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NON-SMALL CELL LUNG NON-SMALL CELL LUNG CANCER 2006 CANCER 2006

RADIOTHERAPYRADIOTHERAPY

Prof Dr Serdar ÖZKÖKProf Dr Serdar ÖZKÖKEge University Medical SchoolEge University Medical SchoolDepartment of Radiation Department of Radiation Oncology Oncology

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Stage I-IIStage I-II NSCLC NSCLC

Postoperative RTPostoperative RT

Curative RTCurative RT

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PORT Meta-analysis(PORT Meta-analysis Trialist Group; Lancet 1998; 352;9124: 257)

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PORT Meta-Analysis PORT Meta-Analysis CriticismCriticism

26% of the cases were stage I.26% of the cases were stage I. There wasn’t enough information about There wasn’t enough information about

mediastinal lymph node dissection.mediastinal lymph node dissection. KPS was evaluated only in three trials.KPS was evaluated only in three trials. Nonpublished trials were included.Nonpublished trials were included.

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PORT Meta-Analysis PORT Meta-Analysis CriticismCriticism

Concerns about RT techniquesConcerns about RT techniques Treating with Co 60Treating with Co 60 Wide RT portalsWide RT portals Insufficient total RT dose Insufficient total RT dose High fractionation dose High fractionation dose BED values were not calculatedBED values were not calculated No 3-D PlanningNo 3-D Planning

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PORTPORT

(+) Surgical margin(+) Surgical margin Insufficient surgeryInsufficient surgery Parietal Pleura InvasionParietal Pleura Invasion N2N2 N1 (High risk of local recurrence)N1 (High risk of local recurrence)

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Curative Radiotherapy in Curative Radiotherapy in Stage I-II NSCLCStage I-II NSCLC

2-D Radiotherapy (60-66 Gy)2-D Radiotherapy (60-66 Gy) 3-D Conformal RT (66 Gy ) 3-D Conformal RT (66 Gy ) Stereotactic RTStereotactic RT

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STEREOTASTEREOTACCTITICC RAD RADIIOTERAPOTERAPYYSTEREOTASTEREOTACCTITICC RAD RADIIOTERAPOTERAPYY

Hypofractionated 3-D Hypofractionated 3-D RT for small target RT for small target volumesvolumesImmobilisation Immobilisation

is importantis important

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Hypofractionated SRT for Hypofractionated SRT for Lung TumorsLung Tumors

AdvantagesAdvantages

1- Shortened Treatment Course1- Shortened Treatment Course

2- Adoption of a smaller irradiated volume2- Adoption of a smaller irradiated volume

DisadvantagesDisadvantages

1- Uncertain effects of altered fractionation1- Uncertain effects of altered fractionation

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4 Fx, 4-10 noncoplanar RT 4 Fx, 4-10 noncoplanar RT portalsportals

45 patients ( 22 of them were 45 patients ( 22 of them were Stage IA and 13 of them were Stage IA and 13 of them were Stage IB)Stage IB)

Complete response: 16%, Complete response: 16%,

Partial response: 84%Partial response: 84%

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ASCO 2005ASCO 2005

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Stage 3-AStage 3-A

Surgery ?Surgery ? Chemoradiotherapy ?Chemoradiotherapy ?

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Outcomes Update of North Outcomes Update of North American Intergroup Trial American Intergroup Trial 0139 (R9309)0139 (R9309)

Phase III Study of Concurrent Phase III Study of Concurrent Chemotherapy and Chemotherapy and

Radiotherapy Radiotherapy (CT/RT) versus CT/RT followed (CT/RT) versus CT/RT followed by Surgical Resection for by Surgical Resection for

StageStageIIIA(pN2) NSCLCIIIA(pN2) NSCLC

RTOG (chair), SWOG, NCIC CTG, RTOG (chair), SWOG, NCIC CTG, ECOG, CALGB and NCCTGECOG, CALGB and NCCTG

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Lung Intergroup Trial 0139Lung Intergroup Trial 0139SStratificatiotratificatio

nn

KPS 70-80 vs 90-KPS 70-80 vs 90-100 T1 vs T2 vs T3100 T1 vs T2 vs T3

RANDOMIRANDOMISATIONSATION

Cisplatin, 50 mg/m2 IV d1, 8, 29, 36 Etoposide, 50mg/m2 IV d1-5, 29-33Thoracic RT, 45 Gy(1.8 Gy/d), d1

Re-evaluationRe-evaluation

2-4 months after 2-4 months after RTRT

Re-evaluationRe-evaluation

7 days before 7 days before completion of RT completion of RT

InduInductionction

KKT/RTT/RT

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Lung Intergroup Trial 0139Lung Intergroup Trial 0139

No Progression

SurgerySurgery

Continuation of Continuation of RT without RT without

interruptioninterruption

ConsolidationConsolidation

cisplatin cisplatin -- etoposide X 2etoposide X 2

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Intergroup 0139Intergroup 0139

T1-3,pN2,Mo, technically resectable, T1-3,pN2,Mo, technically resectable, 429 patients429 patients

Median Follow-up 81 monthsMedian Follow-up 81 months Thoracotomy 81%, Complete resection Thoracotomy 81%, Complete resection

71%71% ToNo: 15% - No: 38%ToNo: 15% - No: 38% DFS: 12.8 vs 10.5 monthsDFS: 12.8 vs 10.5 months OS: 23.6 vs 22.2 monthsOS: 23.6 vs 22.2 months

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Registration

3 cycles platinium based CT

Response randomisation Stratification: response, pathology, center

No responseExcluded from trial

Surgical ResectionThoracic RT 60 Gy, 2 Gy/f

Trial DesignTrial Design

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EORTC 08941EORTC 08941

Pathological N2, technically Pathological N2, technically unresectable unresectable

Induction CT to 579 patients, Induction CT to 579 patients, Randomisation of 332 patientsRandomisation of 332 patients

Response rates 62%Response rates 62% Complete resection 50%Complete resection 50%

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Stage 3-A Stage 3-A

Chemoradiotherapy for:Chemoradiotherapy for:

multiple positive lymph node multiple positive lymph node stations, capsulery invasion, stations, capsulery invasion,

Bulky N2Bulky N2

PneumonectomyPneumonectomy

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Stage 3-BStage 3-B

Radiotherapy is standardRadiotherapy is standard Chemoradiotherapy for high performance Chemoradiotherapy for high performance

status patientsstatus patients SequentiallySequentially Concurrent (Eşzamanlı)Concurrent (Eşzamanlı)

Radiotherapy after induction CTRadiotherapy after induction CT Concurrent CRT after induction CTConcurrent CRT after induction CT Consolidation after concurrent CRTConsolidation after concurrent CRT

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Concurrent vs SequentialConcurrent vs SequentialChemoradiotherapyChemoradiotherapy

Concurrent Concurrent SequentialSequential

No.of patientsNo.of patients 156156 158158ToxicityToxicity 8.9% 8.9% 5% 5%ResponseResponse 84% 84% 66% 66%MS(months)MS(months)16.5*16.5* 13.313.35 year Surv.5 year Surv. 16% 16% 9% 9%

p<0.05p<0.05CT:MVP (Mitomycin, Vindesine, Cisplatin)CT:MVP (Mitomycin, Vindesine, Cisplatin)RT: Split CourseRT: Split CourseFuruse K. J. Clin Oncol 1999; 17: 2692Furuse K. J. Clin Oncol 1999; 17: 2692

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RTOG 9410: Sequential RTOG 9410: Sequential vs Concurrentvs Concurrent

Sequential ConcurrentSequential Concurrent Conc. Conc.(HFRT)(HFRT)

MSMS 14.614.6 17*17* 15.615.6Non-Hem.Non-Hem.Tox. (Gr 3-4)Tox. (Gr 3-4) 30%30% 48%48% 62**%62**%Local Rec.Local Rec. 38%38% 33%33% 25**%25**%

*p= 0.038*p= 0.038 **p < 0.05**p < 0.05

Curran: ASCO, 2003Curran: ASCO, 2003

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Combined Chemoradiotherapy Regimens of Paclitaxel and Carboplatin for Locally Combined Chemoradiotherapy Regimens of Paclitaxel and Carboplatin for Locally Advanced Non–Small-Cell Lung Cancer: A Randomized Phase II Locally Advanced Multi-Advanced Non–Small-Cell Lung Cancer: A Randomized Phase II Locally Advanced Multi-

Modality Protocol Modality Protocol Chandra P. Belani, Chandra P. Belani,

Journal of Clinical OncologyJournal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 5883-5891, Vol 23, No 25 (September 1), 2005: pp. 5883-5891

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Chemoradiotherapy for Locally Chemoradiotherapy for Locally Advanced NSCLCAdvanced NSCLC

Chemoradiotherapy is the standard Chemoradiotherapy is the standard treatment.treatment.

In patients <70 year old and weight In patients <70 year old and weight loss less than 5 –10%, KPS 70% and loss less than 5 –10%, KPS 70% and above above

Concurrent chemoradiotherapy can be Concurrent chemoradiotherapy can be applied in experienced radiation applied in experienced radiation oncology clinics in a multidisciplinary oncology clinics in a multidisciplinary manner.manner.

In other cases the treatment is In other cases the treatment is radiotherapyradiotherapy

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3 D Conformal Treatment Planning3 D Conformal Treatment Planning

Doses above 70 Gy could not be Doses above 70 Gy could not be delivered with standard RT.delivered with standard RT.

With conformal RT: With conformal RT: Doses above 70 Gy can be achieved. Doses above 70 Gy can be achieved.

(better survival with doses above 79 (better survival with doses above 79 Gy)Gy)

Irradiated Lung Volume Irradiated Lung Volume Critical organ doses Critical organ doses

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GTVGTV

Primary tumorPrimary tumor Nodal diameter above 1 cm or Nodal diameter above 1 cm or

nodes revealed by PETnodes revealed by PET

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Prophylactic Mediastinal Prophylactic Mediastinal RT ?RT ?

Isolated Lymph Node Recurrence 0 – Isolated Lymph Node Recurrence 0 – 10%10%

Hayman JA, JClinOncol 19:2001

Bradley J, Int J Radiat Oncol Biol 318-328- 2005

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PETPET

To be involved in RT PlanningTo be involved in RT Planning

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Induction and Concurrent Chemotherapy With High-Dose Thoracic Conformal Radiation Induction and Concurrent Chemotherapy With High-Dose Thoracic Conformal Radiation Therapy in Unresectable Stage IIIA and IIIB Non–Small-Cell Lung Cancer: A Dose-Therapy in Unresectable Stage IIIA and IIIB Non–Small-Cell Lung Cancer: A Dose-

Escalation Phase I Trial Escalation Phase I Trial Mark A. Socinski, Mark A. Socinski, Journal of Clinical OncologyJournal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: , Vol 22, No 21 (November 1), 2004:

pp. 4341-4350pp. 4341-4350

Stage III 25 patientsStage III 25 patients Induction CT: 2 cycle Induction CT: 2 cycle

(Carbo,Pac.,İrin.)(Carbo,Pac.,İrin.) 3D Conformal RT: 78-90 Gy3D Conformal RT: 78-90 Gy Concurrent CT: Carboplatin- Concurrent CT: Carboplatin-

Paclitaxel)Paclitaxel) Oesophagitis: 16% (grade 3)Oesophagitis: 16% (grade 3) Response Rates: 60%Response Rates: 60%

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Induction and Concurrent Chemotherapy With High-Dose Thoracic Conformal Radiation Induction and Concurrent Chemotherapy With High-Dose Thoracic Conformal Radiation Therapy in Unresectable Stage IIIA and IIIB Non–Small-Cell Lung Cancer: A Dose-Therapy in Unresectable Stage IIIA and IIIB Non–Small-Cell Lung Cancer: A Dose-

Escalation Phase I Trial Escalation Phase I Trial Mark A. Socinski, Mark A. Socinski, Journal of Clinical OncologyJournal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: , Vol 22, No 21 (November 1), 2004:

pp. 4341-4350pp. 4341-4350

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3D- Conformal RT Trials3D- Conformal RT Trials

CTCT

TrialsTrials No of No of patientspatients

Stage Stage III (%)III (%)

Dose Dose (Gy)(Gy)

ENIENI Ind. (%)Ind. (%) Conc.Conc. EosophEosophagitisGragitisGrade 3 ade 3

ToxTox

Grade 3Grade 3M.SurvM.Surv

(%)(%)

MaguireMaguire 9494 7474 73.6-8073.6-80 ++ 2727 -- 33 1616 13.0 3A13.0 3A

10.0 3B10.0 3B

SimSim 152152 100100 50-8150-81 -- 5454 -- 33 1414 18.1 18.1 Kom.Kom.

11.7 RT11.7 RT

HaymanHayman 104104 6666 63-63-102.9102.9

-- 2424 -- 77 11 16 III16 III

BradleyBradley 179179 4141 70.9-70.9-90.390.3

-- 1414 -- 33 1010 ??

WuWu 5050 9292 69-7869-78 ++ -- -- 44 22 1818

MarksMarks 4444 9898 73,6-73,6-86,486,4

++ -- -- 99 77 1818

SocinskiSocinski 6262 100100 60-7460-74 ++ ++ ++ 88 00 2424

BelderbosBelderbos 5656 5353 54-54-101.3101.3

-- -- -- 00 55 ??

SocinskiSocinski 2929 100100 78-9078-90 ++ ++ ++ 1616 44 2424

Socinski, Journal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: pp. 4341-4350

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IMRT(Intensity Modulated IMRT(Intensity Modulated Radiotherpy)Radiotherpy)

Advanced form of 3-D conformal Advanced form of 3-D conformal RTRT

Main beams divided to multipl Main beams divided to multipl beamletsbeamlets

Every beamlet has an intensity Every beamlet has an intensity between between 0 – 100 0 – 100%.%.

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RadRadiiaationtion sourcesource

Beam ModifierBeam Modifier

TargetTarget

Conventional RT

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IMRTIMRT

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3D-RT vs IMRT3D-RT vs IMRT

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IMRT is not standard for IMRT is not standard for lung cancer TILL... lung cancer TILL...

Tumor movements have to be taken Tumor movements have to be taken into considerationinto consideration

Improvements for dose calculation Improvements for dose calculation algoryhtms algoryhtms

The effects of low dose irradiation for The effects of low dose irradiation for large lung volumes have to be large lung volumes have to be clarifiedclarified

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TomotherapyTomotherapy

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CyberCyberKnifeKnife

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Only technology is not sufficientOnly technology is not sufficient

Experience is importantExperience is important