farmakologi anti kanker

8/10/2019 Farmakologi Anti Kanker

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FARMAKOLOGI

OBAT ANTI KANKERPSFKKO

Universitas Gadjah Mada2014


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* CELL - CYCLE SPECIFIC DRUGS : = phase non specific

Paling efektif jika cell tersebut aktif dalamcell cycle

- Class Type ObatAlkylating Nitrogen mustard Chlorambucil, cyclophosphamide

agent MelphalanAlkyl sulfonate BusulfanTriazine DTICMetal salt Cisplatin

Natural product Antibiotic Actinomycin -D

DaunorubicinDoxorubicin


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Identify Candidate Compounds

Screening

Preclinical Evaluation

Production and Formulation

Phase I, II, III, IV Clinical Trials

General Medical Practice

Toxicology Pharmacology Biochemistry

ONCOLOGYDrug development

Steps in cancer drug development


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Procedure for the Development, Testing and Use of Chemotherapeutic Drugs

Drugs Development

Random Screening Logical Design

Animal Data

Formulation

Phase 1 Trials (Toxicity maximum tolerateddose)Phase 2 Trials (Efficacy in different tumours)

Phase 3 Trials (Comparative Randomizedstudies)

Clinically Useful New Agent

Use AsAdjuvant If

Circumstances Exist

Combine With OtherActive Agent In

Advanced Disease


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Identification of candidate compounds: Natural products

Drug Type Source

Antitumor antibiotic (daunorubicin, doxorubicin) Streptomyces fungus

Vinca alkyloid (vincristine, vinblastine) Vinca rosea plant

Taxane Yew tree

Camptothecin (topotecan, CPT-11) Camptotheca accuminata tree

Podophyllin (etoposide, teniposide) Podophyllum peltatum plant

Bryostatin, dolastatin, halichondrin Marine organisms

Grever MR, Chabner BA. Cancer: Principles & Practice of Oncology . 1997;387-388.Haskell CM. Cancer Treatment . 1995;35-36.


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Grever MR, Chabner BA. Cancer: Principles & Practice of Oncology . 1997;385-394.

Identification of candidate compounds: Molecular-targeted screening


Computer-aided construction ofmolecules

Mutant oncogenes (BCR-ABL)Aberrant tumor suppressor genes (RB)

Protein kinases

Transcription activators


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Prostate

IN VITRO HUMAN TUMOR CELL LINE PANELS

OvarianMelanomaCNSBreastColonLung

Preclinical developmentfollowed by broad-based clinical trials

In Vivo tumor panel human tumor xenograft studies

Specific disease -oriented Phase I/II trials

Targeted preclinical development

Nonspecific antitumor activity Highly specific antitumor activity

Adapted from NCI drug screening strategy,1985.


Screening for anticancer activity


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Target level Maximum tolerated dose Spectrum of activity

Cellular level Dose-limiting toxicities Schedule dependency

Efficacy Route administration

Cross resistance

Combination therapies

IN VITRO IN VIVO

Preclinical evaluation of cytotoxic agents

Mechanis m of act ion Stage I Stage II


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Preclinical studies in mice, rats,and dogs provide an importantbridge from in vitro studies toclinical studies

Objectives Define major toxicities Identify initial safe starting dose

for clinical trials

Use of animal models in evaluation of cytotoxic agents


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Study Phase Objectives Patient Population

Phase I Identify maximum tolerated dose Small (3-6 patients/dose level) Define key toxicities Various tumor types

Phase II Evaluate tumor response Larger than Phase I (10-50 Determine whether drug patients/treatment group)warrants Phase III study More uniform disease characteristics

Phase III Compare new treatment with Larger than Phase II (100s ofstandard patients/treatment group)

Support marketing approval Same tumor type Broader patient pool

Phase IV Integrate clinical study experience Very large cohorts (100s-1000s)into general clinical practice Represent general patient Monitor safety after approval population


Clinical evaluation of cytotoxic agents


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Response rate

Survival

Disease-free survival

Time to disease progression

Duration of response

Quality of life

Pharmacoeconomics

Clinical trials: Efficacy endpoints


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Adapted from World Health Organization, 1980.

Clinical endpoints: Complete remission


PrimaryTumor

Nodes

Metastases

Disappearance of all clinical,radiologic and biologic

signs of tumor

Treatment


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Treatment

Decrease of the multiple of twotumor diameters by at least 50%

ONCOLOGYDrug developmentClinical endpoints: Partial remission



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Increase of the multiple of twotumor diameters by at least 25%


Clinical endpoints: Disease progression


Treatment


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Contraindications for Chemotherapy

A. ABSOLUTE CONTRAINDICATIONS- Terminal diseases (patients with very short life expectancy)- Pregnancy (first trimester)- Septicaemia- Coma

B. RELATIVE CONTRAINDICATION- Infants under 3 months- Old age (in particular elderly patients with slow-growing tumours with lowsensitivity to chemotherapy)

- Very low performance status (less than 40)- Severe organ failure (for certain drugs) e.g. kidney, heart, liver, bone-marrow- Brain metastases (if not treatable by radiotherapy)- Dementia- Inability of patient to attend clinic regularly- Lack of co-operation on part of patient- Tumour resistance to anticancer chemotharapy


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Osteosarcoma

Incidence : 2,1 cases/ 1000.000Peak : 10-14 yrs. : = 1,6 : 1

Goal : cure with Preoperative Chemo +Limb Sparing/Amputation + Adjuvant Chemo

Prognosis : 5 y DFS : 60%-65%Amputation alone : 5Y.S : 12%-15%Combine Modality: 5Y.S : 60%-70%


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TREATMENT NEO ADJUVANT

PREOPERATIVE CHEMOTHERAPYSURGERYADJUVANT CHEMOTHERAPYRehabilitationPsychological Support

HUVOS SYSTEM FOR HISTOLOGIC GRADING


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HUVOS SYSTEM FOR HISTOLOGIC GRADINGOf Effect of CHEMOTHERAPY on Primary OSTEOSARCOMA

Grade EffectI Little or no effect identifiedII Areas of acellular tumor osteoid,necrotic,and/or

fibrotic material attributable to the effect ofchemotherapy with other areas of histologicallyvariable tumor

III Predominant areas of acellular tumor osteoid,necrotic ,and/or fibrotic material attributableto the effect of chemotherapy,with onlyscattered foci of histologically viable tumor cellsidentified

IV No Histologic evidence of viable tumor identifiedwithin the entire specimen

From Huvos AG et al Arch.Pathol Lab Med 101:14-18,1977 with permission

THE GRADING SYSTEM FOR HISTOLOGIC RESPONSE


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THE GRADING SYSTEM FOR HISTOLOGIC RESPONSEof CHEMOTHERAPY on Primary OSTEOSARCOMA (Modified)

Grade EffectPOOR RESPONSE

I No effect identifiedII 5% to 95% viable tumor remaining

GOOD RESPONSE

III Scattered foci of viable tumor seen( < 5% of the tumor )

IV No viable tumor seen in extensive sampling(at least a full cross-section of the tumor)


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Histological Grading of Resected TumorSpecimen.

5 Years DFS by HUVOS IV : 91%

III : 72%II : 66%

I : 50%


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CELL - CYCLE NON SPECIFIC DRUGS

Efektif pada cell baik yang active dalam cell cycleataupun yang sedang resting

~ : Photon irradiation

- Class Type ObatAlkylating Nitrogen mustard Mechlorethamine

agent Nitrosurea Carmustine = BCNULomustine = CCNUSemustine = methyl CCNU


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ONCOLOGYCancer biology

Tumor growth and detection

10 12

10 9

time

Diagnosticthreshold

(1cm)

Undetectablecancer

Detectablecancer

Limit ofclinical

detection

Hostdeath

N u m

b e r o

f

c a n c e r c e

l l s


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early lateNo response to therapy10 12

1 kg

10 9

1 g

10 6

1 mg

10 3 1ug

1induction consolidation maintenance cure

clinicallydietectabtumor

long-termremission

immuneresistance host

humoral +cellular

numberof tumourcells inthe body

DIAGRAMMATIG PRESENTATION OF THE REDUCTION OF THENUMBER OF TUMOUR CELLS IN THE BODY

kecenderungan tumorberkembang


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ONCOLOGYCancer biology

Malignant tumor cells can remaindormant yet viable for years

Emergence from dormancy can leadto disease recurrence

Possible mechanisms: Cells may arrest in G 0 phase Rate of cell death counterbalances rate ofcell division

Dormancy of tumor cells

Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;141.


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ONCOLOGYPrinciples of chemotherapy

Busulfan Cytosine Etoposide Bleomycin L-asparaginase

Carmustine Arabinoside Teniposide Dactinomycin Hydroxyurea

Chlorambucil Floxuridine Vinblastine Daunorubicin Procarbazine

Cisplatin Fluorouracil Vincristine Doxorubicin

Cyclophosphamide Mercaptopurine Vindesine Mitomycin-c

Ifosfamide Methotrexate Taxoids Mitoxantrone

Melphalan Plicamycin

AlkylatingAgents

Anti-Metabolites

MitoticInhibitors

Antibiotics Others

Classification of cytotoxic agents

ONCOLOGY


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DNA synthesis

Antimetabolites

DNA

DNA transcription DNA duplication

Mitosis

Alkylating agents

Spindle poisons

Intercalating agentsCellular level

Action sites of cytotoxic agents

ONCOLOGY


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6-MERCAPTOPURINE

6-THIOGUANINE

METHOTREXATE

5-FLUOROURACIL

HYDROXYUREA

CYTARABINE

PURINE SYNTHESIS PYRIMIDINE SYNTHESIS

RIBONUCLEOTIDES

DEOXYRIBONUCLEOTIDES

DNA

RNA

PROTEINS

MICROTUBULESENZYMES

L-ASPARAGINASE

VINCA ALKALOIDS

TAXOIDS

ALKYLATING AGENTS

ANTIBIOTICS

ETOPOSIDE

Action sitesof cytotoxic agents


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CYCLOPHOSPHAMIDE

4-OH CYCLOPHOSPHAMIDE

ALDOPHOSPHAMIDE

PHOSPHORAMIDEMUSTARD

4-KETOCYCLOPHOSPHAMIDE

CARBOXYPHOSPHAMIDE

ACROLEIN

HEPATICCYTOCHROMES

P 450ACTIVATION

CYTOTOXICITYTOXICITY

INACTIVATION ALDEHYDE

DEHYDROGENASE

Cyclophosphamide

Metabolism of cytotoxic agents


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Mucositis

Nausea/vomiting

DiarrheaCystitis

Sterility

Myalgia

Neuropathy

Alopecia

Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis

Side effects of chemotherapy


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ONCOLOGYPatient management

Cancer patient management: Solid tumors

Therapeutic decision

Clinical findings

Cancer diagnosis

Therapeutic intention

Biopsy CT scans

Staging/Grading


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Tumor markers:Examples

Prostatecancer

PSA

EAP

Testicularcancer

AFP, hCG

Pancreaticcancer

CA 19-9

BreastcancerCA 15-3

Ovariancancer

CA 125

Tretter C. Current Cancer Therapeutics. 1998;224-237.Rosenbaum EH. Everyones Guide to Cancer Therapy, 3rd ed. 1997;616-622.

Haskell CM. Cancer Treatment, 4th ed. 1995;322-337.Berek JS. Cancer Treatment, 4th ed. 1995;628-634.

ONCOLOGY


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TNM classification

Tumor

Nodes

Metastasis


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Tumor extent/staging

Localized disease= limited stage

ChemotherapyRadiotherapy

SurgeryImmunotherapy

Hormonal therapyPalliative care

Tumor extent/staging

Metastatic disease

ExtentResectable

tumorNonresectable

tumor

Operablepatient

Inoperablepatient

Surgery+ Radiation therapy+ Chemotherapy

+ Hormonal-immunotherapy

Radiation therapyChemotherapyHormonal therapyImmunotherapy

and/or


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Classification: Leukemias (NON SOLID CANCER)


Morphology andcytochemistry (ie, lineage)

Maturational stage

Genotype

Scheinberg DA, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;2293-2321.Deisseroth AB, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;2321-2343.


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Staging: Lymphomas

Shipp AA, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997:2165-2220.


Number of nodal sites involved Presence of disease above or

below diaphragm Presence or absence of

systemic symptoms Presence or absence of

extranodal disease


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Surgery in cancer

Rosenberg SA. Cancer: Principles & Practice of Oncology, 5th ed. 1997;295-306.


Tissue acquisition for histologic disease

Primary treatment modality in localized disease(alone or in combination with other treatment modalities)

Reduction of tumor bulk Resection with intent to cure

Treatment of oncologic emergencies

Reconstruction or rehabilitation

Palliation of tumor-related symptoms

Prophylactic use in high-risk patients


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Teletherapy (eg, orthovoltage,

supervoltage, intraoperativeradiotherapy, stereotaxic radiosurgery)

Brachytherapy (eg, internal radiationtherapy, interstitial radiation therapy,intracavitary radiation, intraluminalradiation therapy)

Radiation therapy

Hellman S. Cancer: Principles & Practice of Oncology, 5th ed. 1997;307-332.

ONCOLOGY


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Chemotherapy

Cytotoxic agent Hormonal therapy

Biologic therapy

Systemic therapies

Haskell CM. Cancer Treatment. 4th ed. 1995;31-56.


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Pola Sensititivitas Kanker terhadap Sitostatika--------------------------------------------------------------------------------------------------------Kelompok I : Kanker dengan sitostatika mutakhir menghasilkan efek

sitoreduktif yang cepat dan kesembuhan umumnya terjadipada kanker yang secara intrinsik sensitif terhadap kemoterapisitostatika (contohnya: leukemia limfoblastik akut pada anakanak, penyakit Hodgkin, beberapa jenis limfoma non-Hodgkin,kanker testis, dan lain lain).

Kelompok II : Kanker yang biasanya berespon baik pada saat permulaandiberikan sitostatika namun kemudian sering berubahmenjadi refrakter` terhadap sitostika berikutnya (contohnya:kanker payudara, kanker paru sel kecil, kanker ovarium yangkambuh, dan lain lain).

Kelompok III : Tumor yang secara intrinsik resisten terhadap hampir semuakemoterapi sitostatika (contohnya: melanoma maligna,kanker colon, dan lain lain)

------------------------------------------------------------------------------------------------------


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Problems of Schedules in CombinationChemotherapy

Choice of drug used in combinations :(a) empirical basis :

- drugs most effective in a tumour type, whenused alone

- no cross resistance, different mechanism ofaction

- toxicity spectrum of drugs differing from eachother : no additive toxicity

(b) information from animal models : gives little directinformation

ONCOLOGY


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INCREASED EFFICACY

Different mechanisms of action Compatible side effectsDifferent mechanisms of resistance

ACTIVITY SAFETY

Aim of combination therapy


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Theoritical Basis for the Effect ofCombination Chemotherapy

Cell Kinetic Factors

1. Drugs with differing toxicities to host tissues and different mechanism of actionmay, when used in combinations :(a) increase tumour-cell kill without a corresponding increase in host

toxicity :improved preferential killing

(b) allow fore more rapid host recovery and better selectivity :more rapid preferential killing

(c) kill various segment of neoplastic cells in different phases of the cycle :more complete remissions , delay of resistant cell

populations

2. Additive toxicity to host tissues without additive tumour-cell kill results indecreas ed effectiveness of combinations, or oven preferential killing of normalhost cell


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Factors to be Considered in the Planning of Chemotherapy

A. FACTOR TO BE CONSIDERED IN THE PLANNING OF CHEMOTHERAPY- Choice of drug

- Dose- Route- Schedule- Single or combination- Sequence

B. FACTOR RELATED TO THE PATIENT- Age, sex- Socio-economic status- Nutritional status- Performance status- Bone-marrow reserve- Pulmonary, renal, hepatic and cardiac function- Associated diseases

- Possible individual drug metabolismC. FACTORS RELATED TO THE TUMOUR- Histology, histological subtypes, grading- Primary or metastatic- Site of metastases- Dimension of tumour mass (if possible cell kinetic characteristics)- Presence of effusion (possible reservoir of drug activity)


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A. FACTOR TO BE CONSIDERED IN THE PLANNING OFCHEMOTHERAPY- Choice of drug- Dose- Route

- Schedule- Single or combination- Sequence


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B. FACTOR RELATED TO THE PATIENT- Age, sex- Socio-economic status- Nutritional status

- Performance status- Bone-marrow reserve- Pulmonary, renal, hepatic and cardiac function- Associated diseases- Possible individual drug metabolism


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C. FACTORS RELATED TO THE TUMOUR- Histology, histological subtypes, grading- Primary or metastatic- Site of metastases- Dimension of tumour mass (if possible cellkinetic characteristics)- Presence of effusion (possible reservoir of drugactivity)

ONCOLOGY


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Performance status scalesCorrespondence between ECOG and Karnofsky scales

Grade Criteria (simplified) % Functional status

0 Normal activity 100 Able to carry on normal activity;no special care is needed

90

1 Symptoms but ambulatory 80

70 Unable to work; able to live at home;cares for most personal needs;a varying amount of assistance is needed

2 In bed 50% of time 40 Unable to care for self; requiresequivalent of institutional or hospital

30 care; disease may be progressing rapidly

4 100% bedridden 2010

5 Dead 0 Dead

ECOG KARNOFSKY


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TAX 323/EORTC TAX 323/Q of L TAX 324/Dana Farber TAX GORTEC 2000 01

Clinical Trials

in Head & Neck Cancer


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TAX 323/EORTC

Neck dissection

InoperableSCCHNStage 3/4

Stratification:1 tumour site

Institution

Taxotere (75 mg/m)Cisplatin (75 mg/m)

5-FU (750 mg/m/dx5)

TCF arm:

Q 3 weeks x 4 cycles

Cisplatin (100 mg/m)5-FU (1000 mg/m/dx5)

CF arm:

Q 3 weeks x 4 cycles

Radiotherapy(~70 Gy over

7 weeks)Follow-up

Surgery for residualdisease

R

Eva Remenar et al. ASCO 2006, abstract 5516.Jacques Bernier et al. ASCO 2006, abstract 5522.


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Primary objective PFS (Progression free survival)

Secondary objectives Response after chemotherapy and overall

Local symptoms Duration of response Time to treatment failure Survival Toxicity Quality of life (QOL)

TAX 323/EORTC: Study objectives PFS = Progression freesurvival


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PF (n=181)N (%)

TPF (n=177)N (%)

Performance status(EGOC)

01

91 (50.3)90 (49.7)

90 (50.8)86 (48.6)

Median age (years,range)

53 (30 71) 53 (31 70)

GenderMaleFemale

162 (89.5)19 (10.5)

159 (89.8)18 (10.2)

TAX 323/EORTC: Patient characteristics


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PF (n=181)N (%)

TPF (n=177)N (%)

Primary tumour siteOral cavityOropharynxHypopharynxLarynx

32 (17.7)84 (46.4)52 (28.7)13 (7.2)

31 (17.5)81 (45.8)53 (29.9)12 (6.8)

Tumour grading

Grade 1 + 2Grade 3 = 4U + X

122 (64.7)31 (17.1)28 (15.4)

111 (62.7)40 (22.5)26 (14.7)

TAX 323/EORTC: Patient/tumour characteristics


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TAX 323/EORTC: Progression-free survival

Median: 12.7 months (10.2 14.2)

Median: 8.4 months (95% CI: 7.5 9.6)

Years

0 1 2 3 4 5 0

20

40

60

80

100 Cox model (primary): p=0.006Hazard ratio=0.7295% CI (0.56 0.91)Unadjusted log-rank test: p=0.006

Randomisedarm

CF

TCF

PFS = Progression free

survival


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TAX 323/EORTC: Overall survival

Eva Remenar et al.,ASCO 2006,abstract 5516

P r o

b a

b i l i t y

( % )

CF TCF

Mean survival 14.2 m 18.6 m

Hazard ratio 0.73 [0.56 0.90]

p-value 0.0052

010

20

30405060

708090

100

0 6 12

18

24

30

36

42

48 54

Months

60

66

72

TCFCF

Phase III

OS = Overall

survival

Survival from high grade localised osteosarcoma: combined


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Survival from high grade localised osteosarcoma: combinedresult and prognostic factors from three European

Osteosarcoma Intergroup RCT (Whelan,et al. Annals of Oncology 23:1607-16,2012)

- 1067 pts with localised extremity osteosarcoma 3 RCT- Standard treatment : Doxorubicin 75mg/m 2 and Cisplastin 100

mg/m 2

- Comparators :- Add of MTX (BO02/80831)- Multidrug regimen (BO03/80861)- Dose intense schedule (BO06/80931)

Standard protocols


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Treatment Protocols by Trial


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Pattern of recurrence

OS = Overall survival


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Survival

Overall survival : 5-years: 56% (95% CI 53-59%) 10-years: 52% (95% CI 49-55%)

Progression Free Survival : 5-years: 43% (95% CI 40-46%) 10-years: 42% (95% CI 39-46%)

No difference of survival between trials /treatment arms

PFS = Progression free

survival


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Osteosarcoma ChemotherapyProtocols


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Neoadjuvant chemotherapy for osteosarcoma of theextremities with metastases at presentation: recent experience

at the Rizzoli Institute in 57 patients treated with cisplatin,doxorubicin, and a high dose of methotrexate and ifosfamide

(Bacci G, et al. Annals of Oncology 14:1126-34, 2003)

Patients < 40 yo, with newly diagnosed HGOE with metastases atpresentation

New protocol therapy higher dose in Ifosfamide and MTX Site of metastases :

Lung 43 pts Bone 3 pts Lung and bone 9 pts Lymph node 2 pts

Neoadjuvantchemotherapy


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Results

Primary tumor Clinical and radiological response to

chemotherapy 79% Histological response of the primary tumor:

Good (54%) , Poor (46%)

Bacci G, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patientstreated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Annals of Oncology 14:1126-34, 2003


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Results Metastases response to chemotherapy

Type of response Metastases Response

Radiologicalresponse

- Lung only (43 pts) - Complete : 5 pts- Partial : 10 pts

- Stable : 26 pts- Mixed : 2 pts

Radiologicalresponse

- Bone only (3 pts)- Bone and lung (9 pts)

- Stable : 8 pts- Progressive : 4 pts

Surgical treatmentand histologicalreponse

140 resected metastases in the26 patients with pulmonarynodules

- Good : 53%- Poor : 46%

Bacci G, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients

treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Annals of Oncology 14:1126-34, 2003


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Outcomes

Bacci G, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patientstreated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Annals of Oncology 14:1126-34, 2003

EFS = Event free survival


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Terapi Suportif pd Manajemen Kanker


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Terapi Suportif pd Manajemen Kanker

Tujuan pengobatankanker tercapai:

kuratif: sembuh /disease free survival >

paliatif: keluhankomplikasi kanker (-)/


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SyAnti cancer drugs setting

Primary chemotherapy Neo adjuvant setting Induction therapy (pre-

main modality th/)

Adjuvant setting (post-main modality th/) Chemo-radiation:

- chemotherapy as as radiosensitizer- concomitant / concurrent chemo-radiation- sandwich chemoradiation

Sequential setting


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Surgery

Radiation +Chemotherapy asRadiosensitizer

AdjuvantChemotherapy

Adjuvant Therapy ofMusculoskeletal Tumors:

-Early / locally stage


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Surgery Chemotherapypost surgery

Sequential Therapy of

Neoadjuvantchemotherapy

Locally advancedstageBulky tumors


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