NSCLC localmente avanzato

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Presentation transcript:

NSCLC localmente avanzato MARTA SCORSETTI M.D. Direttore Radioterapia e Radiochirurgia Istituto Clinico Humanitas marta.scorsetti@humanitas.it 1 1

2013 In patients with infiltrative stage III (N2,3) NSCLC and performance status 0-1 being considered for curative-intent treatment, combination platinum-based chemotherapy and radiotherapy (60-66 Gy) are recommended (Grade 1A) Remark: Dose escalation of radiotherapy is not recommended (except in a clinical trial) Remark: For patients with stage IIIB NSCLC, once daily thoracic radiotherapy plus platinum-based doublet chemotherapy is recommended

Why Did 74.0 Gy Fail? Speculation and Conjecture W.J. Curran A. Bezjak H. Choy Why Did 74.0 Gy Fail? Speculation and Conjecture Walter J Curran, Jr, MD Radiation Therapy Oncology Group Chairman Executive Director, Winship Cancer Institute of Emory University Georgia Research Alliance Eminent Scholar

RTOG 0617 Primary Objective To compare the overall survival of patients treated with high-dose versus standard-dose conformal radiation therapy with concurrent chemotherapy. To compare the overall survival of patients treated with cetuximab versus without cetuximab with concurrent chemoradiotherapy.

RTOG 0617: Trial Design Stratify: -RT Technique (IMRT vs 3D) -Perf Status (0 vs 1) -Histology (squam vs other) -PET staging (yes vs no) 5

RTOG 0617: Survival by RT Dose 18-Month Survival Rate 66.9% 53.9% Median Survival Time 28.7 months 19.5 months

RTOG 0617: Local Tumor Failure 18-Month Local Progression Rate 34.3% 25.1%

RTOG 0617: Distant Failure 18-Month Failure Rate 47.8% 42.4%

Hypothesis 1: Unbalanced Arms Despite employing standard stratification features, some known or unknown features predictive for toxicity and/or treatment resistance were imbalanced between the arms.

Hypothesis 1: Unbalanced Arms Stratification features employed: RT Technique (IMRT vs 3-D Conformal RT) Zubrod Performance Status Use of PET in Staging Histology (Squamous vs Non-Squamous)

Pretreatment Characteristics   60 Gy (n=213) 74 Gy (n=206) Age (median)  64 Gender Male 59% 58% Female 41% 42% Race Other 12% 14% White 88% 86% RT Technique 3DCRT 54% 53% IMRT 46% 47% PET Staging 91% 89% Histology Adenocarcinoma 39% 35% Squamous NSCLC NOS 19% 18% AJCC Stage Stage IIIA Stage IIIB 67% 33% 64% 36%

Hypothesis 1: Unbalanced Arms Any Unknown Features in Play? Predictors of Treatment Resistance? Predictors of Sensitivity to Toxicity?

100 NSCLC Patients at U Michigan Kaplan-Meier Estimates of Overall Survival According to the Serum MicroRNA Signature P = 0.001 Low risk (N=53) MST = 36.6months High risk (N=47) MST = 13.3 months

Analysis of miRNA Signature and RT Dose Bi, …Kong, U Michigan BED < 100Gy, low risk, MST = 33.4 Months (N=38) BED < 100Gy, high risk, MST = 9.9 Months (N=33) BED ≥ 100Gy, low risk, MST = 38.9 Months (N=15) BED ≥ 100Gy, high risk, MST = 19.3 Months (N=14) Log-rank P = 0.001 Patients with high risk miRNA signature benefited from high dose RT, while low risk pts did not.

Hypothesis 2: RT Delivery Issues To meet RT dose constraints, less optimal RT was delivered to the 74 Gy arm patients, leading to poor RT dose distribution and an influence on toxicity and/or tumor control.

RTOG 0617: Dosimetric Data Distribution   60 Gy (n=203) Mean (Median) 74 Gy (n=197) GTV Volume (cc) 125 (92)  129 (96) Heart V5 (%) 47 (46) 46 (46) Heart V50 (%) 7 (4) 11 (6) Lung V20 (%) 29  (29) 31 (32) Esophagus Dose (Gy) 25 (25) 30 (29) Esophagus V60 (%) 15 (13) 26 (26) Mean Margin CTV to PTV (mm) 8 (7)

As scored by institution No significant difference RTOG 0617 Definitely, Probably, or Possibly Related to Treatment (CTCAE Version 3.0) Standard Dose: 60 Gy High Dose: 74 Gy (n=213) Grade (n=206) 3 4 5 Worst non-hematologic 98 (46%) 21 (10%) 2 (1%) 95 23 (11%) 10 (5%) Worst overall 99 (47%) 57 (27%) 86 (42%) 65 (32%) Grade 5 Events (n=2) (n=10) As scored by institution No significant difference 1 Pulmonary 1 Sudden death 2 Pulmonary 1 Thrombosis 1 Upper GI Hemorrhage 1 Pulmonary Hemorrhage 1 Pneumonia NOS 1 Esophageal 1 TE fistula 1 Sepsis 1 Death NOS

Esophagitis Standard Dose: 60 Gy High Dose: 74 Gy Esophagitis/ Dysphagia (n = 213) (n = 206) Grade 2 198 (93%) 163 (79%) Grade 3 15 (7%) 43 (21%) p-value 0.0003

Per Protocol vs. Not per protocol Multivariate Cox Model Covariate Comparison (RL) HR (95% CI) p-value Radiation dose 60 Gy v 74 Gy 1.51 (1.12, 2.04) 0.007 Histology Non-squam v Squam 1.31 (0.99, 1.75) 0.061 Max esophagitis grade <3 vs ≥3 1.52 (1.06, 2.20) 0.024 Heart Contour Per Protocol vs. Not per protocol 0.67 (0.47, 0.96) 0.029 GTV Continuous 1.001 (1.000, 1.002) 0.038 Heart V50(%) 1.017 (1.004, 1.030) 0.008 Backwards Selection: Exit criteria p>0.10 Two-sided p-values Removed from model: Age (continuous), overall RT review (per protocol vs. not per protocol), and lung V5 (continuous)

What might have happened? 74 Gy given over too long an interval? Possibly. Unreported Toxicity? Chemotherapy delivery/compliance? No evidence of this RT compliance; GTV misses? Under review Heart dose

Hypothesis 3: Pt-Reported Outcomes (PRO) may help Patient-reported outcomes were effectively collected in the trial and may be illuminating.

RTOG 0617 PRO Methods QOL was collected prospectively via a validated lung cancer instrument: Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) FACT-TOI = Physical Well Being (PWB) + Functional Well Being (FWB) + Lung Cancer Subscale (LCS) Data was collected at baseline, 3 months & 12 months via clinically meaningful changes of >2 points for PWB, FWB or LCS, or >5 points for TOI

Change in Lung Cancer Symptoms (LCS) LCS Decline

Results: Baseline FACT and OS Baseline QOL (whether PWB, FWB, or FACT-TOI) also predicted for survival in multivariate analysis, p=<0.02 independent of RT dose assignment. Every 10 points higher on the FACT-TOI at baseline corresponded to a 14% decreased risk of death Is this the unknown variable not used in stratification?

Why Did 74.0 Gy Fail? Still under many realms of investigation 74.0 Gy as delivered in this trial of this patient subgroup is associated with poorer survival than standard dose RT The results provides greater support for more RT dose/volume investigations for stage III NSCLC

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Contrasting results of altered fractionation in randomised trials Cécile Le Péchoux Contrasting results of altered fractionation in randomised trials Over the years, several randomized trials evaluating ≠ altered fractionation schedules: Contrasting results Necessity of an individual patient data meta-analysis (IPD) to evaluate a potential benefit from modified fractionation radiotherapy schedules Hyperfractionnated: higher number of fractions with smaller dose per fraction compared with conventional RT Accelerated: reduced overall treatment time (OTT) compared with conventional fractionation and Hyperfractionated and accelerated 34

Altered fractionation Weekly D 1O Gy 31,5 Gy 24 Gy 22,5 Gy 20 Gy 12 Gy 15 Gy 60 Gy/30 fr DD = 2 Gy *ECOG 64 Gy CHARTWEL 66 Gy CHART=TD 54 Gy/36 fr DD: 3X1,5 Gy ECOG=TD 57,6 Gy/36 fr DD : 1,5-1,8-1,5 Gy CHARTWEL=60 Gy/40 fr DD : 3X1,5 Gy PMCI=60 Gy/30 fr DD : 2X2 Gy RTOG=69,6 Gy/58 fr DD : 2X1,2 Gy CCTG=60Gy/40 fr DD : 2X1,5 Gy 5 days Week-end Week-end Week-end Week-end Week-end Week-end Week-end Week-end Week-end Split course:2 wks

NSCLC-Patient characteristics (n=2,000) Conventional RT=944 pts Modified RT=1056pts Patients Age % <60 28 60-69 42 70+ 30 Gender (male) 75% Disease Performance Status % 0 42 1 58 Stage % I / II 17 IIIA 43 IIIB 40 Histology (squamous) 60% 8 randomized trials: 2,000 pts (90% of all known randomized pts) between 1989 and 2005 4 trials with chemotherapy in the 2 arms (carboplatin, cisplatin-etoposide or carboplatin-paclitaxel) 36

Overall survival NSCLC Very accelerated RT Category Trial No. Deaths / No. Entered Exp. RT Conv. RT O-E Variance Hazard Ratio HR [95% CI] Experimental RT better | Conventional RT PMCI 88C091 48/48 52/53 -0.8 24.3 PMCI 88C091 CT 51/51 56/56 6.0 25.6 CHART 316/338 217/225 -29.4 120.7 ECOG 2597 51/60 55/59 -7.4 25.8 CHARTWEL 132/150 0.2 65.8 CHARTWELCT 40/53 47/53 -6.4 21.2 Subtotal 638/700 559/596 -37.8 283.4 0.88 [0.78;0.98] Moderately accelerated RT Gliwice 2001 26/29 27/29 -1.4 13.2 0.90 [0.52;1.54] Hyperfractionated RT - identical total dose NCCTG 902451 34/39 35/35 -7.0 15.7 NCCTG 942452 111/125 108/121 -2.6 54.6 145/164 143/156 -9.6 70.3 0.87 [0.69;1.10] Hyperfractionated RT - increased total dose RTOG 8808 155/163 156/163 76.9 0.92 [0.74;1.15] Total 964/1056 885/944 -55.2 443.7 Test for heterogeneity: 2 9 = 9.74 p = 0.37 I = 8 % Test for interaction: 3 = 0.17 = 0.98 0.88 [0.80;0.97], p=0.009 0.25 1.00 4.00 60Gy/6wks vs 60/3wks BID 60Gy/6wks vs 60/3wks CT 60Gy/6wks vs 54 Gy/12d TD 64Gy/6,4Wks vs 57,6Gy/2,5wks TD 66 Gy vs 60Gy/2,5wks TD 66 Gy vs 60Gy/2,5wks CT TD 72Gy/8wks vs 72/5,5wks 60Gy/30/6wks vs 60/40/6wks SC 60Gy/30/6wks vs 69,6/6wks BID

Overall and Progression-Free Survival NSCLC Modified radiotherapy, overall survival Conventional radiotherapy, overall survival Modified radiotherapy, progression-free survival Conventional radiotherapy, progression-free survival Survival (%) 20 40 60 80 100 Time from randomisation (Years) 1 2 3 4 5 >6 10.5 4.9 9.1 5.1 15.9 19.7 10.8 8.3 In favor of modified RT Absolute benefit OS Absolute benefit PFS At 3 yrs 3.8% 1.4% At 5 yrs 2.5% -0.2% HR, p 0.88, p=0,009 0.94, p=0.19

Conclusions Modified fractionation radiotherapy significantly improves overall survival in NSCLC No significant effect on progression-free survival or loco-regional failure (BURDEN OF DISTANT FAILURE) Increased acute esophageal toxicity (OR=2.44, p=0,01) in experimental treatments Higher technology RT, better selection of patients: encouraging results in recent studies with better management of toxicity! LARGE STUDIES NEEDED: 60-66 Gy with platin based ccCTRT still the standard 39

MO23 RADIOTHERAPY II Four-dimensional Gallium-68 perfusion PET/CT scans can improve radiotherapy planning through functional avoidance of lung Shankar Siva Peter MacCallum Cancer Centre Melbourne How to adapt the treatment plan during the course of RT in case of perfusion modification? This is only an image at one time Is it possible to perform this study on a large cohort and to correlate it with an evaluation of toxicity 14 patients RT plan optimised to spare functionally perfused and high perfused lung volume Conclusion : a large improvement was observed mainly for the treatment plan optimized to the high perfused lung volume

Background High local recurrence rates in stage III NSCLC PD on imaging: 30-40 % Bronchoscopy series: 80 % Most recurrences are irresectable Low success rates with second line systemic treatment for local recurrences 15-25 % remissions Median OS 4-8 months Dramatic improvement of imaging and RT techniques (SBRT, VMAT …) High-dose irradiation is technically feasible in selected patients 41 41

Question 1: Is it safe? Retrospective (except 1) Small series Grade 5 aortic toxicity = 25 % with composite doses ≥ 120 Gy (vs. 0% for patients receiving <120 Gy) (p = 0.047) to 1 cm3 of the aorta (Evans et al. Radiother Oncol 2013). Safe if Accumulated V20 of the lungs is < 16 % Accumulated Dmax to the heart < 115 Gy3 Accumulated Dmax to the trachea < 89 Gy3 and < 85 Gy3 to the oesophagus. (Meijneke et al. Radiother Oncol 2013). Retrospective (except 1) Small series Different treatments (primary and re-RT) Short follow-up Different second-line therapy Different endpoints Often no detailed DVH parameters available 42 42

Conclusion: Is it safe? Many uncertainties remain Possibly safe when conservative constraints are used. Repair possibilities: Many unknowns. Use cumulative doses Use elastic deformation algorithms  Importance of patient information! 43 43

Question 2: Is it worthwhile? Overall survival: Unclear Median OS: 13 months after a median interval between primary therapy and RT for recurrence 19 months Patients also receive systemic therapy Progression-free survival  postpone systemic treatment: Likely Median TTP (any place): 10 months Quality of life: No data Symptom control vs. palliative doses: Unclear 44 44

Question 3: Can we select patients for high-dose re-irradiation? Probably (rational): Good general condition Single recurrence Preferably suitable for SBRT Doses and fractionation similar to those of primary lung cancer? Lesion diameter < 3-4 cm Cumulative doses to OAR below constraints for primary irradiation based on elastic deformation 45 45

General conclusion In selected patients, high-dose re-irradiation may be considered Most realistic aim in the majority of patients: postpone systemic treatment Inform your patient about the uncertainties  Obvious need for a randomised (phase II) trial 46 46

Future directions Improve patients selection (Gene profile, microRNA signature) Predictors of Sensitivity to Toxicity (IL-6, TGFβ….) Improve protocol for delineation of target volume and OAR, increase RT dose/volume investigations Well designed large randomized trials (No induction/consolidation chemotherapy) 47 47

PERSONALIZED MEDICINE: A PARADIGM SHIFT IN HEALTHCARE The right treatment At the right dose For the right patient At the right time For the best outcome