Curative Management in Oncology Care dr. Djohan Kurnianda, Sp.PD - KHOM Holistic Cancer Management : Curative Curative Management in Oncology Care Block IX 2016 Johan Kurnianda, disampaikan oleh: Wigati Dhamiyati Dengan beberapa modifikasi Division of Hematology-Medical Oncology; Radiotherapy devision Department of Internal Medicine; Department of Radiology Medicine Faculty Gadjah Mada University Yogyakarta Block IX, December 27, 2006 Week 6 (International Programme)

Pendahuluan 1 dari 3 laki-laki & 1 darii 4 wanita akan menderita kanker. Terapi masa kini menyembuhkan 60% dari pasien kanker tersebut. Sebagian lagi adalah kanker yang tidak bisa sembuh , namun bisa dikelola cukup lama dan banyak yang dapat hidup bersama kankernya dengan kwalitas hidup yang baik

Bagaimana mengelola pasien onkologi Tentukan permasalahn utama dan tujuan terapi bersama pasien dan keluarga. Jelas problem klinis dengan tegas. Bersikap bijak dengan berbagai opsi terapi, second opinion dan terhadap permintaan pasien. Terhadap diagnosis dan progresivitas penyakit SELALU sampaikan dengan jujur. Kalau diperlukan libatkan psikolog atau psikiater.

Prosedur Diagnosis Kanker : dilakukan invasive tissue biopsy. Fine needle aspiration/ AJH. Cytogenetic study. Molecular marker Terapi definitif hanya dilakukan pada pasien dengan histopatologi yang sudah tegak.

Definisi: Cure Dikerjakan nya siklus terapi sesuai kasus Terapi yang berhasil pada satu penyakit Berkaitan dengan onkologi : eradikasi total sel kanker dengan masa bebas rekuren yang panjang. Kuratif : cenderung untuk mengatasi penyakit dan mempromosikan pemulihan

Manajemen Kuratif vs. Palliatif pada Onkologi Parameter kuratif Paliatif Goals of treatment Disease free survival (DFS) MengurangiSimptom Quality of life(QOL) Survival panjang Strategi Terapi Agresif/ sangat agresif Kurang agresif

Curative / remissive therapy Incureable Presentation Death Palliative care Hospice

Faktor –faktor yang mempengaruhi terapi kuratif Type tumor Stadium penyakit Better local treatment Terapi sistemik Prognostic markers (clinical/molecular/genetic) Terapi Targeted.

Faktor –faktor yang mempengaruhi terapi kuratif Type tumor Stadium penyakit Better local treatment Terapi sistemik Prognostic markers (clinical/molecular/genetic) Terapi Targeted.

Responsivitas pada Kemoterapi Curable tumors ♥ Testicular cancer ♥ Choriocarcinoma ♥ Hodgkin’s lymphoma ♥ Non-Hodgkin’s lymphoma ♥ Childhood cancer Incurable tumors ♥ Soft tissue sarcoma ♥ Brain cancer ♥ Head and neck carcinoma ♥ Non-oat cells carcinoma ♥ Bladder cancer Sensitivitas /Responsivitas pada Radioterapi sama dengan pada Kemoterapi

Lance Amstrong Suffered of testicular cancer Lung and brain metastasis Complete response with surgery and chemotherapy 6 times winner of Tour de France

Faktor –faktor yang mempengaruhi terapi kuratif Type tumor Stadium penyakit Better local treatment Terapi sistemik Prognostic markers (clinical/molecular/genetic) Terapi Targeted.

Five-year Survival Rate berbagai kasus berbasis Stadium Stage Breast Cancer NSCLC Colon Cancer Melanoma Maligna I 98% 50-75% >75% II 76-88% 35-40% 70% 75% III 49-56% 10-15% 55-70% 40% IV 16% 5% 25% 10%

Faktor –faktor yang mempengaruhi terapi kuratif Type tumor Stadium penyakit Better local treatment Terapi sistemik Prognostic markers (clinical/molecular/genetic) Terapi Targeted.

KANKER PAYUDARA: Local treatment advances dr. Djohan Kurnianda, Sp.PD - KHOM Holistic Cancer Management : Curative KANKER PAYUDARA: Local treatment advances Modified radical mastectomy Conservation of the breast Radical mastectomy Per- operative radiotherapy Post operative radiotherapy Block IX, December 27, 2006 Week 6 (International Programme)

Radioterapi pasca mastektomi simpel BREAST CONSERVING TREATMENT Pengangkatan jaringan tumor + sebagian jaringan sehat sekitarnya (payudara relatif masih utuh) efek kosmetik yang baik Terapi radiasi merupakan terapi utama Dosis radiasi eksterna: 50 – 60 Gy Booster lokal: implantasi iridium atau elektron Mastektomi simpel yaitu: padaT1, T2 dan T3. Kgb tidak diangkat Radiasi lokal (tumor bed) dosis 50 Gy. padaT3: tambahan 10 Gy Alternatif: radiasi elektron Limfonodi (Kgb) : 50 Gy

1350 pts with adenocarcinoma ≤ 15 from AV(anal verge) with operable tumors Preop short course (25 Gy/5 fxs) vs selective postoperative chemo/RT (45 Gy/25 fxs) and 5FU (CI or bolus) for ≤1 mm margins Sebag-Montefi ore, Lancet 2009

Suvival Rate pada kanker cervix dengan terapi radiasi dan kombinasi Stage IA: 90-100% Stage IB: 70-90% Stage II: 50-60% Stage III : 30-40% Stage IV : 5%

Faktor –faktor yang mempengaruhi terapi kuratif Type tumor Stadium penyakit Better local treatment Ditambahkan Terapi sistemik Prognostic markers (clinical/molecular/genetic) Terapi Targeted.

dr. Djohan Kurnianda, Sp.PD - KHOM Holistic Cancer Management : Curative Simulation of Impact of Chemotherapy Annual Odds of Recurrence: Nil = 15%/Yr CMF = 11.4%/Yr (Reduced by 24%) AC = 10%/Yr (Reduced by 12%) 100 80 % Free of Recurrence 60 40 AC CMF 20 Nil 2 4 6 8 10 Years Block IX, December 27, 2006 Week 6 (International Programme)

Tamoxifen – Adjuvant tx Recurrence as First Event Mortality From Any Cause 100 100 Tamoxifen (~5 y) 91.8 Tamoxifen (~5 y) 90 87.4 90 79.2 Control 89.3 78.9 Control 80 74.9 80 80.1 Tamoxifen (~5 y) Tamoxifen (~5 y) Node -ve 70 Node -ve 75.6 70 73.3 64.3 Control 74.2 Control 61.4 60 60 59.7 Node +ve 50 58.3 Node +ve % Alive % Recurrence-free 50 50.5 40 40 44.5 30 30 Absolute Recurrence Reduction Absolute Mortality Reduction 20 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 20 Node -ve: 5.6% SD 1.3: 2P<0.00001 Node +ve: 10.9% SD 2.5: 2P<0.00001 10 10 5 10+ 5 10+ Years Years Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451.

Stage III Overall Survival of Colorectal Cancer : Without vs Stage III Overall Survival of Colorectal Cancer : Without vs. With Chemotherapy Stage TN 5-yr OS 5-yr OS adjuvant chemo IIIa T1-2, N1 (1-3 nodes) 59.8% 71% IIIb T3-4, N1 42% 51% IIIc Tany, N2 ( 4 nodes) 27.3% 32% Greene, Ann Surg 2002; 236:416

Faktor –faktor yang mempengaruhi terapi kuratif Type tumor Stadium penyakit Better local treatment Terapi sistemik Prognostic markers (clinical/molecular/genetic) Terapi Targeted.

IPI stratifies risk by clinical factors in aggressive NHL Prognostic factors (APLES) Age >60 years Performance status >1 LDH >1 x normal Extranodal sites >1 Stage III or IV Risk category Factors Low (L) 0 or 1 Low-intermediate (LI) 2 High-intermediate (HI) 3 High (H) 4 or 5 OS 100 50 Patients (%) L LI HI H 0 2 4 6 8 10 30 20 10 Death rate per year H HI Patients (%) LI L 0 2 4 6 8 10 Year International non-Hodgkin’s lymphoma prognostic factors project. N Engl J Med. 1993;329:987-994.

Potential of Clinical Utility of Serum HER-2/neu Oncoprotein Concentrations in Patients with Breast Cancer Carney et al Clinical Chemistry, 49 : 1579 – 98, 2003

Survival in Colon Cancer Patients : Correlation With Blood Vessel Number and VEGF Levels (Takahashi et al. Arch Surg. 1997;132:541.)

Cytogenetics As Prognostic Factors in AML Favorable : t(8;21), inv16, t(15;17) Intermediate : normal, -Y, +6, +8; others not considered favorable or unfavorable Poor : Translocations or inversion of chromosome 3, monosomy 5 or 7, t(6;9), t(9;22), abn 11q23, or complex

SWOG/ECOG Adult AML; Age <56: Cytogenetics and Survival 100 At Risk Deaths Estimated (CI) at 5 Years Favorable 121 53 55% (45%-64%) Intermediate 278 168 38% (32%-44%) Unfavorable 184 162 11% (7%-16%) 80 60 Survival (%) 40 20 Heterogeneity of 3 groups: P<.0001 2 4 6 8 Years After Entering Study Slovak et al. Blood. 2000.

Distinct Types of Diffuse Large B-cell Lymphoma Identified by Gene Expression Profiling All patients GC B-like Activated B-like P=0.01 Probability GC B-like DLBCL Activated B-like DLBCL Overall survival (yrs) All patients Low clinical risk pts Low clinical risk High clinical risk P=0.002 GC B-like Activated B-like P=0.05 Probability Overall survival (yrs) Alizadeh et al, Nature 403: 503, 2000

Lymph node negative breast cancer <55yr Supervised classification for Prognosis 70 significant prognosis genes good signature poor rankorder metastases (white = +) 78 tumors threshold

Survival of breast cancer based-on genetic profiles

Faktor –faktor yang mempengaruhi terapi kuratif Type tumor Stadium penyakit Better local treatment Terapi sistemik Prognostic markers (clinical/molecular/genetic) Terapi Targeted.

Targeted Molekul yang Ideal Expressed/over expressed dengan prevalensi tinggi dari kanker tersebut. Expressed pada posi kecil sel normal Mempunyai peran yang penting dalam pengembangan atau perkembangan kanker.

Biological Targets pada terapi kanker dr. Djohan Kurnianda, Sp.PD - KHOM Holistic Cancer Management : Curative Tumour cell 1. Growth factors and growth-factor receptors HER family, VEGF/R, c-kit/SCFR 2. Signal transduction pathways Ras, raf, MAPK, MEK, ERK, protein kinase C, PI3K 1 2 3. Tumour-associated antigens/markers Gangliosides, CEA, MAGE, CD20, CD22 6 6. Extracellular matrix/ angiogenic pathways MMPs, VEGF, integrins 3 4 5 5. Cell-survival pathways Cyclin-dependent kinases, mTOR, cGMP, COX-2, p53, Bcl-2 4. Proteasome Block IX, December 27, 2006 Week 6 (International Programme)

Courtesy of Tan Y O 2005

Monoclonal antibody for NHL : Rituximab CD20 antigen hydrophobic, 35 kD phosphoprotein expressed only on B lineage cells present in >90% of B-cell lymphomas important for cell cycle initiation and differentiation does not shed or rapidly modulate off cell surface Rituximab chimeric molecule with a murine antigen binding domain human k constant region human IgG1 constant region CD20 antigen B cell Rituximab

GELA-LNH 98.5: 5-year OS 100 80 60 40 20 R-CHOP 58% Overall survival (%) CHOP 45% p<0.007 0 1 2 3 4 5 6 7 Years Coiffier B, et al. Blood 2004;104:388a (Abstract 1383)

HER-2 Proto-Oncogene Also known as ErbB2/c-erbB2/ HER-2/neu Is located in chromosome 17 Encodes 185 k-DA transmembrane tyrosine kinase growth factor receptor Its drive tumor induction and growth Amplified in 20%-30% of breast cancer and has prognostic value HER-2 proto-oncogene amplification usually accompanied by its protein overexpression

Trastuzumab : humanized anti-HER2 monoclonal antibody dr. Djohan Kurnianda, Sp.PD - KHOM Holistic Cancer Management : Curative High affinity (Kd=0.1nM) and specificity 95% human, 5% murine decreased potential for immunogenicity has HER-2 epitopes recognized by hypervariable murine antibody fragment Block IX, December 27, 2006 Week 6 (International Programme)

Trastuzumab REDUCES THE RISK OF RECURRENCE BY NEARLY HALF dr. Djohan Kurnianda, Sp.PD - KHOM Holistic Cancer Management : Curative Trastuzumab REDUCES THE RISK OF RECURRENCE BY NEARLY HALF 100 80 60 40 20 % Months from randomisation 5 10 15 25 1 year Trastuzumab Observation 127 220 Recurrences p<0.0001 2-year DFS 86 77 Piccart et al 2005 Block IX, December 27, 2006 Week 6 (International Programme)

A Vision for Patient-Tailored Combination Therapy : The Future of Mapping Molecular Networks (Petricoin III et, JCO, 23 : 3614 - 3621, 2005)

Optimisasi Manajemen kuratif pada perawatan Onkologi Stadium awal Marker prognostik (clinical/genomic/proteomic) Terapi Individual / tailored treatment

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