In spite of the promising results of mass screening programs to increase the number of early breast cancer patients, breast cancer still remains the leading cause of death in women in their fifth decade of life in most developed countries. While adjuvant chemotheraphy regimens have improved the life expectance for patience with early breast cancer, locally advanced (stage IIIb) and metastatic (stage IV) breast cancer remain an incurable disease.  ...

Zie: Summary, Conclusions and Future Directions

Dolsma, Willemtje Vrougje,

Dolsma, Willemtje Vrougje

University of Groningen

   University of GroningenCombined modality treatment in breast cancerDolsma, Willemtje VrougjeIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1999Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dolsma, W. V. (1999). Combined modality treatment in breast cancer. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019lorcedtes lniry of)naryrlowSumm ary,, Conclusionsand Future Directionswith:row:apySUMMARY, CONCLUSIONS AND FUTURE DIRECTIONSIn spi te of  the promising resul ts of  mtrssscreening; programs to increase the number ofearly breast cancer patients, breast cancer stillremmins the leading cause oltdeath in womenin thcir fifth decade of lile in most developedcountnes.\X/hile adjuvant chemotherapy regimens haveimproved the life expectance for patients withe:rrly breast car-rcer, locally advanced (stageIIIb) and metastatic (stage IV) brearst cancerremain an incurable disease.As the clisease Free I 0 years survival drops to:rlmost zero in paticnts with more than threeinvolved lvmph nodes, there is an urgent needfor nei,v treatments to improve the elficarcy ofadjuvant tre:ltnent fàr this category of pa-t ients.The hope oFan effective treatment for theseprrtients is not only based on the use of newdrugs, but also on optimizing ancl ir-rtensi-$,ing the use ofdrugs that are alreacly availa-ble. Also of great import:rnce is the improvedunderstanding of the way in which anti cancerdrugs aflèct the tumour and normal tissuedynamics. In that respect problerrs of drug rc-sistance :lnd treatmeÍlt related toxicity are ofutmost importance :rnd subject of this thesis.High-dose ablat ive chcmotherapv wi th atenfold higher dose comp:rred to standardchemotherapy is nowadays leasiblc, bccruse ofthe support of growth Factors, aurologousbone marrow trar-rsplantation (ABM'f) and/orper ipheral  stem ccl l  t ransplantat ion (PSCT).The t reatment re lated rnorbid i ty  and theimpact on local control :rnd long-term survi-v. r l  of  rhc abler ivc ch.moth.r . rpy regimcrrs inp:rtients with locally advar-rced and metastaticbreast cancer has also becn described in thisthesis.In Chapter 2 a review has been givcn how tocircumvent the problem of drug rcsistance,when using high-dose chernotherapy regi-mens fo l lowed by the support  of  growthfactors and/or peripheral stem cell reir-rfusion.It was ribserved, that in the period afïer abla-tive chemotherapy there was an improvedhaematological recovery and a reduced dura-tion of fever and l-rospitalisation by the addi-tion of pcripheral blood stem cells compareclto autologous bone marrow and growth factorsupport alone.Also :rttention l"ras been paid to the problemof the presence of tumour cells not only inbone marrow but also in peripheral blood.l 'he new appro,rch ro prorecl  t issue againsrchemotherapeutic drugs by transferring drugresistant genes into tissue that r-reeds this resis-tance lor its protection has been emphasized.If contamir-ration with replication competentretrovirus and the transfer of drug resistantgenes into turnour cells cirn be avoided, the useoltdrug resistant genes lor the circurnventionof  chemotherapy- induced toxic i ty  may beuseful in the future.Furthermore, indications for high-dose che-motherapy in pat ients wi th sol id tumourssuch as germ cell carcinomas, breast cancer,ovarian cancer and tumours ofyoung adultslike Ewing sarcoma has been discussed withspecial attention for this type of treatment inbreast cancer patients.Not only the resul ts of  h igh-dose chemo-therapy ir-r breast cancer patients with rneta-static disease has been described, but also theresults ofhigh-dose chernotherapy in the ad-j uvan t  se r t i ng  i n  pa t i en t s  w i t h  ex tens i vec{ise:rse in the a-rilla. -l'hc results did show notr>nly :rn irnprove ment of the disease lree sur-vival to 7Bo/o at a medi:rn observation of 50montl'rs, but also an incre:rse of radiopneu-monitis up to 507o.In Chapter 3 an ir-rduction chemotherapyrcgin-ren Followed by a dosc intensificationwith autologous bone marrow reinfusion hasbeen reportecl in patients with locally advan-:::j:ï. IIIb or disserninated stage IV breastLi 56 pre- or perimenopausal women withrr . rge I I Ib -  s tagc IV bre,rr r  c , rncer i t  was l r -tempted to reach a st:rte of complete respon-se  by . r  r em iss i on  i nduc r i on  reg imen  con ta i n -ing prednisor-re, 5-fl uorouracil, methotrexare,doxorubicin and vincristir-re.If successful, patients received an intensifica-tion regimen, consistir-rg of cyclophosphami-de 7 glm' :rnd etoposide 1 .5 g/mt rvith auto-logous horre rnar low reinfusion.=-+-=-L-==---z-O;=-a79=q--=-z=:--=O=q-fhirty-two paticnts who l-rad no evidence ofdiscase after inductior-r chemotherapv receivcd:rutologous bonc marrow reinÍirsion aftcr thedose intensi f icat ion regimen. Af ter  a medianobse rvat ion of  4 vears I  1/  19 p:r t ients wi thstage IIIb bre:rst c:rncer were free ofdisease.In the stage IV group,  onlv a re lat ivelv longt ime to proqression of  15 months w:rs obse r-ved.I t  was concluded, that  th is approach pro-longed disease free surviv:rl in stagc IIlb breastc:rncer p:rtients, but does probabll' not influ-ence the surv ival  in stage IV pat icnts.In Chapter 4 the long te rm results of a phasel l  s tudy consist ing of  induct ion chemothera-pv lollorvcd by closc itrtensific:rtion supporteclwi th autologous bone marrow reinfusion inpre- or perirnenop,rusal patients rvitb st:rgcIV or stagc IIIb breast crurcer has lreen re-portcd.'Iwelve p:rticnts i.vith stage IIIb ancl l7 pa-tients with stage IV brcast cancer received adose inter-rs i f icat ion chemotherapy regirncnFoUorvecl by autologous bone marrow reinfu-sion :rFter complcte response with indr-rctionchemothcrapy.lntensi f icnt ion consistecl  of  cyclophosphe-mide 7 gi m' :rnd ctoposidc 1.5 g/m' in 24 pa,-t ients ar-rd th iotepa 800 mg/m' and mitoxan-r ro r r c  50 - -5  r ng / rn  i n  5  p . r r i t l r r s .-I-he rnedi;rn obscrvation time .was 7 vcurs.-I'he median surviv:rl of thc paticnts with staseIIIb was 80 n'ronths. l-l 'rirtv-three pe rcent ofthe patier-rts had a discase fiee sr,rrvii,al of moreth:rn I vears.For pat ients wi th stage IV thc median surv i -val  rvas 38 months.Although the results especiall,v in the group ofpat icr l ts  wi th stage I I Ib are promisi r - rg,  de-l ln i rc conclusion.  har c ro ewlr i t  complrr ' . r r iv .studies,  that  have been in i t iated.In Chapter 5 the outcome of cardiac toxicitystudies in 27 stage lllb ancl stage IV prc- :rndper imenopausal  b least  cancer p:r t ients,  whowere more th:rn one vear:r f tcr  induct ion che-motherapv fàllowed by ablative chemothe ra-p1' with autologotts bone m:rrrow resctle com-binecl rvith rac{iotherapv, I-ras bcer-r cvalu:rted.-l'hc rnajoriry of the patients (24) received acunrulat ive dose of  300 n-rg/m'doxorubic in,rvhile 3 patients reccivecl a cumulative dose ofepirubic in 480 mg/rn ' .l w c n r y  P à t i c n t s  r c c e i v c d  . r  m i t o r : r n t r u n cbased ablative regimer-r. Seventeen of 20 pa-ticr-rts with stagc IIIb cliscase receivcd 50-(r(rClrav (Gy) locoregional  radiotherapv af tcr:rblative chemotherapv.Cardiac cvaluation consisted of a clinical func-tional classification according to the New YorkHeart Association (NYHA) standard with l2-lcad clectrocardiogr:un (ECIG) and left ven-triculal ejectior.r fraction (tVL.F) by L.CG-gated radio nuclide angiograpl.rvwith a LVEFol < 51o/o as thc lower cut-ofï value. Only Ipatient who had a double transpl:rnt with a 4year interval developed heart Íailure two weeksa f t c r  t he  second  t r : 1nsp l1 rn t .  He r  LVF IFdropped f rom 58% tot  137o.' fhe ot l - rcr  26 pat ients had no c l in ical  s igns orsvmptoms of cardiac toxicity (NYFIA classi-f icat ion 1) .l - hese  resu l t s  , r r c  hampe  r cd  by  a  l i r n i t edfbilow-up ancl ,r srnall number of events. Forthis reason the in-rp:rct of subclinical c:rrdiactoxic iw on the long ternr  is  not  c lear andr)ced5 cont inucd cv. t lu. tL iorL.Lr Chapter 6 the pulmonarv function afterablative che motherapv with atrtologous [tonemarÍow rescue and loco regional r:rdiothera-py in 17 prc-  and per imenopaus:r l  pat ientswitfr :rclvanccd (stage tllb) breast clncer h:rsbeen reported.l)ulmonary toxicity wàs retrospectivelv ana-lysed not only bv cv:rluation of pulmor-rarvsigns and symptoms before, clurir-rg and afierthe complet ion of  therapv,  but  a lso the ana-l1'sis of chest X-rays t:rken befbre cl"remothe-rapy,  beFore racl iotherapy and at  3 and (rmonths lfter radiotherapy and thereaftcr oncea ycar.Pul rrronary function tcsts i nclude spirornetrvarr . l  s i r rg le l r re.r rh , l i f fus i r rg c,rp.rc i ry.  Ftr r rc-tional data are described :rs perccntages ofpredicted values,  bascd on indiv idual  heightand age. Puln-ronarv function parameters wereconsidcrccl:rbnormal when bclow 807o of thepredicted value.Clinical symptoms were graclec{ according toRot l . r rvel l  in  mi ld (grade l )  reclu i r ing noÏ:l:Ï::: and rnarkecl (gracle 2) requiring' fhe incidence ofand 2) in our studrradiothcrapl' or wpletion the coursedinss arc supportfr.tncrional rests arIn th is l imi ted ser i rt icnts (median 41ment compromiseunexpected high irmonir is .  l t  is  st rocaused by the intrtherapy' regirnen.lr-r Chapter 7 thespect ivelv pulrnonor convent ional lyrapv ancl radiothrtients rvith nrorc tlvolved.Bcrween 1994 ulstage I I  and I I [brcr :tie nrs wcre r:tndon-cycles of5-Íluorouphospharnide ( l .Etof FL,C ancl high cphosphamic i e ,  t l(Cl-C) with haenrA l l  pa t i cn r s  r ecctherapv. 1-he irnlRernarks and Íutln  pat ients wirhatrd clisscrnin;rrert ients,  the usc rstrpporrcd bl'auport  (ABM'f)t ransplanrat ioncornbined u ' i thbeen the subjetl-re l:rst decacle.As :r result oÍ tchemotherapvntent  wt th a rcgical  compl icaStill too little issequelac like e:mo l t : r r v  t o r ia l though prel il i fè  anal l 's is  asbreast cancetfb l lo lv-up pt80e dose ofantronef ) n ^ ^d 50-66py aftercal func-trewYorkwl tn  I  l -Ieft ven-y ECC-ra LVEFOnly Iwith a 4vo weeksr LVE,Fslgns orA classi-l imired:nts. ForI cardiaclear andon afterus boneothera-)atientscer hasiy ana-]onaryd afterlothe-rnd 6'oncenerry'unc-:s of' ioh rwereÍrtheg t ono1ngThe incidence of clinical symproms (grade 1and 2) in our study was 53olo ccurring duringradiotherapy or within 2 months after com-pletion the course ofradiotherapy. These fin-dings are supported by the outcome of thefunctional tests and the chest X-ray analysis.In this limited series oF 17 relatively oung pa-tients (median 43 years) wirhout prerrear-ment compromised long function, there is anunexpected high incider-rce of radiation pneu-monitis. It is strongly suggested that this iscaused by the inter-rsificarion of the chemo-therapy regimen.In Chapter 7 the purpose is to analyse pro-spectively pulmonary Function aFter ablativeor conventionally dosed adjuvar-rt chemothe-rapy and radiotherapy in breast cancer p:l-tients with more rhan rhree lymph nodes in-volved.Between 1994 and 1998, 62 patienrs withstage II and IIlbreast cancer were studied. Pa-tients were randomised to receive ither I: fivecycles of 5-fluorouracil, epirubicin and cyclo-phosphamide (FEC) or group II: four cyclesof FEC and high dose chemotherapy (cyclo-phosphamide,  th io tepa and carbop la t in(CTC) with haematopoietic stem cell rescue.All  patients received locoregional radio-therapy. The impact of both schemes andRemarks  and Íu tu re  perspec t ivesradiotherapy on the pulmonary status (clini-cal symptoms, chest X-ray and tests) was ana,lysed.The main resulrs were: one parient died frompulmonary toxiciry and 12 developed pneu-monitis in the high dose group versus 10 pa-tients with pneumonitis in the control group(n.s.). C)ne year aFter the radiotherapy 6 pa-tients in the high-dose group and 1 in thestandard dose group had significant X-ray pa-thology (p < 0.005). FEC chemotherapy ledto a 60/o reduction in the transfer-factor forcarbonmonoxide (T1g6) and 15% reductionin the difFusing capacity ofthe alveolocapil-lary membrane (D-). Radiotherapy in rhehigh-dose chemotherapy group led to a de-crease oi l6.Jolo anci 2-.30o. respecrively. lnthe control group rhis was B.2olo and 12.9o/o(p < 0.002) After 12 monrhs the excess toxi-ciry in the high-dose group had disappeared.The conclusion of this study is that high-dosechemotherapy adds to the changes broughtabout by radiotherapy especially as far as themembrane factor in rhe pulmonary functionis  concerned.  Th is  add i t iona l  e fFec t  i s ,however, reversible. The incider-rce of signifi-cant X-ray pathology ofthe lungs is higher inthe high-dose group, but clinical symptoma-tology is the same.z-=--=u-=zO=-=-O==-@L.r patients with locally advanced (stage IIIb)and disseminated (stage IV) trreast cancer pa-t ients,  the use of  h igh-dose chemotherapysupported by autologous bone marrow rrans-port  (ABMT) and/or  per ipheral  stem cel ltransplantation (PSCT) with growth Íirctorscombined with locoregional radiotherapy hasbeen the subject of extensive research overthe last decade.As a result of the improved support ablativechemotherapy is nowadays a Feasible treat-ment with a reduced number of haematolo-gical complications.Still too litrle is known about treatment relatedsequelae like early and late crrdiac and/or pul-mona ry  t ox i c i t y  and  t he  qua l i t y  o f  I i f e ,although preliminary data lrom the qualiry oflife analysis as part of a randomised adjuvantbreast cancer study show that after a halfyearfo l low-up per iod there was no di f ferencebetween pat ients who received or  d id notreceive high-dose chemotherapy erncl moreover both groups did not differ from healthyindividual.s in that respect.A goal for the future will be ro determine sub-groups of patienrs, that might benefit fromclose intensi f icat ion regimens and ro l imi ttreatment related toxicity to an acceptablelevel.Rapid technological progress concerning de-tect ion of  tumour cel ls  in the per ipheralblood, the easier access ro peripheral stem celltechnology, the potential use ofdrug resistanrgenes for tissue protection and conlormal ra-diotherapy techniques to firrther reduce the ir-radiated volumes of the heart ar-rd the lungmay allow further exrension oFthis treatment.In the future new anti cancer drugs like pa-clitaxel and topoisomerase I inhibitors mightalso become useful in high-dose chemothera-py regimens. 8l

Combined modality treatment in breast cancer

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University of Groningen Digital Archive

ARTS repository - University of Groningen

   University of GroningenCombined modality treatment in breast cancerDolsma, Willemtje VrougjeIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1999Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dolsma, W. V. (1999). Combined modality treatment in breast cancer. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 07-06-2022lorcedtes lniry of)naryrlowSumm ary,, Conclusionsand Future Directionswith:row:apySUMMARY, CONCLUSIONS AND FUTURE DIRECTIONSIn spi te of  the promising resul ts of  mtrssscreening; programs to increase the number ofearly breast cancer patients, breast cancer stillremmins the leading cause oltdeath in womenin thcir fifth decade of lile in most developedcountnes.\X/hile adjuvant chemotherapy regimens haveimproved the life expectance for patients withe:rrly breast car-rcer, locally advanced (stageIIIb) and metastatic (stage IV) brearst cancerremain an incurable disease.As the clisease Free I 0 years survival drops to:rlmost zero in paticnts with more than threeinvolved lvmph nodes, there is an urgent needfor nei,v treatments to improve the elficarcy ofadjuvant tre:ltnent fàr this category of pa-t ients.The hope oFan effective treatment for theseprrtients is not only based on the use of newdrugs, but also on optimizing ancl ir-rtensi-$,ing the use ofdrugs that are alreacly availa-ble. Also of great import:rnce is the improvedunderstanding of the way in which anti cancerdrugs aflèct the tumour and normal tissuedynamics. In that respect problerrs of drug rc-sistance :lnd treatmeÍlt related toxicity are ofutmost importance :rnd subject of this thesis.High-dose ablat ive chcmotherapv wi th atenfold higher dose comp:rred to standardchemotherapy is nowadays leasiblc, bccruse ofthe support of growth Factors, aurologousbone marrow trar-rsplantation (ABM'f) and/orper ipheral  stem ccl l  t ransplantat ion (PSCT).The t reatment re lated rnorbid i ty  and theimpact on local control :rnd long-term survi-v. r l  of  rhc abler ivc ch.moth.r . rpy regimcrrs inp:rtients with locally advar-rced and metastaticbreast cancer has also becn described in thisthesis.In Chapter 2 a review has been givcn how tocircumvent the problem of drug rcsistance,when using high-dose chernotherapy regi-mens fo l lowed by the support  of  growthfactors and/or peripheral stem cell reir-rfusion.It was ribserved, that in the period afïer abla-tive chemotherapy there was an improvedhaematological recovery and a reduced dura-tion of fever and l-rospitalisation by the addi-tion of pcripheral blood stem cells compareclto autologous bone marrow and growth factorsupport alone.Also :rttention l"ras been paid to the problemof the presence of tumour cells not only inbone marrow but also in peripheral blood.l 'he new appro,rch ro prorecl  t issue againsrchemotherapeutic drugs by transferring drugresistant genes into tissue that r-reeds this resis-tance lor its protection has been emphasized.If contamir-ration with replication competentretrovirus and the transfer of drug resistantgenes into turnour cells cirn be avoided, the useoltdrug resistant genes lor the circurnventionof  chemotherapy- induced toxic i ty  may beuseful in the future.Furthermore, indications for high-dose che-motherapy in pat ients wi th sol id tumourssuch as germ cell carcinomas, breast cancer,ovarian cancer and tumours ofyoung adultslike Ewing sarcoma has been discussed withspecial attention for this type of treatment inbreast cancer patients.Not only the resul ts of  h igh-dose chemo-therapy ir-r breast cancer patients with rneta-static disease has been described, but also theresults ofhigh-dose chernotherapy in the ad-j uvan t  se r t i ng  i n  pa t i en t s  w i t h  ex tens i vec{ise:rse in the a-rilla. -l'hc results did show notr>nly :rn irnprove ment of the disease lree sur-vival to 7Bo/o at a medi:rn observation of 50montl'rs, but also an incre:rse of radiopneu-monitis up to 507o.In Chapter 3 an ir-rduction chemotherapyrcgin-ren Followed by a dosc intensificationwith autologous bone marrow reinfusion hasbeen reportecl in patients with locally advan-:::j:ï. IIIb or disserninated stage IV breastLi 56 pre- or perimenopausal women withrr . rge I I Ib -  s tagc IV bre,rr r  c , rncer i t  was l r -tempted to reach a st:rte of complete respon-se  by . r  r em iss i on  i nduc r i on  reg imen  con ta i n -ing prednisor-re, 5-fl uorouracil, methotrexare,doxorubicin and vincristir-re.If successful, patients received an intensifica-tion regimen, consistir-rg of cyclophosphami-de 7 glm' :rnd etoposide 1 .5 g/mt rvith auto-logous horre rnar low reinfusion.=-+-=-L-==---z-O;=-a79=q--=-z=:--=O=q-fhirty-two paticnts who l-rad no evidence ofdiscase after inductior-r chemotherapv receivcd:rutologous bonc marrow reinÍirsion aftcr thedose intensi f icat ion regimen. Af ter  a medianobse rvat ion of  4 vears I  1/  19 p:r t ients wi thstage IIIb bre:rst c:rncer were free ofdisease.In the stage IV group,  onlv a re lat ivelv longt ime to proqression of  15 months w:rs obse r-ved.I t  was concluded, that  th is approach pro-longed disease free surviv:rl in stagc IIlb breastc:rncer p:rtients, but does probabll' not influ-ence the surv ival  in stage IV pat icnts.In Chapter 4 the long te rm results of a phasel l  s tudy consist ing of  induct ion chemothera-pv lollorvcd by closc itrtensific:rtion supporteclwi th autologous bone marrow reinfusion inpre- or perirnenop,rusal patients rvitb st:rgcIV or stagc IIIb breast crurcer has lreen re-portcd.'Iwelve p:rticnts i.vith stage IIIb ancl l7 pa-tients with stage IV brcast cancer received adose inter-rs i f icat ion chemotherapy regirncnFoUorvecl by autologous bone marrow reinfu-sion :rFter complcte response with indr-rctionchemothcrapy.lntensi f icnt ion consistecl  of  cyclophosphe-mide 7 gi m' :rnd ctoposidc 1.5 g/m' in 24 pa,-t ients ar-rd th iotepa 800 mg/m' and mitoxan-r ro r r c  50 - -5  r ng / rn  i n  5  p . r r i t l r r s .-I-he rnedi;rn obscrvation time .was 7 vcurs.-I'he median surviv:rl of thc paticnts with staseIIIb was 80 n'ronths. l-l 'rirtv-three pe rcent ofthe patier-rts had a discase fiee sr,rrvii,al of moreth:rn I vears.For pat ients wi th stage IV thc median surv i -val  rvas 38 months.Although the results especiall,v in the group ofpat icr l ts  wi th stage I I Ib are promisi r - rg,  de-l ln i rc conclusion.  har c ro ewlr i t  complrr ' . r r iv .studies,  that  have been in i t iated.In Chapter 5 the outcome of cardiac toxicitystudies in 27 stage lllb ancl stage IV prc- :rndper imenopausal  b least  cancer p:r t ients,  whowere more th:rn one vear:r f tcr  induct ion che-motherapv fàllowed by ablative chemothe ra-p1' with autologotts bone m:rrrow resctle com-binecl rvith rac{iotherapv, I-ras bcer-r cvalu:rted.-l'hc rnajoriry of the patients (24) received acunrulat ive dose of  300 n-rg/m'doxorubic in,rvhile 3 patients reccivecl a cumulative dose ofepirubic in 480 mg/rn ' .l w c n r y  P à t i c n t s  r c c e i v c d  . r  m i t o r : r n t r u n cbased ablative regimer-r. Seventeen of 20 pa-ticr-rts with stagc IIIb cliscase receivcd 50-(r(rClrav (Gy) locoregional  radiotherapv af tcr:rblative chemotherapv.Cardiac cvaluation consisted of a clinical func-tional classification according to the New YorkHeart Association (NYHA) standard with l2-lcad clectrocardiogr:un (ECIG) and left ven-triculal ejectior.r fraction (tVL.F) by L.CG-gated radio nuclide angiograpl.rvwith a LVEFol < 51o/o as thc lower cut-ofï value. Only Ipatient who had a double transpl:rnt with a 4year interval developed heart Íailure two weeksa f t c r  t he  second  t r : 1nsp l1 rn t .  He r  LVF IFdropped f rom 58% tot  137o.' fhe ot l - rcr  26 pat ients had no c l in ical  s igns orsvmptoms of cardiac toxicity (NYFIA classi-f icat ion 1) .l - hese  resu l t s  , r r c  hampe  r cd  by  a  l i r n i t edfbilow-up ancl ,r srnall number of events. Forthis reason the in-rp:rct of subclinical c:rrdiactoxic iw on the long ternr  is  not  c lear andr)ced5 cont inucd cv. t lu. tL iorL.Lr Chapter 6 the pulmonarv function afterablative che motherapv with atrtologous [tonemarÍow rescue and loco regional r:rdiothera-py in 17 prc-  and per imenopaus:r l  pat ientswitfr :rclvanccd (stage tllb) breast clncer h:rsbeen reported.l)ulmonary toxicity wàs retrospectivelv ana-lysed not only bv cv:rluation of pulmor-rarvsigns and symptoms before, clurir-rg and afierthe complet ion of  therapv,  but  a lso the ana-l1'sis of chest X-rays t:rken befbre cl"remothe-rapy,  beFore racl iotherapy and at  3 and (rmonths lfter radiotherapy and thereaftcr oncea ycar.Pul rrronary function tcsts i nclude spirornetrvarr . l  s i r rg le l r re.r rh , l i f fus i r rg c,rp.rc i ry.  Ftr r rc-tional data are described :rs perccntages ofpredicted values,  bascd on indiv idual  heightand age. Puln-ronarv function parameters wereconsidcrccl:rbnormal when bclow 807o of thepredicted value.Clinical symptoms were graclec{ according toRot l . r rvel l  in  mi ld (grade l )  reclu i r ing noÏ:l:Ï::: and rnarkecl (gracle 2) requiring' fhe incidence ofand 2) in our studrradiothcrapl' or wpletion the coursedinss arc supportfr.tncrional rests arIn th is l imi ted ser i rt icnts (median 41ment compromiseunexpected high irmonir is .  l t  is  st rocaused by the intrtherapy' regirnen.lr-r Chapter 7 thespect ivelv pulrnonor convent ional lyrapv ancl radiothrtients rvith nrorc tlvolved.Bcrween 1994 ulstage I I  and I I [brcr :tie nrs wcre r:tndon-cycles of5-Íluorouphospharnide ( l .Etof FL,C ancl high cphosphamic i e ,  t l(Cl-C) with haenrA l l  pa t i cn r s  r ecctherapv. 1-he irnlRernarks and Íutln  pat ients wirhatrd clisscrnin;rrert ients,  the usc rstrpporrcd bl'auport  (ABM'f)t ransplanrat ioncornbined u ' i thbeen the subjetl-re l:rst decacle.As :r result oÍ tchemotherapvntent  wt th a rcgical  compl icaStill too little issequelac like e:mo l t : r r v  t o r ia l though prel il i fè  anal l 's is  asbreast cancetfb l lo lv-up pt80e dose ofantronef ) n ^ ^d 50-66py aftercal func-trewYorkwl tn  I  l -Ieft ven-y ECC-ra LVEFOnly Iwith a 4vo weeksr LVE,Fslgns orA classi-l imired:nts. ForI cardiaclear andon afterus boneothera-)atientscer hasiy ana-]onaryd afterlothe-rnd 6'oncenerry'unc-:s of' ioh rwereÍrtheg t ono1ngThe incidence of clinical symproms (grade 1and 2) in our study was 53olo ccurring duringradiotherapy or within 2 months after com-pletion the course ofradiotherapy. These fin-dings are supported by the outcome of thefunctional tests and the chest X-ray analysis.In this limited series oF 17 relatively oung pa-tients (median 43 years) wirhout prerrear-ment compromised long function, there is anunexpected high incider-rce of radiation pneu-monitis. It is strongly suggested that this iscaused by the inter-rsificarion of the chemo-therapy regimen.In Chapter 7 the purpose is to analyse pro-spectively pulmonary Function aFter ablativeor conventionally dosed adjuvar-rt chemothe-rapy and radiotherapy in breast cancer p:l-tients with more rhan rhree lymph nodes in-volved.Between 1994 and 1998, 62 patienrs withstage II and IIlbreast cancer were studied. Pa-tients were randomised to receive ither I: fivecycles of 5-fluorouracil, epirubicin and cyclo-phosphamide (FEC) or group II: four cyclesof FEC and high dose chemotherapy (cyclo-phosphamide,  th io tepa and carbop la t in(CTC) with haematopoietic stem cell rescue.All  patients received locoregional radio-therapy. The impact of both schemes andRemarks  and Íu tu re  perspec t ivesradiotherapy on the pulmonary status (clini-cal symptoms, chest X-ray and tests) was ana,lysed.The main resulrs were: one parient died frompulmonary toxiciry and 12 developed pneu-monitis in the high dose group versus 10 pa-tients with pneumonitis in the control group(n.s.). C)ne year aFter the radiotherapy 6 pa-tients in the high-dose group and 1 in thestandard dose group had significant X-ray pa-thology (p < 0.005). FEC chemotherapy ledto a 60/o reduction in the transfer-factor forcarbonmonoxide (T1g6) and 15% reductionin the difFusing capacity ofthe alveolocapil-lary membrane (D-). Radiotherapy in rhehigh-dose chemotherapy group led to a de-crease oi l6.Jolo anci 2-.30o. respecrively. lnthe control group rhis was B.2olo and 12.9o/o(p < 0.002) After 12 monrhs the excess toxi-ciry in the high-dose group had disappeared.The conclusion of this study is that high-dosechemotherapy adds to the changes broughtabout by radiotherapy especially as far as themembrane factor in rhe pulmonary functionis  concerned.  Th is  add i t iona l  e fFec t  i s ,however, reversible. The incider-rce of signifi-cant X-ray pathology ofthe lungs is higher inthe high-dose group, but clinical symptoma-tology is the same.z-=--=u-=zO=-=-O==-@L.r patients with locally advanced (stage IIIb)and disseminated (stage IV) trreast cancer pa-t ients,  the use of  h igh-dose chemotherapysupported by autologous bone marrow rrans-port  (ABMT) and/or  per ipheral  stem cel ltransplantation (PSCT) with growth Íirctorscombined with locoregional radiotherapy hasbeen the subject of extensive research overthe last decade.As a result of the improved support ablativechemotherapy is nowadays a Feasible treat-ment with a reduced number of haematolo-gical complications.Still too litrle is known about treatment relatedsequelae like early and late crrdiac and/or pul-mona ry  t ox i c i t y  and  t he  qua l i t y  o f  I i f e ,although preliminary data lrom the qualiry oflife analysis as part of a randomised adjuvantbreast cancer study show that after a halfyearfo l low-up per iod there was no di f ferencebetween pat ients who received or  d id notreceive high-dose chemotherapy erncl moreover both groups did not differ from healthyindividual.s in that respect.A goal for the future will be ro determine sub-groups of patienrs, that might benefit fromclose intensi f icat ion regimens and ro l imi ttreatment related toxicity to an acceptablelevel.Rapid technological progress concerning de-tect ion of  tumour cel ls  in the per ipheralblood, the easier access ro peripheral stem celltechnology, the potential use ofdrug resistanrgenes for tissue protection and conlormal ra-diotherapy techniques to firrther reduce the ir-radiated volumes of the heart ar-rd the lungmay allow further exrension oFthis treatment.In the future new anti cancer drugs like pa-clitaxel and topoisomerase I inhibitors mightalso become useful in high-dose chemothera-py regimens. 8l

English

University of Groningen Research Database

  
 University of Groningen
Combined modality treatment in breast cancer
Dolsma, Willemtje Vrougje
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
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Publisher's PDF, also known as Version of record
Publication date:
1999
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Dolsma, W. V. (1999). Combined modality treatment in breast cancer s.n.
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Download date: 11-02-2018
lorced
tes ln
iry of
)nary
rlow
Summ ary,, Conclusions
and Future Directions
with
:row
:apy
SUMMARY, CONCLUSIONS AND FUTURE DIRECTIONS
In spi te of  the promising resul ts of  mtrss
screening; programs to increase the number of
early breast cancer patients, breast cancer still
remmins the leading cause oltdeath in women
in thcir fifth decade of lile in most developed
countnes.
\X/hile adjuvant chemotherapy regimens have
improved the life expectance for patients with
e:rrly breast car-rcer, locally advanced (stage
IIIb) and metastatic (stage IV) brearst cancer
remain an incurable disease.
As the clisease Free I 0 years survival drops to
:rlmost zero in paticnts with more than three
involved lvmph nodes, there is an urgent need
for nei,v treatments to improve the elficarcy of
adjuvant tre:ltnent fàr this category of pa-
t ients.
The hope oFan effective treatment for these
prrtients is not only based on the use of new
drugs, but also on optimizing ancl ir-rtensi-
$,ing the use ofdrugs that are alreacly availa-
ble. Also of great import:rnce is the improved
understanding of the way in which anti cancer
drugs aflèct the tumour and normal tissue
dynamics. In that respect problerrs of drug rc-
sistance :lnd treatmeÍlt related toxicity are of
utmost importance :rnd subject of this thesis.
High-dose ablat ive chcmotherapv wi th a
tenfold higher dose comp:rred to standard
chemotherapy is nowadays leasiblc, bccruse of
the support of growth Factors, aurologous
bone marrow trar-rsplantation (ABM'f) and/or
per ipheral  stem ccl l  t ransplantat ion (PSCT).
The t reatment re lated rnorbid i ty  and the
impact on local control :rnd long-term survi-
v. r l  of  rhc abler ivc ch.moth.r . rpy regimcrrs in
p:rtients with locally advar-rced and metastatic
breast cancer has also becn described in this
thesis.
In Chapter 2 a review has been givcn how to
circumvent the problem of drug rcsistance,
when using high-dose chernotherapy regi-
mens fo l lowed by the support  of  growth
factors and/or peripheral stem cell reir-rfusion.
It was ribserved, that in the period afïer abla-
tive chemotherapy there was an improved
haematological recovery and a reduced dura-
tion of fever and l-rospitalisation by the addi-
tion of pcripheral blood stem cells comparecl
to autologous bone marrow and growth factor
support alone.
Also :rttention l"ras been paid to the problem
of the presence of tumour cells not only in
bone marrow but also in peripheral blood.
l 'he new appro,rch ro prorecl  t issue againsr
chemotherapeutic drugs by transferring drug
resistant genes into tissue that r-reeds this resis-
tance lor its protection has been emphasized.
If contamir-ration with replication competent
retrovirus and the transfer of drug resistant
genes into turnour cells cirn be avoided, the use
oltdrug resistant genes lor the circurnvention
of  chemotherapy- induced toxic i ty  may be
useful in the future.
Furthermore, indications for high-dose che-
motherapy in pat ients wi th sol id tumours
such as germ cell carcinomas, breast cancer,
ovarian cancer and tumours ofyoung adults
like Ewing sarcoma has been discussed with
special attention for this type of treatment in
breast cancer patients.
Not only the resul ts of  h igh-dose chemo-
therapy ir-r breast cancer patients with rneta-
static disease has been described, but also the
results ofhigh-dose chernotherapy in the ad-
j uvan t  se r t i ng  i n  pa t i en t s  w i t h  ex tens i ve
c{ise:rse in the a-rilla. -l'hc results did show not
r>nly :rn irnprove ment of the disease lree sur-
vival to 7Bo/o at a medi:rn observation of 50
montl'rs, but also an incre:rse of radiopneu-
monitis up to 507o.
In Chapter 3 an ir-rduction chemotherapy
rcgin-ren Followed by a dosc intensification
with autologous bone marrow reinfusion has
been reportecl in patients with locally advan-
:::j:ï. 
IIIb or disserninated stage IV breast
Li 56 pre- or perimenopausal women with
rr . rge I I Ib -  s tagc IV bre,rr r  c , rncer i t  was l r -
tempted to reach a st:rte of complete respon-
se  by . r  r em iss i on  i nduc r i on  reg imen  con ta i n -
ing prednisor-re, 5-fl uorouracil, methotrexare,
doxorubicin and vincristir-re.
If successful, patients received an intensifica-
tion regimen, consistir-rg of cyclophosphami-
de 7 glm' :rnd etoposide 1 .5 g/mt rvith auto-
logous horre rnar low reinfusion.
=
-
+
-
=
-
L
-
=
=
-
-
-
z
-
O
;
=
-
a
79
=q
-
-
=
-
z
=:
-
-
=
O
=
q
-fhirty-two 
paticnts who l-rad no evidence of
discase after inductior-r chemotherapv receivcd
:rutologous bonc marrow reinÍirsion aftcr the
dose intensi f icat ion regimen. Af ter  a median
obse rvat ion of  4 vears I  1/  19 p:r t ients wi th
stage IIIb bre:rst c:rncer were free ofdisease.
In the stage IV group,  onlv a re lat ivelv long
t ime to proqression of  15 months w:rs obse r-
ved.
I t  was concluded, that  th is approach pro-
longed disease free surviv:rl in stagc IIlb breast
c:rncer p:rtients, but does probabll' not influ-
ence the surv ival  in stage IV pat icnts.
In Chapter 4 the long te rm results of a phase
l l  s tudy consist ing of  induct ion chemothera-
pv lollorvcd by closc itrtensific:rtion supportecl
wi th autologous bone marrow reinfusion in
pre- or perirnenop,rusal patients rvitb st:rgc
IV or stagc IIIb breast crurcer has lreen re-
portcd.
'Iwelve 
p:rticnts i.vith stage IIIb ancl l7 pa-
tients with stage IV brcast cancer received a
dose inter-rs i f icat ion chemotherapy regirncn
FoUorvecl by autologous bone marrow reinfu-
sion :rFter complcte response with indr-rction
chemothcrapy.
lntensi f icnt ion consistecl  of  cyclophosphe-
mide 7 gi m' :rnd ctoposidc 1.5 g/m' in 24 pa,-
t ients ar-rd th iotepa 800 mg/m' and mitoxan-
r ro r r c  50 - -5  r ng / rn  i n  5  p . r r i t l r r s .
-I-he 
rnedi;rn obscrvation time .was 7 vcurs.
-I'he 
median surviv:rl of thc paticnts with stase
IIIb was 80 n'ronths. l-l 'rirtv-three pe rcent of
the patier-rts had a discase fiee sr,rrvii,al of more
th:rn I vears.
For pat ients wi th stage IV thc median surv i -
val  rvas 38 months.
Although the results especiall,v in the group of
pat icr l ts  wi th stage I I Ib are promisi r - rg,  de-
l ln i rc conclusion.  har c ro ewlr i t  complrr ' . r r iv .
studies,  that  have been in i t iated.
In Chapter 5 the outcome of cardiac toxicity
studies in 27 stage lllb ancl stage IV prc- :rnd
per imenopausal  b least  cancer p:r t ients,  who
were more th:rn one vear:r f tcr  induct ion che-
motherapv fàllowed by ablative chemothe ra-
p1' with autologotts bone m:rrrow resctle com-
binecl rvith rac{iotherapv, I-ras bcer-r cvalu:rted.
-l'hc 
rnajoriry of the patients (24) received a
cunrulat ive dose of  300 n-rg/m'doxorubic in,
rvhile 3 patients reccivecl a cumulative dose of
epirubic in 480 mg/rn ' .
l w c n r y  P à t i c n t s  r c c e i v c d  . r  m i t o r : r n t r u n c
based ablative regimer-r. Seventeen of 20 pa-
ticr-rts with stagc IIIb cliscase receivcd 50-(r(r
Clrav (Gy) locoregional  radiotherapv af tcr
:rblative chemotherapv.
Cardiac cvaluation consisted of a clinical func-
tional classification according to the New York
Heart Association (NYHA) standard with l2-
lcad clectrocardiogr:un (ECIG) and left ven-
triculal ejectior.r fraction (tVL.F) by L.CG-
gated radio nuclide angiograpl.rvwith a LVEF
ol < 51o/o as thc lower cut-ofï value. Only I
patient who had a double transpl:rnt with a 4
year interval developed heart Íailure two weeks
a f t c r  t he  second  t r : 1nsp l1 rn t .  He r  LVF IF
dropped f rom 58% tot  137o.
' fhe 
ot l - rcr  26 pat ients had no c l in ical  s igns or
svmptoms of cardiac toxicity (NYFIA classi-
f icat ion 1) .
l - hese  resu l t s  , r r c  hampe  r cd  by  a  l i r n i t ed
fbilow-up ancl ,r srnall number of events. For
this reason the in-rp:rct of subclinical c:rrdiac
toxic iw on the long ternr  is  not  c lear and
r)ced5 cont inucd cv. t lu. tL iorL.
Lr Chapter 6 the pulmonarv function after
ablative che motherapv with atrtologous [tone
marÍow rescue and loco regional r:rdiothera-
py in 17 prc-  and per imenopaus:r l  pat ients
witfr :rclvanccd (stage tllb) breast clncer h:rs
been reported.
l)ulmonary toxicity wàs retrospectivelv ana-
lysed not only bv cv:rluation of pulmor-rarv
signs and symptoms before, clurir-rg and afier
the complet ion of  therapv,  but  a lso the ana-
l1'sis of chest X-rays t:rken befbre cl"remothe-
rapy,  beFore racl iotherapy and at  3 and (r
months lfter radiotherapy and thereaftcr once
a ycar.
Pul rrronary function tcsts i nclude spirornetrv
arr . l  s i r rg le l r re.r rh , l i f fus i r rg c,rp.rc i ry.  Ftr r rc-
tional data are described :rs perccntages of
predicted values,  bascd on indiv idual  height
and age. Puln-ronarv function parameters were
considcrccl:rbnormal when bclow 807o of the
predicted value.
Clinical symptoms were graclec{ according to
Rot l . r rvel l  in  mi ld (grade l )  reclu i r ing no
Ï:l:Ï::: 
and rnarkecl (gracle 2) requiring
' fhe 
incidence of
and 2) in our studr
radiothcrapl' or w
pletion the course
dinss arc support
fr.tncrional rests ar
In th is l imi ted ser i r
t icnts (median 41
ment compromise
unexpected high ir
monir is .  l t  is  st ro
caused by the intr
therapy' regirnen.
lr-r Chapter 7 the
spect ivelv pulrnon
or convent ional ly
rapv ancl radiothr
tients rvith nrorc tl
volved.
Bcrween 1994 ul
stage I I  and I I [brcr :
tie nrs wcre r:tndon-
cycles of5-Íluorou
phospharnide ( l .Et
of FL,C ancl high c
phosphamic i e ,  t l
(Cl-C) with haenr
A l l  pa t i cn r s  r ecc
therapv. 1-he irnl
Rernarks and Íut
ln  pat ients wirh
atrd clisscrnin;rrer
t ients,  the usc r
strpporrcd bl'au
port  (ABM'f)
t ransplanrat ion
cornbined u ' i th
been the subje
tl-re l:rst decacle.
As :r result oÍ t
chemotherapv
ntent  wt th a rc
gical  compl ica
Still too little is
sequelac like e:
mo l t : r r v  t o r i
a l though prel i
l i fè  anal l 's is  as
breast cancet
fb l lo lv-up pt
80
e dose of
antrone
f ) n ^ ^
d 50-66
py after
cal func-
trewYork
wl tn  I  l -
Ieft ven-
y ECC-
ra LVEF
Only I
with a 4
vo weeks
r LVE,F
slgns or
A classi-
l imired
:nts. For
I cardiac
lear and
on after
us bone
othera-
)atients
cer has
iy ana-
]onary
d after
lothe-
rnd 6
'once
nerry
'unc-
:s of
' ioh r
were
Írthe
g t o
no
1ng
The incidence of clinical symproms (grade 1
and 2) in our study was 53olo ccurring during
radiotherapy or within 2 months after com-
pletion the course ofradiotherapy. These fin-
dings are supported by the outcome of the
functional tests and the chest X-ray analysis.
In this limited series oF 17 relatively oung pa-
tients (median 43 years) wirhout prerrear-
ment compromised long function, there is an
unexpected high incider-rce of radiation pneu-
monitis. It is strongly suggested that this is
caused by the inter-rsificarion of the chemo-
therapy regimen.
In Chapter 7 the purpose is to analyse pro-
spectively pulmonary Function aFter ablative
or conventionally dosed adjuvar-rt chemothe-
rapy and radiotherapy in breast cancer p:l-
tients with more rhan rhree lymph nodes in-
volved.
Between 1994 and 1998, 62 patienrs with
stage II and IIlbreast cancer were studied. Pa-
tients were randomised to receive ither I: five
cycles of 5-fluorouracil, epirubicin and cyclo-
phosphamide (FEC) or group II: four cycles
of FEC and high dose chemotherapy (cyclo-
phosphamide,  th io tepa and carbop la t in
(CTC) with haematopoietic stem cell rescue.
All  patients received locoregional radio-
therapy. The impact of both schemes and
Remarks  and Íu tu re  perspec t ives
radiotherapy on the pulmonary status (clini-
cal symptoms, chest X-ray and tests) was ana,
lysed.
The main resulrs were: one parient died from
pulmonary toxiciry and 12 developed pneu-
monitis in the high dose group versus 10 pa-
tients with pneumonitis in the control group
(n.s.). C)ne year aFter the radiotherapy 6 pa-
tients in the high-dose group and 1 in the
standard dose group had significant X-ray pa-
thology (p < 0.005). FEC chemotherapy led
to a 60/o reduction in the transfer-factor for
carbonmonoxide (T1g6) and 15% reduction
in the difFusing capacity ofthe alveolocapil-
lary membrane (D-). Radiotherapy in rhe
high-dose chemotherapy group led to a de-
crease oi l6.Jolo anci 2-.30o. respecrively. ln
the control group rhis was B.2olo and 12.9o/o
(p < 0.002) After 12 monrhs the excess toxi-
ciry in the high-dose group had disappeared.
The conclusion of this study is that high-dose
chemotherapy adds to the changes brought
about by radiotherapy especially as far as the
membrane factor in rhe pulmonary function
is  concerned.  Th is  add i t iona l  e fFec t  i s ,
however, reversible. The incider-rce of signifi-
cant X-ray pathology ofthe lungs is higher in
the high-dose group, but clinical symptoma-
tology is the same.
z
-
=
-
-
=
u
-
=
z
O
=
-
=
-
O
=
=
-
@
L.r patients with locally advanced (stage IIIb)
and disseminated (stage IV) trreast cancer pa-
t ients,  the use of  h igh-dose chemotherapy
supported by autologous bone marrow rrans-
port  (ABMT) and/or  per ipheral  stem cel l
transplantation (PSCT) with growth Íirctors
combined with locoregional radiotherapy has
been the subject of extensive research over
the last decade.
As a result of the improved support ablative
chemotherapy is nowadays a Feasible treat-
ment with a reduced number of haematolo-
gical complications.
Still too litrle is known about treatment related
sequelae like early and late crrdiac and/or pul-
mona ry  t ox i c i t y  and  t he  qua l i t y  o f  I i f e ,
although preliminary data lrom the qualiry of
life analysis as part of a randomised adjuvant
breast cancer study show that after a halfyear
fo l low-up per iod there was no di f ference
between pat ients who received or  d id not
receive high-dose chemotherapy erncl more
over both groups did not differ from healthy
individual.s in that respect.
A goal for the future will be ro determine sub-
groups of patienrs, that might benefit from
close intensi f icat ion regimens and ro l imi t
treatment related toxicity to an acceptable
level.
Rapid technological progress concerning de-
tect ion of  tumour cel ls  in the per ipheral
blood, the easier access ro peripheral stem cell
technology, the potential use ofdrug resistanr
genes for tissue protection and conlormal ra-
diotherapy techniques to firrther reduce the ir-
radiated volumes of the heart ar-rd the lung
may allow further exrension oFthis treatment.
In the future new anti cancer drugs like pa-
clitaxel and topoisomerase I inhibitors might
also become useful in high-dose chemothera-
py regimens. 8l


   University of GroningenCombined modality treatment in breast cancerDolsma, Willemtje VrougjeIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1999Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dolsma, W. V. (1999). Combined modality treatment in breast cancer. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 09-09-2023lorcedtes lniry of)naryrlowSumm ary,, Conclusionsand Future Directionswith:row:apySUMMARY, CONCLUSIONS AND FUTURE DIRECTIONSIn spi te of  the promising resul ts of  mtrssscreening; programs to increase the number ofearly breast cancer patients, breast cancer stillremmins the leading cause oltdeath in womenin thcir fifth decade of lile in most developedcountnes.\X/hile adjuvant chemotherapy regimens haveimproved the life expectance for patients withe:rrly breast car-rcer, locally advanced (stageIIIb) and metastatic (stage IV) brearst cancerremain an incurable disease.As the clisease Free I 0 years survival drops to:rlmost zero in paticnts with more than threeinvolved lvmph nodes, there is an urgent needfor nei,v treatments to improve the elficarcy ofadjuvant tre:ltnent fàr this category of pa-t ients.The hope oFan effective treatment for theseprrtients is not only based on the use of newdrugs, but also on optimizing ancl ir-rtensi-$,ing the use ofdrugs that are alreacly availa-ble. Also of great import:rnce is the improvedunderstanding of the way in which anti cancerdrugs aflèct the tumour and normal tissuedynamics. In that respect problerrs of drug rc-sistance :lnd treatmeÍlt related toxicity are ofutmost importance :rnd subject of this thesis.High-dose ablat ive chcmotherapv wi th atenfold higher dose comp:rred to standardchemotherapy is nowadays leasiblc, bccruse ofthe support of growth Factors, aurologousbone marrow trar-rsplantation (ABM'f) and/orper ipheral  stem ccl l  t ransplantat ion (PSCT).The t reatment re lated rnorbid i ty  and theimpact on local control :rnd long-term survi-v. r l  of  rhc abler ivc ch.moth.r . rpy regimcrrs inp:rtients with locally advar-rced and metastaticbreast cancer has also becn described in thisthesis.In Chapter 2 a review has been givcn how tocircumvent the problem of drug rcsistance,when using high-dose chernotherapy regi-mens fo l lowed by the support  of  growthfactors and/or peripheral stem cell reir-rfusion.It was ribserved, that in the period afïer abla-tive chemotherapy there was an improvedhaematological recovery and a reduced dura-tion of fever and l-rospitalisation by the addi-tion of pcripheral blood stem cells compareclto autologous bone marrow and growth factorsupport alone.Also :rttention l"ras been paid to the problemof the presence of tumour cells not only inbone marrow but also in peripheral blood.l 'he new appro,rch ro prorecl  t issue againsrchemotherapeutic drugs by transferring drugresistant genes into tissue that r-reeds this resis-tance lor its protection has been emphasized.If contamir-ration with replication competentretrovirus and the transfer of drug resistantgenes into turnour cells cirn be avoided, the useoltdrug resistant genes lor the circurnventionof  chemotherapy- induced toxic i ty  may beuseful in the future.Furthermore, indications for high-dose che-motherapy in pat ients wi th sol id tumourssuch as germ cell carcinomas, breast cancer,ovarian cancer and tumours ofyoung adultslike Ewing sarcoma has been discussed withspecial attention for this type of treatment inbreast cancer patients.Not only the resul ts of  h igh-dose chemo-therapy ir-r breast cancer patients with rneta-static disease has been described, but also theresults ofhigh-dose chernotherapy in the ad-j uvan t  se r t i ng  i n  pa t i en t s  w i t h  ex tens i vec{ise:rse in the a-rilla. -l'hc results did show notr>nly :rn irnprove ment of the disease lree sur-vival to 7Bo/o at a medi:rn observation of 50montl'rs, but also an incre:rse of radiopneu-monitis up to 507o.In Chapter 3 an ir-rduction chemotherapyrcgin-ren Followed by a dosc intensificationwith autologous bone marrow reinfusion hasbeen reportecl in patients with locally advan-:::j:ï. IIIb or disserninated stage IV breastLi 56 pre- or perimenopausal women withrr . rge I I Ib -  s tagc IV bre,rr r  c , rncer i t  was l r -tempted to reach a st:rte of complete respon-se  by . r  r em iss i on  i nduc r i on  reg imen  con ta i n -ing prednisor-re, 5-fl uorouracil, methotrexare,doxorubicin and vincristir-re.If successful, patients received an intensifica-tion regimen, consistir-rg of cyclophosphami-de 7 glm' :rnd etoposide 1 .5 g/mt rvith auto-logous horre rnar low reinfusion.=-+-=-L-==---z-O;=-a79=q--=-z=:--=O=q-fhirty-two paticnts who l-rad no evidence ofdiscase after inductior-r chemotherapv receivcd:rutologous bonc marrow reinÍirsion aftcr thedose intensi f icat ion regimen. Af ter  a medianobse rvat ion of  4 vears I  1/  19 p:r t ients wi thstage IIIb bre:rst c:rncer were free ofdisease.In the stage IV group,  onlv a re lat ivelv longt ime to proqression of  15 months w:rs obse r-ved.I t  was concluded, that  th is approach pro-longed disease free surviv:rl in stagc IIlb breastc:rncer p:rtients, but does probabll' not influ-ence the surv ival  in stage IV pat icnts.In Chapter 4 the long te rm results of a phasel l  s tudy consist ing of  induct ion chemothera-pv lollorvcd by closc itrtensific:rtion supporteclwi th autologous bone marrow reinfusion inpre- or perirnenop,rusal patients rvitb st:rgcIV or stagc IIIb breast crurcer has lreen re-portcd.'Iwelve p:rticnts i.vith stage IIIb ancl l7 pa-tients with stage IV brcast cancer received adose inter-rs i f icat ion chemotherapy regirncnFoUorvecl by autologous bone marrow reinfu-sion :rFter complcte response with indr-rctionchemothcrapy.lntensi f icnt ion consistecl  of  cyclophosphe-mide 7 gi m' :rnd ctoposidc 1.5 g/m' in 24 pa,-t ients ar-rd th iotepa 800 mg/m' and mitoxan-r ro r r c  50 - -5  r ng / rn  i n  5  p . r r i t l r r s .-I-he rnedi;rn obscrvation time .was 7 vcurs.-I'he median surviv:rl of thc paticnts with staseIIIb was 80 n'ronths. l-l 'rirtv-three pe rcent ofthe patier-rts had a discase fiee sr,rrvii,al of moreth:rn I vears.For pat ients wi th stage IV thc median surv i -val  rvas 38 months.Although the results especiall,v in the group ofpat icr l ts  wi th stage I I Ib are promisi r - rg,  de-l ln i rc conclusion.  har c ro ewlr i t  complrr ' . r r iv .studies,  that  have been in i t iated.In Chapter 5 the outcome of cardiac toxicitystudies in 27 stage lllb ancl stage IV prc- :rndper imenopausal  b least  cancer p:r t ients,  whowere more th:rn one vear:r f tcr  induct ion che-motherapv fàllowed by ablative chemothe ra-p1' with autologotts bone m:rrrow resctle com-binecl rvith rac{iotherapv, I-ras bcer-r cvalu:rted.-l'hc rnajoriry of the patients (24) received acunrulat ive dose of  300 n-rg/m'doxorubic in,rvhile 3 patients reccivecl a cumulative dose ofepirubic in 480 mg/rn ' .l w c n r y  P à t i c n t s  r c c e i v c d  . r  m i t o r : r n t r u n cbased ablative regimer-r. Seventeen of 20 pa-ticr-rts with stagc IIIb cliscase receivcd 50-(r(rClrav (Gy) locoregional  radiotherapv af tcr:rblative chemotherapv.Cardiac cvaluation consisted of a clinical func-tional classification according to the New YorkHeart Association (NYHA) standard with l2-lcad clectrocardiogr:un (ECIG) and left ven-triculal ejectior.r fraction (tVL.F) by L.CG-gated radio nuclide angiograpl.rvwith a LVEFol < 51o/o as thc lower cut-ofï value. Only Ipatient who had a double transpl:rnt with a 4year interval developed heart Íailure two weeksa f t c r  t he  second  t r : 1nsp l1 rn t .  He r  LVF IFdropped f rom 58% tot  137o.' fhe ot l - rcr  26 pat ients had no c l in ical  s igns orsvmptoms of cardiac toxicity (NYFIA classi-f icat ion 1) .l - hese  resu l t s  , r r c  hampe  r cd  by  a  l i r n i t edfbilow-up ancl ,r srnall number of events. Forthis reason the in-rp:rct of subclinical c:rrdiactoxic iw on the long ternr  is  not  c lear andr)ced5 cont inucd cv. t lu. tL iorL.Lr Chapter 6 the pulmonarv function afterablative che motherapv with atrtologous [tonemarÍow rescue and loco regional r:rdiothera-py in 17 prc-  and per imenopaus:r l  pat ientswitfr :rclvanccd (stage tllb) breast clncer h:rsbeen reported.l)ulmonary toxicity wàs retrospectivelv ana-lysed not only bv cv:rluation of pulmor-rarvsigns and symptoms before, clurir-rg and afierthe complet ion of  therapv,  but  a lso the ana-l1'sis of chest X-rays t:rken befbre cl"remothe-rapy,  beFore racl iotherapy and at  3 and (rmonths lfter radiotherapy and thereaftcr oncea ycar.Pul rrronary function tcsts i nclude spirornetrvarr . l  s i r rg le l r re.r rh , l i f fus i r rg c,rp.rc i ry.  Ftr r rc-tional data are described :rs perccntages ofpredicted values,  bascd on indiv idual  heightand age. Puln-ronarv function parameters wereconsidcrccl:rbnormal when bclow 807o of thepredicted value.Clinical symptoms were graclec{ according toRot l . r rvel l  in  mi ld (grade l )  reclu i r ing noÏ:l:Ï::: and rnarkecl (gracle 2) requiring' fhe incidence ofand 2) in our studrradiothcrapl' or wpletion the coursedinss arc supportfr.tncrional rests arIn th is l imi ted ser i rt icnts (median 41ment compromiseunexpected high irmonir is .  l t  is  st rocaused by the intrtherapy' regirnen.lr-r Chapter 7 thespect ivelv pulrnonor convent ional lyrapv ancl radiothrtients rvith nrorc tlvolved.Bcrween 1994 ulstage I I  and I I [brcr :tie nrs wcre r:tndon-cycles of5-Íluorouphospharnide ( l .Etof FL,C ancl high cphosphamic i e ,  t l(Cl-C) with haenrA l l  pa t i cn r s  r ecctherapv. 1-he irnlRernarks and Íutln  pat ients wirhatrd clisscrnin;rrert ients,  the usc rstrpporrcd bl'auport  (ABM'f)t ransplanrat ioncornbined u ' i thbeen the subjetl-re l:rst decacle.As :r result oÍ tchemotherapvntent  wt th a rcgical  compl icaStill too little issequelac like e:mo l t : r r v  t o r ia l though prel il i fè  anal l 's is  asbreast cancetfb l lo lv-up pt80e dose ofantronef ) n ^ ^d 50-66py aftercal func-trewYorkwl tn  I  l -Ieft ven-y ECC-ra LVEFOnly Iwith a 4vo weeksr LVE,Fslgns orA classi-l imired:nts. ForI cardiaclear andon afterus boneothera-)atientscer hasiy ana-]onaryd afterlothe-rnd 6'oncenerry'unc-:s of' ioh rwereÍrtheg t ono1ngThe incidence of clinical symproms (grade 1and 2) in our study was 53olo ccurring duringradiotherapy or within 2 months after com-pletion the course ofradiotherapy. These fin-dings are supported by the outcome of thefunctional tests and the chest X-ray analysis.In this limited series oF 17 relatively oung pa-tients (median 43 years) wirhout prerrear-ment compromised long function, there is anunexpected high incider-rce of radiation pneu-monitis. It is strongly suggested that this iscaused by the inter-rsificarion of the chemo-therapy regimen.In Chapter 7 the purpose is to analyse pro-spectively pulmonary Function aFter ablativeor conventionally dosed adjuvar-rt chemothe-rapy and radiotherapy in breast cancer p:l-tients with more rhan rhree lymph nodes in-volved.Between 1994 and 1998, 62 patienrs withstage II and IIlbreast cancer were studied. Pa-tients were randomised to receive ither I: fivecycles of 5-fluorouracil, epirubicin and cyclo-phosphamide (FEC) or group II: four cyclesof FEC and high dose chemotherapy (cyclo-phosphamide,  th io tepa and carbop la t in(CTC) with haematopoietic stem cell rescue.All  patients received locoregional radio-therapy. The impact of both schemes andRemarks  and Íu tu re  perspec t ivesradiotherapy on the pulmonary status (clini-cal symptoms, chest X-ray and tests) was ana,lysed.The main resulrs were: one parient died frompulmonary toxiciry and 12 developed pneu-monitis in the high dose group versus 10 pa-tients with pneumonitis in the control group(n.s.). C)ne year aFter the radiotherapy 6 pa-tients in the high-dose group and 1 in thestandard dose group had significant X-ray pa-thology (p < 0.005). FEC chemotherapy ledto a 60/o reduction in the transfer-factor forcarbonmonoxide (T1g6) and 15% reductionin the difFusing capacity ofthe alveolocapil-lary membrane (D-). Radiotherapy in rhehigh-dose chemotherapy group led to a de-crease oi l6.Jolo anci 2-.30o. respecrively. lnthe control group rhis was B.2olo and 12.9o/o(p < 0.002) After 12 monrhs the excess toxi-ciry in the high-dose group had disappeared.The conclusion of this study is that high-dosechemotherapy adds to the changes broughtabout by radiotherapy especially as far as themembrane factor in rhe pulmonary functionis  concerned.  Th is  add i t iona l  e fFec t  i s ,however, reversible. The incider-rce of signifi-cant X-ray pathology ofthe lungs is higher inthe high-dose group, but clinical symptoma-tology is the same.z-=--=u-=zO=-=-O==-@L.r patients with locally advanced (stage IIIb)and disseminated (stage IV) trreast cancer pa-t ients,  the use of  h igh-dose chemotherapysupported by autologous bone marrow rrans-port  (ABMT) and/or  per ipheral  stem cel ltransplantation (PSCT) with growth Íirctorscombined with locoregional radiotherapy hasbeen the subject of extensive research overthe last decade.As a result of the improved support ablativechemotherapy is nowadays a Feasible treat-ment with a reduced number of haematolo-gical complications.Still too litrle is known about treatment relatedsequelae like early and late crrdiac and/or pul-mona ry  t ox i c i t y  and  t he  qua l i t y  o f  I i f e ,although preliminary data lrom the qualiry oflife analysis as part of a randomised adjuvantbreast cancer study show that after a halfyearfo l low-up per iod there was no di f ferencebetween pat ients who received or  d id notreceive high-dose chemotherapy erncl moreover both groups did not differ from healthyindividual.s in that respect.A goal for the future will be ro determine sub-groups of patienrs, that might benefit fromclose intensi f icat ion regimens and ro l imi ttreatment related toxicity to an acceptablelevel.Rapid technological progress concerning de-tect ion of  tumour cel ls  in the per ipheralblood, the easier access ro peripheral stem celltechnology, the potential use ofdrug resistanrgenes for tissue protection and conlormal ra-diotherapy techniques to firrther reduce the ir-radiated volumes of the heart ar-rd the lungmay allow further exrension oFthis treatment.In the future new anti cancer drugs like pa-clitaxel and topoisomerase I inhibitors mightalso become useful in high-dose chemothera-py regimens. 8l

Combined modality treatment in breast cancer

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