Lung Cancer: Radiotherapy · Contralateral lung (solitary nodule) Suspected multiple lung cancers (based on the presence of biopsy- proven synchronous lesions or history of lung cancer)w,x

1

Lung Cancer: Radiotherapy ESO-‐ESMO La*n-‐America 2018 Talented students… colleagues

Selected topics for talented… •  Bio-‐IGRT…PET/CT planning •  A flavour of NCCN -‐ RT -‐ NSCLL •  NSCLC…RT by stages •  SCLC…RT LD vs ED •  Oligo M1

2

A bad enemy… or not so…

Mortality…

The RT nodal nightmare…

conebeam CT + respiratory gai*ng + VMAT

multiple closed targets = VMAT high gradient dose-deposit

non-‐coplanar fields

morfology functional Multimodal imaging

PET/CT impact total NSCLC SCLC Changes target definiBon 36% 43% 26% Treatment-‐intent (c to p) 20% 22% 9%

PET/CT dose planning ! (2/5; 1/5 paBents need a change)


11

NCCN Guidelines Index NSCLC TOC Discussion NCCN Guidelines Version 4.2016 Non-Small Cell Lung Cancer NCCN Evidence BlocksTM

jPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. kSee Principles of Surgical Therapy (NSCL-B). lSee Principles of Radiation Therapy (NSCL-C). nAfter surgical evaluation, patients likely to receive adjuvant chemotherapy may be

oSee Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D). qSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E). rR0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic residual tumor.

MEDIASTINAL BIOPSY FINDINGS INITIAL TREATMENT ADJUVANT TREATMENT See NSCL-3 T1-3, N0-1 (including T3 with multiple nodules in same lobe)

Surgeryk,n Resectable

Medically inoperable

Surgical resectionk + mediastinal lymph node dissection or systematic lymph node sampling

chemoradiationl,q (NSCL-14)

T1-2, T3 (other than invasive), N2 nodes positivei

• Brain MRI with contrast • FDG PET/CT scan,j if not previously done

See Treatment according to clinical stage (NSCL-2) Definitive concurrent chemoradiationl,q

N0–1

N2 Margins negative (R0)r Sequential chemotherapyo (category 1) + RTl Chemoradiationl Margins positive

Surveillance (NSCL-14) R1r

R2r (sequential or concurrent ) Concurrent

o q Surveillance (NSCL-14) Surveillance

Negative for M1 disease

Positive

(category 1) or Induction chemotherapyo ± RTl Progression See Treatment for Metastasis limited sites (NSCL-13) or distant disease (NSCL-15) Definitive concurrent chemoradiationl,q

Surgeryk ± chemotherapyo (category 2B) ± RTl (if not given) RTl (if not given) ± chemotherapyo See Treatment for Metastasis limited sites (NSCL-13) or distant disease (NSCL-15)

No apparent progression Local Systemic

T3 (invasion), N2 nodes positive

Negative for M1 disease

Positive See Treatment for Metastasis limited sites (NSCL-13) or distant disease (NSCL-15)

• Brain MRI with contrast • FDG PET/CT scan,j if not previously done

Printed by Eduardo Alvarado on 4/21/2016 9:45:34 AM. For personal use only. Not approved for distribution. Copyright © 2016 National Comprehensive Cancer Network, Inc., All Rights Reserved.

treated with induction chemotherapy as an alternative. Note: For more information regarding the categories and definitions used for the NCCN Evidence BlocksTM, see page EB-1. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. NSCL-8 Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.


hMethods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. jPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. kSee Principles of Surgical Therapy (NSCL-B). lSee Principles of Radiation Therapy (NSCL-C). oSee Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D).

rR0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic residual tumor. wLesions with different cell types (eg, squamous cell carcinoma, adenocarcinoma) may be different primary tumors. This analysis may be limited by small biopsy samples. However, lesions of the same cell type are not necessarily metastases. xFor guidance regarding the evaluation, workup, and management of subsolid pulmonary nodules, please see the diagnostic evaluation of a nodule suspicious for lung cancer (DIAG-1).

CLINICAL PRESENTATION ADJUVANT TREATMENT Separate pulmonary nodule(s), same lobe (T3, N0-1), or ipsilateral non-primary lobe (T4, N0-1)

Stage IV (N0, M1a): Contralateral lung (solitary nodule) Suspected multiple lung cancers (based on the presence of biopsy- proven synchronous lesions or history of lung cancer)w,x

Surgeryk

Treat as two primary lung tumors if both curable • Chest CT with contrast • FDG PET/CT scan (if not previously done)j • Brain MRI with contrast

N0–1

N2

Chemotherapyo Surveillance (NSCL-14) Surveillance (NSCL-14) Margins negative (R0)r

Margins positive

Sequential chemotherapyo (category 1) + RTl

R1r

R2r

Chemoradiationl (sequential or concurrent ) o q Concurrent chemoradiationl,q

Surveillance (NSCL-14) Surveillance (NSCL-14)

See Evaluation (NSCL-1) Disease outs ide of chest No disease outside of chest

See Systemic Therapy for Metastatic Disease (NSCL-16)

Pathologic mediastinal lymph node evaluationh N2-3

N0-1 See Systemic Therapy for Metastatic Disease (NSCL-16)

See Initial Treatment (NSCL-10)


qSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E). Note: For more information regarding the categories and definitions used for the NCCN Evidence BlocksTM, see page EB-1. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. NSCL-9 Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Selected topics for talented… •  Bio-‐IGRT…PET/CT planning •  A flavour of NCCN -‐ RT -‐ NSCLL •  NSCLC…RT by stages •  I SBRT •  II •  III CRT / PCI / AFxT •  PORT: CT + RT vs RT •  SCLC…RT LD vs ED •  Oligo M1

14

NSCLC Stage I

Stage I •  20% NSCLC stage I

•  60-‐70% OS 5y (including RT ) •  SBRT as an alterna*ve

•  20% stage I are inoperables

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Non-Small Cell Lung Cancer!

NCCN Evidence Blocks™

Version 4.2016 NCCN.org

Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines®, and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Continue!


eT3, N0 related to size or satellite nodules. gTesting is not listed in order of priority and is dependent upon clinical circumstances, institutional processes, and judicious use of resources. hMethods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. iSolid tumors <1 cm and purely non-solid tumors <3 cm that are CT and PET negative have a low likelihood of positive mediastinal lymph nodes and pre- resection pathologic mediastinal evaluation is optional. jPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. kSee Principles of Surgical Therapy (NSCL-B).

lSee Principles of Radiation Therapy (NSCL-C). mInterventional radiology ablation is an option for selected patients. nAfter surgical evaluation, patients likely to receive adjuvant chemotherapy may be treated with induction chemotherapy as an alternative. oSee Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D). pExamples of high-risk factors may include poorly differentiated tumors (including lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]), vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and incomplete lymph node sampling (Nx). These factors independently may not be an indication and may be considered when determining treatment with adjuvant chemotherapy. qSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E).

CLINICAL ASSESSMENT PRETREATMENT EVALUATIONg INITIAL TREATMENT

Stage IA (peripheral T1ab, N0)

Stage IB (peripheral T2a, N0) Stage I (central T1ab–T2a, N0) Stage II (T1ab–2ab, N1; T2b, N0) Stage IIB (T3, N0)e Stage IIIA (T3, N1)

• PFTs (if not previously done) • Bronchoscopy (intraoperative preferred) • Pathologic mediastinal lymph node evaluationh,i • FDG PET/CT scanj (if not previously done)

• PFTs (if not previously done) • Bronchoscopy • Pathologic mediastinal lymph node evaluationh • FDG PET/CT scanj (if not previously done) • Brain MRI with contrast (Stage II, IIIA Stage IB [category 2B])

Negative mediastinal nodes Positive mediastinal nodes

Operable Medically inoperablek

Negative mediastinal nodes

Positive mediastinal nodes

Operable

Medically k inoperable

Surgical exploration and resectionk + mediastinal lymph node dissection or systematic lymph node sampling Definitive RT including stereotactic ablative radiotherapyl (SABR)m See Stage IIIA (NSCL-7) or Stage IIIB (NSCL-11) Surgical exploration and resectionk,n + mediastinal lymph node dissection or systematic lymph node sampling N0 N1 Definitive chemoradiationl,q See Stage IIIA (NSCL-7) or Stage IIIB (NSCL-11)

Definitive RT including SABR l

See Adjuvant Treatment (NSCL-3)

See Adjuvant Treatment (NSCL-3) Consider adjuvant chemotherapy (category 2B) for high- risk stages IB-IIIAp

o


Note: For more information regarding the categories and definitions used for the NCCN Evidence BlocksTM, see page EB-1. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. NSCL-2 Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

SBRT Stereotactic Body Radiation Therapy SABR Stereotactic Ablative Radiation Therapy

60 Gy (80%) 60 Gy (60%)

PTV X 60 Gy

Older RT PTV X 75 Gy

PTV X 100 Gy

SABR

57 Gy

Senan, Palma, Lagerwaard, J Thorac Dis 2011

60 Gy in 3 differents ways…

Senthi et al Lancet Oncology 2012

5 yr LC 89.5% 5 yr RC 87.3% 5 yr DC 80.1%

@ 3 years aYer SBRT

60 Gy /8 Fx 60 Gy/3 Fx •  Meta-analysis (Senthi 2012): •  BED10 ≥ 100 to maximize local control •  BED3 ≤ 240 to keep risk of fatal toxicity to 1%.

Centrality…

Timmerman et al JCO 2006 Haasbeek et al JTO 2011

RTOG 0813: ASTRO 2015

•  Several population-based studies suggest SABR better for OS: •  Palma, Amsterdam Cancer Registry, JCO 2010 •  Haasbeek, Netherlands Cancer Registry, Annals of Oncology 2011 •  Shirvani, SEER-Medicare, IJROBP 2012

•  At least 3 RCTs launched comparing SABR with standard or less- hypofractionated regimens •  SPACE (Sweden) – completed, abstract available •  CHISEL (Australia) – completed, maturing •  LUSTRE (Canada)

SABR vs. older techniques

SABR could be an op*on for trea*ng operable stage I NSCLC. Because of the small pa*ent sample size and short follow-‐up, addi*onal randomised studies comparing SABR with surgery in operable pa*ents are warranted. metastases

regional

local

Stage I Peripheral Non-‐Small Cell Lung Cancer: NRG Oncology RTOG 0915 (NCCTG N0927). Int J Radiat Oncol Biol Phys. 2015 Nov 15;93(4):757-‐64

98 pts Extreme fracBonaBon 1 fx! 34 Gy (1fx) vs 48 (4fx) = 97% vs 91% primary control (1y)

SBRT (Stereotac)c Body Radia)on Therapy): technologies

cone-beam CT + VMAT volumetric arc therapy

SBRT vs Surgery

SBRT in central loca)ons

SBRT “centrals”

event / outcome SABRT Non-‐SABRT pneumoni*s 11% 13% Treatment-‐related deaths < 1% 1,1% @2 y ms 71 months 47 months @3y ms 60 months 38 months Median OS 37 months 17 months

SABRT

Non-‐SABRT

OS @ 5y

CSS @ 5y

Meta-‐analyses of current evidence suggested that lobectomy provides beber long-‐term survival outcomes for stage I NSCLC pa*ents.

•  15 publica*ons 315 pa*ents •  loca*on (central v peripheral) does not influence survival •  local control (3yr-‐DFS) ≥ 85% with doses BED ≥ 100 Gy10 •  mortality ≤ 1% with BED≤ 210 Gy3 •  ↑toxicity G 3-‐4 in central tumors, but < 9%

SBRT thoracic central sites

NSCLC stage II


lSee Principles of Radiation Therapy (NSCL-C). oSee Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D). pExamples of high-risk factors may include poorly differentiated tumors (including lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]), vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and incomplete lymph node sampling (Nx). These factors independently may not be an indication and may be considered when determining treatment with adjuvant chemotherapy.

qSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E). rR0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic residual tumor. sIncreasing size is an important variable when evaluating the need for adjuvant chemotherapy.

FINDINGS AT SURGERY ADJUVANT TREATMENT Stage IA (T1ab, N0) Margins negative (R0)r

Margins positive (R1, R2)r Observe Reresection (preferred) or RTl (category 2B)

Surveillance (NSCL-14)

Stage IB (T2a, N0); Stage IIA (T2b, N0)

Stage IIA (T1ab-T2a, N1) Stage IIB (T3, N0; T2b, N1)

Stage IIIA (T1-3, N2; T3, N1)

Margins negative (R0)r

Margins positive (R1, R2)r Margins negative (R0)r

Margins positive R1r

R2r


Margins positive R1r R2r

Observe or Chemotherapyo for high-risk patientsp Reresection (preferred) ± chemotherapyo,s or RTl ± chemotherapyo (chemotherapy for stage IIA) Chemotherapyo (category 1) Reresection + chemotherapyo or Chemoradiationl,q (sequential or concurrent) Reresection + chemotherapyo or Concurrent chemoradiationl,q Chemotherapyo (category 1) or Sequential chemotherapyq + RTl (N2 only) Chemoradiationl,q (sequential or concurrent) Concurrent chemoradiationl,q


Note: For more information regarding the categories and definitions used for the NCCN Evidence BlocksTM, see page EB-1. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. NSCL-3 Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

NSCLC stage III

10 retrospec*ve studies 5 (12,896 pa*ents) OS 4 (981 pa*ents) radia)on pneumoni)s 4 (1339 pa*ents) radia)on oesophagi)s 3DCRT and IMRT similar OS (HR=0.96,P=0.477) IMRT reduced grade2 radia'on pneumoni's (RR=0.74,P=0.009) IMRT increased grade3 radia'on oesophagi's (RR=2.47,P=0.000)

OS

low-‐dose RT + Lager T & N + cord + lung constrains ???

CRT superior

RT combination with CT and / or bioagents


kSee Principles of Surgical Therapy (NSCL-B). lSee Principles of Radiation Therapy (NSCL-C). oSee Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D). tRT should continue to definitive dose without interruption if patient is not a surgical candidate. uIf full-dose chemotherapy is not given concurrently with RT as initial treatment, give

CLINICAL PRESENTATION INITIAL TREATMENT ADJUVANT TREATMENT Superior sulcus tumor (T3 invasion, N0-1)

Superior sulcus tumor (T4 extension, N0-1)

Preoperative concurrent chemoradiationl,q

Possibly resectablek

Unresectablek

Preoperative concurrent chemoradiationl,q

Definitive concurrent chemoradiationl,q,t,u

Surgical reevaluation Resectable

Unresectable

Surgeryk + chemotherapyo Surveillance (NSCL-14)

Surgeryk + chemotherapyo

Complete definitive RTl + chemotherapyq


Surveillance (NSCL-14)

qSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E). additional 2 cycles of full-dose chemotherapy. Note: For more information regarding the categories and definitions used for the NCCN Evidence BlocksTM, see page EB-1. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. NSCL-5 Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.



kSee Principles of Surgical Therapy (NSCL-B). lSee Principles of Radiation Therapy (NSCL-C). oSee Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D). qSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E). rR0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic

tRT should continue to definitive dose without interruption if patient is not a surgical candidate. uIf full-dose chemotherapy is not given concurrently with RT as initial treatment, give additional 2 cycles of full-dose chemotherapy. vConsider RT boost if chemoradiation is given as initial treatment.

CLINICAL PRESENTATION INITIAL TREATMENT ADJUVANT TREATMENT

Chest wall, proximal airway, or mediastinum (T3 invasion, N0-1 Resectable T4 extension, N0-1)

Stage IIIA (T4, N0-1) Unresectable

Surgeryk (preferred)

or

Concurrent chemoradiationl,q or Chemotherapyo


Margins positive

Definitive concurrent chemoradiationl,q,t,u (category 1)

Surgeryk

R1r

R2r


Margins positive (R1, R2)r

Chemotherapyo Reresection + chemotherapyo or Chemoradiationl,q (sequential or concurrent) Reresection + chemotherapyo or Concurrent chemoradiationl,q

Observe

Reresectionv

Surveillance (NSCL-14) Surveillance (NSCL-14) Surveillance (NSCL-14) Surveillance (NSCL-14)



residual tumor. Note: For more information regarding the categories and definitions used for the NCCN Evidence BlocksTM, see page EB-1. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. NSCL-6 Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

stage III

•  heterogeneus group: ~ resectability, medias*num bulky (>2-‐3 cm Ø short, mul*ple gg gruped, > 2 sta*ons) , staging methods (imaging CT/PET, invasive), TNM categories

s III: RT dose •  RTOG-‐7301 60 Gy improved LC

•  RTOG-‐0617 74 Gy inferior to 60 Gy (↔ cardiac dose contribu*on ?) 25 years of practice…

74 Gy radia*on given in 2 Gy frac*ons with concurrent chemotherapy was not beber than 60 Gy plus concurrent chemotherapy for pa*ents with stage III non-‐small-‐cell lung cancer, and might be potenBally harmful. Addi*on of cetuximab to concurrent chemoradia*on and consolida*on treatment provided no benefit in overall survival for these pa*ents.

RTOG 0617 - PRO resultados

•  3D vs IMRT and quality of life •  Not randomized •  IMRT less QOL deterioration although

treating more extensive volumes!

RTOG 0617 - intra - story

s III: nodal elec)ve RT •  < 7-‐10% relapses in gg not involved and even less with PET guided RT

•  High doses on small volumen (new paradigm)

PET-‐TAC FUSION CONEBEAM VERIFICATION

FUSION PET-TAC

CONE BEAM

RC by PET-‐TAC

Lung and nodal SBRT

Results: 3 RCTs and 3 cohort studies -‐  No difference in ELECTIVE NODAL FAILURE: IFRT and ENI among RCTs ( p=0.46), cohort studies (p=0.97) or combined (p=0.64). Conclusion: This meta-‐analysis provides evidence of no significant difference in incidence of ENF between IFRT and ENI.

s III: PCI no effect on OS (RTOG 0214)

EORTC QLQ-‐C30 significant decline self reported cogni*ve func*on Hopkins verbal learning test

Int J Radiat Oncol Biol Phys 2013

PCI sIII NSCLC Meta-analysis PlosOne 2014 12 trial (6 RCTs) 1,718 NSCLC pts reduced risk of brain mets p = 0.00001 OS favored non-PCI p = 0.004

Lancet. 2016 Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial.

Whole brain RT questionable for non-S-RS candidates

Survival

Quality of life

QUALYs

NSCLC Altered Frac*ona*ons

•  meta-analysis individual data (Mauguen et al,2012: 12 ECCC - 2685 pts)

OS @ 5y 8.8% vs 10.5%

NSCLC

NSCLC


jPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT scan positive in the mediastinum, lymph node status needs pathologic confirmation. lSee Principles of Radiation Therapy (NSCL-C). qSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E).

CLINICAL ASSESSMENT PRETREATMENT EVALUATION INITIAL TREATMENT

Stage IIIB (T1–3, N3)

• PFTs (if not previously done) • FDG PET/CT scanj (if not previously done) • Brain MRI with contrast • Pathologic confirmation of N3 disease by: ¢ Mediastinoscopy ¢ S u p r a c l a v i c ul a r lymph node biopsy ¢ Thoracoscopy ¢ N e e d l e biopsy ¢ Mediastinotomy ¢ E U S biopsy ¢ E B U S biopsy

N3 negative

N3 positive

Metastatic disease

See Initial treatment for stage I–IIIA (NSCL-8)

Definitive concurrent chemoradiationl,q,u (category 1) See Treatment for Metastasis limited sites (NSCL-13) or distant disease (NSCL-15)


uIf full-dose chemotherapy is not given concurrently with RT as initial treatment, give additional 2 cycles of full-dose chemotherapy. Note: For more information regarding the categories and definitions used for the NCCN Evidence BlocksTM, see page EB-1. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. NSCL-11

NSCLC RT postopera*ve •  Why consider PORT? •  R1 resection (positive margins) •  R0 resection with positive nodes

RT postopera*ve

• meta-analysis (Billiet 2014: 11 ECC - 2387 pts) results ~ technology

local relapse technology

Cobalt 60

OS technology cobalt 60

Co60 a killer…

•  Several subsequent observational studies suggest some value for PORT •  Data sources: •  ANITA trial (post hoc analysis – IJROBP 2008) •  SEER (JCO 2006) •  National Cancer Database (JTO 2014) •  PORT in N2 disease is the current topic of the Phase III European LUNG-ART randomized trial (EORTC 22055) – dose is 54 Gy in 30 fractions

PORT Based on Nodal Status

All patients N0

N1 N2

Onco Targets Ther. 2016; 9: 921–928. Adjuvant chemotherapy plus radiotherapy is superior to chemotherapy following surgical treatment of stage IIIA N2 non-‐small-‐cell lung cancer CT + RT vs CT 2,125 postoperaBve chemoradiotherapy (POCRT) 3,047 cases of POCT.

OS

DFS …no DFS…

14 trials evalua*ng surgery versus surgery plus radiotherapy. Individual data 11 trials 2343 par*cipants (1511 deaths) Significant adverse effect of PORT on survival an 18% rela*ve increase in risk of death Equivalent to an absolute detriment of 5% at two years (2% to 9%) Reduc*on on overall survival from 58% to 53% Subgroup analyses showed no differences in effects of PORT by any par*cipant subgroup covariate.

survival

local recurrence

dose > 45 Gy

-‐ Overall survival was not significantly different between surgical and definiBve radiotherapy arms -‐ Larer trials using concurrent radiochemotherapy (ccRT/CT) showed beber survival at 2 years -‐ ccRT/CT trials, survival in the surgical arms tended to have an excess early mortality before 6 months -‐ treatment associated mortality was higher in the surgical arms -‐ progression-‐free survival, no significant differences largest trial advantage for the surgical arm -‐ Induc*on therapy followed by resec*on or defini*ve radiochemotherapy curaBve treatment op*ons stage III NSCLC, -‐ Individual treatment: interdisciplinary evalua*on and counseling. -‐ Based on heterogeneity in these stages research on predic*ve factors suppor*ng individual therapy selecBon.

Selected topics for talented… •  Bio-‐IGRT…PET/CT planning •  A flavour of NCCN -‐ RT -‐ NSCLL •  NSCLC…RT by stages •  SCLC…RT LD vs ED •  TRT *ming/ AFxT LD/ PCI / TRT in ED •  Oligo M1

81

SCLC Limited extension

Govindan JCO 2006

Incidence & survival ( LD vs ED )

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Small Cell Lung Cancer

Version 1.2016 NCCN.org

Version 1.2016, 06/02/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Continue!

NCCN Guidelines Version 1.2016 Small Cell Lung Cancer NCCN Guidelines Index SCLC Table of Contents Discussion TESTING RESULTS INITIAL TREATMENTj ADJUVANT TREATMENT

gSee Principles of Surgical Resection (SCL-A). hMediastinal staging procedures include mediastinoscopy, mediastinotomy, endobronchial or esophageal ultrasound-guided biopsy, and video-assisted thoracoscopy. If endoscopic lymph node biopsy is positive, additional mediastinal staging is not required. iPathologic mediastinal staging is not required if the patient is not a candidate for surgical resection or if non-surgical treatment is pursued. jSee Principles of Supportive Care (SCL-B). kSelect patients may be treated with chemotherapy/RT as an alternative to surgical resection. lSee Principles of Chemotherapy (SCL-C). mSee Principles of Radiation Therapy (SCL-D).

Clinical stage T1-2, N0

Limited stage in excess of T1-2, N0

Pathologic mediastinal stagingg,h,i negative

Pathologic mediastinal stagingg,h positive or medically inoperable or decision made not to pursue surgical resection Good PS (0-2) Poor PS (3-4) due to SCLC Poor PS (3-4) not due to SCLC

Lobectomyg,k (preferred) and mediastinal lymph node dissection or sampling N0

N+

Chemotherapyl Concurrent chemotherapyl+ mediastinal RTm

Good performance status (PS 0-2) Poor PS (3-4) due to SCLC Poor PS (3-4) not due to SCLC

Chemotherapyl + concurrent thoracic RTm (category 1) Chemotherapyl ± RTm

Individualized treatment including supportive carej

See Response Assessment + Adjuvant Treatment (SCL-5)

Chemotherapyl + concurrent RTm (category 1) Chemotherapyl ± RTm

Individualized treatment including supportive carej




Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. SCL-3 Version 1.2016, 06/02/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

TRT LD: doses & frac)ona)on HR = 0,8 [95% IC: 0,6-‐1]

TRT LD: d & Fx

SCLC SCLC

•  Fx Altered + risk of death in SCLC: similar magnitude than NCSLC but NS (p>0.05).

•  Pts with poor PS less benefited. •  - esofagitis severe: HR=2.41. •  - cardio-toxicity: HR=2.96. •  - hematologic toxicity ~ CT.

Thoracic RT LD: d & Fx

TRT LD: )ming QT y RT

• gitis (RR: 0,55)

early TRT esophagitis

All pts

CT not delivered

> 80 years In elderly patients with limited-stage small-cell lung cancer, modern CRT appears to confer an additional OS advantage beyond that achieved with CT alone in a large population-based cohort

8,637 patients, 3,775 (43.7%) received CT and 4,862 (56.3%) received CRT

Elderly patients (age ≥ 70 years) limited-stage small-cell lung cancer clinical stage I to III CT or CRT National Cancer Data Base 2003- 2011

J Clin Oncol. 2015 Role of Chemoradiotherapy in Elderly Patients With Limited-Stage Small-Cell Lung Cancer. Corso CD et al.

Results: 12 trials 2668 pa*ents. 9 trials 2305 pa*ents Median follow-‐up 10years ‘earlier or shorter’vs ‘later or longer’thoracic radiotherapy = overall survival. OS was significantly in favour of ‘earlier or shorter’ radiotherapy compliant with CT The absolute gain between ‘earlier or shorter’ versus ‘later or longer’ thoracic radiotherapy in 5-‐year overall survival for similar CT compliance trials was 7.7% ‘earlierorshorter’ thoracicradiotherapywas associated with a higher incidence of severe acute oesophagiBs

PCI LD SCLC EORTC QLQ-‐C30 significant decline self reported cogni*ve func*on Hopkins verbal learning test

RTOG 0212

Int J Radiat Oncol Biol Phys 2013

NCCN Guidelines Version 1.2016 Small Cell Lung Cancer NCCN Guidelines Index SCLC Table of Contents Discussion RESPONSE ASSESSMENT FOLLOWING INITIAL THERAPY ADJUVANT TREATMENT

bBrain MRI is more sensitive than CT for identifying brain metastases and is preferred over CT. mSee Principles of Radiation Therapy (SCL-D). nNot recommended in patients with poor performance status or impaired neurocognitive function.

• Chest x-ray (optional) • Chest/liver/adrenal CT with IV contrast whenever possible • Brain MRIb (preferred) or CT with IV contrast whenever possible, if prophylactic cranial irradiation (PCI) to be given • Other imaging studies, to assess prior sites of involvement, as clinically indicated • CBC, platelets • Electrolytes, LFTs, Ca, BUN, creatinine

Complete response or partial response

Stable disease

Primary progressive disease

SURVEILLANCE After recovery from primary therapy: • Oncology follow-up visits every 3–4 mo during y 1–2, every 6 mo during y 3–5, then annually 4 A t every visit: H&P, chest imaging, bloodwork as clinically indicated • New pulmonary nodule should initiate workup for potential new primary • Smoking cessation intervention, see the NCCN Guidelines for Smoking Cessation

Limited stage

• PET/CT is not recommended for routine follow-up

For Relapse, see Subsequent Therapy (SCL-6)

See Subsequent Therapy/ Palliative Therapy (SCL-6)

Extensive stage

PCIm,n (category 1)

PCI m,n + thoracic RT m,o


oSequential radiotherapy to thorax in selected patients with low-bulk metastatic disease and complete response (CR) or near CR after systemic therapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

SCL-5 Version 1.2016, 06/02/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

SCLC Extensive Disease

NCCN Guidelines Version 1.2016 Small Cell Lung Cancer NCCN Guidelines Index SCLC Table of Contents Discussion

Extensive stage (See ST-1 for TNM Classification)

jSee Principles of Supportive Care (SCL-B). lSee Principles of Chemotherapy (SCL-C).

STAGE INITIAL TREATMENTj Combination chemotherapyl including supportive carej See NCCN Guidelines for Palliative Care Extensive stage without localized symptomatic sites or brain metastases

Extensive stage + localized symptomatic sites

Extensive stage with brain metastases

• Good PS (0-2) • Poor PS (3-4) due to SCLC • Poor PS (3-4) not due to SCLC

Individualized therapy including supportive carej See NCCN Guidelines for Palliative Care • SVC syndrome • Lobar obstruction • Bone metastases

Spinal cord compression

Chemotherapyl ± RTm to symptomatic sites If high risk of fracture due to osseous structural impairment, consider orthopedic stabilization and palliative external-beam RTm RTm to symptomatic sites before chemotherapy unless immediate systemic therapy is required. See NCCN Guidelines for Central Nervous System Cancers

Asymptomatic

Symptomatic

May administer chemotherapy first, with whole-brain RTm after chemotherapyl

Whole-brain RTm before chemotherapy,l unless immediate systemic therapy is indicated



mSee Principles of Radiation Therapy (SCL-D). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

SCL-4 Version 1.2016, 06/02/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

PCI ED

•  RCT trial EORTC PCI ↓ % brain mts and improves DFS/OS SCLC-EDD

any!!!

10 Endpoint: 1-yr OS: 33% (TRT) vs. 28% (no TRT) p=0.066 20 Endpoint: 2-yr OS: 13% (TRT) vs. 3% (no TRT) p=0.004 Lancet 2014

meta-‐analysis of 2 randomized trials TRT improves overall survival and progression-‐free survival in paBents with extensive stage SCLC, with a small incremental risk of esophageal toxicity.

Results: Five retrospec*ve studies 1691 pa*ents 315 of them received PCI In resected pa*ents, PCI improved overall survival (HR: 0.52, 95% CI: 0.33-‐0.82) and reduced brain metastasis risk (RR: 0.50, 95%CI: 0.32-‐0.78).


103

NSCLC or SCLC M1 oligo rec


Disseminated metastases jSee Principles of Surgical Therapy (NSCL-B). kSee Principles of Radiation Therapy (NSCL-C). lInterventional radiology ablation is an option for selected patients.

See Systemic Therapy for Metastatic Disease (NSCL-16) pSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E). ccSee NCCN Guidelines for Central Nervous System Cancers. ffSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F).

Locoregional recurrence

Distant metastases

THERAPY FOR RECURRENCE AND METASTASIS Endobronchial obstruction Resectable recurrence Mediastinal lymph node recurrence Superior vena cava (SVC) obstruction

Severe hemoptysis

No prior RT Prior RT

• Laser/stent/other surgeryj • External-beam RT or brachytherapyk • Photodynamic therapy • Reresection (preferred)j • External-beam RT or SABRk,l Concurrent chemoradiationk,p Systemic therapyff • Concurrent chemoradiationk,p (if not previously given) • External-beam RTk • SVC stent • External-beam RT or brachytherapyk • Laser or photodynamic therapy or embolization • Surgery

No evidence of disseminated disease Evidence of disseminated disease

Observation or Systemic therapyff (category 2B) See Systemic Therapy for Metastatic Disease (NSCL-16)

Localized symptoms Palliative external-beam RTk Diffuse brain metastases Bone metastasis Limited metastasis

Palliative external-beam RTk,cc • Palliative external-beam RTk + orthopedic stabilization, if risk of fracture • Consider bisphosphonate therapy or denosumab See pathway for Stage IV, M1b, limited sites (NSCL-13)



Note: For more information regarding the categories and definitions used for the NCCN Evidence BlocksTM, see page EB-1. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. NSCL-15


hMethods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. jPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. kSee Principles of Surgical Therapy (NSCL-B). lSee Principles of Radiation Therapy (NSCL-C). bbAggressive local therapy may be appropriate for selected patients with limited-site oligometastatic disease. ccSee NCCN Guidelines for Central Nervous System Cancers. ddMay include adrenalectomy or RT (including SABR). eePatients with N2 disease have a poor prognosis and systemic therapy should be considered.

CLINICAL ASSESSMENT PRETREATMENT EVALUATION INITIAL TREATMENT

Stage IV, M1b: limited sitesbb

• Pathologic mediastinal lymph node evaluationh • Bronchoscopy • Brain MRI with contrast • FDG PET/CT scanj (if not previously done)

Braincc

Adrenal Pathologic diagnosis by needle or resection

Surgical resection,k followed by whole brain RTl (WBRT) (category 1) or stereotactic radiosurgeryl (SRS) or SRS + WBRTl (category 1 for one metastasis) or SRSl alone Local therapy for adrenal lesiondd (if lung lesion curable, based on T and N stage) (category 2B)ee or See Systemic Therapy for Metastatic Disease (NSCL-16)

T1-2, N0-1; T3, N0

T1-2, N2; T3, N1-2; Any T, N3; T4, Any N

Surgical resection of lung lesionk or SABR of lung lesionl or Chemotherapyff

Chemotherapyff

Surgical resection of lung lesionk or SABR of lung lesion



ffSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F). Note: For more information regarding the categories and definitions used for the NCCN Evidence BlocksTM, see page EB-1. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 4.2016, 02/29/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. NSCL-13

Oligometastatic NSCLC

AJCC staging subcategorizing metasta*c disease -‐ intra-‐thoracic (M1a) -‐ a single extra thoracic site (M1b) -‐ diffuse metastases (M1c). technological advances abla*ve doses of radiotherapy intra-‐ and extra-‐cranial disease sites (SABR) shorter *me periods and minimal associated toxicity. improvements in systemic therapy, including pla*num-‐based doublet chemotherapy, molecular agents targe*ng oncogene-‐addicted NSCLC, and immunotherapy in the form of checkpoint inhibitors, have led to extended survival radiaBon and immunotherapy, poten*ally synergis*c, effects in order to further improve progression-‐free and overall survival.

Slide courtesy Dr. D Gomez MDACC

MDACC/Colorado/LHSC Trial

First clinical evidences prospecBve + radomized… SBRT consolidaBve NSCLC! …2016

Key Eligibility Criteria: u  Stage IV NSCLC ≤ 3 metastatic lesions after 1st-line systemic

therapy. Regional nodes counted a 1 lesion, regardless of number of nodes

u  1st-line therapy ≥ 4 cycles of platinum doublet or ≥ 3 months of TKI for EGFR mutations or ALK re-arrangements.

Gomez DR, et al. Lancet Oncol 2016;

Gomez DR, et al. Lancet Oncol 2016;

Primary Endpoint = PFS

2012 – 2016 NSCLC 74 pts estables o respondedores 1ra línea QT < 3 mets (75% SBRT) PFS 3.9 vs 11.9 meses (p= 0.005)

< 3 stable mets

Oligometastatic SCLC: RTOG 0937

PCI + SBRT cosolidation

PACIFIC study, progression-free survival 17 months durvalumab group 1 year longer than the placebo group this duration is unprecedented in stage III NSCLC new distant lesions more in the placebo group than in the durvalumab group. brain metastasis developed in (11.0% vs. 5.5%). radiotherapy anti–PD-L1–mediated pneumonitis, Treatment-related adverse 67.8% durvalumab vs 53.4% placebo. Immune-mediated adverse events was 24.2% with durvalumab and 8.1% with placebo.

“seed and soil”

Progress involve NSCLC clinical trial design: -‐ varia*ons in RT dose, frac*ona*on, field volume -‐ scheduling with ICIs -‐ systemic an*tumour immunity

treatment related imaging changes TRIC

immunoT-‐naive

immunoT-‐treated

radia*on necrosis pathologicaly confirmed

Selected conclusions for talented…2017 RT is an innovated and decisive component of lung cancer treatment •  Bio-‐IGRT…PET/CT planning: gold standard, limited nodal RT •  A flavour of NCCN -‐ RT: important role in cure + palliaBon •  NSCLC…RT by stages •  I SBRT: equivalent to S; tech dependent •  II: PORT R+, N1-‐2, inducBon CRT? •  III CRT standard 60 Gy/ PCI less mets/ AFxT no cost-‐eficient •  PORT: CT + RT vs RT growing evidence… •  SCLC…RT LD early TRT; PCI in CR. ED TRT yes PCI less mets •  Oligo M1… SBRT efficient! (survivors!) + systemic therapy

126

See you next time in Madrid! [email protected]

Resected: evolution @5y

Blue dead CT yes or not Gold aive no CT Gray alive with CT Red toxic death CT

Documents

Lung Cancer: Radiotherapy · Contralateral lung (solitary nodule) Suspected multiple lung cancers (based on the presence of biopsy- proven synchronous lesions or history of lung cancer)w,x