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

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

2 Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. M. Morris et al, NEJM, 340: , 1999.

3 Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. M. Morris et al, NEJM, 340: , RT (n=193) RT+Chemo (n=195) 5y overall survival 58% 73% (p=0.004) LR recurrence 35% 19% (p<0.001) Distant relapse 33% 14% (p<0.001) RT: 45 Gy + brachytherapy (total dose = 85 Gy) Chemo: cddp (75mg/m 2, d1), 5Fu (1g/m 2 /d, d1-4), x3

4 Combined chemo- and radiotherapy treatment How does it work How should RT and Chemo be combined What are the goals for combining RT and Chemo

5 Combined chemo- and radiotherapy treatment Spatial co-operation (e.g. breast carcinoma) Independent cell kill (e.g. Hodgkin lymphoma) Interaction (e.g. H&N, cervix, NSCLC) diluted toxicity (e.g. Hodgkin lymphoma)

6 Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial M. Overgaard et al., N. Engl. J. Med., 337: , 1997

7 Combined chemo- and radiotherapy treatment Spatial co-operation (e.g. breast carcinoma) Independent cell kill (e.g. Hodgkin lymphoma) Interaction (e.g. H&N, cervix, NSCLC) diluted toxicity (e.g. Hodgkin lymphoma)

8 Stage I and II Hodgkin disease (very favorable and favorable categories) RT CH CH+RT (EF, 40 Gy) (MOPP/ABVD) (IF, = 40 Gy) 10 y over. survival 80-90% 80-90% 90% Complications (RR) -leukemia lymphoma solid tumor cardiac

9 Combined chemo- and radiotherapy treatment Spatial co-operation (e.g. breast carcinoma) Independent cell kill (e.g. Hodgkin lymphoma) Interaction (e.g. H&N, cervix, NSCLC) diluted toxicity (e.g. Hodgkin lymphoma)

12 Combined chemo- and radiotherapy treatment Effect RT Dose Additivity Supra-additivity Effect RT+CH RT Effect RT+CH RT Dose Dose

13 DOSE MODIFICATION FACTOR IN SA-NH TUMOR AFTER SINGLE IRRADIATION COMBINED WITH FLUDARABINE (800 mg/kg) GROWTH DELAY ± SE (days) Absolute Growth Delay DMF = 1.57 RT alone Normalized Growth Delay DMF = RADIATION DOSE (Gy)

14 Combined chemo- and radiotherapy 1.0E+00 SF 1 treatment 0 D 2D SF 1 SF 2 Supra-additivity 1.0E-01 S.F. 1.0E E-03 Dose (Gy)

15 Combined chemo- and radiotherapy treatment E+00 RT 1.0E-01 S.F. 1.0E-02 RT+CH 1.0E-03 Dose (Gy)

16 Combined chemo- and radiotherapy treatment Enhancement Non-interaction Inhibition 1.0E E E+00 RT RT RT 1.0E E E-01 S.F. S.F. S.F. 1.0E-02 RT+CH 1.0E-02 RT+CH 1.0E-02 RT+CH 1.0E-03 Dose (Gy) 1.0E-03 Dose (Gy) 1.0E-03 Dose (Gy) Redrawn from Steel

17 Radio-enhancement by dfdc of a human squamous cell carcinoma cell line (SQD9) Surviving Fraction DMF=1.3 DMF=1.3 DMF=1.3 Rx alone dfdc (5 µm) for 3 h prior to Rx α β (Gy -1 ) (Gy -2 ) Rx Rx + dfdc Absorbed dose (Gy)

18 Combined chemo- and radiotherapy treatment Isobologram analysis Dose agent B Uncertainty Supra-additivity Infra-additivity ([A] x,[b] x+y=0.1 ) S.F.=0.1 ([A] x,[b] 0.1 -[A] x ) Dose agent A Redrawn from Steel

19 Combined chemo- and radiotherapy treatment Isobologram analysis: Etoposide (VP-16) for 60 min before and 30 min after RT From Hennequin et al., 1996

20 Rationales for combining chemotherapeutic agents and ionizing radiation modulation of DNA/chromosome repair regulation of tumor cell proliferation increased tumor cell loss enhancement of nucleoside analogue- induced apoptosis by IR increased tumor cell re-oxygenation

21 Effect of F-ara-A on DNA DSB induced by ionizing radiation Fraction of activity released RT alone RT + F-ara-A (100 µm for 1h) Absorbed dose (Gy)

22 EFFECT OF F-ara-A ON DNA DSB REPAIR AFTER SINGLE DOSE IRRADIATION (25 Gy) IN SA-NH CELLS 100 PERCENT OF INITIAL DAMAGE F-ara-A (100 µm) 1h prior to RT RT alone TIME AFTER IRRADIATION (h)

23 EFFECT F-ara-A ON CHROMOSOME BREAK REPAIR AFTER SINGLE DOSE IRRADIATION (4 Gy) IN HUMAN LYMPHOCYTES PERCENT OF INITIAL DAMAGE RT alone F-ara-A (100 µm) 0.5 h prior to RT TIME AFTER IRRADIATION (min.) From Jayanth et al.

24 CELL CYCLE REDISTRIBUTION INDUCED BY FLUDARABINE (800 mg/kg) IN SA-NH TUMOR BrdUrd CONTENT 0 h 3 h 6 h 12 h 15 h 18 h 24 h 36 h DNA CONTENT

25 Effect of gemcitabine on radiation-induced apoptosis in SA-NH tumor in vivo 8 dfdc (50 mg/kg) alone Apoptosis (%) dfdc 36h prior to 25 Gy 25 Gy alone Hours after treatment From Milas et al.

26 Combined chemo- and radiotherapy treatment: Cellular / molecular interaction Antimetabolites DNA damage Chromosome Cell Apoptosis induction repair aberration Cycle 5-Fu - -/+ - + MTX HU -/+ + + dfdc F-ara-A

27 Combined chemo- and radiotherapy treatment: Cellular / molecular interaction Plant derivatives DNA damage Chromosome Cell Apoptosis induction repair aberration Cycle Vinca-alcaloides - + Etoposide Camptothecine - -/+ -/+ Taxanes

28 Combined chemo- and radiotherapy treatment: Cellular / molecular interaction Antibiotics DNA damage Chromosome Cell Apoptosis induction repair aberration Cycle Adriamycin - -/+ -/+ + Mitomycin-C - Bleomycin - -/+ + Actinomycin-D + -

29 Combined chemo- and radiotherapy treatment: Cellular / molecular interaction Alkylating agents DNA damage Chromosome Cell Apoptosis induction repair aberration Cycle Cis-platinum BCNU + - Cyclophosphamide -

30 Combined chemo- and radiotherapy treatment Cellular / molecular interaction or Tissular interaction

31 Modulation of regrowth delay in SA-NH tumor by fractionated irradiation and fludarabine administration Mean tumor diameter ± se (mm) control Fludarabine (400 mg/ kg) q.d. x4 4.5 Gy q.d. x4 Fludarabine 3h prior to RT Time after first fraction (day)

32 Taxol (60 mg/kg)-induced MCA-4 tumor reoxygenation Untreated 24 h Relative frequency (%) h 48 h Tumor oxygen pressure (mm Hg) From Milas et al.

33 THE CONCEPT OF THERAPEUTIC RATIO DMF = 2.0 EFFICACY Tumor radiosensitization Normal tissue radio-toxicity DMF = 1.2 Therapeutic Ratio = DMF T DMF NT

34 Combined chemo- and radiotherapy treatment:normal tissue toxicity Acute effect Late effect Antimetabolites 5-Fu ++ (GI, skin) MTX ++ (GI) HU ++ (GI) dfdc ++ (GI) ± (lung) F-ara-A ++ (GI) ± (SNC) Alkylating agents cis-platinum ++ (GI) + (kidney) BCNU ++ (GI) + (lung) cyclophosphamide ++ (GI, skin) + (lung, bladder, SNC) Antimetabolites adriamycine ++ (GI, skin) + (heart, lung) mitomycin-c ++ (GI, BM) + (lung) bleomycin ++ (skin, GI) + (skin, lung) actinomycine-d ++ (GI, BM, skin) + (lung) Plant derivatives Vinca-alcaloides - (GI, BM) Etoposide Taxanes + (GI)

35 Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. M. Morris et al, NEJM, 340: , RT (n=193) RT+Chemo (n=195) Early toxicity (G3-5) 10 (5%) 88 (45%) Early toxicity* (G3-5) 4 (2%) 20 (10%) Late toxicity (G3-5) 22 (11%) 24 (12%) * non hematologic only RT: 45 Gy + brachytherapy (total dose = 85 Gy) Chemo: cddp (75mg/m 2, d1), 5Fu (1g/m 2 /d, d1-4), x3

36 Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. M. Morris et al, NEJM, 340: , Enhancement factor Effect on tumor control Local relapse Early Late Effect on normal tissue toxicity

37 Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. M. Merlano et al, NEJM, 327: , Enhancement factor Effect on tumor control Local relapse Early Late Effect on normal tissue toxicity RT: 70 Gy, 7 weeks RT+CH: 3 x 20 Gy, 9 weeks; cddp (20mg/m 2 /d, d1-5)-5fu (200 mg/m 2 /d, d1-5) x4

38 Combined chemo- and radiotherapy treatment Objective-oriented design of clinical trials Benefit of RT+Chemo is due to tissular interaction Anti-proliferation-based efficacy and toxicity More data needed to design combined RT+Chemo trial based on cellular/molecular interaction Equal dose trial <> equal toxicity trial

Chemo-radiation and targeted agents: biological basis

Chemo-radiation and targeted agents: biological basis 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, 3:1137113,