Chemo-radiation and targeted agents: biological basis

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Diana Wiggins
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1 Chemoradiation and targeted agents: biological basis Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for highrisk cervical cancer. M. Morris et al, NEJM, 3: , Prof. Vincent GREGOIRE Université Catholique de Louvain, Cliniques Universitaires StLuc Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for highrisk cervical cancer. M. Morris et al, NEJM, 3: , (n=193) Chemo (n=19) y overall survival 8% 73 (p=.) LR recurrence 3% 19% (p<.1) Distant relapse 33% 1% (p<.1) Combined chemo and radiotherapy Spatial cooperation (e.g. breast carcinoma) Independent cell kill (e.g. Hodgkin lymphoma) Interaction (e.g. H&N, cervix, NSCLC) diluted toxicity (e.g. Hodgkin lymphoma) : Gy brachytherapy (total dose 8 Gy) Chemo: cddp (7mg/m, d1), Fu (1g/m /d, d1), x3 Postoperative radiotherapy in highrisk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 8b Trial M. Overgaard et al., N. Engl. J. Med., 337: 999, 1997 Prophylactic cranial in SCLC (metaanalysis, n=981) Aupérin et al., NEJM 31: 76, 1999

2 Combined chemo and radiotherapy Spatial cooperation (e.g. breast carcinoma) Independent cell kill (e.g. Hodgkin lymphoma) Interaction (e.g. H&N, cervix, NSCLC) diluted toxicity (e.g. Hodgkin lymphoma) Stage I and II Hodgkin disease (very favorable and favorable categories) CH CH (EF, Gy) (MOPP/ABVD) (IF, Gy) 1 y over. survival 89% 89% 9% Complications (RR) leukemia lymphoma 1.. solid tumor cardiac Combined chemo and radiotherapy H&N SCC: MACHNC Spatial cooperation (e.g. breast carcinoma) Independent cell kill (e.g. Hodgkin lymphoma) Interaction (e.g. H&N, cervix, NSCLC) diluted toxicity (e.g. Hodgkin lymphoma) Pignon et al., Lancet 3: 999, H&N SCC: MACHNC Combined chemo and radiotherapy Effect Dose Additivity Supraadditivity Effect CH Effect CH Pignon et al., Lancet 3: 999, Dose Dose

3 DOSE MODIFICATION FACTOR IN SANH TUMOR AFTER SINGLE IRRADIATION COMBINED WITH FLUDARABINE (8 mg/kg) GROWTH DELAY ± SE (days) Absolute Growth Delay DMF = 1.7 Normalized Growth Delay DMF = 1. alone RADIATION DOSE (Gy) Combined chemo and radiotherapy D D 1.E 1 1 SF 1 SF 1 Supraadditivity SF 1.E1 1.E 1.E3 Combined chemo and radiotherapy Combined chemo and radiotherapy E Enhancement Noninteraction Inhibition E 1.E 1.E 1.E1 1.E1 1.E1 1.E1 1.E CH 1.E 1.E3 CH 1.E 1.E3 CH 1.E 1.E3 CH 1.E3 Redrawn from Steel Radioenhancement by dfdc of a human squamous cell carcinoma cell line (SQD9) Surviving Fraction 1 α β DMF=1.3 (Gy 1) (Gy) Rx DMF=1.3 Rx dfdc DMF=1.3 Rx alone dfdc ( µm) for 3 h prior to Rx Rationales for combining chemotherapeutic agents and ionizing radiation Absorbed dose (Gy)

EFFECT FaraA ON CHROMOSOME BREAK REPAIR AFTER SINGLE DOSE

INDUCED BY FLUDARABINE (8 mg/kg) IN SANH TUMOR PERCENT OF INITIAL

h prior to 6 8 1 TIME AFTER IRRADIATION (min.) From Jayanth et al.

gemcitabine on radiationinduced apoptosis in SANH tumor in vivo

1 36 8 6 7 8 96 Hours after From Milas et al.

FaraA / / Combined chemo and radiotherapy : Plant derivatives

4 EFFECT FaraA ON CHROMOSOME BREAK REPAIR AFTER SINGLE DOSE IRRADIATION ( Gy) IN HUMAN LYMPHOCYTES CELL CYCLE REDISTRIBUTION INDUCED BY FLUDARABINE (8 mg/kg) IN SANH TUMOR PERCENT OF INITIAL DAMAGE alone FaraA (1 µm). h prior to TIME AFTER IRRADIATION (min.) From Jayanth et al. BrdUrd CONTENT h 3 h 6 h 1 h 1 h 18 h h 36 h DNA CONTENT Effect of gemcitabine on radiationinduced apoptosis in SANH tumor in vivo Apoptosis (%) 8 6 Gy alone dfdc ( mg/kg) alone dfdc 36h prior to Gy Hours after From Milas et al. Combined chemo and radiotherapy : Antimetabolites Fu MTX HU dfdc FaraA / / Combined chemo and radiotherapy : Plant derivatives Vincaalcaloides Etoposide Camptothecine Taxanes / / Combined chemo and radiotherapy : Antibiotics Adriamycin MitomycinC Bleomycin ActinomycinD / / /

$regrowth delay in SANH tumor by fractionated irradiation and fludarabine administration Biological modifiers as adjuvants to radiotherapy Mean tumor diameter ± se$ (mm) 1 13 11 9 7 control Fluda

5 Combined chemo and radiotherapy : Alkylating agents Cisplatinum BCNU Cyclophosphamide Combined chemo and radiotherapy or Tissular interaction Modulation of regrowth delay in SANH tumor by fractionated irradiation and fludarabine administration Biological modifiers as adjuvants to radiotherapy Mean tumor diameter ± se (mm) control Fludarabine ( mg/ kg) q.d. x. Gy q.d. x Fludarabine 3h prior to 1 1 Time after first fraction (day) The EGF receptor EGFR overexpression: poor local tumor control after long overall times HNSCC (DAHANCA) HNSCC (CHA) Eriksen et al., IJROBP 8: 6166, Atasoy et al., Exp Strahlenther Klin Strahlenbiol 13: 391,

6 EGFR and repopulation during FaDu hscc C anti EGFR Ab; A 31 tumours: 1 EGFReceptor c 1x 3x SD18Gy 18Gy 1x TCD (Gy) 6 T clon = 9.8d [;1] T clon = 3.d [1.7;] Day [13;3] RDI pab Radiobiological hypoxia 1 3 Time after start of 18Gy 3x SD/1xC SD/3xC Petersen, IJR, 3 EGFR inhibitor and RxTh in HNSCC efficacy THE CONCEPT OF THERAPEUTIC RATIO DMF =. EFFICACY Tumor radiosensitization Normal tissue radiotoxicity DMF = 1. Therapeutic Ratio = DMF T DMF NT Bonner, Lancet Oncol 1 Combined chemo and radiotherapy :normal tissue toxicity Acute effect Late effect Antimetabolites Fu (GI, skin) MTX (GI) HU (GI) dfdc (GI) ± (lung) FaraA (GI) ± (SNC) Alkylating agents cisplatinum (GI) (kidney) BCNU (GI) (lung) cyclophosphamide (GI, skin) (lung,bladder, SNC) Antimetabolites adriamycine (GI, skin) (heart, lung) mitomycinc (GI, BM) (lung) bleomycin (skin, GI) (skin, lung) actinomycined (GI, BM, skin) (lung) Plant derivatives Vincaalcaloides (GI, BM) Etoposide Taxanes (GI) Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for highrisk cervical cancer. M. Morris et al, NEJM, 3: , (n=193) Chemo (n=19) Early toxicity (G3) 1 (%) 88 (%) Early toxicity* (G3) (%) (1%) Late toxicity (G3) (11%) (1%) * non hematologic only : Gy brachytherapy (total dose 8 Gy) Chemo: cddp (7mg/m, d1), Fu (1g/m /d, d1), x3

7 Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for highrisk cervical cancer. M. Morris et al, NEJM, 3: , Treatment of advanced squamouscell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. M. Merlano et al, NEJM, 37:111111, 199. Enhancement factor Effect on tumor control Local relapse Early Late Effect on normal tissue toxicity Enhancement factor 1 Effect on tumor control Local relapse Early Late Effect on normal tissue toxicity : 7 Gy, 7 weeks CH: 3 x Gy, 9 weeks; cddp (mg/m /d, d1)fu ( mg/m /d, d1) x Skin reaction Dysphagia Xerostomia Most Common Adverse Events % Toxicity Mucositis/Stomatitis Fatigue/Malaise Infusion reaction # All Gr # Listed for its relationship to cetuximab * p <., ** p <.1, Fisher s exact test (N=1) Gr. 3/ E (N=8) All Gr. 97* ** Gr. 3/ 3** 3* Combined chemo and radiotherapy Objectiveoriented design of clinical trials Benefit of Chemo is due to tissular interaction Antiproliferationbased efficacy and toxicity More data needed to design combined Chemo trial based on cellular/molecular interaction Equal dose trial <> equal toxicity trial Bonner, NEJM, 6

Combined drug and ionizing radiation: biological basis. Prof. Vincent GREGOIRE Université Catholique de Louvain, Cliniques Universitaires St-Luc

Combined drug and ionizing radiation: biological basis Prof. Vincent GREGOIRE Université Catholique de Louvain, Cliniques Universitaires St-Luc Pelvic radiation with concurrent chemotherapy compared with