PRINCIPLES OF ONCOLOGICAL TREATMENT: CHEMO-, ENDOCRIN AND TARGETED THERAPIES. Magdolna Dank

Transcription

1 PRINCIPLES OF ONCOLOGICAL TREATMENT: CHEMO-, ENDOCRIN AND TARGETED THERAPIES Magdolna Dank

2 Modalities of treatment in cancer Surgery Radiotherapy 1/3 of patients can be cured, effective when tumor has not metastasized Chemotherapy: 50 % of the patients can be treated with chemotherapy contributing to cure in % of patients New mechanism of action drugs: endocrin th., TKI, Mab---cure?

3 Action sites of cytotoxic agents Principles of chemotherapy Antibiotics Antimetabolites S (2-6h) G2 (2-32h) Vinca alkaloids M (0.5-2h) Mitotic inhibitors Taxoids Alkylating agents Cell cycle level G1 (2- h) G0

4 History of Chemotherapy Era of modern chemotherapy began in early 1940s (WWII) Goodman and Gilman first administered nitrogen mustard to patients with lymphoma 1943(!) nitrogen mustard was developed as a war gas rather than as a medicine toxic effects on the lymphatic system led to clinical trials

5 Chemotherapy Chemotherapy attacks tumors at the cellular level by interrupting processes or inhibiting substances necessary for cellular replication and life During the cell cycle, there is replication of the entire genome and division of the cell into genetically identical daughter cells Goals of Cancer Chemotherapy Cure Prolong survival Palliation Radiosensitive

6 Number of cancer cells Cancer biology Tumor growth and detection Diagnostic threshold (1cm) time Undetectable cancer Detectable cancer Limit of clinical detection Host death

7 Action sites of cytotoxic agents Principles of chemotherapy DNA synthesis Antimetabolites DNA Alkylating agents DNA transcription DNA duplication Cellular level Intercalating agents Mitosis Spindle poisons

8 Treatment- with Chemotherapy Chemotherapy: -the use of cancer-fighting drugs injected intravenously or orally -is a useful treatment for metastasized cancers PALLIATIVE TH. -chemo following surgery increases the survival rate for some stages ADJUVANT TH -chemo helps relieve symptoms of advanced cancer -regional chemo: drugs are injected into the artery which leads to cancerous areas (may be fewer side effects) intraperitoneal intrathecal TACE, TAE Treats malignant lesions in the liver. Through very small catheters, a specially trained physician will deliver chemotherapy medicine directly to the tumor using image guidance. Also involves the injection of materials (metal coils or special gels) that physically block the blood vessels feeding the tumor. Optimizes the ability to shrink or eradicate tumors by targeting them precisely and blocking their blood flow. Requires only a small incision in the groin area. Most often, the procedure takes approximately two hours, but requires an overnight stay for observation.

9 Cancer chemotherapy can be curative in Acute Leukemias Wilm s Tumour Ewing s Sarcoma Choriocarcinoma Hodgkin s Disease Lymphosarcoma Burkitts lymphoma Testicular Teratomas Seminomas In children

10 Chemotherapy can have only Palliative effect in Breast Cancer+ Mab, TKI Ovarian Cancer+ Mab,PARP Endometrial Cancer Prostatic Cancer endocrin! Chronic Lymphatic Leukemia Chronic Myeloid Leukemia Head & Neck Cancer Lung (small cell) Cancer Colorectal cancer, but with MAb combination

11 Chemotherapy is less sensitive in Gastric cancer Subtypes!! Carcinoma of esophagus Renal carcinoma Targeted therpay is the standard HCC TKI, and TACE/TAE NSCLC-targeted th, IMMUNTH!! Malignant Melanoma Immuntherapy or targeted therapy is the standard Sarcoma

12 Adjuvant & Neoadjuvant chemotherapy Adjuvant chemotherapy: Chemotherapy given after surgery or irradiation to destroy micrometastasis & prevent development of metastases. Neo-adjuvant chemotherapy: Chemotherapy given before surgery or radiotherapy in order to diminish the volume of large primary neoplasm

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14 Side effects of chemotherapy Mucositis Alopecia Pulmonary fibrosis Nausea/vomiting Diarrhea Cystitis Sterility Myalgia Neuropathy Cardiotoxicity Local reaction Renal failure Myelosuppression Phlebitis

15 Side effect of targeted therapy: mucositis 15

16 Hand-foot syndrome targetet therapy AE. 16

17 Aim of combination therapy INCREASED EFFICACY ACTIVITY SAFETY Different mechanisms of action Different mechanisms of resistance Compatible side effects

18 Case report: Metronomic weekly cisplatin and irinotecan as 3 rd line salvage treatment for extensive stage small cell lung cancer 69 y/o male smoker diagnosed of extensive stage small cell lung cancer Presented with extensive disease with numerous mediastinal lymphadenopathies and multiple hepatic lesions. First line therapy : Carboplatin+etopside q3wks, temporary improvement then progressed in 3 months. Palliative radiotherapy for RLL obstruction 2 nd line chemotherapy: Topotecan with further disease progression and was told that he had no more treatment options left. Treated with weekly cisplatin and CPT-11 (Irinotecan) for 18 weeks and had near complete remission. Only low grade hematological and GI toxicity were encountered throughout the treatment.

19 Before chemo 12 weeks after chemo 18 weeks After chemo + +, a

20 Personalized medicine Old paradigm: Trial and Error Medicine" action In case of success: became an innovativ medicine and part of the standard of care

21 Personalized medicine New paradigm: Personalized Medicine Testing required, which leads to adequate treatment observation test treatment Predictive for the response The Trial and Error Medicine circle disrupted

22 Personalized medicine Why is it important? Diagnosis Saves lifeyears Diagnosis Saves money

23 Definition of presonalized medicine: Personalized medicine refers to the tailoring of medical treatments to the individual characteristics of each patient Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not. President s Council of Advisors on Science and Technology (PCAST), Priorities for Personalized Medicine, September, 2008

24 The role of biomarkers prediction Follow-up prognosis The tumor mass heterogeneity! Differences between characteristics of primary and metastatic lesion

25 Personalized medicine biomarker examples Selection of the appropriate drug Breast cancer trastuzumab HER2 Drug dose Colon cancer irinothecan UGT1A1 Drug efficacy CML Gleevec Quant BCR-ABL Stage CLL Campath Minimal residual Illiness Relapse risk Breast cancer Oncotype DX Multivariance Analysis Risk factor Breast cancer BRCA testing Risk analysis

26 Tumor HGF NRPs TGFβ bfgf VEGF PDGF Ang Eph BRAF RAS PI3K ERK MEK Endothelial cell & Pericyte AKT mtor

27 LUX-Lung 2: Effect of Afatinib in a patient with brain metastasis from EGFR L858R mutant lung cancer Baseline After 1 cycle Yang CH et al. Poster number: Presented at the American Society of Clinical Oncology, Chicago, Illinois, 2008

28 Tumor Density on CT Scan A sample: Renal cancer, Sunitinib-Induced Hypodensity in a Patient With Tumor Stabilization by RECIST C Before After Faivre SJ, et al. J Clin Oncol. 2009;27:e

29 Phase II Study of Brivanib in Advanced HCC: Biological Activity Pretreatment Posttreatment* Case A Case B *Tumor volume may be increasing or stable overall in Case A following brivanib treatment, but the viable diameter was reduced. Park JW, et al. Clin Cancer Res. 2011;17: Finn RS, et al. Clin Cancer Res. 2012;18:

30 First targeted therapies: hormone positive breast cancer

31 Targeted therapy The first molecular target for cancer therapy was the nuclear receptor for the female sex hormone estrogen (ER), required by many breast cancers for growth. Estrogen bound to its nuclear receptor (ER) will activate expression of specific genes involved in cell growth and proliferation.

32 Targeted therapy on the ER pathway Selective Estrogen Receptor Modulators (SERMs) tamoxifen Estrogen Receptor inhibitors fulvestrant Inhibitors of estrogen synthesis aromatase inhibitors anastrozole letrozole Exemestane brain hair liver breast Breast cancer Fat tissue muscles

33 Idő (hónap) In the last 3 decades, the therapy improvements in mcrc resulted in increased survival rates! 3 0 Median OS BSC 1980s 1990s 2000s FU 1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC Rothenberg, et al. JCO 2003; 4. Hurwitz, et al. NEJM Cunningham, et al. NEJM 2004; 6. Van Cutsem, et al. NEJM Van Cutsem, et al. JCO 2007; 8. Van Cutsem, et al. JCO Grothey, et al. Lancet 2012 Irinotecan 1 Capecitabine 2 Oxaliplatin 3 Bevacizumab 4 Cetuximab 5,6 Panitumumab 7 Aflibercept 8 Regorafenib 9 ramucirumab 2015

34 How to decide about the first-line therapy in mcrc? van Cutsem et al., Ann Oncol 25 (Supplement 3): iii1 iii9, 2014; accessed ; D Arnold Colorectal cancer case discussion ESMO 2015 ecco.hybridwebcast.com/ecc2015/library ; Patient s characteristics Molecular characteristics Comorbiditi es Previous adjuvant th. RAS BRAF Age Performance status MSI high TRIPLET FOLFOXIRI* DOUBLET FOLFOX FOFIRI XELOX +/- Biological th MONOTHERAPY Fluoropyrimidine MSI, microsatellite instability; mcrc, metastatic colorectal cancer. ; * FOLFOXIRI: oxaliplatin és irinotecan alkalamzási előírás alapján nem rendelkezik indikációval; a Roch nem javasolja ennek a protokollnak a használatát Tumor charateristics Patient preference Tumour burden Tumor localization Resecability Quality of life Toxicity

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36 Longer survival.. That is the future!

37 Thank You