overview of neoadjuvant chemotherapy in breast cancer
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Overview of Neoadjuvant Chemotherapy in Breast Cancer
Dr. Vinod Raina MD, FRCPProfessor of Medical Oncology
All India Institute of Medical SciencesNew Delhi
These Power Point presentations are free to download only for academic purposes, with due acknowledgements to authors and this website.
Suggest a new term: Primary Systemic Therapy (PST)
Refers to post diagnosis systemic therapy Takes into account order of administration, intended
subsequent treatment and efficacy of systemic intervention
Other terms used are down staging, induction therapy, preoperative systemic therapy, neoadjuvant chemotherapy.
Kaufmann JCO 2003 International Expert Panel
Clinical rationale for increasing use
of neoadjuvant chemotherapy
Studies in experimental tumour models
Excellent clinical response rates in locally advanced breast cancer (T3,T4 or TxN2)
Pathological CRs of up to 15%
Adjuvant chemotherapy has survival benefit in node positive and negative breast cancer
Breast-conservation possible
PST; For whom it is standard of care?
For patients with inoperable breast cancer inflammatory breast cancer involvement of ipsilateral supra or
infraclavicular nodes i.e. N3 disease.
stages IIIA-B or T3-4 disease ?
Locally advanced breast cancer
In India it forms 30 % of all breast cancers at some centers.
Our own data at AIIMS 1998
For whom can PST be recommended as an alternative to AST ?
Most large randomized trials of PST versus AST indicate that these therapies offer equivalent disease free and overall survival benefits.
For operable breast cancer, PST can be considered as an alternative to AST
For patients who are deemed appropriate candidates for mastectomy but who desire less extensive surgery (breast conservation surgery). Success rate 5-36 %.
Also in patients who can technically have a lumpectomy first but whose physical appearance will be less damaged if PST is given first.
PST; May also be advisable in patients who have medical
contraindications to surgery or if they simply wish to delay surgery i.e. pregnant patient diagnosed in second and third trimester.
PST offers an optimal test situation for evaluation of new compounds and detection of new biologic or molecular discriminants of either response or resistance
pCR may be used as a surrogate for survival, lesscumbersome than overall survival and less time consuming.
NSABP B-18Clinical and Pathological Responses
36%
20%
43%
cCRcCR(249 patients)(249 patients)
cPRcPR(296 patients)(296 patients)
cSD + cPDcSD + cPD(140 patients)(140 patients)
4%p Non-p Non-
InvasiveInvasive(n=26)(n=26)
9% p Completep Complete(n=63)(n=63)
23%
p Invasivep Invasive(n=160)(n=160)
Clinical responses
(number of patients=658)
NSABP B18Overall survival and response to chemotherapy
5yr survival Path CR = 87% Clin PR = 68% Clin NR = 64%
p<0.0001
0 1 2 3 4 550
60
70
80
90
100
path CR
clin PRclin NR
years
dist
ant d
isea
se-fr
eesu
rviv
al (%
)
Data from: Fisher et al, J Clin Oncol 1988; 16: 2672-2685
NSABP B-18: updated results.
In pre-op arm 36 % patients had a complete clinical response
Axillary node down staging in preop. patients 59% vs. 42 % path negative nodes
Highly significant correlation between tumor response and path nodal status.
87 % patients with complete clinical response hadpath neg nodes
More likely to have lumpectomy 68% vs. 59 %,statistically not different
No difference in disease free and overall survival
Author Local Distant BreastAnd No.of Follow-up Failure Failure Survival ConservationGroup Patient Stage (months) Rate Rate Rate (PST vs. AST)
Fisher, NASBP 1,523 T1-3, N0-1, M0 96 * * * 67% versus 60%
P=0.002
Gianni, ECTO 892 T1-3, N0-1, M0 23 NA NA NA 71% versus 35% P
< 0.0001
Van der Hage, 698 T1c-4d, N0-1, M0 56 * * * 37% versus 21% Eortc NA
Jakesz, ABCSG 423 T1-3, N0-2, M0 NA ‡ * * *NA
Scholl, S6 390 T2-3, N0-2, M0 66 * * * 82% versus 77%
Overview of Randomized Trials Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in
the Breast Cancer
*No Statistical difference
B-18 trial: unanswered questions.
Is there a need for further chemotherapy
Those who show a good response may not require further treatment and those who show
a poor response may require different drugs.
Whether favorable prognosis warrants exposure to known toxicity of treatment
B 20 showed that adding adjuvant chemotherapy in node negative women improved disease free survival significantly
NSABP B20 trial removes possible concerns about preoperative chemotherapy in patients with favorable tumor size, receptor status and histology.
General consensus: that there is no group that is not benefited by chemotherapy: very small palpable tumors, node positive and negative, ER positive and negative, all benefit.
PST; Which regimen and how much
Anthracycline based chemo was standard, but changing fast
A minimum of 3-4 cycles, additional cycles may be considered for responding patients to maximize response and to improve chances of breast conservation
Use of Taxanes and sequential therapies can increase rate of pCR / successful breast conservation surgery / node negative patients by 50%.
Trastuzumab and other targeted therapies are under investigation.
PST: Rate of successful breast –conservation surgery
It correlates with clinical response and size of the primary tumor
Patients with a complete clinical response may have a successful breast conservation rate of 90 %.
In the largest trial so far no statistically significant difference was found in local recurrence free survival between patients treated with PST (4 cycles of AC) and those treated with AST (4 cycles of AC)
Local recurrence after BCT
5-6% in those who achieve CR
9.7% in those who do not achieve CR
Local recurrence did not correlate with the sizeof the primary tumor before treatment
Poor response to PST is a predictor of poor prognosis and high risk of recurrence
A demonstrable response may have a positive outcome on the psyche
PST; poor response
Immediate surgical intervention is indicated?
Alternative chemotherapy i.e. non cross resistant agents like Taxanes an obvious choice, about 50 % patients can respond but require close monitoring.
Trastuzumab and other new targeted therapies are still under investigation and should not be used outside clinical trials
Smith 2002 JCO.
PST: How should the diagnosis be confirmed before PST
Core biopsy most appropriate Highest diagnostic accuracy by
doing three biopsies, 14 gauge needle
PST; Should markers be assessed before PST
Typing of tumor and assessment of surgical grade impossible because of changes due to chemo, hence preferably to be done on core tissue .
Similarly ER/ PR and Her 2 or Ki67 to be done on core tissue before PST.
Pathological nodal status is not available reg. prognosis and radiotherapy (a major drawback)
However pathological nodal status after PST of relevant prognostic importance
Data not clear reg. need for axillary biopsy or sentinel node before chemotherapy.
Can breast conservation be increased by PST ?
Study Breast Conservation
(%)
p
Scholl, 1994
82 vs 77
ns
Makris, 1998
89 vs 78
0.004
Fisher, 1998
67 vs 60
0.002
(RCTs of neoadjuvant vs adjuvant chemotherapy)
How, when and how often should the effect of PST be monitored
Palpation of lump and axillary nodes at the start of each cycle
Mammography and ultrasound are additional tools
MRI and PET of the breast being studied
How should tumor location be documented
Collaboration of surgical, medical oncologist and radiologist
Two major problems can occur:
Either a very quick and complete response so that the primary lesion cant be identified
Or no response, in that case surgeon may have to intervene.
Precise documentation of the tumor on sketch, inserting clips or coils in the center of the lesion or placing a tattoo
Stereo-tactic localization using mammography is another option
Complete pathological CR becoming more common, so it could become a major issue .
PST; Surgical treatment of the tumor
To obtain clear margins of > 1 mm
No compromise should be made on surgical margins to obtain better cosmetic result
No difference in PST and AST in 8 year local recurrence rates
Patients less than 40 years and those with larger tumors, high rates of tumor proliferation or close or involved margins are at higher risk of local recurrence
There is an increased rate of second surgical procedures.
Role of Postoperative chemotherapy after PST
Till date no data to support or negate the use of chemotherapy after PST
Data may become available from NSABP B 27 or
from
European Cooperative trial in Operable Breast Cancer
PST:When and where should postoperative radiotherapy be administered
Same indications as for adjuvant treatment
Decision should be based on pre-PST findings.
No definitive data on the importance of nodal status after PST and need for axillary radiotherapy
Radiotherapy is not a substitute to surgery, loco-regional control is inadequate when patient is treated with RT alone.
PST: Unresolved issues.
New compounds that are directed against specific molecular targets need to be tested in this setting.
Axillary nodal issue still not convincingly resolved
But it is here to stay
Role of Docetaxel in neo-adjuvant therapy for breast cancer
Rationale for the use of Docetaxel in PST
Activity in anthracycline-resistant MBC
Superior activity observed in patients with poor prognosis disease
Most effective drug in first-line MBC (single, combined)
No cardio toxicity as with paclitaxel
More lab & clinical activity in breast cancer than paclitaxel
Longer half life than paclitaxel
Important questions for Docetaxel
Does the addition of Docetaxel to an anthracycline-containing regimen have beneficial effects?
Clinical and pathological responses Breast conservation Survival
Should Docetaxel be given concurrently with or following an anthracycline-containing regimen and what is the best schedule?
What about role of trastuzumab in HER2 over-expressing tumors?
Neoadjuvant Taxotere
The Aberdeen TrialNSABP B27GEPARDUO
Neoadjuvant Taxotere
The Aberdeen TrialNSABP B27GEPAR-DUO
4 cycles of Taxotere
4 cycles of CVAP
No
Response
Response Ra nd omi
se
All Patients4 cycles of CVAP
First Phase
Smith et al, JCO 2002
Tax301 StudyConducted by the Aberdeen Breast
Group
Second phase
4 cycles of Taxotere
Final Assessm
ent / Surgery
Aberdeen Tax 301Objective clinical response rates
1st phase: 4 cycles CVAP
Response % of patients
Complete 15
Partial 52
Stasis 33
Progression 1
ORR - 67%N=162 patients; 4 cycles of CVAP given to all patients
Aberdeen Tax301Objective clinical response rates2nd phase: responding patients
CVAP n=52
Taxotere n=52
Response % %
Complete 33 56
Additional partial 31 29
Maintained partial 29 6
Progression 4 0
ORR 64 85*
* p=0.03
Aberdeen Tax 301Objective clinical response rates
2nd phase: non-responding patients
Response % of patients
Complete 11
Partial 36
Stasis 31
Progression 9
ORR - 47%N=55 patients; additional 4 cycles of Taxotere given
Aberdeen Tax301 Aberdeen Tax301
Type of surgeryType of surgery undertaken
Breast conservation surgeryTaxotere 67%
CVAP 48%
Conservation Mastectomy0
20
40
60
80
100 Taxotere
CVAP
Type of surgery
% o
f pat
ient
s
(p<0.01)
Tax 301 Overall Survival
Time (months)
Median Follow - up: 60 months
Surv
ival
pro
babi
lity
1.0
0.9
0.8
0.7 20
40
60
80
100
Log rank p=0.04TaxotereCVAP
97%
78%
Neoadjuvant Taxotere
The Aberdeen TrialNSABP B27GEPAR-DUO
NSABP B-27 Operable Breast CancerOperable Breast Cancer
RandomizationRandomization
AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs
AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs
AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs
SurgerySurgery Taxotere x 4Taxotere x 4 SurgerySurgery
SurgerySurgery Taxotere x 4Taxotere x 4
Bear et al, J Clin Oncol 2003; 21
( 2411 pts )
40%
45%
100100
8080
6060
4040
2020
00
%%
p < 0.001p < 0.001
ACACN=1502N=1502
AC Taxotere AC Taxotere N=687N=687
65%
26%
NSABP B-27 Clinical ResponseNSABP B-27 Clinical Response
cCRcCRcPRcPRcNRcNR
14% 9%
NSABP B-27 Pathological Response (pCR) in Breast
p < 0.001
AC TaxotereN=786
ACN=1567
3.9%
9.8%
7.2%
18.9%20
10
0
30 No TumourNon-Invasive
26.1%13.7%
Adapted from Bear et al, J Clin Oncol 2003; 21
NSABP B-27:Proportion of Patients with negative axillary lymph
nodes
58.2
p < 0.001p < 0.001
ACACN=1534N=1534
AC TaxotereAC TaxotereN=752N=752
8080
6060
4040
2020
00
%%
50.8
Bear et al, J Clin Oncol 2003; 21
NSABP B-27: Breast Conservation: Breast Conservation
p = 0.7061 63
8080
6060
4040
2020
00
%%
ACAC(N=1492)(N=1492)
AC TaxotereAC TaxotereN=718N=718
Bear et al, J Clin Oncol 2003; 21
Neoadjuvant Taxotere
The Aberdeen TrialNSABP B27GEPAR-DUO
GEPARDUO trial
von Minckwitz et al., J Clin Oncol 1999von Minckwitz et al., J Clin Oncol 2001
Surg
ery
Surg
ery
GeparduoGeparduo
T T 2 cm 2 cm (stage I,II)(stage I,II)
(N=913) (N=913) AT + Tam
AC-T +TAMAdriamycinAdriamycin
TaxotereTaxotere
AdriamycinAdriamycinCyclophosphamideCyclophosphamide
TaxotereTaxotere
Treatment regimens
4 cycles AC followed by 4 cycles of Taxotere• Doxorubicin 60 mg/m² (day 1 q 22)• Cyclophosphamide 600 mg/m² (day 1 q 22)• Taxotere 100 mg/m² (day 1 q 22)
4 cycles AT• Doxorubicin 50 mg/m² (day 1 q 15)• Taxotere 75 mg/m² (day 1 q 15)• G-CSF (days 5-10)
Tamoxifen 20mg /day at same time
Adapted from G.Raab – SABCS ’03, Abs#241, Poster
0%
20%
40%
60%
80%
100%
AT AC-T
CompletePartialStasisProgress
(n=(n=421421)) (n=(n=425425))
57.4%32.5%
29.4%
44.7%
10.1%21.1%
Clinical responses in the breast
GEPAR-GEPAR-DUODUO Pathologic Complete Remission (pCR)Pathologic Complete Remission (pCR)
P < 0.001
No Tumor In situ residuals only
AC Taxotere(442 pts)
AT(443 pts)
3.8%
7.7%
6.3%
16.1%
11.5%
22.4%
20%20%
10%10%
00
30%30%
Adapted from G.Raab – SABCS ’03, Abs#241, Poster
Effect on tumour in axillary lymph nodes
60.7%55.4%
6060%%
4040%%
2020%%
00 AT(n=443)
8080%%
AC Taxotere(n=442)
80%80%
74.9%
65.5%60%60%
40%40%
20%20%
00AT
(n=443)AC Taxotere
(n=442)
GEPAR-GEPAR-DUODUO Effect on breast conservation surgery
AC->Taxotere :
Increased Complete Clinical response
Increased pCR rates Increased number of patients with no axillary node
involvement
Increased breast conservation
GEPAR-DUO : Conclusions
Author Clinical Pathologic Breast And No.of Complete Response* Conservation Group Patient Stage Regimen Response(%) (%) Rate
NSABP 2,411 T1-3, N0-1, M0 AC x 4 40 9.8 61
AC x 4, Doc x 4 65 18.7 63
Von Minckwitz 913 T2-3, N0-2, M0 AT x 4 q2w 32.5 7.7 65
GABG AC x 4, Doc x 4 57.4 16.1 75
Untch, AGO 475† T2-4d, N0-2, M0 ET x 4 NA 10 55
Epi x 3, Tax x 3 q2w 18 66
Von minckwitz 248 T2-3, N0-2 AT x 4 q2w 5.7 10.3 69
GABG AT x 4 q2w + Tam 12.5 9.1 69
Penault-Llorca 200‡ NA AC NA 6 45
France AT 15 56
Buzdar 174 T1-3, N0-1, M0 FAC x 4 24 18 35
Houston Tax x 4 27 6 46
Smith 104 T2-4, N0-2, M0 CVAP x 8 33 15.4§ 48
CVAP x 4, Tax x 4 56 30.8§ 67
Overview of Rand. Trial comparing different Primary Systemic Therapy Regimens in Breast
Cancer
*No invasive or in situ tumor cells in the removed breast
Summary neoadjuvant Taxotere
Taxotere offers meaningful benefits to patients:
Highly effective in reducing tumour size Increases clinical responses Increases complete pathological response Increases Nodal clearance Increases breast conservation Improved survival in Aberdeen trial Potential for non-anthracycline combinations
Primary Systemic Chemotherapy
It is here to stay Effective, improved results in
combination Increased rates of breast conservation Better cosmesis Surrogate marker of improved survival Rescue measures can be taken early
rather than late
PST; Drawbacks
Pathological staging not available Improved survival not proven Whether post operative chemotherapy is
beneficial not known Can create problems in Radiotherapy Newer options: AI, Trastuzumab
Thanks
Adjuvant vs neoadjuvant chemotherapy in breast cancer: randomised studies
same84 vs 82T0 - T4309Makris, 1998
86 vs 78*59 vs 55IIa - IIIa414Scholl, 1994
86 vs 7881 vs 72*IIb,IIIa271Semiglazov,1994
54 vs 55sameT2,T369Mauriac, 1999
73 vs 72NRI,II204Ragaz, 1999
OS(%)
DFS(%)
StageNo. pts
Study
Fisher, 1998 1523 T1 - T3 67 vs 67 80 vs 80
(Data from: Wolf and Davidson, J Clin Oncol 2000; *p<0.05)
PST: Endocrine therapy remains attractive
When it is desirable to avoid chemotherapy As a second choice for selected patients,
elderly women with impaired organ function or low PS, or high surgical risk
A positive ER, PgR is a requisite. AI more active and better tolerated, thus
preferred in postmenopausal patients. No data in premenopausal patients.
Locally advanced breast cancer
Increased public awareness, national breast screening
10-20% of patients - LABC (T3, T4 or N2)
Haagensen & Stout, 1943 48% local recurrence 3% 5 year survival
If radical mastectomyperformed
}
Alternative treatment strategies for LABC
Radiotherapy Chemotherapy Chemoradiotherapy Clinical responses of 60-70% with
various chemotherapies
Pathological complete response (pCR) in neoadjuvant Taxotere studies
13% (B18)
* **
**
*pCR incorporates lymph nodes
single
agent
concurrent sequential
Pathological Response and Survival(Miller and Payne grading system)
51.0
0.9
0.8
0.7
0.6
0.5
0.40 20 40 60 80 100 120 months
surv
ival
p=0.003*p=0.003*
43
21
Ogston et al, 2003
Aberdeen Tax301 Aberdeen Tax301 Pathological responses
Hutcheon et al, SABCS 2003
*p=0.06
5
19%pNR
pCR 31%*15%
17%15%4
23%27%3
17%19%2
2%1
Taxoteren = 52
CVAPn = 52
Miller & Payne Grade of Pathological
Response
NSABP B18: Updated results
Still no difference in overall survival Pathological complete response - 85%
year survival at 9 years
67% vs 75%56% vs 60%50 and over
71% vs 65%55% vs 46%49 and under
OSNeoadj vs adj
DFINeoadj vs adj
Age
Wolmark et al, 2001
NSABP B-27 trial
All patients receive initial AC chemo
Group I; No further treatment
Group II: 4 cycles of Docetaxel after surgery
Group III: 4 cycles of Docetaxel before surgery
NSABP-B27
Clinical complete response rates 36-40% vs 65 %
Path CR 9 % and 18 %
PST:Is there a role for endocrine treatment alone
Conventionally response rates with endocrine therapy are far inferior
In a largest trial so far of 337 patients, a pCR was observed in only 1.5 % patients. Eiermann et al. Ann Oncol 2001.
But things may be changing soon, Aromatase inhibitors have shown better responses in small studies.
Aberdeen Tax301Aberdeen Tax3012nd phase: non-responding patients
5
15pNR
pCR 1
64
133
112
1
Taxoteren = 46
Miller & Payne Gradeof Pathological
Response
20 (44%) patients had a grade 3,4 or 5 response
Taxotere and paclitaxel
• Similar mechanisms of action, but some differencesTaxotere has: Greater affinity for tubulin Longer half-life Longer intracellular retention Lower cardio toxicity with doxorubicin
PST: scientific basis
Pulmonary metastases in animals underwent growth spurt on removal of primary tumor, this can be overcome by prior chemotherapy
Growth fractions in cell populations suggest micro metastases might respond differently to preoperative chemotherapy
Goldie–Coldman hypothesis suggests that resistance to chemotherapy was a function of time, hence early treatment might be better.
TAX 301 Study Conclusions
After 4 cycles of CVAP and Taxotere: Increased the complete response rate to 62% in
initially responsive patients vs. 34% for continued CVAP
pCR of 31% (ITT analysis)
increased 5 year DFS and Survival
Achieve a higher rate of Breast conservation
• Patients unresponsive to primary CVAP chemotherapy receiving further sequential Taxotere achieve :
– 47% Clinical ORR– 1 Complete pathological response
TAX 301 Study Conclusions
NSABP B-27 : Conclusions
Clinical Complete Response:40% vs 65% (63% )
Pathologic Complete Response:13.7% vs 26.1% (91% )
Negative Axillary Nodes:50.8% vs 58.2% (16% )
The addition of preoperative Taxotere to preoperative AC resulted in a significant increase in the rates of:
PST; Early rand. trial
Scholl et al from Institut Curie
414 premenopausal women, T2,T3,N0-N1
4 cycles CAF followed by RT (surgery only for those who did not have CR) VS Surgery followed by 4 cycles of same chemo
FU 54 months OS better in primary chemo arm, no difference in disease free survival or local recurrence
Bordeaux trial
272 women with lesions more than 3 cms rand between mastectomy and chemo if nodes positive VS initial chemotherapy followed by RT/ surgery
34 months FU patients with initial chemo better overall survival, however more isolated recurrence occurred in these patients.
79% (B18)29% of tumours < 2cm in the B18 study
single agent
concurrent sequential
Clinical response rates in neoadjuvant Taxotere studies
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