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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