Neoadjuvante Therapy of Breast Cancer
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Transcript of Neoadjuvante Therapy of Breast Cancer
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Neoadjuvante Therapy Neoadjuvante Therapy of Breast Cancerof Breast Cancer
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
• Cancer statistics• Genesis of cancer• Cancer in detail • Treatment of cancer • Prevention• Follow-up• NEWS• Research
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
INCIDENCE OF CANCERINCIDENCE OF CANCER
• Colorectal cancer• Breast cancer • Lung Cancer• Prostate cancer• Cervix carcinoma
Meaning of • Prevention and• risk - behavior
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Principles of treatment for Principles of treatment for malignant disease at an early malignant disease at an early
stagestage
• most possible radical removal of tumour with
maximal protection of healthy structures and
precise indication.
• preventing the growth of possible metastasis
depending on the availability of effective
treatment and tumour characteristics
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Principles of treatment for Principles of treatment for malignant disease with distant malignant disease with distant
metastasesmetastases
• Maintain organ function• Quality of life• Prolongation of life with consideration of QoL
and tolerance of treatment • Psychological support, if wished for • Adequate pain management
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Treatment modalities for Treatment modalities for malignant diseasesmalignant diseases
• Surgery• Radiation therapy• Chemotherapy• Anti-hormone therapy• Antibodies• Disturbance of the capillary supply• Gene manipulation
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Main feedback mechanisms of cell division Main feedback mechanisms of cell division and their down-regulation in the and their down-regulation in the
development of cancer.development of cancer.
1. Independence of cell replication from exogeneous growth factors.
2. Insensitivity to growth factors – inhibition signaling
3. Resistance to induction of apoptosis 4. Unlimited span of life5. Neoangiogenesis 6. Cellular mobility and cell growth in foreign tissue
Hanahan & Weinberg, Cell 100: 57, 2000.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Cancer treatment in breast cancer as an example
Treatment dependent from
• Tumour characteristics• time of treatment• desired short- and middle term results
At a cleat long-term goal of a disease free survival
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Characteristics of breast Characteristics of breast cancer cells cancer cells
• Growthhormone receptors HER-2/neu-Protein overexpression
• Differentiationhistopathological differentiation
• Dissemination lymph node infiltration
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
* NEOADJUVANT THERAPY
* ADJUVANT THERAPY
* PALLIATIV THERAPY
Medical-oncologic form of Medical-oncologic form of treatment in malign diseasestreatment in malign diseases
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Medical-oncologic treatment is administered pre-surgical
NEOADJUVANT THERAPYNEOADJUVANT THERAPY
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Administration of substances that known to inhibit cell division (chemotherapy, anti-
hormone therapy) pre-operatively with the goal to decrease tumour size and thereby
decrease the extension of surgical intervention.
Response to neoadjuvant therapy is a parameter for tumour cells and their
treatment sensitivity (!)
CONCEPT OF NEOADJUVANT CONCEPT OF NEOADJUVANT THERAPY IN BREAST CANCERTHERAPY IN BREAST CANCER
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
1. ZEITVERSÄUMNIS by surgery-delay (= potential danger for the patient?)
2.Quality of treatment result in comparison to post-surgery (adjuvant) therapy
3. Advantages?
Open question conserning the concept of Open question conserning the concept of neoadjuvant therapy in breast cancer.neoadjuvant therapy in breast cancer.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
STUDY DESIGN
1.523 patients with breast cancer, who received
747 pre-surgery (neoadjuvant) chemotherapy759 post-surgery (adjuvant) chemotherapy
Chemotherapy scheme: AC
NEOADJUVANT THERAPY IN NEOADJUVANT THERAPY IN BREAST CANCER:BREAST CANCER:
NSABP B-27 STUDYNSABP B-27 STUDY
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
TUMOR SIZE <2cm 2.1-5.0cm >5.1cm
COMPLETE REMISSION 57% 35% 17%PARTIAL REMISSION 22% 46% 58%STABLE DISEASE 15% 16% 22%PROGRESSION 5% 3% 3%
NEOADJUVANT THERAPY IN NEOADJUVANT THERAPY IN BREAST CANCER:BREAST CANCER:
NSABP B-27 STUDYNSABP B-27 STUDY
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
TUMOR SIZE <2cm 2.1-5.0cm >5.1cm
INITIAL PRESENTATION 79% 63% 8%
AFTER CHEMOTHERAPY 81% 71% 22%
NEOADJUVANT THERAPY IN BREAST NEOADJUVANT THERAPY IN BREAST CANCER: EINFLUSS AUF CANCER: EINFLUSS AUF
BRUSTERHALTENDE CHIRURGIE.BRUSTERHALTENDE CHIRURGIE.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
NEOADJUVANT ADJUVANT
DISEASE FREE 67% 67%
5-YEAR-SURVIVAL 80% 80%
NEOADJUVANT THERAPY IN NEOADJUVANT THERAPY IN BREAST CANCER : SURVIVAL DATA BREAST CANCER : SURVIVAL DATA
IN THE NSABP-B27 STUDY.IN THE NSABP-B27 STUDY.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
1. Neoadjuvant therapy is possible
2. Neoadjuvant therapy reduces tumour size and allows reduced surgical intervention
3. Patients have no disadvantage with a delay of surgery
NEOADJUVANT THERAPY IN NEOADJUVANT THERAPY IN BREAST CANCER : CONCLUSION BREAST CANCER : CONCLUSION
FROM THE NSABP-B27 STUDY.FROM THE NSABP-B27 STUDY.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
EXTREMITY CONSERVING SURGERY IN EXTREMITY CONSERVING SURGERY IN TUMOURS OF THE BONE : 30-YEAR-TUMOURS OF THE BONE : 30-YEAR-RESULTS OF THE DEPARTMENT OF RESULTS OF THE DEPARTMENT OF
ORTHOPEDIC, UNIVERSITY HOSPITALORTHOPEDIC, UNIVERSITY HOSPITAL
Period 1 Period 2 Period 3(1965-1974) (1975-1984) (1985-1994)
Died 116 (71.6%) 104 (53.3%) 152 (37.3%)Alive 46 (28.4%) 91 (46.7%) 256 (62.7%)
3-year-survival 76 (46.9%) 120 (61.5%) 295 (72.3%)
R. Kotz et al., 2000
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
* Is administered after surgery in patients who have no clinical manifestation of distant-metastases, however the probability of disease relapse.
* Goal: prolongation of disease-free interval and survival time
ADJUVANT THERAPYADJUVANT THERAPY
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
DECISION CRITERIA FOR ADJUVANT DECISION CRITERIA FOR ADJUVANT THERAPYTHERAPY
* Probability of relapse (= metastases) * Probability of treatment efficacy * Therapy-associated toxicity in relation to treatment result
* Only statistical consulting, not individual
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ADJUVANT THERAPY: PROGNOSTIC DISEASE VARIABLES
* Affected local lymph nodes * Tumour size * Radical surgery concerning the removal of tumour cells * Tumour characteristics that can be influenced biologically and therapeutically * Biologic characteristics of the tumours that make a relapse probable
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
RATIONALE OF ADJUVANT RATIONALE OF ADJUVANT THERAPYTHERAPY
* Small tumour cell clusters (<3mm) are not visible even with the best radiological methods. Their presence can only be assumed using the known risk factors.
* Disseminated tumour cells “awaken” from their „dormant state“, growth and form undetectable metastases.
* small tumour cell cluster are treatable more effectively than large, radiological detectable metastases
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ADJUVANT THERAPY IN BREAST CANCER:ADJUVANT THERAPY IN BREAST CANCER:
RISK FACTORS FOR LATER FORMATION RISK FACTORS FOR LATER FORMATION OF METASTASESOF METASTASES
* Involvement of axillar lymph nodes (none, 1-3, 4-10, >10)
* estrogen receptor status (POSITIV / NEGATIV)
* histological grading (G1-4)
* tumour size
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ADJUVANT THERAPY IN BREAST ADJUVANT THERAPY IN BREAST CANCER: THERAPY OPTIONENCANCER: THERAPY OPTIONEN
* Radiation therapy
* Anti-hormone therapy
* Chemotherapy
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
FUNCTION OF ESTROGEN RECEPTOR
1. Localisation within the tumour cell
2. Interaction with estrogen causes activation of cell growth
3. Blockade inhibits growth of malignant cells
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
* Breast cancer cells of about 50% of all patients develops and growth under the influence of estrogen.
* Tamoxifen blocks the estrogen receptor competitively.
ADJUVANT THERAPY IN BREAST ADJUVANT THERAPY IN BREAST CANCER: THERAPY OPTIONEN CANCER: THERAPY OPTIONEN
TAMOXIFENTAMOXIFEN
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
TAMOXIFEN AS ADJUVANT TAMOXIFEN AS ADJUVANT THERAPY IN BREAST CANCERTHERAPY IN BREAST CANCER
Patients 37.000 women from 55 worldwide, randomized studies (<1990 - 1995);
= 87% of worldwide data.
Estrogen receptor (ER)- positive18.000 patients with ER-positive tumours
12.000 patients with unknown
Median Follow-up10 Years
Statistical methodsIntention-to-treat, metaanalysis
EBCTCG, LANCET 351: 1451, 1998
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
REDUCTION OF RELAPSE AND REDUCTION OF RELAPSE AND MORTALITY USING TAMOXIFEN IN MORTALITY USING TAMOXIFEN IN
DEPENDENCY OF TREATMENT DEPENDENCY OF TREATMENT DURATIONDURATION
Relapse Mortality 2p
1 Year 18 3 10 3 <.00001/.0006 2 Years 25 2 15 2 <.00001/.00001 5 Years 42 3 22 4 <.00001/.00001 Total 27 2 15 2 <.00001/.00001
EBCTCG, LANCET 351: 1451, 1998
% Reduction of
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
REDUCTION OF RELAPSE AND REDUCTION OF RELAPSE AND
MORTALITY USING TAMOXIFEN IN MORTALITY USING TAMOXIFEN IN DEPENDENCY OF ESTROGEN RECEPTOR. DEPENDENCY OF ESTROGEN RECEPTOR.
Relapse Mortality 2p
1 Year 20 mg/day 18 4 12 5 30 - 40 mg/day 22 5 11 5 >.1/.1 5 Years 20 mg/day 45 4 21 6
30 - 40 mg/day 49 5 32 6 >.1/.1
EBCTCG, LANCET 351: 1451, 1998
% REDUCTION OF
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Relapse Mortality 2p ER low 6 11 3 11 ER unknown 37 8 21 9 ER positive 50 4 28 5
Subtotal 43 3 23 4 <.00001/.00001 ER+ vs. ER- <.00001/.005
EBCTCG, LANCET 351: 1451, 1998
% REDUCTION OF
REDUCTION OF RELAPSE AND MORTALITY USING REDUCTION OF RELAPSE AND MORTALITY USING TAMOXIFEN IN DEPENDENCY OF ESTROGEN RECEPTORTAMOXIFEN IN DEPENDENCY OF ESTROGEN RECEPTOR
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
SECONDARY DISEASES AFTER 5-YEARS SECONDARY DISEASES AFTER 5-YEARS OF TAMOXIFEN-TREATMENT IN OF TAMOXIFEN-TREATMENT IN
PATIENTS WITH BREAST CANCER. PATIENTS WITH BREAST CANCER.
EVENTS/1000 YEAR 10-YEAR-RISK/1000
TAM. KONTR. 2p TAM. KONTR. DIFFERENZ KONTRALATERALE MAMMACARCINOM-INZIDENZ
93/23.6 159/21.0 <.00001 26 47 -21 5
GEBÄRMUTTERKREBS-INZIDENZ 43/26.9 9/23.6 <.0001 11 3 +9 2
GEBÄRMUTTERKREBS-MORTALITÄT 7/26.4 0/23.2 .02 2 0 +2 0.8
EBCTCG, LANCET 351: 1451, 1998
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
RESULTS OF BREAST CANCER RESULTS OF BREAST CANCER
PROPHYLAXIS IN WOMEN WITH GENETIC PROPHYLAXIS IN WOMEN WITH GENETIC DISPOSITION USING TAMOXIFEN.DISPOSITION USING TAMOXIFEN.
Study design
13.388 women with genetic disposition (high risk)
20 mg tamoxifen/day for 5 yearsPlacebo-controlled
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
DEFINITION OF INCREASED DEFINITION OF INCREASED GENETIC DISPOSITION FOR BREAST GENETIC DISPOSITION FOR BREAST
CANCER DEVELOPMENTCANCER DEVELOPMENT
1. Age > 60 Years
2. 35-59 years with an anamnesis of lobular carcinoma in situ or a 5-year-risk of >1.66% including
* one first degree relatives or * two aunts with breast cancer with breast cancer * preceding breast biopsy to verify radiological suspect areas * pathologic diagnose of a atypical hyperplasia
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
RESULTS OF BREAST CANCER RESULTS OF BREAST CANCER
PROPHYLAXIS IN WOMEN WITH GENETIC PROPHYLAXIS IN WOMEN WITH GENETIC DISPOSITION USING TAMOXIFEN.DISPOSITION USING TAMOXIFEN.
Tamoxifen Placebo
invasive breast cancer 85 154non-invasive carcinomas 31 59
Bone fractures 47 71Endometrial carcinoma 33 14Thromboembolis 99 70
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ADJUVANT CHEMOTHERAPY IN ADJUVANT CHEMOTHERAPY IN BREAST CANCER BREAST CANCER
Relapse -23.5 2.1% <.00001Death -15.3 2.4% <.00001
Lancet 352: 930, 1998.
Reduction of yearly risk using chemotherapy
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
REDUCTION OF RELAPSE AND REDUCTION OF RELAPSE AND
MORTALITY USING TAMOXIFEN AND MORTALITY USING TAMOXIFEN AND CHEMOTHERAPY IN BREAST CANCERCHEMOTHERAPY IN BREAST CANCER
Relapse Mortality 2p
5 year tamoxifen vs. 0 -46 4 -22 5
5 year tamoxifen + chemotherapy vs. chemotherapy-52 8 -47 9 >.1 />.1
EBCTCG, LANCET 351: 1451, 1998
% Reduction of
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ADJUVANT THERAPY IN ADJUVANT THERAPY IN BREAST CANCERBREAST CANCER
CONCLUSIONCONCLUSION
Adjuvant therapy with tamoxifen and/or chemotherapy leads to a significant reduction of incidence of metastases and mortality.
Choice of treatment modality depends on tumour characteristics
Improve of criteria's for selection is necessary to identify patients with a principally good prognosis.
Patients with breast cancer and their existing data patientinnen mit mammacarcinom sollte auf grund vorliegender daten adjuvante therapie empfohlen werden
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
* Is administered after clinical manifestation of distant metastasis into organs and bone
* Aims: introduce a remission, increase of survival time and palliation of symptoms
PALLIATIV THERAPYPALLIATIV THERAPY
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
* Anti-hormone therapy
* Chemotherapy
* Antibody
* Radiation therapy
* Palliativ and supportiv therapy
PALLIATIV THERAPY PALLIATIV THERAPY MODALITIESMODALITIES
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
PROGNOSTIC ORIENTATED PROGNOSTIC ORIENTATED TREATMENT IN METASTATIC TREATMENT IN METASTATIC
BREAST CANCER BREAST CANCER
Good prognosis defined by:
* Hormone-receptor positively
* formation of metastasis into skin, bone, lymph
node, connective tissue
* Interval between primary diagnosis and relapse >2 years
Anti-hormone therapy (estrogen withdrawal)
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
PROGNOSTIC ORIENTATED PROGNOSTIC ORIENTATED TREATMENT IN METASTATIC TREATMENT IN METASTATIC
BREAST CANCERBREAST CANCER
Poor prognosis defined by:
* hormone receptor-negativity
* formation of metastasis into organs (liver, lung).
* interval between primary diagnosis and relapse <2 years
cytostatic chemotherapy
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
TREATMENT OF GENERALIZED TREATMENT OF GENERALIZED BREAST CANCERBREAST CANCER
Treatment in dependency of
* Estrogen receptor status
* Her-2/neu – positively
* Criteria for prognosis
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ANTI-HORMONE THERAPY OF ANTI-HORMONE THERAPY OF METASTASISED CARCINOMA METASTASISED CARCINOMA
Hormone withdrawal
* surgical
* pharmacological
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ANTI-HORMONE THERAPY OF ANTI-HORMONE THERAPY OF METASTASISED CARCINOMAMETASTASISED CARCINOMA
Competitive hormone receptor blockade
* Estrogene
* Testosterone
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ANTI-HORMONE THERAPY IN ANTI-HORMONE THERAPY IN METASTASISED BREAST METASTASISED BREAST
CANCERCANCER
Pre-menopausal
* Ovariectomy
* LH-RH-agonist
* Tamoxifen
Post-menopausal
* Aromataseinhibitors (letrozol, anastrozol)
* Tamoxifen
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
OLD AND NEW CHEMOTHERAPEUTICS:
A SELECTIONOld New
Fluorouracil CarboplatinMethotrexat Capecitabine
EpirubicinVinca Alkaloide GemcitabineCyclophosphamid IrinotecanIfosfamid Lipos.Etoposid DoxorubicinCisplatin Topotecan
Vinorelbine
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
POSITIVE RESULTS OF NEW POSITIVE RESULTS OF NEW CHEMOTHERAPEUTICS IN MALIGN CHEMOTHERAPEUTICS IN MALIGN
DISEASEDISEASE
Testicular carcinomaBreast cancerLung cancerColon carcinomaOvarian carcinoma
Bladder carcinomaPancreatic cancer
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ADVANCES OF CHEMOTHERAPY ADVANCES OF CHEMOTHERAPY 5-year survival rate for different malignant 5-year survival rate for different malignant
diseasesdiseases1960-1993 (USA)1960-1993 (USA)
97
96
82
82
43
18
8
83
62
63
40
18
12
3
0 50 100
Thyroid
Testis
Breast
Lymphoma
Leukemia
Lung
Pancreas19601993
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Influence of growth factors Influence of growth factors on tumour growthon tumour growth
Antibody inhibit growthReceptor
Growth factor
TumorprogressionNo growth
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
USE OF CHEMOTHERAPY PLUS A USE OF CHEMOTHERAPY PLUS A MONOCLONAL ANTIBODY AGAINST HER2 MONOCLONAL ANTIBODY AGAINST HER2 FOR METASTATIC BREAST CANCER THAT FOR METASTATIC BREAST CANCER THAT
OVEREXPRESSES HER2/NEU. *OVEREXPRESSES HER2/NEU. *
Slamon et al., N Engl J Med,Vol.344,No.11 ·March 15,2001
Progression Free Survival
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Use of Chemotherapy plus a Monoclonal Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Antibody against HER2 for Metastatic
Breast Cancer that Overexpresses Breast Cancer that Overexpresses HER2/neuHER2/neu
Slamon et al., N Engl J Med,Vol.344,No.11 ·March 15,2001
Overall Survival
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
CHEMOTHERAPY PLUS TRASTUZUMAB CHEMOTHERAPY PLUS TRASTUZUMAB (HERCEPTIN) IN HER-2/NEU OVEREXPRESSING (HERCEPTIN) IN HER-2/NEU OVEREXPRESSING METASTATIC BREAST CANCER: RESULTS OF A METASTATIC BREAST CANCER: RESULTS OF A
RANDOMIZED PHASE-III STUDY.RANDOMIZED PHASE-III STUDY.
CHEMO+T CHEMO p
Response 50% 32% <0.001
Duration 9.1 MOS. 6.1 MOS. <0.001
1-year-death rate 22% 33% =0.008
overall survival 25.1 MOS. 20.3 MOS. =0.046
D.J. SLAMON ET AL., NEJM 344: 783, 2001
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ANTIBODY THERAPY OF ANTIBODY THERAPY OF MALIGNANT DISEASESMALIGNANT DISEASES
Antibody Tumour
TRASTUZUMAB Breast cancer
(Pancreatic cancer)
(Gastric cancer)
??
RITUXIMAB Lymphoma
CETUXIMAB Head and Neck Cancer
Colon carcinoma
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
OPEN QUESTIONS CONCERNING OPEN QUESTIONS CONCERNING THE TREATMENT OF MALIGNANT THE TREATMENT OF MALIGNANT
DISEASESDISEASES
* Role of chemoprevention * Surgical modalities* Improve of treatment modalities
- new chemotherapeutics - optimizing endocrine therapy
- new drug combination * Factors to predict biology of disease and response to treatment* Biological treatment modalities (antibodies, cytokines, inhibition of neo-angiogenesis) * Gene therapy