Role of Radiation in Role of Radiation in Lung CancerLung Cancer

Eyad Alsaeed MD , FRCPCEyad Alsaeed MD , FRCPCConsultant Radiation OncologyConsultant Radiation Oncology

Prince Sultan Hematology Oncology Prince Sultan Hematology Oncology CenterCenterKFMCKFMC

EpidemiologyEpidemiology

Cancer is a leading cause of death Cancer is a leading cause of death worldwide: it accounted for 7.9 million worldwide: it accounted for 7.9 million deaths (around 13% of all deaths) in deaths (around 13% of all deaths) in 20072007

making it the number one cancer killer making it the number one cancer killer in both men and women worldwidein both men and women worldwide . .

Exceeding the combined Exceeding the combined mortality mortality of breast , ovarian , of breast , ovarian , cervical cancer for cervical cancer for women.women.Prostate cancer for menProstate cancer for men..

IN KSAIN KSA

In 2002 lung and bronchial cancer In 2002 lung and bronchial cancer were the third leading cause of death were the third leading cause of death in menin men. .

tenth leading cause of death in womententh leading cause of death in women..

Cancer Incidence for Most Common Sites Cancer Incidence for Most Common Sites (2004)(2004)

CancerCancerMalMalee

FemalFemalee

All All %%

Breast Breast 151578378379879811.511.5

CRCCRC3663662812816476479.39.3

NHLNHL3323322242245565568.08.0

LeukemiaLeukemia2412411941944354356.26.2

ThyroidThyroid87873283284154156.06.0

LiverLiver23123193933243244.64.6

LungLung23323363632962964.24.2

HDHD16616698982642643.83.8

SkinSkin1361361251252612613.73.7

Brain, Brain, CNSCNS

1471471001002472473.53.5

ProstateProstate214214--2142143.13.1

StomachStomach14114170702112113.03.0

BladderBladder16016041412012012.92.9

UterusUterus--1171171171171.71.7

OvariesOvaries--1081081081081.51.5

All OthersAll Others100910098668661875187526.926.9

TotalTotal347834783491349169606960100100

Risk FactorsRisk Factors

Cigarette responsible Cigarette responsible about 80% of lung about 80% of lung cancer&100% SCLCcancer&100% SCLC

Radon gas the second Radon gas the second causecause

7

Lung cancer Lung cancer occupational exposureoccupational exposure

AsbestosAsbestos NickelNickel ChromiumChromium ArsenicArsenic RadonRadon

naturally occurring inert gas & decay product of Uranium-238 particularly found in stone houses daughter products emit -particles, delivering radiation to depth = 41-71 m RR 1.3-1.8

Since 1970 the prevalence of Since 1970 the prevalence of smoking has increased in Saudi smoking has increased in Saudi Arabia, as in the rest of the world, Arabia, as in the rest of the world, and this will likely lead to a lung and this will likely lead to a lung cancer epidemic in the coming cancer epidemic in the coming decades decades

Presenting SymptomsPresenting Symptoms

11..LocalLocalcough, cough, DyspneaDyspnea , , hemoptysis, pleuritic pain hemoptysis, pleuritic pain

22..NodalNodal recurrent laryngeal/ phrenic, SVCO, recurrent laryngeal/ phrenic, SVCO,

esophageal compressionesophageal compression33..DistantDistant

bony pains, brain metsbony pains, brain mets44 . .NonspecificNonspecific, initial symptoms such as weight , initial symptoms such as weight

loss, weakness, anorexia, and malaiseloss, weakness, anorexia, and malaise 55..ParaneoplasticParaneoplastic

LUNG CANCERLUNG CANCERparaneoplastic syndromesparaneoplastic syndromes: : (2%)(2%)

HypercalcemiaHypercalcemia (ectopic (ectopic parathyroid hormone,more parathyroid hormone,more common in SCC,mental status common in SCC,mental status changes, hypotensionchanges, hypotension

Cushing's SyndromeCushing's Syndrome (2% of (2% of SCLC,ectopic ACTH SCLC,ectopic ACTH secretion,HTN,hirsutism,moon secretion,HTN,hirsutism,moon face,buffalo hump,truncal face,buffalo hump,truncal obesity,thin skin,bruising, obesity,thin skin,bruising, abdominal striae.poor prognosisabdominal striae.poor prognosis

SIADH SIADH (10% of SCLC.ectopic (10% of SCLC.ectopic ADH secretion. hyponatremia. ADH secretion. hyponatremia. Seizures) not affect the Seizures) not affect the prognosisprognosis

Eaton-Lambert Syndrome Eaton-Lambert Syndrome (impaired release of (impaired release of acetylcholine ,muscle strength acetylcholine ,muscle strength improves with repetitive improves with repetitive movement,SCLC movement,SCLC

Pulmonary Hypertrophic Pulmonary Hypertrophic OsteoarthropathyOsteoarthropathy (common in (common in Adenoca, periosteal inflammation Adenoca, periosteal inflammation causing bone and joint pain (usually causing bone and joint pain (usually in knees or ankles), tibial in knees or ankles), tibial tenderness,digit clubbing, elevating tenderness,digit clubbing, elevating alk phos,x-ray -- periosteal alk phos,x-ray -- periosteal inflammation and elevation,bone inflammation and elevation,bone scan -- intense generalized scan -- intense generalized increased uptake, especially in long increased uptake, especially in long bonesbones

Peripheral NeuropathyPeripheral Neuropathy PolymyositisPolymyositis DermatomyositisDermatomyositis Digit ClubbingDigit Clubbing DICDIC VIPOMA (VIPOMA (flushing, diarrhea, flushing, diarrhea,

hypotension = carcinoid syndromehypotension = carcinoid syndrome GynecomastiaGynecomastia 2% of SCLC2% of SCLC

INVESTIGATIONINVESTIGATION

1- Sputum cytology1- Sputum cytology ( 3 samples , can diagnos central lesion 80%)( 3 samples , can diagnos central lesion 80%) < 20% in small peripheral lesion< 20% in small peripheral lesion 2- FNA : 90% accuracy2- FNA : 90% accuracy 3-CT chest , abdomen ( s/s 70%)3-CT chest , abdomen ( s/s 70%) MRI( if CT reveal uncerain medistinal or MRI( if CT reveal uncerain medistinal or

vertebral)vertebral) 4- Bronchoscopy4- Bronchoscopy 5- Mediastinoscopy5- Mediastinoscopy 6- VAT6- VAT 7- Staging work up (brain , bone)7- Staging work up (brain , bone)

04/18/2312

PFT for Radical RTPFT for Radical RT Consensus conference in Cambridge:Consensus conference in Cambridge: FEV1 FEV1 ≥≥ 40% 40% FVC FVC ≥≥ 45% 45% DLCO DLCO ≥≥ 45% 45% pO2 pO2 ≥≥ 60 mmHg 60 mmHg pCO2 < 50mmHGpCO2 < 50mmHG O2 sat. O2 sat. ≥≥ 90% 90%

contraindications to curative large field RTcontraindications to curative large field RT– pt on home Opt on home O22 with such poor pulmonary function from benign with such poor pulmonary function from benign

lung dz that life lung dz that life expectancy is < 6 moexpectancy is < 6 mo

Prognostic FactorsPrognostic Factors

Most important are Most important are PS, extent, and PS, extent, and weight lossweight loss..

Host: Host: PS, weight loss*, sexPS, weight loss*, sex

Tumor Tumor Histo: no difference for advanced disease.Histo: no difference for advanced disease.extentextent

Treatment: Treatment: operability, radiation dose, high dose cisplatinum.operability, radiation dose, high dose cisplatinum.

PATHOLOGYPATHOLOGYWHO ClassificationWHO Classification

I. BenignI. Benign II. Dysplasia and CISII. Dysplasia and CIS III. MalignantIII. Malignant 1. Squamous cell carcinoma 30%1. Squamous cell carcinoma 30%

– and spindle cell carcinomaand spindle cell carcinoma 2. Small cell carcinoma 18%2. Small cell carcinoma 18%

– 1.Oat cell 2.Intermediate cell 3.Combined cell1.Oat cell 2.Intermediate cell 3.Combined cell 3. Adenocarcinoma 40%3. Adenocarcinoma 40%

– 1.Acinar 2.Papillary 3.Bronchoalveolar 1.Acinar 2.Papillary 3.Bronchoalveolar 4.Mucus secreting4.Mucus secreting 4. Large cell carcinoma 15%4. Large cell carcinoma 15%

– 1.Giant cell 2.Clear cell1.Giant cell 2.Clear cellOthersOthers

5. Combined epidermoid + adenocarcinoma5. Combined epidermoid + adenocarcinoma 6. Carcinoid6. Carcinoid 7. Bronchial gland (cylindroma, mucoepidermoid, others)7. Bronchial gland (cylindroma, mucoepidermoid, others) 8. Papillary tumors of surface epithelium8. Papillary tumors of surface epithelium 9. Mixed tumors and carcinomas (carcinosarcomas, etc.)9. Mixed tumors and carcinomas (carcinosarcomas, etc.) 10. Sarcomas10. Sarcomas 11. Unclassified11. Unclassified 12. Mesotheliomas (A.localized, B.diffuse)12. Mesotheliomas (A.localized, B.diffuse)   Up to 45% contain 2 histologic patternsUp to 45% contain 2 histologic patterns..

SCLC STAGINSCLC STAGINGG

LIMITED DISEASELIMITED DISEASE30%30%

EXTENSIVE DISEASEEXTENSIVE DISEASE70%70%

Ihde et al. In: DeVita et al, eds. Cancer: Principles & Practice of Oncology. 5th ed.Lippincott-Raven; 1997:911-949.

SCLC: StagingSCLC: Staging Limited disease (LD)Limited disease (LD)

– Confined to one hemithorax and Confined to one hemithorax and regional lymph nodes, including regional lymph nodes, including ipsilateral supraclavicular lymph nodesipsilateral supraclavicular lymph nodes

Extensive disease (ED)Extensive disease (ED) – Extends beyond one hemithorax or Extends beyond one hemithorax or

involves contralateral mediastinal, hilar, involves contralateral mediastinal, hilar, or supraclavicular lymph nodes, and/or or supraclavicular lymph nodes, and/or pleural effusion with positive cytology pleural effusion with positive cytology

SCLC Stage Distribution at SCLC Stage Distribution at DiagnosisDiagnosis

LD:LD: approximately 30 approximately 30––40% of patients . Most 40% of patients . Most patients with 2-year disease-free survival come patients with 2-year disease-free survival come from this groupfrom this group

ED:ED: approximately 60 approximately 60––70% of patients.70% of patients.

Common sites of metastasis include:Common sites of metastasis include:

– Bone, 19Bone, 19––38%38%

– Liver, 17Liver, 17––34%34%

– Bone marrow, 17Bone marrow, 17––23%23%

– Brain, 0Brain, 0––14%14%

– Lymph nodes, 7Lymph nodes, 7––25%25%

– Soft tissue, 3Soft tissue, 3––11%11%

SCLC Stage Distribution at Diagnosis: SCLC Stage Distribution at Diagnosis: 1989–19961989–1996

0

10

20

30

40

50

60

70

80P

erce

ntag

e of

Pat

ient

s

Total Males Females

Localized

Regional

Distant

Unstaged

7%7% 7%7% 6%6%

18%18%

62%62%

13%13%17%17%

64%64% 61%61%

12%12% 13%13%

20%20%

Data from Ries et al, eds. SEER Cancer Statistics Review, 1973-1997. National Cancer Institute; 2000.

Importance of XRT in SCLCChemotherapy vs Chemotherapy + RT

• JP Pignon, et al. NEJM. 327:1618-1624, 1992. - meta-analysis– 2,103 pt with limited stage SCLC from 13 randomized trials comparing chemo

alone to chemo + RT– end-point: survival– RR of death with addition of RT = 0.86– administration of thoracic RT produced a 14% reduction in the mortality rate– conclusions :

• (1) limited stage SCLC, addition of thoracic RT produced a 14% reduction in mortality rate, corresponding to a 5% greater 3-yr survival

• (2)benefit of radiation was greatest in pt < 55 yr

pt agechemo alonechemo + RT

3-yr OS rateall pt10%15%

< 55 yr9%17%

> 70 yr10%9%

20

Importance of XRT in SCLCChemotherapy vs Chemotherapy + RTnot only survival but also Local control

• P Warde, et al. J Clin Onc. 10:890-895, 1992. - meta-analysis chemochemo + RT

2-yr LR rate77%52%

2-yr OS rate16%23%

−1,911 pt with limited stage SCLC from 11 randomized trials −end-points: survival, loco-regional control, toxicity−odds of surviving 2 yr with RT vs without RT = 1.53−overall increase in 2-yr survival = 5.4% (p<0.05)−odds of thoracic failure at 2 yr with RT vs without RT = 3.02−overall increase in 2-yr thoracic control = 25.3% (p<0.05)−conclusions :addition of thoracic RT to chemotherapy produces a modest improvement in survival and a large improvement in intrathoracic control in pts with limited stage SCLC

Common Treatment Common Treatment ApproachApproach

Extensive DiseaseExtensive DiseaseStandard regimens for SCLC are Standard regimens for SCLC are

considered to considered to be CAV or EP, or be CAV or EP, or CAV/EP alternating regimen.CAV/EP alternating regimen. ++

Prophylactic Cranial IrradiationProphylactic Cranial Irradiation

Limited DiseaseLimited DiseaseSame chemotherapySame chemotherapy

++Concurrent Thoracic RadiotherapyConcurrent Thoracic Radiotherapy

++Prophylactic Cranial IrradiationProphylactic Cranial Irradiation

2222

Timing of Chemo/RTTiming of Chemo/RT1- 1- N Murray, et al. N Murray, et al. J Clin Onc.J Clin Onc. 11:336-344, 1993. - 11:336-344, 1993. -

NCINCI -RCT -RCT RT - 2RT - 2ndnd cycle (n=155) cycle (n=155)RT - 6RT - 6thth cycle (n=153) cycle (n=153)p-valuep-value

CR rateCR rate64%64%56%56%NSNS

median PFSmedian PFS15 mo15 mo12 mo12 mo0.0360.036

3-yr PFS rate3-yr PFS rate26%26%19%19%0.0360.036

median survivalmedian survival21 mo21 mo16 mo16 mo0.0080.008

3-yr OS rate3-yr OS rate30%30%21%21%0.0060.006

5-yr OS rate5-yr OS rate20%20%11%11%0.0060.006

3-yr LR rate3-yr LR rate>50%>50%>50%>50%NSNS

randomization:(1) early RT = radiation given concurrently with 2nd cycle of chemotherapy(2) late RT = radiation given concurrently with 6th cycle of chemotherapy

conclusions :early thoracic irradiation improves progression-free survival and overall survival

Pre-Chemo vs Post-Chemo Pre-Chemo vs Post-Chemo VolumesVolumes

Kies, et al. Kies, et al. J Clin Onc.J Clin Onc. 4:592-600, 1987.4:592-600, 1987. –– SWOG SWOG Liengswangwong, et al. Liengswangwong, et al. J Clin Onc.J Clin Onc. 12:496-502, 1994.12:496-502, 1994. - -

Mayo ClinicMayo Clinic conclusionsconclusions : use of post-chemo tumor : use of post-chemo tumor

volume volume did notdid not – increase the risk of marginal recurrenceincrease the risk of marginal recurrence– Improve median survivalImprove median survival– Improve median RFS Improve median RFS

2424

AT Turrisi, et al. AT Turrisi, et al. NEJM.NEJM. 1999. 1999. - ECOG - ECOG QD RT = 45 Gy in 1.8 Gy fx qdQD RT = 45 Gy in 1.8 Gy fx qd BID RT = 45 Gy in 1.5 Gy fx bid BID RT = 45 Gy in 1.5 Gy fx bid

QD RTQD RTBID RTBID RTp-valuep-value

response rate response rate –– overall overall87%87%87%87%NSNS

CRCR49%49%56%56%NSNS

PRPR38%38%31%31%NSNS

median survivalmedian survival19 mo19 mo23 mo23 mo0.040.04

2-yr OS rate2-yr OS rate41%41%47%47%0.040.04

5-yr OS rate5-yr OS rate16%16%26%26%0.040.04

2 yr failure-free survival rate2 yr failure-free survival rate24%24%29%29%0.100.10

local failure ratelocal failure rate52%52%36%36%0.060.06

treatment related toxicitytreatment related toxicityQD RTQD RTBID RTBID RTp-p-valvalueue

grade 3-4 myelosuppressiongrade 3-4 myelosuppression85%85%87%87%NSNS

grade 3 esophagitis (unable to swallow solids, grade 3 esophagitis (unable to swallow solids, narcotic use, G-tube) narcotic use, G-tube)

11%11%27%27%0.0010.001

grade 4 esophagitis (hospitalization or grade 4 esophagitis (hospitalization or perforation)perforation)

5%5%5%5%NSNS

deathdeath5 pt 5 pt (2%)(2%)

6 pt 6 pt (3%)(3%)

NSNS

2525

PCI PCI –– 25Gy/10f 25Gy/10f R Arriagada1995.R Arriagada1995. - Institut Gustave-Roussy, France - Institut Gustave-Roussy, France

PCI (n=145)PCI (n=145)no PCI (n=149)no PCI (n=149)p-valuep-value

2-yr brain met rate2-yr brain met rate40%40%67%67%< 0.0001< 0.0001

2-yr survival rate2-yr survival rate29%29%21%21%NSNS

conclusions = PCI given to those with complete remission after initial therapy significantly decreases the risk of brain mets without increasing neurotoxicity at 2.5 yr, and there is a trend toward improved survival

A Gregor, et al. 1997. – UKCCCR/EORTC

conclusions :(1)for limited stage SCLC in complete remission after initial therapy, PCI significantly decreases the likelihood of brain relapse(2)higher doses were more effective (no difference in brain met rate was seen with 2400 cGy vs no PCI)

2626

PCI- PCI- meta-analysismeta-analysis ( LD )( LD )

Auperin, R Arriagada, et al. Auperin, R Arriagada, et al. NEJM.NEJM. 341:476-484, 1999. - Institut Gustave-341:476-484, 1999. - Institut Gustave-Roussy, FranceRoussy, France

median f/u = 5.5 yr median f/u = 5.5 yr PCI (n=526)PCI (n=526)no PCI (n=461)no PCI (n=461)p-valuep-value

3-yr OS rate3-yr OS rate21%21%15%15%0.010.01

3-yr DFS rate3-yr DFS rate22%22%13.5%13.5%0.0010.001

3-yr brain mets rate3-yr brain mets rate33%33%59%59%0.0010.001

3-yr other mets rate3-yr other mets rate42%42%46%46%NSNS

3-yr LRR rate3-yr LRR rate44%44%45%45%NSNS

conclusions : addition of PCI in pt with limited stage SCLC in complete remission after chemo results in significantly improved3-yr OS and DFS and 50% reduction in the incidence of brain mets.

Prophylactic cranial Irradiation in Prophylactic cranial Irradiation in Extensive Small Cell LungExtensive Small Cell Lung Cancer ( NEJM )Cancer ( NEJM )

Inclusion CriteriaInclusion Criteria : :

Age 18 -75Age 18 -75 PS (0 PS (0 –– 2) 2) Documented extensive SCLC before starting CTRDocumented extensive SCLC before starting CTR Response after 4 Response after 4 –– 6 cycle 6 cycle Interval of no more than 5/52 between the last cycle Interval of no more than 5/52 between the last cycle

of CT and Radiationof CT and Radiation No evidence of brain metastasesNo evidence of brain metastases No Hx of Rad to H/N areaNo Hx of Rad to H/N area No Hx of CS use No Hx of CS use No Previous or other current cancerNo Previous or other current cancer

PCI :-PCI :-

2 lateral fields2 lateral fields Co , 4 Co , 4 –– 18 MV 18 MV Daily RX / 5 weeksDaily RX / 5 weeks Dose was 20Gy / 5Dose was 20Gy / 5––8 fx8 fx 24 Gy / 12 fx24 Gy / 12 fx 25 Gy/ 10 fx25 Gy/ 10 fx 30 Gy/ 10 30 Gy/ 10 ––12 fx12 fx

. Radiation started 4 . Radiation started 4 –– 6 weeks after CT 6 weeks after CT

Point in the study:-Point in the study:-

End Point : Development of symptomatic End Point : Development of symptomatic brain metastases including :brain metastases including :

1- HA1- HA 2- N/V2- N/V 3- cognitive or affective disturbance 3- cognitive or affective disturbance 4- Seizures 4- Seizures 5- Focal neurological symptoms5- Focal neurological symptoms

Role of PCIRole of PCI?? ??

The role of PCI in patient who do not have complete The role of PCI in patient who do not have complete response to CTR is unclearresponse to CTR is unclear

- -Usually they donUsually they don’’t have complete responset have complete response

ResultsResults

- Patient in the irradiation group had a Patient in the irradiation group had a lower risk of symptomatic brain lower risk of symptomatic brain metastasesmetastases

- Cumulative risk of brain metastases Cumulative risk of brain metastases within 1 year was :within 1 year was :

14.6% in the irradiation group.14.6% in the irradiation group.40.4% in the control group .40.4% in the control group .- The 1 year survival rate was 27.1% in - The 1 year survival rate was 27.1% in

irradiation group and 13.3% in the irradiation group and 13.3% in the control group.control group.

Cumulative Incidence of Symptomatic Brain Cumulative Incidence of Symptomatic Brain MetastasesMetastases. .

Disease-free SurvivalDisease-free Survival

Overall SurvivalOverall Survival

ConclusionConclusion::

PCI reduce the incidence of symptomatic PCI reduce the incidence of symptomatic brain metbrain met

and prolongs DFS + OSand prolongs DFS + OS

AUC = area under the plasma concentration-versus-time curve.*May be 45 Gy bid.†Turrisi et al. N Engl J Med. 1999;340:265-271. ‡Hainsworth and Greco. Semin Oncol. 1999;26(suppl 2):60-66.

Current Standard RegimensCurrent Standard Regimensfor First-Line Therapyfor First-Line Therapy

LD ED

Cisplatin 60–80 mg/mCisplatin 60–80 mg/m22 d 1 d 1

Etoposide 80–120 mg/mEtoposide 80–120 mg/m22 d 1-3 d 1-3

Concurrent RT (45–50 Gy)Concurrent RT (45–50 Gy)q 3 wkq 3 wk††

Carboplatin AUC 6Carboplatin AUC 6 d 1d 1

Etoposide 80–100 mg/mEtoposide 80–100 mg/m22 d 1–3 d 1–3

Concurrent RT (45–50 Gy)*Concurrent RT (45–50 Gy)*q 3 wkq 3 wk‡‡

oror

Cisplatin 60–80 mg/mCisplatin 60–80 mg/m22 d 1 d 1

Etoposide 80–120 mg/mEtoposide 80–120 mg/m22 d 1–3 d 1–3

q 3 wkq 3 wk††

Carboplatin AUC 5–6Carboplatin AUC 5–6 d 1d 1

Etoposide 80–100 mg/mEtoposide 80–100 mg/m22 d 1–3 d 1–3

q 3 wkq 3 wk‡‡

oror

LDLD EDED

Complete response (%)Complete response (%) 45-7545-75 10-3010-30

Median survival (mo)Median survival (mo) 15-2315-23 6-116-11

2-year survival (%)2-year survival (%) 20-4720-47 10-2010-20

5-year survival (%)5-year survival (%) 10-2610-26 1-21-2

Outcomes of First-Line Therapy Outcomes of First-Line Therapy with Current Standard Optionswith Current Standard Options

NSLC

Staging

MX of NSLCMX of NSLC

1A : SURGEY alone 1A : SURGEY alone R/O Rad : 1- InoperableR/O Rad : 1- Inoperable 2- + ve margin2- + ve margin

IIA IIA –– 2B (T2N0 , T1N1, T2N1 , T3N0) 2B (T2N0 , T1N1, T2N1 , T3N0) Surgey + Chemotherapy ( CALBG , Surgey + Chemotherapy ( CALBG ,

NCIC,IALT ) NCIC,IALT ) R/O Rad : 1- InoperableR/O Rad : 1- Inoperable 2- + ve margine2- + ve margine 3- Nodal ECE3- Nodal ECE

DEFINITIONSDEFINITIONS IIIAIIIA (T3 N1 or T1-T3, N2) (T3 N1 or T1-T3, N2)

– N2 = single-digit nodes (station 1-9)N2 = single-digit nodes (station 1-9) Station 7 = subcarinalStation 7 = subcarinal Station 4 = low paratrachealStation 4 = low paratracheal Station 2 = high paratrachealStation 2 = high paratracheal Station 5 / 6 = AP window (accessible via anterior med.) Station 5 / 6 = AP window (accessible via anterior med.)

IIIBIIIB (any T, N3 or T4 (any T, N3 or T4 – N3 = ipsilateral scalene or supraclavicular nodesN3 = ipsilateral scalene or supraclavicular nodes– T4 = invading major organ or satellite nodule T4 = invading major organ or satellite nodule

same lobesame lobe

IIIA :IIIA :

Operable Operable 1- chemo 1- chemo –– restage restage –– if no progression if no progression ––

surgery surgery ––chemo +/- rad if : 1- + marginechemo +/- rad if : 1- + margine 2- nodal ECE2- nodal ECE

2- Concurrent chemorad ( 45 GY) 2- Concurrent chemorad ( 45 GY) ––restage restage ––if no progression surgery if no progression surgery –– chemochemo

If progression cont chemorad to (61 Gy)If progression cont chemorad to (61 Gy)

RTOG 9309RTOG 9309

NSCLC IIIA, pN2

Cisplatin + VP16 q3wk x 2, concurrent with RT

Thoracic RT 45 Gy

Surgery RT to 61 Gy

2 additional cycles chemotherapy to both groups

ASTRO 2003

RTOG 9309 :RTOG 9309 : NSCLC IIINSCLC IIIA, A, CRT vs CRT + S CRT vs CRT + S

SurgerySurgeryNo SurgeryNo Surgery

LF + N + DMLF + N + DM15 %15 %28 %28 %

Median PFSMedian PFS14 mo14 mo12 mo12 mo

Median survival Median survival 22 mo22 mo22 mo22 mo

Cancer deathCancer death71 % 71 % 81 %81 %

Treatment deathTreatment death11 %11 %2 %2 %

RTOG 9309 :RTOG 9309 : NSCLC IIINSCLC IIIA, A, CRT vs CRT + S CRT vs CRT + S

Surgery reduces progression but is Surgery reduces progression but is associated with more treatment deathsassociated with more treatment deaths

More cancer deaths in no surgery More cancer deaths in no surgery group, despite more chemotherapygroup, despite more chemotherapy

Despite significantly improved PFS , Despite significantly improved PFS , surgery did not improve overall survivalsurgery did not improve overall survival

Longer F/U may demonstrate a benefitLonger F/U may demonstrate a benefit

Stage IIIAStage IIIA

Approximately 20 % of all stage IIIA Approximately 20 % of all stage IIIA resectableresectable

Different clinical gradations of N2 disease, Different clinical gradations of N2 disease, with differing prognoses:with differing prognoses:– Easily visible on CXR / CT = Easily visible on CXR / CT = ““bulkybulky”” N2 N2– Single station enlarged nodeSingle station enlarged node– Normal CT, only positive at mediastinoscopyNormal CT, only positive at mediastinoscopy– Normal CT, -ve mediastinoscopy, only found at Normal CT, -ve mediastinoscopy, only found at

final, post-resection pathology = final, post-resection pathology = ““incidentalincidental”” N2N2

Inoperable IIIAInoperable IIIA : :

1- Concurrent chemorad (63 Gy ) 1- Concurrent chemorad (63 Gy ) +adjuvant chemo ( RTOG 9410 )+adjuvant chemo ( RTOG 9410 )

2- Induction chemo 2- Induction chemo –– rad rad (sequential)(sequential)

3- Rdaiation alone3- Rdaiation alone

Option depends on patient , PS , Option depends on patient , PS , Wt loss.Wt loss.

Radiation and Radiation and Chemotherapy for St Chemotherapy for St III NSCLCIII NSCLC

CALBG 1990CALBG 1990 Arm1 RT 60Gy/30fArm1 RT 60Gy/30f Arm 11 Vinblastine /CPP x Arm 11 Vinblastine /CPP x 2 cycles2 cycles

followed by RT 60Gy/30ffollowed by RT 60Gy/30f Interim analysisInterim analysis favored combined favored combined

modality with modality with median Smedian S 13.6 mos vs 13.6 mos vs 9.7 mos9.7 mos

Dillman,R NEJM 1990:323,940

Radiation and Radiation and Chemotherapy for St Chemotherapy for St III NSCLCIII NSCLC11

RTOG 88-08RTOG 88-08Arm 1 Standard RT 60 Gy/30fArm 1 Standard RT 60 Gy/30f

Arm 11 Vinblastine/CPP x 2cycles followed by 60 Arm 11 Vinblastine/CPP x 2cycles followed by 60 Gy/30fGy/30f

Arm 111 RT bid fractionation 69.6 Gy/1.2 Gy/fractionArm 111 RT bid fractionation 69.6 Gy/1.2 Gy/fraction

Results Median SResults Median S

Arm 1---11.4 moArm 1---11.4 mo. Arm 11---13.8 mo.. Arm 11---13.8 mo.

Arm111---12.3 mo.Arm111---12.3 mo.

Sequential therapy became the standardSequential therapy became the standard

J. Nat. Cancer Inst.. 1995: 87,3

Concurrent Chemotherapy Concurrent Chemotherapy and Radiotherapy St IIIand Radiotherapy St III

RTOG 94-10RTOG 94-10 SIII,IIISIII,III, KPS> 70, wt loss <5%, KPS> 70, wt loss <5% Arm I VLB/CPP followed by 63 GyArm I VLB/CPP followed by 63 Gy Arm II VLB/CPP concurrent with 63 GyArm II VLB/CPP concurrent with 63 Gy Arm III Oral VP-16/CPP concurrent with Arm III Oral VP-16/CPP concurrent with bidbid RT 69Gy RT 69Gy Results Median SResults Median S Arm I 14.6 mo.Arm I 14.6 mo. Arm II Arm II 17 mo.17 mo. Arm III 15.6Arm III 15.6 Concurrent therapy has become standard Concurrent therapy has become standard

therapytherapy

IIIBIIIB

IF Localized & no pleural effusionIF Localized & no pleural effusion As IIIAAs IIIA

If pleural effusion or Stage IVIf pleural effusion or Stage IV PS ( 0-2) Palliative PS ( 0-2) Palliative

chemotherapy+Rad chemotherapy+Rad PS (3-4) Best supportive carePS (3-4) Best supportive care

RESULTSRESULTS

Local-Regional ControlLocal-Regional Control Surgical Stage 1-2:Surgical Stage 1-2: 85-90%85-90% Surgical Stage T3/N2:Surgical Stage T3/N2: 80%80% After sleeve lobectomy:After sleeve lobectomy: 60%60%    5 Year Overall Survival5 Year Overall Survival   Stage IStage I 50%50% Stage IIStage II 30%30% Stage IIIaStage IIIa 15%15% Stage IIIbStage IIIb 5%5% Stage IVStage IV 1%1%   All stagesAll stages 13%13%

Survival Curves Lung Survival Curves Lung CancerCancer

50%

30%

17%

2%

Pancoast's syndrome and Pancoast's syndrome and superior (pulmonary) sulcus superior (pulmonary) sulcus

tumorstumors

PANCOASTPANCOAST

Tumors located at the upper part Tumors located at the upper part of the pulmonary sulcus near the of the pulmonary sulcus near the thoracic inlet may correctly be thoracic inlet may correctly be regarded as superior sulcus regarded as superior sulcus tumors, although the inferior tumors, although the inferior margins of the superior sulcus are margins of the superior sulcus are not well defined.not well defined.

CLINICAL PRESENTATIONCLINICAL PRESENTATION

Lesions in the superior sulcus may result Lesions in the superior sulcus may result in:in:

shoulder and arm pain (in the distribution shoulder and arm pain (in the distribution of the C8, T1, and T2 dermatomes)of the C8, T1, and T2 dermatomes)

Horner's syndrome, and weakness and Horner's syndrome, and weakness and atrophy of the muscles of the hand, a atrophy of the muscles of the hand, a constellation of symptoms referred to as constellation of symptoms referred to as Pancoast's syndrome .Pancoast's syndrome .

The majority of patients with superior The majority of patients with superior sulcus tumors present with one or more of sulcus tumors present with one or more of these complaints.these complaints.

CLINICAL PRESENTATIONCLINICAL PRESENTATION

shoulder and arm shoulder and arm pain (in the pain (in the distribution of the distribution of the C8, T1, and T2 C8, T1, and T2 dermatomes)dermatomes)

Horner's syndrome, Horner's syndrome, and weakness and and weakness and atrophy of the atrophy of the muscles of the muscles of the hand.hand.

What is make it What is make it unresectable?unresectable?

Involvement of :Involvement of :

1.1. Brachial plexus Brachial plexus grossly grossly

2.2. Subclavin artery Subclavin artery

3.3. Vertebral bodyVertebral body

4.4. Esophagus Esophagus

5.5. Medistainal L.NMedistainal L.N

6.6. Distance Metastasis Distance Metastasis

Induction chemoradiation and surgical resection for non-Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus T3 - T4 small cell lung carcinomas of the superior sulcus T3 - T4 N1: N1: SWOG,IG(SWOG,IG(PhaseIIPhaseII) ROUCH) ROUCH

CONCLUSIONSCONCLUSIONS::

(1) This combined modality (1) This combined modality treatment is feasible in a treatment is feasible in a multi-institutional multi-institutional setting.setting.

(2) the pathologic complete (2) the pathologic complete response rates were highresponse rates were high

(3) resectability and overall (3) resectability and overall survival were improved survival were improved compared with historical compared with historical experience, especially for experience, especially for T4 tumors, which usually T4 tumors, which usually have a grim prognosis.have a grim prognosis.

3 patients3 patientstx related tx related deathdeath

65 %65 %CR or CR or micro micro

residualresidual

70%70%Complete Complete resectionresection

55%55%2 y 2 y survivalsurvival