ESRA KAYTAN SAĞLAM, MD Istanbul University Oncology Institute

Transcription

1 USE OF RADIOSENSITIZERS IN ONCOLOGY ESRA KAYTAN SAĞLAM, MD Istanbul University Oncology Institute

2 According to cell type: Radiosensitive tumors (embryojenic tumors, lymphomas) Moderate sensitives (Squamous cell, adenocarsinoma) Radioresistant (sarcomas, melanoma) Hypoxia Mitotic phases (G1, M radiosensitive) The number of clonogenic cell

3 HYPOXIA Chronic hypoxia necrotic center Transiently occluded blood vessel..acute hypoxia

4 Oxygen enhancement ratio (OER) Ratio of doses under hypoxic to- aerobic conditions to yield the same biologic effect OER: 2 Gy 3 2 Gy 2

5 The correlation between pretreatment head and neck tumor oxygenation and local-regional disease control RadiotherOncol Jan;26(1):45-50.

6 Anti Hipoksik Factors Intrinsic Factors P Re-oxygenation P Fractionated radiotherapy Extrinsic Factors Augmentation of Tumor Oxygenation HBO, Carbogen, ARCON Efaproxiral Erythropoietin Sensitization of hypoxic cells Pharmacologic targeting of hypoxic cells Biologic modifiers of radiation response High LET radiation

7 HBO Multi-center randomized trial Head and neck cancer MRC 1.(1977) % vs 30% (LR contol) P<0.01 MRC 2.(1986) % vs 41% (LR contol) P<0.05 Cervix cancer MRC (1978) % vs 47% (LR contol) P<0.01 Lung cancer MRC (60 Gy) 51 15% vs 8% (OS - 2) MRC (36 Gy/6 fr) % vs 12% (OS - 2) p<0.05 Bladder cancer MRC (1978) % vs 30%(OS - 5)

8 CARBOGEN P 5% CO2 + 95% O2 P Breath ;before 3-4 minutes and during the RT P The use of ARCON (accelerated radiotherapy with carbogen and nicotinamide) P Cervix, head and neck cancer and brain tumors Int J Radiat Oncol Biol Phy, 2004; 59(3):

9 EORTC Trial (1999) Glioblastoma Multiforme, 115 patients Accelerated RT 60 Gy/4 weeks (1.5 Gyx2) 1. RT + carbogen 2. RT + nicotinamide 3. ARCON Median survival 10.1 m 9.7 m 11.1 month Gis Toxicity %8 %44 %32

10 ARCON P Head and neck cancer 215 patients P Phase II trial P %97 stage III IV, larenx %46 Hypopharenx %23 Oropharenx %23 Nicotinamid mg/kg, 1-1,5 hours prior to radiotherapy 3 years loco-regional control: 69% Hipopharenx 88% larenx/oropharenx Nausea/vomiting 10% patients, 2002; 52:

11 EFAPROXIRAL (RSR-13) sentetik allosteric hb modifier of hemoglobin structure that shift the oxyhemoglobin dissociation curve to the right and thus increase o 2 to hypoxic tissues delivery Patients with brain metastases 538 pts, RT + Oxygen ± efaproxiral Metastatic lung cancer (%54) and breast (%20) cancer Significant improvement in median survival time in breast patients 515 pts, metastatic lung and breast cancer Br J Cancer 2006; 94: RT ± efaproxiral: OS: 5.4 months vs 4.4 months Response rate lung and breast cancer 7% vs 13% JCO 2006; 24(1); 13-15

12 ERYTHROPOIETIN RTOG 85-27, double-blind, placebo-controlled randomized trial 351 pts, oral cavity, oropharyngeal, hypopharynx ve larynx Ca RT: Gy ±epoetin beta 300 IU/kg,3 day/w Local progression free survival RR: 1.62 (%95 CI , p: ) OS: RR: 1.39 ( , p: 0.002) Lancet. 2003;362(9392):

13 SENSTIZATION OF HYPOXIC CELLS The2-nitroimidazolesare onesuch classof compoundsthataremetabolizedinto theiractiveform underhypoxicconditions. P Misonidazole: a double-blind randomized trial P DAHANCA 2 trial: 626 patients, pharyngeal ca, stage I-IV laryngeal stage II -V split course RT + Misonidazole (11 gr/m2) Local control: 41% vs 34% NS Pharyngeal ca LC: 38% vs 27% p<0.05 Periperal neuropathy: %26! Int J Rad Oncol BiolPhy; 1989, 16:

14 Misonidazole IIIB IVA Cervix Ca RT vs RT + Miso 400 mg/m2/d 2-4h before RT 119 pts median survival 1.9 y vs 1.6 y NS Locally advanced NSCLC RT (60 Gy) vs RT + Miso 400 mg/m2/d 2-4h befo RT 268 pts median survival 8 m vs 7.4 m NS CR 27% vs 21% High-grade astrocytoma RT ( Gy) vs RT + Miso (0.6 3 g/m2) 711 pts (meta-analysis) OR: 0.92 (95%CI )

15 Etanidazole P Less neurotoxicity, superior lipophilic P RTOG phase III randomized trial, Head and neck cancer 521 pts, RT (66 Gy733 fr) ± etanidazole (2 mg/m2/3 x weekly) 2 years local control 40% vs 40% Median survival 41% vs 43% Radiother Oncol 1991; 20, 129-5

16 Nimorazole DAHANCA 5 phase III trial Larynx and pharynx squamous cell cancer: RT ± 1.2 mg/m2 nimorazol 4 years loco-regional control: %52 vs %33 P: years survival: %49 vs %33 RR: 0.69 Standard of care in Denmark Radiother Oncol 1998; 46: 135

17 PHARMACOLOGIC TARGETING OF HYPOXIC CELLS Mitomycin C: Cytotoxic to hypoxic cells. Yale University P 195 pts, RT: 68 Gy ± Mit. C (1. ve 43. days) Local control: 54% vs 76% p:0.003 Survival 42% vs 48% Cell Prolif. 2002; 35, 86-92

18 Vienna University Trial Covan RT vs CHART ± Mitomycin C 239 pts, 85% stage T3-4, 79% Lymp nod (+) 3 years loco-regional control: %31 vs %48 vs %32 3 years survival: %24 vs %41 vs %31 p: 0.03 Hyperfractionated accelerated mucositis (mit C 90%) Grade 3 or 4 hematologic toxicity, Thrombocytopenia %18 Radiother Oncol 2000; 57: 119

19 Porfiromycin: Derivative of Mitomycin C P Yale Ünv., Phase III trial, Head and Neck Cancer Conv. RT + Mit.C vs Conv. RT + Porfiromycin Median follow-up 6 years, Toxicity was equivalent in the two arms 5 years local relaps free survival: %91.6 vs %72.7 P years DFS: %72.8 vs %52.9 P: years OS: %49 vs %54 Int J Radiat Oncol Biol Phy, 2005; 61:

20 Tirapazamin (SR-4233, WIN 59075) Abioreductive agent preferentially should be cytotoxic to hypoxic cells in vitro. Drug is given before or after irradiation times more effective in anaerobic conditions DNA double-strand breaks

21 Locally advanced Head and Neck squamous cell cancer Trans Tasman Radiation Oncology Group (TROG) 122 pts: RT (70 Gy) + Cisplatin + Tirapazamine RT + Cisplatin + 5FU DFS (3y) %55 vs %44 Locoregional DFS (3y): %84 vs %66 Febrile neutropenia and mucositis JCO 2005; 23: 79

22 TUMOR HYPOXI - Tirapazamin Tumor hypoxia assessment with 18 F-misonidazole PET scanningwas performed in 45 pts Hypoxia: 75% Stage III-IV HNC 1. RT+ Cisplatin + 5FU 2. RT+ Cisplatin+Tripazamine Locoregional failure: %40 vs %13 JCO 2006; 24: 2098

23 Fig 1. S0222 treatment schema Tirapazamin Limited Stage SCLC SWOG 0222 trial, Le, Q.-T. X. et al. J Clin Oncol; 27:

24 Fig 2. (A) Progression-free survival for S0222 patients 72 pts 31 pts (46%): Grade 4 adverse events, mostly hematological 17 pts (25%): Grade 3 to 4 RT esophagitis Response rate: 63% (95% CI, 49% to 74%). Le, Q.-T. X. et al. J Clin Oncol; 27: Copyright American Society of Clinical Oncology

25 BIOLOGIC MODIFIERS OF RADIATION RESPONSE EGFR-1 overexpresyonu: Poor prognostic factor Cetuximab (C225): Monoclonal Ab. EGFR a endojen ligantlardan daha yüksek afinitede, tamamen bağlanarak hücre içi aktivasyonu önler Head and neck ca%100 (+) 4 Fish (+) HNC Colorectal-pancreas ca Fish (-)

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27 HEAD and NECK CA/RT + Cetuximab P Locally advanced head and neck cancer 213 pts RT (70 Gy/35 fr, Hfrx Gy/60-64 con. Boost 72 Gy/42 fr) 211 pts RT + Cetuximab (400 mg/m2, 250 mg/m2/w) Median locoregional control: OS: m vs 14.9 m 49 m vs 29 m (p:0.003) PFS için RR: 0.70 p:0.006 NEJM 2006; 354:

28 HEAD and NECK CA/CT-RT+ Cetuximab SCCHN, T1-4, N2b,c-3 RT: IMRT(87%) 3DCRT conc.boost 66Gy/30 fr (T1), 72 Gy/40-42 fr CR (RT±CT) (70%) PR (RT±CT) (26%) 3 year DFS 87% OS 91% JCO, 28(1), 8-14, 2010

29 RECTAL CANCER + RT + CETUXIMAB P locally advanced rectal cancer, 60 pts P Single-agent cetuximab in three doses, followed by weekly cetuximab plus 5-fluorouracil (5-FU), concomitantly with RT. P Pathological response (%63.3) in 38 pts P Thirty-one pts (77%) presented with acnelike ras P Grade 3 gastrointestinal toxicity; 2 pts Int JRadiatOncol Biol Phy2009;73(2):466

30 Thank You