Concurrent and sequential chemoradiotherapy. P. Van Houtte Department of Radiation Oncology Institut Jules Bordet

Transcription

1 Concurrent and sequential chemoradiotherapy and radiotherapy for NSCLC P. Van Houtte Department of Radiation Oncology Institut Jules Bordet

2 RADIOTHERAPY & CHEMOTHERAPY A very old concept «Benzene could be combined with radiation in treating leukemia because both are myelotoxins» F. Billings in 1905 published in 1922 Nitrogen mustard in lung cancer Roswit & Kaplan 1951 Are we still in the dark?

3 INTERACTIONS BETWEEN DRUGS & RT POSSIBLE MECHANISMS Spatial co-operation : induction or adjuvant treatment the most used schedule Simple addition of anti-tumor effect : implies to have different type of toxicity Protection of normal tissues : induction treatment? Enhancement of tumor response : our dream

4 RADIOTHERAPY & CHEMOTHERAPY INDUCTION CT ADVANTAGES Drugs are less effective after RT (vascular access) Systemic treatment is not delayed Assessment of drug efficacy (maintenance CT) Tumor shrinkage: better oxygenation RT efficacy PROBLEMS Delayed local treatment Problem of drug resistance volume reduction tissue protection

5 Metaanalysis RT vs Sequential RT and CT LUNG CA : Cambridge Metaanalysis Brit. Med. J Radical RT vs Radical RT + CT S ur v i v a l (cisplatin-based trials) Events Totals RT + CT RT Patients at risk Months RT+CT RT In the 2 meta-analyses Absolute benefit of CT-RT 4% at 2 years 2% at 5 years New meta-analysis to directly compare concomitant RT-CT versus sequential RT-CT NSCLC Collaborative Group BMJ (1995) 311:

6 RADIO-CHEMOTHERAPY CONCURRENT APPROACH Benefits both the local and metastatic disease may be treated possibility to obtain a radiosensitizing effect Drawbacks increase acute and late toxicity radiation and drugs dosage to be adapted logistic problems

7 EORTC TRIAL DDP & RT LUNG CA Schaake-Koning et al N.Engl.J.Med R RT RT+ weekly 30mg/m2 DDP RT+ daily 6mg/m2 DDP Local control is an important matter

8 NSC LUNG CANCER : RADIOCHEMOTHERAPY QUESTIONS Can we used safely the new drugs? Is concurrent superior to sequential approach? What is the best sequence? Induction followed by concurrent chemoradiotherapy Concurrent chemoradiotherapy followed by adjuvant CT What is the place of maintenance chemotherapy? Is there a place for targeted therapies?

9 RADIOCHEMOTHERAPY LUNG CA. RT vs Sequential vs Concurrent CT-RT trials % Median survival 2 Y Survival 0 RT alone Seq Conc RT alone Seq Conc Arriagada Dilman Sause Furuse Curran Fournel Zatloukal

10 CONCURRENT vs SEQUENTIAL CHEMORADIOTHERAPY IN NSCLC The Cochrane Database of Systematic Reviews. Study Concurrent n/n Sequential n/n Relative Risk 95% CI Relative Risk 95%CI Curran / / ( 0.79,1.05 ) Fourmel /103 80/ ( 0.71,1.01 ) Zatloukal /52 43/ ( 0.61,0.95) Total ( 0.78,0.95 ) P= favours concurrent favours sequential

11 Concomitant radio-chemotherapy (RT-CT) versus sequential RT-CT in locally advanced non-small cell lung cancer (NSCLC): A meta-analysis using individual patient data from randomised clinical trials A. Auperin, E. Rolland, W.J. Curran, K. Furuse, P. Fournel, J. Belderbos, G. Clamon, H.C. Ulutin, L. Stewart, C. Le Pechoux, on behalf of the NSCLC Collaborative Group Data presented during the Seoul meeting

12 Concomitant RT-CT versus sequential RT-CT in locally advanced NSCLC : Inclusion criteria Randomized trials: R Radiotherapy + Concomitant chemotherapy Radiotherapy + Sequential chemotherapy Accrual completed before 2004 Patients and treatment characteristics: Unresectable locally advanced non small cell lung cancer First line therapy

13 Seven eligible trials Number of Period Median Patients patients of accrual follow-up (y) alive CALGB West Japan LCG RTOG GMMA Ankara All dead 0 GLOT-GFPC NPC Prague * EORTC * data not available Data from 6 trials available: 1205 patients (92%)

14 Overall survival Trial No. Deaths / No. Entered RT + conc CT RT + seq CT Hazard Ratio HR [95% CI] CALGB /46 39/ [0.73;1.72] Median follow-up: 6 years WJLCG 131/ / [0.61;0.99] RTOG / / [0.65;0.98] GMMA Ankara 95 15/15 15/ [0.41;1.82] GLOT-GFPC NPC 87/102 96/ [0.60;1.07] EORTC /80 66/ [0.69;1.39] Total 521/ / [0.74;0.95] Test for heterogeneity: p = 0.66 I 2 = 0 % RT + conc CT better RT + seq CT better RT + cc CT effect: p = 0.004

15 Overall survival 100 HR=0.84 [0.74;0.95], p=0.004 Survival (%) Absolute benefit in OS with concomitant CT: At 2 years: At 3 years: At 5 years: 5.3% 5.7% 4.5% > 5 Time from randomisation (Years) 15.1 RT + conc CT RT + seq CT

16 Cumulative incidence of loco-regional progression (5 trials) 100 HR=0.77 (95%CI: ), p=0.01 Risk of recurrence (%) Absolute reduction in LRP with concomitant CT: At 1 year: At 2 years: At 3 years: - 4.5% - 5.6% - 6.0% RT + conc CT RT + seq CT > 5 Time from randomisation (Years)

17 Sequential or Concurrent Radio-chemotherapy Efficacity Toxicity Easy Complexity

18 RADIOCHEMOTHERAPY LUNG CA. Sequential vs Concurrent trials Median S 2 Y Surv gr.3 esophagitis Seq Conc Seq Conc Seq Conc Furuse RTOG GLOT Petruzelka IMRT Amifostine?

19 NSC LUNG CANCER : RADIOCHEMOTHERAPY The so-called new drugs Docetaxel Paclitaxel Vinorelbine Tirapazamine Gemcitabine Are very good radiosensitizers

20 RADIOCHEMOTHERAPY FOR NSCLC CALGB TRIAL E. Vokes JCO 2002 DDP (80 mg/m2) DDP + 66 Gy + New drug New drug Gemcitabine Paclitaxel Vinorelbine Doses (mg/m 2 ) Induction Concurrent with RT Number patients CR + PR MS (months) Year survival 37 % 29 % 40 %

21 Phase II CALGB trial NSCLC E. Vokes JCO 2003 Paclitaxel Vinorelbine Gemcitabine N. pat Neutropenia G4 (%) Platelets G4 (%) Esophagitis G3/4 (%) 35 / 4 13 / / 17 Dyspnea 3 & 4 (%) Vomiting 3 & 4 (%) ARDS (%) 4 2 0

22 Induction vs adjuvant chemotherapy Only small phase II trials

23 ECLWP PROTOCOL R A N D RT + CT CT CT RT + CT Chemotherapy Cisplatin 60 mg/m² D1-22 Vinorelbine 25 mg/m² D Gemcitabine 1 g/m² D Radiochemotherapy RT 66 Gy, 2Gy/fx Cisplatin 60 mg/m² D1-22 Vinorelbine 15 mg/m² D1-22 Gemcitabine 200 mg/m² D8-29

24 ECLWP PROTOCOL for NSCLC induction vs adjuvant chemotherapy N whole treatment CT dose intensity Response rate Median survival 2 Y survival Adjuvant CT CT-RT CT % 63 % 57 % 17 m. 38 % Induction CT CT CT-RT % 79 % 79 % 24 m. 50 %

25 Phase II trials induction vs adjuvant chemotherapy for NSCLC Garrido Docetaxel 40 mg/m 2 d 1-8 Gemcitabine 1200 mg/m 2 d 1-! RT+CT : 60 Gy + weekly Carbo AUC 2 Van Meerbeeck Cisplatine 75 mg/m 2 d 1 Docetaxel 40 mg/m 2 d 1 RT +CT : 66 Gy + weekly Dox 20 mg/m 2 DDP 20 mg/m 2

26 Phase II trials induction vs adjuvant chemoth. for NSCLC (IASLC Seoul) Garr ido Van Meerbeeck CT+RT---- CT CT---CT+RT CT+RT---CT CT-----CT+RT Carbo w.rt DOX-DDP DOX-DDP+RT DOX-GEM ADJ IND ADJ IND N Survival 1Y 2Y 3Y Toxicity grade3/4 Esophagitis Pneumonitis Neutrop. during CT Neutrop. during RT

27 Induction chemotherapy before concurrent CT-RT for NSCLC phasese II/III trials (IASLC Seoul) Vo kes K im N Survival 2Y 3Y Toxicity grade3/4 Esophagitis Pneumonitis Neutrop. during CT Neutrop. during RT CT+RT Carbo w.rt Paclit w CT---CT+RT Carbo-Pacli x2 CT+RT CT+RT Paclt-DDP/w CT-----CT+RT Gem DDP Paclit-DDP+RT

28 The role of docetaxel as maintenance after CT-RT The HOG LUN 01-24/USO-23 trial DDP 50mg/m 2 iv d.1,8,29,36 Etoposide 50mg/m 2 iv d.1-5, RT 59.4 Gy 203 pat. No Prog. R Observation 74 p Docetaxel 73 p 75 mg/m 2 x 3q.3w. Toxicity > G2 Hosp. Toxic death Febrile neutr. Pneum. Results PFS MST Observation Docetaxel 8 % 29 % 5 % 11 % 18 %

29 The SWOG trial with maintenance docetaxel Lung toxicity data Gaspar et al ASTRO 2006 RT-CT DDP-VP pat. CT-RT 343 maintenance Doc. 209 randomized Docetaxel 7 % experienced grade 3 or more pneumonitis Strong correlation with the V20 V20 > 35% worse prognosis and outcome R Gefinitib Observation

30 EGFR & Cetuximab + RT Harari Clin.Cancer Res Human squamous cell carcinoma cell line Bonner N.Engl.J.Med.2006 Head & Neck Ca Type of tumor Head & Neck Colon Pancreas Breast Renal NSCLC Ovary Glioma Tumor with EGFR Expression % % Up to 95 % RT Up to 91 % Up to 90 Er% Up to 80 % Up to 77 % Up to 63 % Rt+Erb Cet.+RT RT

31 Targeted therapies with concurrent RT-CT for NSCLC : Current status Phase III trial : AE-941 no benefit Lu et al ASCO Phase I/II Cetuximab tested with RT or RT-CT Dose of 250 mg/m2 weekly is safe Blumenschein, Hughes, Jensen Phase III trials are on-going RTOG/CALGB with pemetrexed and carboplatin Gefinitib is in phase I trial with taxanes (Ball, Blackstock) Erlotinib with carboplatin-paclitaxel or cisplatine-etoposide : dose escalation to 150 mg daily (Choong) Cox-2 inhibitor : disregarded due to the possibledrug toxicity

32 CONCURRENT RT-CT in NSCLC To use the modern facilities of RT Treatment planning in 3D Take into account the normal tissue tolerance IMRT in selected cases to reduce oesophageal toxicity Image Guided Radiotherapy PET-CT for treatment planning Take into account the GTV volume instead of the TN

33 NSC LUNG CANCER : CT & RT The Learning Process RTOG trial 9106 & 9204 Lee et al Int.J.Radiat.Oncol.Biol.Phys. 52, 2003 Number of patients per institution 4 patients or less > 4 patients Median survival Months 2 Y S 20 % 45 % 3 Y S 13 % 31 % Concurrent radio-chemotherapy with twice per day irradiation

34 From 2 D to 4 D radiotherapy From RT to CHEMO RT 3 DCRT IMRT IGRT 4 D RT Require a precise imaging not only for the treatment planning but also for the treatment delivery

35 Technical evolution in the RT of early lung ca

36 The TNM is not the perfect toy to select patients for a treatment approach Patient treated only with Patient with a small tumor Chemotherapy and an treated with radiotherapy endobronchial prothesis external and endobronchial

37 Post-Induction Gross Tumor Volume- UNC Experience. Rationale for the Induction Approach 102 stage III pts receiving induction chemo followed by TCRT >70 Gy Volumes defined by 3-D plan both preand post-induction Chemo Post-induction GTV predictive of survival

38 CONCURRENT RT-CT in NSCLC Is superior to a sequential approach but Require a precise radiation technique A precise selection of patient to avoid an excessive toxicit The best chemotherapy program is still to be defined but should be cisplatine based. Which drug shoud be added? From etoposide to taxanes, gemcitabine, vinorelbine or pemetrexed The optimal sequence is to be defined (the place of induction or adjuvant chemotherapy) The place of targeted therapies must be addressed in phase III trials Do we still need surgery or how to select patient for surgery or radiotherapy?

39 STEREOTACTIC RADIOTHERAPY FOR STAGE I LUNG CANCER Stade Mountain JCOG JNCCH Onushi Surgery Surgery Surgery RT Ia 67 % 80 % 74 % 77 % Ib 57 % 63 % 53 % 68 % Pathological stage 11O patients treated by stereotactic radiotherapy with a biological dose > 100 Gy

40 RANDOMIZED TRIALS PATHOL. STAGE IIIa «Radiotherapy versus Surgery» Trial Treatment Pat. Median S. Months Intergroup R+C S C R+C C EORTC C Resp R S RTOG C R 45 S No statistical difference in survival 5 Y S %

41 SURGERY or RADIOTHERAPY for STAGE III NSCLCA?

42 STAGE IIIa-b RT or SURGERY Requirements : Surgery The tumor should be resectable A RO resection No place for an incomplete resection The patient should be medically operable T4 potentially resectable Highly selected patients Radiotherapy A dose > 65 Gy or biological equivalent An adequate technique No «palliative» radiotherapy Patient should have a good PS Candidate for a combined approach

43 The local control of the disease is still an important issue for lung cancer Surgery and Radiotherapy are partners but we need to individualize our choice on prognostic factors ( pneumectomy, size of tumor and lymph node, irradiated volume More trials are needed to clarify the issue The current TNM is not the answer to choice the treatment option

44 NSC LUNG CANCER : INDUCTION CT Authors CT RT No Stage Median 2 Y S Pts Surv (m) % Matson CAP 55 S 252 I-III No dif Brodin DDP-VP16 56 C 302 I-III Jett MACC 60 C 121 III No dif Arriagada VCPC 65 C 353 I-III Ben. 65 C Dillman DDP,Vinbl 60 C 180 III Ben 60 C Sause DDP,Vinbl 60 C 490 III Ben 60 C

45 RADIOCHEMOTHERAPY LUNG CA. Sequential vs Concurrent trials Problems of treatment compliance Trials Treatment Sequential Concurrent Furuse 3 cycles CT 25 % 59 % Fournel RT given 59 % 88 % CT given 77 % 3 cycles 100 % 2 cycles 54 % 2 post RT Zatloukal CT 4 cycles 58 % 83 % RT given 64 % 94 %