NeoadjuvantChemotherapyfor Ca Breast

CY Choi

UCH

JHSGR Sep 2004

Synonyms

Primary chemotherapyPrimary chemotherapy NeoadjuvantNeoadjuvant chemotherapy chemotherapy Induction chemotherapyInduction chemotherapy Preoperative chemotherapyPreoperative chemotherapy

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Development

IndicationsIndications:: Inoperable Ca breastInoperable Ca breast Locally advanced Ca breastLocally advanced Ca breast Large operable Ca breastLarge operable Ca breast ? All Biopsy confirmed invasive Ca breast? All Biopsy confirmed invasive Ca breast

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Advantages

1.1. tumour size and allow tumour size and allow breast conservationbreast conservation

2.2. evaluate evaluate chemoresponsivenesschemoresponsiveness of tumour of tumour

3.3. effectiveness of systemic treatment for effectiveness of systemic treatment for micrometastasismicrometastasis

4.4. stimulation of metastatic cancer cell by tumour stimulation of metastatic cancer cell by tumour excisionexcision

5.5. May turn off surgically induced growth factorsMay turn off surgically induced growth factors

6.6. Treat Treat LNLN, , axillary dissection axillary dissection

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Disadvantages

1.1. May treat in situ disease(if only FNA done)May treat in situ disease(if only FNA done)2.2. ability of pathology to act as ability of pathology to act as prognosticprognostic

indicatorindicator3.3. ability of surgical ability of surgical assessment of original assessment of original

tumourtumour after chemotherapy after chemotherapy4.4. ability to evaluate axillary LN statusability to evaluate axillary LN status5.5. ability to evaluate biologic characteristics ability to evaluate biologic characteristics

of tumourof tumour

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Review

LiteratureLiterature

Chemotherapy RegimeChemotherapy Regime

Treatment of axillaTreatment of axilla

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Response to chemotherapy

ClassificationClassification

complete response complete response (( 100%) 100%)

partial response partial response ((>50%)>50%)

static diseasestatic disease

disease progression disease progression ((>25%)>25%)

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Predictors of response to primary chemotherapy pCR is good prognostic factorpCR is good prognostic factor for disease for disease

free and overall survivalfree and overall survival pCR is predictive of complete axillary LN pCR is predictive of complete axillary LN

responseresponse pCR more seen in ER-, anaplastic, small pCR more seen in ER-, anaplastic, small

size tumoursize tumourKuerer, McMasters. J Clin Oncol 1999Kuerer, McMasters. J Clin Oncol 1999

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Perioperative management

MarkMark the tumour before chemotherapy the tumour before chemotherapy MonitorMonitor tumour response regularly tumour response regularly Residual mass in mammogram and USG may not Residual mass in mammogram and USG may not

be viable tissue, ?role of MRI be viable tissue, ?role of MRI (Cancer 1996)(Cancer 1996)

Well planned surgeryWell planned surgery Resection marginResection margin Tumour/breast size ratioTumour/breast size ratio Extent of microcalcificationsExtent of microcalcifications

Evidence

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NSABP-B18 J Clin Oncol 1998

RCT (RCT (PreopPreop vs vs PostopPostop chemotherapy) chemotherapy)

doxorubicin/cyclophosphamide x 4 coursesdoxorubicin/cyclophosphamide x 4 courses

1523 F1523 F

Stage I/II/III Breast cancer (Tumour size 2-5cm Stage I/II/III Breast cancer (Tumour size 2-5cm

60%, >5cm 13%)60%, >5cm 13%)

FU 5yrFU 5yr

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ResultsChemotherapy Chemotherapy regimeregime

PreopPreop PostopPostop

Response*Response* 80% 80% tumor size tumor size >50%>50%

pCR 10%pCR 10%

Nodal response 89%Nodal response 89%

BCTBCT (>5cm)(>5cm)

67.8%67.8% 22%22%

59.8%59.8% 8%8%

•Ipsilateral Ipsilateral recurrencerecurrence•DFSDFS•Overall Overall survivalsurvival(9y)(9y)

8%8%

85.7%85.7%70%70%

6%6%

==70%70%

*Multivariate analysis indicate that clinical tumour size, clinical nodal status were *Multivariate analysis indicate that clinical tumour size, clinical nodal status were independent predictors of complete clinical responseindependent predictors of complete clinical response

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Bordeaux Study Annals of Oncology 1999

RCT (single institution)RCT (single institution) MRM +/- adjuvant chemo vs MRM +/- adjuvant chemo vs Primary chemo+ surgeryPrimary chemo+ surgery(mastectomy >2cm, BCT+RT (mastectomy >2cm, BCT+RT

<2cm)<2cm) Chemotherapy regime:Chemotherapy regime:

3 cycles of epirubicin, vincristine, methotrexate, 3 cycles of epirubicin, vincristine, methotrexate, then 3 cycles of mitomycin C, thiotepa, vindesinethen 3 cycles of mitomycin C, thiotepa, vindesine

272F272F Clinical T>3cmClinical T>3cm Median FU: 124monthsMedian FU: 124months

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ResultsResults Preop chemotherapyPreop chemotherapy

BCT possible in 45%BCT possible in 45%More local recurrencesMore local recurrencesSimilar survivalSimilar survival

LimitationLimitation Treatment arms not really balancedTreatment arms not really balanced

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Milan trials J Clin Oncol 1998

Prospective (Prospective (nonRCTnonRCT)) Chemotherapy regimeChemotherapy regime

3-4 cycles of CMF / FAC / FEC / FNC / adriamycin3-4 cycles of CMF / FAC / FEC / FNC / adriamycin 536F536F T>2.5cmT>2.5cm Median age 49Median age 49 Median FU 65 monthsMedian FU 65 months ResultsResults

Overall response 76% - cCR 16%Overall response 76% - cCR 16% - pCR 3%- pCR 3% - PR 60%- PR 60% Stable disease 5%Stable disease 5% Minor response(<50% reduction) 16%Minor response(<50% reduction) 16% Progressive disease 5%Progressive disease 5%

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BCT possibleBCT possible in 85%(in 62% patients with in 85%(in 62% patients with tumour >5cm)tumour >5cm)

Local relapse after BCT 6.8%Local relapse after BCT 6.8% Response Response in receptor –ve tumour, unrelated to in receptor –ve tumour, unrelated to

age, menopausal status, chemo regimenage, menopausal status, chemo regimen Multivariate analysis showed response to primary Multivariate analysis showed response to primary

chemo and axillary LN involvement correlate with chemo and axillary LN involvement correlate with disease free survivaldisease free survival

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NSABP-B 27 Just closed

Randomised to preop chemotherapyRandomised to preop chemotherapy Gp 1 AC+ TAM -> surgeryGp 1 AC+ TAM -> surgery Gp 2 AC+ TAM -> Gp 2 AC+ TAM -> taxotere taxotere -> surgery-> surgery Gp 3 AC+ TAM -> surgery-> taxotereGp 3 AC+ TAM -> surgery-> taxotere

cT1-3, N0-1cT1-3, N0-1 2411F2411F Results: Results:

no difference in BCT (60%)no difference in BCT (60%) Gp 2 increase pCR(26.1 vs 13.7%)Gp 2 increase pCR(26.1 vs 13.7%)

Pending 5 yr survival 2005Pending 5 yr survival 2005

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EORTC 10902 J Clin Oncol 2001

RCT (RCT (Preop Preop vsvs Postop Postop chemotherapy) chemotherapy) 4 cycles of 5FU, Epirubicin, cyclophosphamide4 cycles of 5FU, Epirubicin, cyclophosphamide 698698F (Yr 1991-1999)F (Yr 1991-1999) (T1c, T2, 3, 5b, N0, 1 and M0)(T1c, T2, 3, 5b, N0, 1 and M0) Median FU 56mosMedian FU 56mos Results:Results:

No difference in OS, PFS, LRRNo difference in OS, PFS, LRR 23% downstaged23% downstaged

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Chemotherapy Regime Which has Which has Response Rate Response Rate ? ? Primary chemotherapy with doxorubicin Primary chemotherapy with doxorubicin

and docetaxel is well tolerated and highly and docetaxel is well tolerated and highly activeactive

TaxaneTaxane to to pCR comparing with FAC pCR comparing with FAC Sequential treatmentSequential treatment schedule is a little schedule is a little

more active than combination therapy, but a more active than combination therapy, but a higher toxicityhigher toxicity

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Role of Sentinel LN biopsy or axillary dissection Incidence of histological negative axillary LN 37% greater Incidence of histological negative axillary LN 37% greater

- - NSABP B-18NSABP B-18

23% has 23% has histological conversionhistological conversion from + to from + to – (MD Anderson)– (MD Anderson)

Can axillary irradiation replace ALNDCan axillary irradiation replace ALND in patients in patients

downstaged from node + to – ?downstaged from node + to – ?

Axillary irradiation without axillary LN dissection may Axillary irradiation without axillary LN dissection may

provide adequate local control in patients with at least a provide adequate local control in patients with at least a

partial response. partial response. Lenert JT. Ann Surg Oncol 99 Lenert JT. Ann Surg Oncol 99

Buzdar AU, J Clin Buzdar AU, J Clin

Oncol 99.Oncol 99.

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SLN

Small sample size, Variable results for SLN Small sample size, Variable results for SLN identification and FN finding(1-11%)identification and FN finding(1-11%)

SLNB is reliable for accurate staging of SLNB is reliable for accurate staging of axillaaxilla in advanced Ca breast in advanced Ca breast Haid A. Cancer 2001Haid A. Cancer 2001

SLN accurately predict axillary LN status in SLN accurately predict axillary LN status in 96% patients(325/340) 96% patients(325/340) ASCO Annual meeting 2002ASCO Annual meeting 2002

FN rateFN rate 9% 9% NSABP B27NSABP B27 4.3% 4.3% MD Anderson CCMD Anderson CC

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Conclusion Neoadjuvant chemotherapy Neoadjuvant chemotherapy

breast conservationbreast conservation survival benefitsurvival benefit

Recommended for Recommended for Stage II, IIIStage II, III Ca breast Ca breast ?extrapolate to early Ca breast?extrapolate to early Ca breast Prognostic value of axillary LNPrognostic value of axillary LN Accuracy of SLNBAccuracy of SLNB not affected not affected Study on QOLStudy on QOL