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MARTA SCORSETTI M.D. Direttore Radioterapia e Radiochirurgia Istituto Clinico Humanitas

NSCLC localmente avanzato. MARTA SCORSETTI M.D. Direttore Radioterapia e Radiochirurgia Istituto Clinico Humanitas marta.scorsetti@humanitas.it. 2013.

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MARTA SCORSETTI M.D. Direttore Radioterapia e Radiochirurgia Istituto Clinico Humanitas

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

  2. 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

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

  4. 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.

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

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

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

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

  9. 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.

  10. 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)

  11. Pretreatment Characteristics

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

  13. 100 NSCLC Patients at U MichiganKaplan-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

  14. Analysis of miRNA Signature and RT DoseBi, …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.

  15. 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.

  16. RTOG 0617: Dosimetric Data Distribution

  17. RTOG 0617Definitely, Probably, or Possibly Related to Treatment (CTCAE Version 3.0)

  18. Esophagitis

  19. Multivariate Cox Model

  20. 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 • Under review

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

  22. 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

  23. Change in Lung Cancer Symptoms (LCS) p=0.024 p=0.7 LCS Decline

  24. 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?

  25. 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

  26. 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 Cécile Le Péchoux

  27. Altered fractionation 60 Gy/30 fr DD = 2 Gy *ECOG 64 Gy CHARTWEL 66 Gy Weekly D 1O Gy 31,5 Gy 24 Gy 22,5 Gy 20 Gy 12 Gy 15 Gy Week-end Week-end Week-end Week-end Week-end 5 days 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 Week-end Week-end Week-end Week-end Split course:2 wks

  28. NSCLC-Patient characteristics (n=2,000) Patients Age % <60 28 60-69 42 70+ 30 Gender (male) 75% Conventional RT=944 pts Modified RT=1056pts • 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)

  29. Overall survival NSCLC Very accelerated RT No. Deaths / No. Entered Category O-E Variance Hazard Ratio HR [95% CI] Trial Exp. RT Conv. 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 132/150 132/150 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 Subtotal 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 Subtotal 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 -6.4 76.9 Subtotal 155/163 156/163 -6.4 76.9 0.92 [0.74;1.15] 0.88 [0.80;0.97], p=0.009 Total 964/1056 885/944 -55.2 443.7 0.25 1.00 4.00 2 2 Test for heterogeneity: = 9.74 p = 0.37 I = 8 % | 9 Experimental RT better Conventional RT better 2 = 0.17 = 0.98 Test for interaction: p 3 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 60/40/6wks SC 60Gy/30/6wks vs 69,6/6wks BID

  30. 100 Overall and Progression-Free SurvivalNSCLC Modified radiotherapy, overall survival Conventional radiotherapy, overall survival 80 Modified radiotherapy, progression-free survival Conventional radiotherapy, progression-free survival 60 Survival (%) 40 19.7 20 15.9 10.8 10.5 8.3 5.1 9.1 4.9 0 0 1 2 3 4 5 >6 Time from randomisation (Years)

  31. 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

  32. MO23 RADIOTHERAPY II Four-dimensional Gallium-68 perfusion PET/CT scans can improve radiotherapy planning through functional avoidance of lungShankar Siva Peter MacCallum Cancer Centre Melbourne • How to adapt the treatment plan during the course of RT in case of perfusion modification? This isonly an image at one time • Is it possible to performthisstudy on a large cohort and to correlateitwith 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

  33. 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

  34. Question 1: Is it safe? • 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. RadiotherOncol 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. RadiotherOncol 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

  35. 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!

  36. 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

  37. 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

  38. 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

  39. Future directions • Improvepatientsselection(Gene profile, microRNAsignature) • 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/consolidationchemotherapy)

  40. 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

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