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