $oiety, the%e
agent% act a% intercalator% in the DN6 do'ble heli7. 9n addition, they are kno4n to chelate divalent cation% and are avid calci'$ binder%. 3he%e
agent% ca'%e %ingle@%tranded DN6 break%, inhibit DN6 re"air, and actively generate 5ree radical% that are ca"able o5 "rod'cing DN6 da$age.
6nthracycline% are ca"able o5 reacting directly 4ith cell $e$brane%, di%r'"ting $e$brane %tr'ct're, and altering $e$brane 5'nction.
Bleo$ycin Bleo$ycin 4a% al%o i%olated 5ro$ the Stre"to$yce% 5'ng'%. 9t% %tr'ct're contain% a DN6@binding 5rag$ent and an ion@binding 'nit. 9t
a""ear% to "rod'ce it% antit'$or action "ri$arily by "rod'cing %ingle@ and do'ble@%tranded break% in DN6, $ainly at %ite% o5 g'anine ba%e%. 3he
dr'g i% "ri$arily e7creted in the 'rine, and increa%ed to7icity $ay be %een in "atient% 4ith i$"aired renal 5'nction.
Mito$ycin 2 Mito$ycin 2 i% another antibiotic that 4a% i%olated 5ro$ the Stre"to$yce% 5'ng'%. 9t i% activated in vivo into an alkylating agent
that can bind DN6, "rod'cing cro%%@link% and inhibition o5 DN6 %ynthe%i%. 9n addition, it ha% a <'inone $oiety that can generate 5ree radical
reaction% %i$ilar to tho%e %een 4ith the anthracycline antibiotic%. 9t i% ad$ini%tered intraveno'%ly and i% degraded "ri$arily by $etaboli%$. 1enal
clearance i% not a $a;or $echani%$ o5 e7cretion.
Mithra$ycin Mithra$ycin i% an antit'$or antibiotic i%olated 5ro$ another Stre"to$yce% %"ecie%. 9t ha% intrin%ic antit'$or "ro"ertie% and i% al%o
e55ective in the $anage$ent o5 hy"ercalce$ia. 9t% "ri$ary $echani%$ o5 action %ee$% to be the inhibition o5 1N6 %ynthe%i%, altho'gh it bind% to
DN6 and "rod'ce% inhibition o5 DN6 and "rotein %ynthe%i%.
So$e o5 the i$"ortant characteri%tic% o5 the antit'$or antibiotic% are li%ted in 3able 8.*-.
Anti#eta+!lites
3he anti$etabolite 5a$ily o5 antineo"la%tic agent% interact% 4ith vital intracell'lar en>y$e%, leading to their inactivation or to the "rod'ction o5
5ra'd'lent "rod'ct% inca"able o5 nor$al intracell'lar 5'nction. 9n general, their %tr'ct're% re%e$ble analog% o5 nor$al "'rine% and "yri$idine%, or
they re%e$ble nor$al %'b%tance% that are vital 5or cell 5'nction. So$e anti$etabolite% are active a% intact dr'g%, and other% re<'ire
biotran%5or$ation to active agent%.
Mechani%$
6ltho'gh $any o5 the%e agent% act at di55erent %ite% in bio%ynthetic "ath4ay%, they a""ear to e7ert their antit'$or activity by di%r'"tion o5
5'nction% cr'cial to the viability o5 the cell. 3he%e e55ect% are '%'ally $ore di%r'"tive to actively "roli5erating cell%( th'%, the anti$etabolite% are
cla%%ed in general a% cell cycleG%"eci5ic agent%.
Dr'g%
6ltho'gh h'ndred% o5 anti$etabolite% have been inve%tigated in cancer treat$ent, only a 5e4 are co$$only '%ed. 3hey incl'de:
*. 3he 5olate antagoni%t, $ethotre7ate, 4hich inhibit% the en>y$e dihydro5olate red'cta%e
,. 3he "'rine antagoni%t%, B@$erca"to"'rine )B@MP, P'rinethol. and B@thiog'anine
3. 3he "yri$idine antagoni%t%, +@5l'oro'racil )+@F?, Fl'oro'racil. and cyto%ine arabino%ide )6ra@2, 2yto%ar@?.
8. 3he ribon'cleotide red'cta%e inhibitor, hydro7y'rea )ydrea.
9n $o%t in%tance%, the anti$etabolite% are '%ed not a% %ingle dr'g% b't in co$bination% beca'%e o5 their cell cycle %"eci5icity and their ca"acity 5or
co$"le$entary inhibition. 6nti$etabolite% co$$only '%ed in the treat$ent o5 gynecologic $alignancie% are %'$$ari>ed in 3able 8.**.
Plant Al-al!ids
3he $o%t co$$on "lant alkaloid% in '%e are the vinca alkaloid%, nat'ral "rod'ct% derived 5ro$ the co$$on "eri4inkle "lant )Einca ro%ea.,
altho'gh the e"i"odo"hylloto7in% and "aclita7el are '%ed 5re<'ently in gynecologic $alignancie% )3able 8.*,.. !ike $o%t nat'ral "rod'ct%, the%e
co$"o'nd% are large and co$"le7 $olec'le%, b't vincri%tine and vinbla%tine di55er only by a %ingle $ethyl gro'" on one %ide chain.
Mechani%$
Eincri%tine and vinbla%tine act "ri$arily by binding to vital intracell'lar $icrot'b'lar "rotein%, "artic'larly t'b'lin. 3'b'lin binding "rod'ce%
inhibition o5 $icrot'b'le a%%e$bly and de%tr'ction o5 the $itotic %"indle, and cell% are arre%ted in $ito%i%. 9n general, thi% cla%% o5 antineo"la%tic
agent i% believed to be cell cycleG%"eci5ic. 6t high concentration%, the%e dr'g% al%o have e55ect% on n'cleic acid and "rotein %ynthe%i%.
Paclita7el )3a7ol. ha% a 'ni<'e $echani%$ o5 action: it bind% "re5erentially to $icrot'b'le% and re%'lt% in their "oly$eri>ation and %tabili>ation.
Paclita7el@treated cell% contain large n'$ber% o5 $icrot'b'le%, 5ree and in b'ndle%, that re%'lt in di%r'"tion o5 $icrot'b'le 5'nction and,
'lti$ately, cell death. 1enal clearance i% $ini$al )+C..
Dr'g%
Einbla%tine i% '%ed "ri$arily in the treat$ent o5 ovarian ger$ cell t'$or%. 9t% "ri$ary to7icity i% $yelo%'""re%%ion. 9n contra%t, vincri%tine ca'%e%
little $yelo%'""re%%ion. 9t% "ri$ary do%e@li$iting to7icity i% "eri"heral ne'ro"athy. Eincri%tine i% '%ed "ri$arily in cervical carcino$a and genital
tract %arco$a%.
6 %econd 5a$ily o5 "lant alkaloid% ha% been doc'$ented to have %igni5icant antit'$or "ro"ertie%. Me$ber% o5 thi% 5a$ily, kno4n a% the
e"i"odo"hylloto7in%, are e7tract% 5ro$ the $andrake "lant. 6ltho'gh the "ri$ary "lant e7tract% had t'b'lin@binding "ro"ertie% %i$ilar to tho%e o5
the vinca alkaloid%, the active derivative%, eto"o%ide and teni"o%ide, do not %ee$ to 5'nction either by inhibiting $itotic %"indle 5or$ation or by
t'b'lin binding. 1ather, they a""ear to 5'nction by ca'%ing %ingle@%tranded DN6 break%. ?nlike $any o5 the other co$"o'nd% that act "ri$arily
by DN6 interaction%, the%e agent% a""ear to be cell cycleG%"eci5ic and %ched'le de"endent. 3he dr'g% are "oorly 4ater %ol'ble and th'% are
ad$ini%tered intraveno'%ly. 3he do%e@li$iting to7icity i% $yelo%'""re%%ion. Other to7icitie% incl'de an in5'%ion rateGli$ited hy"oten%ion, na'%ea,
vo$iting, anore7ia, and alo"ecia.
Paclita7el i% a co$"le7 agent in the cla%% o5 dr'g% kno4n a% ta7ane%. 9t% $a;or to7ic e55ect% incl'de bone $arro4 %'""re%%ion, alo"ecia, $yalgia%,
arthralgia%, and hy"er%en%itivity reaction%. 3he $o%t co$$on do%e@li$iting to7icity i% gran'locyto"enia, altho'gh 4ith certain %ched'le% the
li$iting to7icity i% "eri"heral %en%ory ne'ro"athy. 3he dr'g i% active in cancer% o5 the ovary, endo$etri'$, cervi7, and brea%t.
Doceta7el, a $ore recently a""roved ta7ane antineo"la%tic agent, i% al%o active in ovarian and brea%t cancer. 3he do%e@li$iting to7icity o5
doceta7el i% bone $arro4 %'""re%%ion, "rinci"ally ne'tro"enia.
3o"oi%o$era%e@* 9nhibitor%
3hi% ne4 cla%% o5 antineo"la%tic agent% e7ert% it% cytoto7ic e55ect thro'gh inhibition o5 the en>y$e to"oi%o$era%e@* )3able 8.*3.. 3hi% i% a
critically i$"ortant en>y$e in DN6 re"lication, re"air, and tran%cri"tion. 3o"oi%o$era%e@* inhibitor% bind to the en>y$eGDN6 co$"le7, leading
to "er$anent %trand break% and cell death.
3o"otecan )yca$"tin., the 5ir%t to"oi%o$era%e@* inhibitor a""roved 5or clinical '%e in the ?nited State%, i% active in "latin'$@re5ractory ovarian
cancer. 3he $a;or to7icity o5 the agent i% bone $arro4 %'""re%%ion ),B,,A..
Other A(ents
9n addition to the antineo"la%tic agent% %'$$ari>ed "revio'%ly, there i% another gro'" o5 co$$only '%ed dr'g% that do not 5all into any "artic'lar
cla%%. 3hey have 'ni<'e or "oorly 'nder%tood $echani%$%. 3he only %'ch agent co$$only '%ed in gynecologic $alignancie% i%
he7a$ethyl$ela$ine )e7alen. )3able 8.*8..
"e$ Dru( Trials
6 n'$ber o5 che$othera"e'tic agent% have been %t'died e7"eri$entally b't are not co$$ercially available. Many o5 the%e agent% have already
de$on%trated activity again%t h'$an t'$or%, b't %'55icient evidence to allo4 h'$an e7"eri$entation ha% not yet been ac<'ired. 9n addition, $any
inve%tigational agent% are being %t'died in "ha%e 9 and "ha%e 99 trial%.
Pha%e 9 3rial% 3he%e %t'die% de5ine the %"ectr'$ o5 to7icity o5 a ne4 che$othera"e'tic agent and are co$"lete 4hen the do%e@li$iting to7icity o5
any "artic'lar do%e and %ched'le ha% been de5ined.
Pha%e 99 3rial% 3he%e %t'die% '%'ally '%e the do%e e%tabli%hed 5ro$ "ha%e 9 trial% and a""ly thi% do%e and %ched'le to %elected t'$or ty"e% o5
i$"ortance.
Pha%e 999 3rial% 3he%e %t'die% co$"are one e55ective treat$ent 4ith another in a rando$i>ed 5a%hion.