Post San Antonio & Post EBCC Chemotherapie Aafke H. Honkoop

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1 Post San Antonio & Post EBCC Chemotherapie Aafke H. Honkoop

2 San Antonio BCS & EBCC Presentaties Neoadjuvante chemotherapie (2)
Gemetastaseerde ziekte (2) Posters Neoadjuvante chemotherapie Adjuvante chemotherapie Nieuwe middelen Gemetastaseerde ziekte

3 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

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

5 GEPARTRIO Doseringen: TAC: 75/50/500 mg/m2 Eindpunten studie
NX : 25 d1,8/2500 d1-14 Eindpunten studie Echografische response Pathologische response

6 GEPARTRIO N=620 TAC NX Klin R 72% 67% Echo R 59% 63% BCS 58% 60%
Path CR 5.3% 5.9%

7 GEPARTRIO, conclusies 2/3 heeft uiteindelijk nog response op TAC
TAC meer toxiciteit (hematologisch als ook niet-hematologisch) NX goed alternatief voor TAC

8 Neoadjuvante endocriene therapie versus chemotherapie
T2N1, T3N1-0, T4NOMO (geen IBC) ER+, postmenopausale patienten AI versus Doxorubicine/Paclitaxel 60/200, q 3wkn Eindpunten: Klinische response Echografische response Pathologische response mammasparende operatie Semiglazov, et al

9 Neoadjuvante endocriene therapie versus chemotherapie
Klin R 62.2% 63.5% Tijd tot R 57 dgn 51 dgn Path R 5.2% 8.5% Progressie 9% Sparende OK 60% 59%

10 Neoadjuvante endocriene therapie versus chemotherapie
CONCLUSIES Effectiviteit endocriene therapie gelijk aan chemotherapie Endocriene therapie minder toxisch

11 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

12 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

13 TC versus AC

14 TC versus AC

15 TC versus AC

16 TC versus AC conclusies
TC betere DFS TC minder toxiciteit TC nieuwe standaard

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

18 INT C9741

19 INT C9741

20 INT C9741

21 INT C9741

22 INT C9741

23 INT C9741

24 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-

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

26 INT E1199 Eindpunten : DFS en OS Vergelijking : P versus D
Q1 versus Q3 P3 als standaard versus andere armen (subset ER- P3 versus andere armen) Median follow-up: 46.5 mnd N=4988

27 INT E1199

28 INT E1199

29 INT E1199

30 INT E1199

31 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%

32 GEICAM 9906 6xFEC versus 4xFEC- 8xP in N+ BC

33 GEICAM 9906 Eindpunten: DFS en OS Vergelijking: 6xFEC90
4xFEC90 - 8xP 100 q1wk Median follow-up: 47 mnd N=1248

34 GEICAM 9906

35 GEICAM 9906

36 Geicam 9906

37 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

38 Gemetastaseerd mammacarcinoom
Meta-analyse eerste lijn Taxanen (Piccart) Hoge dosis chemotherapie (Rodenhuis)

39 INCORPORATION OF TAXANES IN FIRST LINE CHEMOTHERAPY FOR ADVANCED BREAST CANCER :
A META-ANALYSIS Statisticians : Tomasz Burzykowski, PhD, Marc Buyse, ScD Presenter : Martine J. Piccart-Gebhart, MD, PhD Statisticians : Tomasz Burzykowski, PhD, Marc Buyse, ScD Clinical Fellows : Gul Atalay, Daniela Rosa Financial support : EORTC Breast Cancer Group

40 In2002 N = 12 trials with inconsistent results Doxorubicin (8), Epirubicin (4) Docetaxel (6), Paclitaxel (6) Survival gain in only one trial (Jassem et al) Greater toxicity and cost with the anthracycline + taxane regimens Febrile neutropenia 8 – 21% (paclitaxel + A) 23 – 33% (docetaxel + A) Cross-over rates – 57%

41 Combination trials : Paclitaxel (P) CCEI Paclitaxel BCSG Jassem
Author Control arm and taxane N Combination trials : Paclitaxel (P) CCEI Paclitaxel BCSG Jassem FAC / ET 267 EORTC 10961 Biganzoli AC / AT 275 UKCCCR AB01 Carmichael EC / ET 705 AGO Luck 516 Combination trials : Docetaxel (D) TAX 306 Study Group Nabholtz AC / AD 429 TAX 307 study Group Mackey FAC / DAC 484 CCC Netherlands Bontenbal FAC / AD 216 French trial Bonneterre FEC / ED 142 Single agent trials : Paclitaxel (P) or Docetaxel (D) ECOG E1193 Sledge A / P 490 EORTC 10923 Paridaens A / D 331 Tax 303 Study Group Chan 98 Total 3953 Bontenbal

42 Individual patient data were collected (not merely summary statistics from the literature):
All relevant trials were included, whether published or not Reporting biases were avoided Data were extensively checked (and resulted in the exclusion of one trial) The power of the analyses was maximized Subgroup analyses (by visceral disease / ER status) could be performed

43 Progression-free survival hazard ratios

44 Overall survival hazard ratios

45 More attention needs to be paid to cross-over
Single agent doxorubicine (at 75 mg/m2) was better than single agent taxane in terms of response rate and PFS in one of 3 trials Taxanes in combination with anthracyclines provide greater chances of "response" remain the treatment of choice when a "response" is desirable The impact of taxanes on progression-free survival appears to be marginal and their impact on survival has not been shown by this meta-analysis of trials conducted in the "empirical" era of oncology More attention needs to be paid to cross-over Strong considerations should be given to trials run in better defined “molecular” sub-populations CLINICAL PRACTICE

46 High-Dose Chemotherapy in Breast Cancer
A ‘Critical Review’, or: Is it dead ? Rodenhuis

47 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)

48 861 Stage IV Patients Randomized 6 studies, 6 different HD regimens

49 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 ? )

50 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

51 5627 Patients with High-Risk Breast Cancer
in 14 Randomized Studies of HD

52 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

53 Dutch National Study of HD-CT in High-Risk Breast Cancer
Recurrence-Free Survival – All 885 Patients 64.3% 58.9% HR = 0.84, p=0.076 March 2005

54 Dutch National Study of HD-CT in High-Risk Breast Cancer
Recurrence-Free Survival – 181 HER2/neu-positives 55.9% 43.9% HR = 1.26, p=0.22

55 Dutch National Study of HD-CT in High-Risk Breast Cancer
Recurrence-Free Survival – 621 HER2/neu-negatives 70.7% 57.7% HR = 0.68, p=0.002 March 2005

56 Dutch National Study of HD-CT in High-Risk Breast Cancer
Overall Survival – 621 HER2/neu-negatives 78.2% 71.0% HR = 0.72, p=0.02 March 2005

57 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

58 HER2/neu Subgroup Analysis
Unplanned subgroup analysis: suspect BUT: The subgroup is very large (621 patients) Not a multiple-testing result Precisely one cut-off value defines subgroups Test for interaction: p < 0.001 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) Makes sense clinically: subgroup analyses of other (non-randomized) high-dose trials

59 Triple Negative Tumors (“basal –like”)
Subgroup Analysis: Triple Negative Tumors (“basal –like”) Basal subtype Luminal subtype HER+ subtype

60 Patients with ‘Triple-negative’ (= basal-like) Tumors
61.8% 49.5% HR=0.67, p=0.087 March 2005

61 Conclusion Dutch Study
HER2-amplified tumors do not respond to HD-alkylators (confirmed) 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) Formal proof to be delivered (prospective study)

62 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 x sensitivity to Cyclophosphamide and Cisplatin/Carboplatin in vitro

63 Out-patient Tandem PBPC-Tx
Pacitaxel 175 mg/m2 q 2 wk x 2 Pacitaxel 175 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 High-risk patients following anthracycline- based chemotherapy. Tumors with HR-defect (IHC & microarray) Endocrine Adj. Therapy Follow-Up

64 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)

65 POSTERS

66 Neoadjuvant chemotherapie
Veel kleine fase II studies Verschillende schema’s, conventioneel of dose-dense Path CR 10-35%

67 Neoadjuvant chemotherapie
12% 80% 54 4xD100, q2wk – 4xAC 60/600, q 2wk 35% 94% 42 4xAC60/600, q 2wk – 4xD100 of P175,q2wk 25% 96% 24 4xEC90/600, q2wk – 2xD35, d1,8,15+X2500, d1-14, q4wk 60% 81 4xEC90/600, q2wk – 4xD75, q2wk 16% 89% 63 4xAC60/600 q3wk – 12xD35, q1wk 34 6xA50+D30 d1,8,15 + X1500, d1-14, q4wk 27% 90% 62 3xG1000 +D 75 d1,8 – V25+E100 d21,29, q6wk 65 % 100 4xFEC100 q3wk – 4xD 100, q3wk pCR K R N Chemotherapie schema 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% 4xEC90/600, q2wk – 2xD35, d1,8,15+X2500, d1-14, q4wk 24 96% 4xAC60/600, q 2wk – 4xD100 of P175,q2wk 42 94% 35% 4xD100, q2wk – 4xAC 60/600, q 2wk 54

68 Neoadjuvant chemotherapie
Ago groep N=93 IBC, gerandomiseerd: 3xE150 – 3xP 250, q 2wk versus 4xEP 90/175 q 3wk Post OK 3xCMF pCR 21% versus 12% GeparDuo studie N=913 LABC, gerandomiseerd 4xAD 50/75, q2wk versus 4xAC 60/600 q 3wk – 4xD 100, q 3wk pCR 7% versus 14% EFS 5 jaar 65% versus 73%

69 Neoadjuvant chemotherapie
EORTC, POCOB, Preoperatief 4xCMF versus postoperatief 4xCMF N= 689, M Follow-up 10 jaar MST versus Mastectomie 37% versus 21% Geen verschil in OS, RFS en LRR Italiaanse studie Inductie chemo 6xCis50E100V25, q2wk Vervolgens S, RT , 6xCMF en evt Tam Indien < pCR, randomisatie (n=35) : niets versus 3xE100-3xD100, q3wk M F-up 6 jr, DFS en OS in behandelgroep 100%, versus 53 en 68%

70 Adjuvant chemotherapy
AGO groep Fase 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%

71 Chemotherapie, nieuwe middelen
E7389, preventie van microtubuline groei Fase II bij taxaan resistentie RR 20%, TTP 2 mnd, weinig neurotoxiciteit Tocosol, Cremophor vrij taxol Fase II, 1e lijn RR 50%, TTP 7 mnd, geen premedic en weinig neurotox. XRP 6258, semisynthetisch taxaan Fase II, bij taxaan resistentie RR 14%, TTP 2 mnd KOS-802, Epothilone D RR 14%, TTP 2-3 mnd, neurotox max gr 2

72 Gemetastaseerd mammacarcinoom
Drie studies Capecitabine + Vinorelbine oraal, Cape Vino 60, d1,8(15), q 3 wk Eerste lijn RR 45-50%, 2e lijn 35%, TTP 3-7 mnd Neutropenie 10-12%, ( 40% bij vino d1,8,15) Vino 25 d1,8 + Doce 75, q 3wk x6 – 6x Cape 2500 N=25, 1e lijn, RR 83%, TTP 28 mnd, geen gr 4 tox. Gemsar 1250 d1,8 + Doce 75, q3wk N=42, 1e lijn RR 80 %, TTP ??, Doce 50 q2wk, N=31, > 65 jr, 1e of 2e lijn RR 38%, TTP 9 mnd, 16% delay ivm neutropenie, weinig tox.

73 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”

74