neoadjuvant chemotherapy
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Treatment given prior to the primary treatment in order tomake the tumor amenable to primary treatment (usuallysurgery or radiation).
Neoadjuvant therapy may include chemotherapy, hormonetherapy &/or radiation therapy.
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Advantages Early assessment of response to chemotherapy. Better prediction of long term outcome. Possible down staging of the disease. Possible organ conservation , surgery with negative margins.
Disadvantages Patients who do not achieve a major response to neoadjuvant
chemotherapy, delay of definitive local treatment could potentially beassociated with disease progression due to delayed definitive therapy.
Exact pathological stage at presentation is not known.
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Aims of neoadjv therapy & treatment options in various breast cancer populationsPopulation Aims Treatment Option
Locally advanced Primary: to improve surgicaloptionsSecondary: to obtain freedom
from diseaseTo gain info on tumor response
Fit & healthy: chemotherapyUnfit & hormone sensitivedisease: endocrine therapy
Operable & candidates foradjuvant chemo
Primary: to obtain freedom fromdiseaseSecondary: to improve surgicaloptions
To gain info on tumor response
Chemotherapy (Ovariansuppression &/or AIs)Sequence Vs CombinationLonger Vs Shorter
Operable & candidates foradjuvant endocrinetherapy alone
Primary: to improve surgicaloptionsSecondary: to gain info on tumor
response
Endocrine treatmentTamoxifen vs Ais
JCO Vol 24, pp 1940-, 2006
Breast cancer
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Advantages Assessment of tumor response to chemotherapy Prompt treatment of the micrometastases May downstage the primary tumor Increases the likelihood of BCS
Disadvantages Loss of prognostic information-ALN status Delayed local or regional therapy Induction of drug resistance
Core biopsy should always be performed prior to neoadjuvantchemotherapy to obtain sufficient tissue to identify histologicsubtype, ER/PR status and Her2 Neu status
Breast cancer
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Indications
1. Locally advanced breast cancer
- Stage IIIB, T4 or N3 cancer
- Stage IIIA inoperable cancer
2. T2 or T3 tumors, to make BCS feasible
Breast cancer
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Breast CancerResults from EBCTCG 2006based on 4700 patients from 11 trials
* If no surgery, generally given radiotherapy
Surgery NeoadjvChemotherapy
Standard Therapy
BCS/None* 62% 46%
Mastectomy 38% 54%
Total 100% 100%
Extent of surgery
Breast cancer
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Breast CancerResults from EBCTCG 2006based on 4700 patients from 11 trials
In the neoadjuvant arm 18% of the women receivedless extensive surgery (BCS or no surgery comparedto mastectomy.
Extent of surgery
Breast cancer
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Breast CancerResults from EBCTCG 2006
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Breast CancerResults from EBCTCG 2006
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Breast CancerResults from EBCTCG 2006
Summary 18% of women in the neoadjuvant arm had a less extensive surgical
procedure. 3% loss in absolute local recurrence risk at 5 yrs. No significant difference in any recurrence, breast cancer mortality or
death by 10 yrs.
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Rectal Cancer
Rectal cancer Patients to consider for neoadjuvant chemoradiotherapy:
T3-4 and/or N+ disease
Low-lying rectal lesions if considering sphincter-sparing procedures
Neoadjuvant CRT compared to RT:
No improvement in OS or PFS
Significant tumor downstaging & local recurrence
No in sphincter-sparing procedures
Preoperative CRT compared to postoperative CRT:
No improvement in OS or PFS
Significant tumor downstaging & local recurrence
? improvement in sphincter-sparing procedures
early and late toxicity
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Rectal CancerSummary of randomized trials
1. Are rectal tumors downstaged (pCR) with neoadjuvant CRT? FFCD 9203 Trial: YES (11.4% CRT v. 3.6% RT; p
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Rectal CancerSummary of randomized trials
3. Does neoadjuvant CRT OS or PFS?
FFCD 9203 Trial: NO - 67.4% / 59.4% (5-year)
Polish Trial: NO -66.2% / 55.6% (4-year)
EORTC 22921 Trial: NO -64.8% / 56.1% (5-year)
German Trial: NO -76% / 68% (5-year)
4. Does neoadjuvant CRT risk of local recurrence // distant recurrence?
FFCD 9203 Trial: YES (8.1% CRT v. 16.5% RT) // NO (36%)
Polish Trial: NO (15.6% CRT v. 10.6% RT) // NO (34.6%)
EORTC 22921 Trial: YES (13.7% CRT v. 5.3%) // NO (34.4% all grps)
German Trial: YES (6% Preop CRT v. 13% Postop CRT) // NO (36% Pre)
NO. But better OS/PFS
Seen in German Trial
YES, risk of local recurrence.
NO risk of distant recurrence
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Bladder CancerSystematic review& meta-analysis
Winquist. JU 2004; 171 : 561
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Pooled HR from 8 combination chemo RCTs : 0.87 (95% CI 0.78-0.96)
13% decrease in risk of death
6.5% absolute improvement in overall survival
Bladder CancerSystematic review& meta-analysis
Winquist. JU 2004; 171 : 561
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Bladder Cancer
Bladder cancer - Modest increase in survival
Does not negatively impact surgical outcome
Appropriate to offer neoadjuvant chemotherapy to every surgicalcandidate with muscle invasive bladder cancer
Can allow bladder conservation with radiation therapy in case of good
response.
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Head & Neck
Head & NeckRationale for neoadjuvant chemo:
With reduced tumor burden radiotherapy is more effective
Drug delivery through intact vasculature
Early treatment of micrometastasis
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Head & Neck
Head & NeckASCO 2006 guidelines: T3 or T4 laryngeal cancers without tumor invasion through cartilage ,
larynx preservation CCRT is an appropriate standard treatment approach
T3supraglottic cancers with minimal or moderate pre-epiglottic invasionare candidates for organ preserving surgery
J Clin Oncol 2006Aug1;24 (22):3693-704
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Head & Neck
Head & NeckRationale for neoadjuvant chemo: Chemoradiation still is the standard for locally advanced HNC
Docetaxelbasedneoadjuvant (TCF) appears to be emerging as the new
standard for induction chemotherapy
The contribution of neoadjuvant chemotherapy to treatment withconcomitantchemoradiation is the topic of prospective studies
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Jan B. Vermorken, N EnglJ Med 2007;357:1695-704.
EORTC 24971/TAX323 INDUCTION CT + LOCOREGIONAL RT
Head & Neck
d k
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EFFECTS OF TPF AND PF THERAPY ON PROGRESSION-FREE SURVIVAL
Head & Neck
d k
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EFFECTS OF TPF AND PF THERAPY ON OVERALL SURVIVAL
Head & Neck
H d & N k
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Jan B. Vermorken, N EnglJ Med 2007;357:1695-704.
EORTC24971/TAX 323 CLINICAL RESPONSE (ITT)
Head & Neck
O t
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Osteosarcoma
Osteosarcoma- 2 yr survival of patients treated with surgery alone 15% only.
Highly chemosensitive tumor.
03 to 04 cycles of neoadjuvant chemotherapy recommended, to befollowed by limb sparing surgery.
Histopathological assessment of %age of tumor necrosis secondary to
neoadjuvant chemotherapy. If >90% tumor necrosis, 3 to 4 cycles ofsame chemo administered in adjuvant setting. Otherwise chemotherapyprotocol changed.
2 yr survival with chemo & surgery 80% for localized disease.
E i
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Ewings sarcoma
Ewings sarcoma- Considered a systemic disease.
Bone marrow examination part of staging workup.
5 yr survival prior to the availability of effective chemotherapeutic agents< 10 %. With chemotherapy, 5 yr OS has improved to 73% for localizeddisease and 35 % for metastatic disease.
9 to 12 weeks of neoadjuvant chemotherapy recommended, followed bylocal therapy (surgery or radiation therapy). Total duration ofchemotherapy 54 weeks.
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sarcomas
Neoadjuvant radiation therapy Smaller field sizes.
Downsizing of tumor, amenable to surgery.
More incidence of wound complications compared to adjuvant radiationtherapy
Neoadjuvant chemotherapy Not a standard at present.
Pt should ideally be enrolled in a clinical trial. If no trial is available,neoadjuvant chemotherapy should be offered to fit and younger patients(< 60 yrs). Chemotherapies have shown response rates of 30 to 40% inmetastatic disease.
Prostate
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NHS Feb 2008
Prostate
Prostate
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Prostate
Neoadjuvant hormone therapy
3 months of neoadjuvant hormone therapy recommended prior toradiation therapy in intermmediate risk disease and 6 months
recommended in high risk disease.
Down sizes the tumor so that smaller fields are required for radiationtherapy.
Controls micro-metastatic disease.
No role prior to surgery, as tumor margins and exact pathologicalgleason grade & score cannot be assessed accurately, as hormonetherapy causes architectural distortion.
Advanced ovarian
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Chemosensitive
Successful
Debulking
Survival
A basis for NACT?
Advanced ovariancancer
Biologic Characteristics of Tumor vs Aggressiveness of Surgeryin ADOVCA
Advanced ovarian
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Advanced ovariancancer
Study Stage of Chemotherapy No. of Outcome
Group disease pts
EORTC* IIb-IV 3 x CP II 3 x CP 319 49%
1995/2001 RD > 1 cm vs 6 x CP risk of death
GOG III-IV 3 x TP II 3 x TP 550 no risk
2002 RD > 1 cm vs 6 x TP reduction
* van der Burg et al (NEJM 1995 [2001])
Rose et al (NEJM, 2004)
Potential Role of Interval Debulking in OCSuboptimally debulked
Advanced ovarian
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100
90
80
70
60
50
40
30
20
10
0
0 2 4 6 8 10
p=0.0032
Years
O N Number of patients at risk:
122 159 84 40 16 5 Surgery138 160 64 21 10 4 No Surgery
Treatment
Survival By Treatment
Advanced ovariancancer
Advanced ovarian
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Phase III trial India (New Delhi) 128 stage III/IV (pleural effusion only) Arm A: primary surgery6 x TC Arm B: 3 x TCIDS3 x TC
Results:
Higher optimal debulking rate in B (p
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396 patients with pN2 (stage IIIA) disease Arm A: chemoradiation (EP + 45 Gy RT)Surgery Arm B: Definitive chemoradiation (EP + 61 Gy)
Results:
pCR 46% in arm A
More treatment related deaths in arm A (8% Vs 2%)
5 yr disease PFS better in arm A (22% Vs 5%)
5 yr OS better in arm A (27% Vs 20%)
Greatest benefit was seen in pN0 & in non-pneumonectomy pts.
Kumar et al, ASCO abstract #5531 (2007)
Neoadjuvant Chemoradiation followed by surgical resection in IIIA (N2 disease)versus definitive chemoradiation without surgeryIntergroup Trial 0139
Advanced NSCLC
Advanced NSCLC
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Neoadjuvant therapy in IIIA topic of prospective trials. Being evaluated in NATCH trial ( Neoadjuvant trial of chemotherapy hope)
Neoadjuvant Chemoradiation followed by surgical resection in IIIA (N2 disease)versus definitive chemoradiation without surgery
Advanced NSCLC
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