Treatment given prior to the primary treatment in order to

make the tumor amenable to primary treatment (usually

surgery or radiation).

Neoadjuvant therapy may include chemotherapy, hormone
therapy &/or radiation therapy.

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 be
associated with disease progression due to delayed definitive therapy.
Exact pathological stage at presentation is not known.
Aims of neoadjv therapy & treatment options in various breast cancer populations
Population Aims Treatment Option
Locally advanced Primary: to improve surgical
options
Secondary: to obtain freedom
from disease
To gain info on tumor response
Fit & healthy: chemotherapy
Unfit & hormone sensitive
disease: endocrine therapy
Operable & candidates for
adjuvant chemo
Primary: to obtain freedom from
disease
Secondary: to improve surgical
options
To gain info on tumor response

Chemotherapy (Ovarian
suppression &/or AIs)
Sequence Vs Combination
Longer Vs Shorter
Operable & candidates for
adjuvant endocrine
therapy alone
Primary: to improve surgical
options
Secondary: to gain info on tumor
response
Endocrine treatment
Tamoxifen vs Ais
JCO Vol 24, pp 1940-, 2006
Breast cancer
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 neoadjuvant
chemotherapy to obtain sufficient tissue to identify histologic
subtype, ER/PR status and Her2 Neu status

Breast cancer
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
Breast Cancer
Results from EBCTCG 2006
based on 4700 patients from 11 trials








* If no surgery, generally given radiotherapy

Surgery Neoadjv
Chemotherapy
Standard Therapy
BCS/None* 62% 46%
Mastectomy 38% 54%
Total 100% 100%
Extent of surgery
Breast cancer
Breast Cancer
Results from EBCTCG 2006
based on 4700 patients from 11 trials




In the neoadjuvant arm 18% of the women received
less extensive surgery (BCS or no surgery compared
to mastectomy.









Extent of surgery
Breast cancer
Breast Cancer
Results from EBCTCG 2006
Breast Cancer
Results from EBCTCG 2006
Breast Cancer
Results 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.

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

Rectal Cancer
Summary of randomized trials
1. Are rectal tumors downstaged (pCR) with neoadjuvant CRT?
FFCD 9203 Trial: YES (11.4% CRT v. 3.6% RT; p<0.0001)
Polish Trial: YES (16.1% CRT v. 0.7% RT; p<0.001)
EORTC 22921 Trial: YES (13.7% CRT v. 5.3%; p<0.001)
German Trial: YES (8% Preop CRT v. 0% Postop CRT)


2. Does neoadjuvant CRT rate of sphincter-sparing surgeries?
FFCD 9203 Trial: NO
Polish Trial: NO
EORTC 22921 Trial: NO
German Trial: NO (Preop vs Postop CRT)
All Studies Show
pCR with CRT

No. But, in German Trial those
Determined to need APR prior
To randomization had rates of
Sphincter-preservation with CRT
Preoperatively.

Rectal Cancer
Summary 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

Bladder Cancer
Bladder cancer
Systematic review & meta-analysis of all known RCTs of neoadjuvant
chemo for T2 T4a, N0/x TCC

16 RCTs identified, 11 with data suitable for survival (2605 pts)

8 RCTs were of cisplatin based combination chemotherapies

Winquist. JU 2004; 171 : 561
Bladder Cancer
Systematic review
& meta-analysis
Winquist. JU 2004; 171 : 561
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 Cancer
Systematic review
& meta-analysis
Winquist. JU 2004; 171 : 561
Bladder Cancer
Bladder cancer -
Modest increase in survival

Does not negatively impact surgical outcome

Appropriate to offer neoadjuvant chemotherapy to every surgical
candidate with muscle invasive bladder cancer

Can allow bladder conservation with radiation therapy in case of good
response.

Head & Neck
Head & Neck
Rationale for neoadjuvant chemo:
With reduced tumor burden radiotherapy is more effective
Drug delivery through intact vasculature
Early treatment of micrometastasis

Head & Neck
Head & Neck
ASCO 2006 guidelines:
T
3
or T
4
laryngeal cancers without tumor invasion through cartilage ,
larynx preservation CCRT is an appropriate standard treatment approach

T3 supraglottic cancers with minimal or moderate pre-epiglottic invasion
are candidates for organ preserving surgery


J Clin Oncol 2006 Aug1;24 (22):3693-704

Head & Neck
Head & Neck
Rationale for neoadjuvant chemo:
Chemoradiation still is the standard for locally advanced HNC

Docetaxel based neoadjuvant (TCF) appears to be emerging as the new
standard for induction chemotherapy

The contribution of neoadjuvant chemotherapy to treatment with
concomitant chemoradiation is the topic of prospective studies
Jan B. Vermorken, N EnglJ Med 2007;357:1695-704.

EORTC 24971/TAX323 INDUCTION CT + LOCOREGIONAL RT
Head & Neck
EFFECTS OF TPF AND PF THERAPY ON PROGRESSION-FREE SURVIVAL
Head & Neck
EFFECTS OF TPF AND PF THERAPY ON OVERALL SURVIVAL
Head & Neck
Jan B. Vermorken, N EnglJ Med 2007;357:1695-704.

EORTC24971/TAX 323 CLINICAL RESPONSE (ITT)
Head & Neck
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 be
followed by limb sparing surgery.

Histopathological assessment of %age of tumor necrosis secondary to
neoadjuvant chemotherapy. If >90% tumor necrosis, 3 to 4 cycles of
same chemo administered in adjuvant setting. Otherwise chemotherapy
protocol changed.

2 yr survival with chemo & surgery 80% for localized disease.

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 localized
disease and 35 % for metastatic disease.

9 to 12 weeks of neoadjuvant chemotherapy recommended, followed by
local therapy (surgery or radiation therapy). Total duration of
chemotherapy 54 weeks.

sarcomas
Neoadjuvant radiation therapy
Smaller field sizes.

Downsizing of tumor, amenable to surgery.

More incidence of wound complications compared to adjuvant radiation
therapy

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% in
metastatic disease.



NHS Feb 2008
Prostate
Prostate
Neoadjuvant hormone therapy

3 months of neoadjuvant hormone therapy recommended prior to
radiation therapy in intermmediate risk disease and 6 months
recommended in high risk disease.

Down sizes the tumor so that smaller fields are required for radiation
therapy.

Controls micro-metastatic disease.

No role prior to surgery, as tumor margins and exact pathological
gleason grade & score cannot be assessed accurately, as hormone
therapy causes architectural distortion.


Chemosensitive


Successful
Debulking
Survival
A basis for NACT?
Advanced ovarian
cancer
Biologic Characteristics of Tumor vs Aggressiveness of Surgery
in ADOVCA
Advanced ovarian
cancer

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 OC
Suboptimally debulked

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 Surgery
138 160 64 21 10 4 No Surgery
Treatment
Survival By Treatment
Advanced ovarian
cancer
Phase III trial India (New Delhi)
128 stage III/IV (pleural effusion only)
Arm A: primary surgery 6 x TC
Arm B: 3 x TC IDS 3 x TC

Results:
Higher optimal debulking rate in B (p<.0001)
Decrease blood loss in B (p<.003)
Reduced postoperative infections (p<.04)
Quality of life score better in B (p<.001)
Disease-free and overall survival not different to date

Kumar et al, ASCO abstract #5531 (2007)
Neoadjuvant Chemotherapy followed by IDS versus Surgery followed by
chemotherapy
A prospective randomized study
Advanced ovarian
cancer
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 surgery
Intergroup Trial 0139
Advanced NSCLC
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