Post San Antonio &Post EBCC

Chemotherapie

Aafke H. Honkoop

San Antonio BCS & EBCC

• PresentatiesNeoadjuvante chemotherapie (2)Adjuvante chemotherapie (4)Gemetastaseerde ziekte (2)

• PostersNeoadjuvante chemotherapieAdjuvante chemotherapieNieuwe middelenGemetastaseerde ziekte

Neoadjuvante chemotherapie

• Comparison of TAC versus NX in patients non-responding to 2 cycles of neoadjuvant TAC- first results of the phase III GEPARTRIO study by the German Breast Group

• Primary endocrine therapy versus chemotherapy in postmenopausal ER-positive patients

Semiglazov, et al

Comparison of Dox/Doce/Cyclo (TAC) versus Vino/Cape ) (NX) in patients non-responding to 2

cycles of neoadjuvant TAC GEPARTRIO

GEPARTRIO

• Doseringen:TAC: 75/50/500 mg/m2

NX : 25 d1,8/2500 d1-14

• Eindpunten studieEchografische response

Pathologische response

GEPARTRIO

N=620 TAC NX

Klin R 72% 67%

Echo R 59% 63%

BCS 58% 60%

Path CR 5.3% 5.9%

GEPARTRIO, conclusies

• 2/3 heeft uiteindelijk nog response op TAC

• TAC meer toxiciteit (hematologisch als ook niet-hematologisch)

• NX goed alternatief voor TAC

Neoadjuvante endocriene therapie versus chemotherapie

• T2N1, T3N1-0, T4NOMO (geen IBC)

• ER+, postmenopausale patienten

• AI versus Doxorubicine/Paclitaxel 60/200, q 3wkn

• Eindpunten:Klinische responseEchografische response Pathologische responsemammasparende operatie

Semiglazov, et al

Neoadjuvante endocriene therapie versus chemotherapie

N=239 Endocrien Chemotherapie

Klin R 62.2% 63.5%

Tijd tot R 57 dgn 51 dgn

Path R 5.2% 8.5%

Progressie 9% 8.5%

Sparende OK 60% 59%

Neoadjuvante endocriene therapie versus chemotherapie

CONCLUSIES

• Effectiviteit endocriene therapie gelijk aan chemotherapie

• Endocriene therapie minder toxisch

Adjuvante chemotherapie

GEICAM 9906; 6xFEC versus 4xFEC -8xP q1wk

4xTC versus 4xAC , Jones et al. Houston

INT C9741 Dose Dense

INT E1199, 4xAC- P1, P3, D1 of D3

Doce/Cyclo (TC) versus Dox/Cyclo (AC) in early breast cancer

• N=1016, N0 en N+• 4 x AC versus 4 x TC• Chemotherapie voor Radiotherapie• Tam na chemotherapie, indien ER+

• Eindpunten:DFS (primair)OS en Toxiciteit (secundair)

Jones et al, Texas

TC versus AC

TC versus AC

TC versus AC

TC versus AC conclusies

• TC betere DFS

• TC minder toxiciteit

• TC nieuwe standaard

Five year follow-up of INT C9741: dose-dense is safe and effective

INT C9741

INT C9741

INT C9741

INT C9741

INT C9741

INT C9741

INT C9741 conclusies

• Dose Dense is superior

• Geen verschil sequentieel versus gelijktijdig

• Data stabiel t.o.v. 3 jaar geleden

• Toxiciteit van DD acceptabel

• Groter voordeel van DD bij ER-

Phase III study of AC followed by P or D Q 1wk or Q 3wk in N+ and N0 high risk Patients: INT E1199

INT E1199

• Eindpunten : DFS en OS

• Vergelijking :P versus D Q1 versus Q3P3 als standaard versus andere armen(subset ER- P3 versus andere armen)

• Median follow-up: 46.5 mnd

• N=4988

INT E1199

INT E1199

INT E1199

INT E1199

INT E1199 conclusies

• Docetaxel en Paclitaxel even effectief

• Q1 wk gelijk aan Q3 wk

• Trend voor een betere DFS P1 tov P3 (meer uitgesproken bij ER-)

• D1 meer gr3/4 tox; 39% versus 24%

GEICAM 99066xFEC versus 4xFEC- 8xP in N+ BC

GEICAM 9906

• Eindpunten: DFS en OS

• Vergelijking: 6xFEC90 4xFEC90 - 8xP 100 q1wk

• Median follow-up: 47 mnd

• N=1248

GEICAM 9906

GEICAM 9906

Geicam 9906

Geicam 9906 conclusies

• Toxiciteit van beide schema’s acceptabel

• FEC - P meer myalgie

• FEC meer neutropenie

• Adjuvant FEC - P effectiever in alle subgroepen tav DFS

• Geen verschil in OS

Gemetastaseerd mammacarcinoom

• Meta-analyse eerste lijn Taxanen

(Piccart)

Hoge dosis chemotherapie

(Rodenhuis)

INCORPORATION OF TAXANES IN FIRST LINE INCORPORATION OF TAXANES IN FIRST LINE CHEMOTHERAPY FOR ADVANCED BREAST CHEMOTHERAPY FOR ADVANCED BREAST

CANCER : CANCER : A META-ANALYSISA META-ANALYSIS

Presenter : Martine J. Piccart-Gebhart, MD, PhDPresenter : Martine J. Piccart-Gebhart, MD, PhDStatisticians : Tomasz Burzykowski, PhD, Marc Buyse, ScDStatisticians : Tomasz Burzykowski, PhD, Marc Buyse, ScD

Clinical Fellows : Gul Atalay, Daniela RosaClinical Fellows : Gul Atalay, Daniela RosaFinancial support : EORTC Breast Cancer GroupFinancial support : EORTC Breast Cancer Group

• In2002In2002• N N = 12 trials with inconsistent results= 12 trials with inconsistent results

– Doxorubicin (8), Epirubicin (4)Doxorubicin (8), Epirubicin (4)– Docetaxel (6), Paclitaxel (6)Docetaxel (6), Paclitaxel (6)

• Survival gain in only one trial (Jassem et al)Survival gain in only one trial (Jassem et al)• Greater toxicity and cost with the anthracycline + Greater toxicity and cost with the anthracycline + taxane regimenstaxane regimens

– Febrile neutropenia 8 – 21% (paclitaxel + A)Febrile neutropenia 8 – 21% (paclitaxel + A) 23 – 33% (docetaxel + A)23 – 33% (docetaxel + A)

– Cross-over ratesCross-over rates 24 – 57% 24 – 57%

TrialTrial AuthorAuthor Control arm and Control arm and taxanetaxane

NN

Combination trials : Paclitaxel (P)Combination trials : Paclitaxel (P)

CCEI Paclitaxel CCEI Paclitaxel BCSGBCSG

JassemJassem FAC / ETFAC / ET 267267

EORTC 10961EORTC 10961 BiganzoliBiganzoli AC / ATAC / AT 275275

UKCCCR AB01UKCCCR AB01 CarmichaelCarmichael EC / ETEC / ET 705705

AGOAGO LuckLuck EC / ETEC / ET 516516

Combination trials : Docetaxel (D)Combination trials : Docetaxel (D)

TAX 306 Study TAX 306 Study GroupGroup

NabholtzNabholtz AC / ADAC / AD 429429

TAX 307 study GroupTAX 307 study Group MackeyMackey FAC / DACFAC / DAC 484484

CCC NetherlandsCCC Netherlands BontenbalBontenbal FAC / ADFAC / AD 216216

French trialFrench trial BonneterreBonneterre FEC / EDFEC / ED 142142

Single agent trials : Paclitaxel (P) or Docetaxel (D)Single agent trials : Paclitaxel (P) or Docetaxel (D)

ECOG E1193ECOG E1193 SledgeSledge A / PA / P 490490

EORTC 10923EORTC 10923 ParidaensParidaens A / DA / D 331331

Tax 303 Study GroupTax 303 Study Group ChanChan A / DA / D 9898

TotalTotal 39533953

Individual patient data were collected (not merely Individual patient data were collected (not merely

summary statistics from the literature):summary statistics from the literature):

• All relevant trials were included, whether published All relevant trials were included, whether published

or notor not

• Reporting biases were avoidedReporting biases were avoided

• Data were extensively checked (and resulted in the Data were extensively checked (and resulted in the

exclusion of one trial)exclusion of one trial)

• The power of the analyses was maximizedThe power of the analyses was maximized

• Subgroup analyses (by visceral disease / ER status) Subgroup analyses (by visceral disease / ER status)

could be performedcould be performed

Progression-freeProgression-free survival hazard ratios survival hazard ratios

Overall survival hazard ratiosOverall survival hazard ratios

• Single agent doxorubicine (at 75 mg/m2) was better than Single agent doxorubicine (at 75 mg/m2) was better than

single single agent taxane in terms of response rate and PFS in agent taxane in terms of response rate and PFS in

one of 3 trialsone of 3 trials

• Taxanes in combination with anthracyclines provide Taxanes in combination with anthracyclines provide

greater chances of "response" remain the treatment of greater chances of "response" remain the treatment of

choice when a "response" is desirablechoice when a "response" is desirable

• The impact of taxanes on progression-free survival appears The impact of taxanes on progression-free survival appears

to be marginal and their impact on survival has not been to be marginal and their impact on survival has not been

shown by this meta-analysis of trials conducted in the shown by this meta-analysis of trials conducted in the

"empirical" era of oncology"empirical" era of oncology

• More attention needs to be paid to cross-overMore attention needs to be paid to cross-over

• Strong considerations should be given to trials run in better Strong considerations should be given to trials run in better

defined “molecular” sub-populationsdefined “molecular” sub-populations

High-Dose Chemotherapyin Breast Cancer

A ‘Critical Review’, or:Is it dead ?

Rodenhuis

High-dose Therapy in Breast Cancer:

• in stage IV patients (phase II) Strong rationale derived from model systems

• High objective response rates • Excellent DFS rate in high-risk

primary breast cancer (phase II)

861 Stage IV Patients Randomized6 studies, 6 different HD regimens

Author Patients Patient Selection Conventional arm High-dose arm High-dose regimen

RFS

Stadtmauer 199 Response to conventional

chemotherapy

max 24xCMF 1xHD CTCb same

Biron (Pegase 03)

180 CR or PR after 4x FEC

no further treatment 1xHD CT better

Lotz (Pegase 04)

61 stage IV; "chemosensitive"

4-6x conv, then 'maintenance'

4-6x conv, then 1xHD

CTM better

Crown (IBDIS-1)

110 Absence of progression to 3

courses Doxorubicin-Docetaxel

4xAT + 4xCMF 4xAT + HD1 + HD2

HD1: ICE; HD2: CT

better

Crump (NCIC)

219 1-st line chemotherapy for

stage IV

2-4x conv 1-2x conv, then 1xHD

CMC better

Schmid 92 1-st line chemotherapy for

stage IV

6-9x Doxorubicin/Paclitaxel

2xHD CEM better

High-Dose Chemotherapy with PBPC-Tx in Advanced Breast Cancer

• High-dose chemotherapy cannot eradicate macroscopic disease

• It may (sometimes) eradicate micrometastases (when any macrometastatic disease is either resected or irradiated

• ( ? but could this also be achieved by conventionally dosed chemotherapy ? )

High-Dose Chemotherapy with PBPC-Tx in High-Risk Breast Cancer

• Over 5500 patients treated in 14 (reported) randomized studies

• Many studies (all underpowered, most too early for OS analysis) show trend for RFS benefit for dose-intensive arm

5627 Patients with High-Risk Breast Cancerin 14 Randomized Studies of HD

AUTHOR PATIENTS SELECTION CONVENTIONAL ARM HIGH-DOSE ARM

RFS analysis

Rodenhuis 885 4N 5xFEC 4xFEC - CTC HD better, p=0.08

Peters 785 10N 4xCAF + ID-CPB 4xCAF + HD-CPB no difference, HD less relapses

Crown 605 4N 4xA + 8xCMF 4xA + HD-C - CT no difference

Tallman 540 10N 6xCAF 6x CAF + CT no difference, HD less relapses

Bergh 525 8N 9xFEC 3xminiFEC + CTCb

9xFEC better

Nitz 403 10N 4x ddEC + 3x ddCMF 2xEC + 2xEC-Thiotepa

HD better, p=0.002

Gianni 382 4N 3xEpi + 6xCMF HD-sequential HD better NS

Basser 344 high-risk 4xAC + 3xCMF 3xE200C4000 HD better, NS

Roché 314 8N 4xFEC 4xFEC + CMA HD better

Zander 307 10N 4xEC + 3xCMF 4xEC + CTM HD better, NS

Coombes 281 4N 6xFEC 3xFEC + CTCb no difference

Tokuda 97 10N 6xCAF 6xCAF + CT HD better, NS

Rodenhuis 81 infraclav biopsy

4xFEC 4xFEC + CTC no difference

Hortobagyi 78 4N/10N 8xCAF 8xCAF + 2xCEP no difference

Dutch National Study of High-Dose Chemotherapy in the Adjuvant Treatment of High-Risk Breast

Cancer (‘N4+ trial’)

• Largest Randomized Study of HD Chemotherapy (N=885)

• No excessive Therapy-Related Mortality (1%)• Study with best patient compliance (e.g. no cross-

over conventional to high-dose arm)• Symmetrical design (HD chemo only difference

between arms)• Cyclophosphamide and ThioTepa not as

continuous and simultaneous infusions• Only study with Pathology Review

0 12 24 36 48 60 72 84 96 108 120

months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Sur

viva

l Pro

babi

lity

443 399 348 299 277 243 181 123 72 36 14 CONV442 413 357 319 296 262 215 146 91 53 17 HD

CONV

HD

Dutch National Study of HD-CT in High-Risk Breast CancerRecurrence-Free Survival – All 885 Patients

58.9%

64.3%

HR = 0.84, p=0.076

March 2005

0 12 24 36 48 60 72 84 96

months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Sur

viva

l Pro

babi

lity

108 93 79 68 60 54 44 33 20 CONV97 87 68 54 47 38 29 18 11 HD

CONV

HD

Dutch National Study of HD-CT in High-Risk Breast Cancer

Recurrence-Free Survival – 181 HER2/neu-positives

HR = 1.26, p=0.22

55.9%

43.9%

0 12 24 36 48 60 72 84 96

months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Sur

viva

l Pro

babi

lity

301 275 243 207 195 169 124 80 47 CONV320 305 273 249 235 211 177 122 77 HD

CONV

HD

Dutch National Study of HD-CT in High-Risk Breast CancerRecurrence-Free Survival – 621 HER2/neu-negatives

HR = 0.68, p=0.002

57.7%

70.7%

March 2005

0 12 24 36 48 60 72 84 96

months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al

Pro

bab

ilit

y

301 290 272 254 234 204 153 106 62 CONV320 313 294 281 263 232 198 137 85 HD

CONV

HD

Dutch National Study of HD-CT in High-Risk Breast CancerOverall Survival – 621 HER2/neu-negatives

78.2%

71.0%

HR = 0.72, p=0.02

March 2005

Predictive Markers for the Optimal Selection of Chemotherapy

• HER2/neu overexpression – decreased sensitivity to alkylator regimens, e.g. CMF– Several retrospective studies: IBCSG and

American Intergroup Study publ. In 1989• HER2/neu overexpression – sensitivity to

anthracyclines– CALBG study– NSABP studies B11 and B15– European consortium– EORTC 10854– NCIC MA.9 Trial– And several others

HER2/neu Subgroup Analysis

Unplanned subgroup analysis: suspectBUT:1. The subgroup is very large (621 patients)2. Not a multiple-testing result

Precisely one cut-off value defines subgroups Test for interaction: p < 0.001

3. Makes sense with respect to biology HER2-positives not associated with BRCA/Fanconi

pathway defects HER2/neu-positives resistant to alkylating agents (in the

absence of Trastuzumab)4. Makes sense clinically: subgroup analyses of other (non-

randomized) high-dose trials

0.5 1 2

0.79 ( 0.65 , 0.97 )

Subgroup

HER2-/ER-

HER2-/ER+

HER2+/ER-

HER2+/ER+

Overall result

HDevents/N

30/68

75/243

23/41

19/42

169/442

Convevents/N

44/75

98/228

21/40

20/53

201/443

HER2/neu and ER

High-dose chemotherapy in patients with advanced breast cancerrecurrence-free survival analysis in subgroups

HD better Conv better

Subgroup estimates 99%, Overall 95% confidence intervals

Subgroup Analysis:Triple Negative Tumors (“basal –like”)

Basal subtype

Luminal subtype

HER+ subtype

0 12 24 36 48 60 72 84 96

months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Sur

viva

l Pro

babi

lity

107 88 69 58 55 50 43 29 17 CONV102 92 75 70 65 62 55 36 19 HD

CONV

HD

Patients with ‘Triple-negative’ (= basal-like) Tumors

HR=0.67, p=0.087

61.8%

49.5%

March 2005

Conclusion Dutch Study

1. HER2-amplified tumors do not respond to HD-alkylators (confirmed)

2. HD-sensitive subgroup present in set of HER2-negative tumors– Luminal-like tumors: part castration effect ?– Basal-like tumors: CTC is effective (HR=0.70)

3. Formal proof to be delivered (prospective study)

High-Dose Alkylating Therapy in Breast Cancer A Testable Hypothesis

• All data from clinical studies are compatible with the existence of a subgroup of breast cancers (+/- 20%) which is exquisitely sensitive to alkylating chemotherapy

• This subgroup is HER2/neu-negative• It may well be characterized by a DNA repair-

deficit (no Homologous Recombination), as caused by– Loss of BRCA 1 or –2– A defect in the Fanconi anemia pathway– Amplification of the EMSY gene

HR-deficiency causes 10-100x sensitivity to Cyclophosphamideand Cisplatin/Carboplatin in vitro

Pacitaxel175 mg/m2

q 2 wk x 2

Pacitaxel175 mg/m2

q 2 wk x 2

Cycloph: 3 g/m2

ThioTepa: 250 mg/ m2

Carbopl: AUC = 10

G-CSF PBPC

Cycloph: 3 g/m2

ThioTepa: 250 mg/ m2

Carbopl: AUC = 10

Endocrine Adj. TherapyFollow-Up

Out-patient Tandem PBPC-Tx

High-risk patientsfollowing anthracycline-based chemotherapy.Tumors with HR-defect(IHC & microarray)

HD Alkylating Chemotherapy in Breast Cancer: not to be Abandoned

• Strong biological and clinical evidence (short of proof) that HD alkylating chemotherapy is very active in a subgroup of breast cancers (20-30%)

• Adequate studies that include these subgroups are desirable, despite the absence of industry funding

• A 30% decrease in mortality due to HD therapy remains very important, even in the era of Trastuzumab and Aromatase Inhibitors (e.g. in triple-negative tumors)

POSTERS

Neoadjuvant chemotherapie

• Veel kleine fase II studies

• Verschillende schema’s, conventioneel of dose-dense

• Path CR 10-35%

Neoadjuvant chemotherapie

Chemotherapie schema N K R pCR

4xFEC100 q3wk – 4xD 100, q3wk 100 65 % 25%

3xG1000 +D 75 d1,8 – V25+E100 d21,29, q6wk 62 90% 27%

6xA50+D30 d1,8,15 + X1500, d1-14, q4wk 34 80% 12%

4xAC60/600 q3wk – 12xD35, q1wk 63 89% 16%

4xEC90/600, q2wk – 4xD75, q2wk 81 60% 25%

4xEC90/600, q2wk – 2xD35, d1,8,15+X2500, d1-14, q4wk

24 96% 25%

4xAC60/600, q 2wk – 4xD100 of P175,q2wk 42 94% 35%

4xD100, q2wk – 4xAC 60/600, q 2wk 54 80% 12%12%80%544xD100, q2wk – 4xAC 60/600, q 2wk

35%94%424xAC60/600, q 2wk – 4xD100 of P175,q2wk

25%96%244xEC90/600, q2wk – 2xD35, d1,8,15+X2500, d1-14, q4wk

25%60%814xEC90/600, q2wk – 4xD75, q2wk

16%89%634xAC60/600 q3wk – 12xD35, q1wk

12%80%346xA50+D30 d1,8,15 + X1500, d1-14, q4wk

27%90%623xG1000 +D 75 d1,8 – V25+E100 d21,29, q6wk

25%65 %1004xFEC100 q3wk – 4xD 100, q3wk

pCRK R NChemotherapie schema

Neoadjuvant chemotherapie

• Ago groepN=93 IBC, gerandomiseerd:3xE150 – 3xP 250, q 2wk versus4xEP 90/175 q 3wkPost OK 3xCMFpCR 21% versus 12%

• GeparDuo studieN=913 LABC, gerandomiseerd4xAD 50/75, q2wk versus4xAC 60/600 q 3wk – 4xD 100, q 3wkpCR 7% versus 14%EFS 5 jaar 65% versus 73%

Neoadjuvant chemotherapie

• EORTC, POCOB, Preoperatief 4xCMF versus postoperatief 4xCMFN= 689, M Follow-up 10 jaarMST versus Mastectomie 37% versus 21%Geen verschil in OS, RFS en LRR

• Italiaanse studieInductie chemo 6xCis50E100V25, q2wkVervolgens S, RT , 6xCMF en evt TamIndien < pCR, randomisatie (n=35) : niets versus 3xE100-3xD100, q3wkM F-up 6 jr, DFS en OS in behandelgroep 100%, versus 53 en 68%

Adjuvant chemotherapy

• AGO groepFase II, N=102, N+ (4-9)

3xE150, q 2wk – 3xP 225, q2wk – 3xC 2500, q 2wk

F-Up 6,5 jr, DFS 72% en OS 78%

Chemotherapie, nieuwe middelen

• E7389, preventie van microtubuline groeiFase II bij taxaan resistentieRR 20%, TTP 2 mnd, weinig neurotoxiciteit

• Tocosol, Cremophor vrij taxolFase II, 1e lijnRR 50%, TTP 7 mnd, geen premedic en weinig neurotox.

• XRP 6258, semisynthetisch taxaanFase II, bij taxaan resistentieRR 14%, TTP 2 mnd

• KOS-802, Epothilone DFase II bij taxaan resistentieRR 14%, TTP 2-3 mnd, neurotox max gr 2

Gemetastaseerd mammacarcinoom

• Drie studies Capecitabine + Vinorelbine oraal, Cape 2000-2500+Vino 60, d1,8(15), q 3 wkEerste lijn RR 45-50%, 2e lijn 35%, TTP 3-7 mndNeutropenie 10-12%, ( 40% bij vino d1,8,15)

• Vino 25 d1,8 + Doce 75, q 3wk x6 – 6x Cape 2500N=25, 1e lijn, RR 83%, TTP 28 mnd, geen gr 4 tox.

• Gemsar 1250 d1,8 + Doce 75, q3wkN=42, 1e lijnRR 80 %, TTP ??,

• Doce 50 q2wk,N=31, > 65 jr, 1e of 2e lijnRR 38%, TTP 9 mnd, 16% delay ivm neutropenie, weinig tox.

OPMERKINGEN & CONCLUSIES

• Piccart : Nieuw paradigma adjuvante therapie: “first select the target than think about the risk”

• Afname presentaties/posters chemotherapie alleen

• Echter: chemotherapie niet dood; “Triple Negative BC” target voor chemotherapie Hoge Dosis voor subgroepen Dose Dense effectief en goed verdraagbaar Nieuwe middelen nog volop in ontwikkeling

• Taxanen adjuvant geen OS voordeel; gevoelige patienten beter identificeren, wellicht niet de “Triple Negative BC”