폐암의 방사선치료RT for NSCLCYong Chan Ahn, MD, PhDDept. of Radiation OncologySamsung Medical CenterSungkyunkwan University School of Medicine
21,577 Consultations (1994~2006)Hepatobi l i ary5.9%Lymphoma &Leuk emi a6.8%H&N11.4%Esophagus1.8%Stomach4.5%Lung18.2%Breast13.6%Cervi x &uterus8.2%Col orectal13.6%Others9.1%Prostate1.4%Brai n5.5%
Staging System• AJCC 7th edition since January 2010• Anatomical extent of disease is expressed byTNM classification:– Prediction of prognosis– Therapeutic decision• 1/6 patients will be classified in to a differentstage category
Primary Tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situT1T1aT1bTumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence ofinvasion more proximal than the lobar bronchus (i.e., not in the main bronchus)*Tumor ≤2 cm in greatest dimensionTumor >2 cm but ≤3 cm in greatest dimensionT2T2aT2bTumor >3 cm but ≤7 cm or tumor with any of the following features (T2 tumors with these features areclassified T2a if ≤5 cm)Involves main bronchus, ≥2 cm distal to the carinaInvades visceral pleura (PL1 or PL2)Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involvethe entire lungTumor >3 cm but ≤5 cm in greatest dimensionTumor >5 cm but ≤7 cm in greatest dimensionT3 Tumor >7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (includingsuperior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in themain bronchus (<2 cm distal to the carina* but without involvement of the carina; or associated atelectasis orobstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobeT4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrentlaryngeal nerve, esophagus, vertebral body, carina, separate tumor nodule(s) in a different ipsilateral lobe* The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchialwall, which may extend proximally to the main bronchus, is also classified as T1a.
Regional Lymph Nodes (N)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilarlymph nodes and intrapulmonary nodes, including involvementby direct extensionN2 Metastasis in ipsilateral mediastinal and/or subcarinal lymphnode(s)N3 Metastasis in contralateral mediastinal, contralateral hilar,ipsilateral or contralateral scalene, or supraclavicular lymphnode(s)
Distant Metastasis (M)M0 No distant metastasis (no pathologic M0; use clinical M tocomplete stage group)M1M1aM1bDistant metastasisSeparate tumor nodule(s) in a contralateral lobe; tumor withpleural nodules or malignant pleural (or pericardial) effusion*Distant metastasis* Most pleural (and pericardial) effusions with lung cancer aredue to tumor. In a few patients, however, multiplecytopathologic examinations of pleural (pericardial) fluid arenegative for tumor, and the fluid is non-bloody and is not anexudate. Where these elements and clinical judgment dictatethat the effusion is not related to the tumor, the effusion shouldbe excluded as a staging element and the patient should beclassified as M0.
AJCC Stage Group (7th edition)T1a/b T2a T2b T3 T4N0 IA IB IIA IIB IIIAN1 IIA IIA IIB IIIA IIIAN2 IIIA IIIA IIIA IIIBN3 IIIB IIIB IIIB IIIB
Radiation and SurgeryRationaleRadiation usually fails in tumor center, andrarely doses at peripherySurgery usually fails at periphery because ofmicroscopic tumor cells left behindSequence of radiation and surgeryPreoperative radiationPostoperative radiationIntraoperative radiation
Limited Surgery and RadiationUsing surgery as boost techniqueFull courses of radiation combined withtumorectomySurgery can be done before or after theirradiationExamplesBreast – lumpectomy + definitive radiationH/N cancer – definitive radiochemotherapy +adjuvant neck dissection
Radiation and ChemotherapyPurpose is not to decrease radiation doseto gain the same effect, but rather toincrease therapeutic index3 strategies:Drugs directly modifying radiation survivalcurve (synergy, sensitizer, potentiator)Drugs specifically affecting tumor responseto radiation (hypoxic sensitizers)Drugs with independent action or additivity
Theoretic Rationales of CMT Spatial cooperation Toxicity independence Reduction of toxicity Enhanced tumor response Prevention of emergence of resistant clones
Staging W/U for NSCLC at SMC• Standard: Chest CT, PFT, Broncho, PET-CT• Optional: Brain MR (if AD)Medically operable vs Medically inoperableEarly, vs Advanced –M1 or wet T4Locally advancedResectablePotentially resectableUnresectableMediastinoscopy &/or EBUSfor all potentially resectablecandidate
Tx Guideline for NSCLC at SMCTT1 T2 T3 T4NN0 IA-IIBOp ± RT/CTx/CRTDefinitive RT aloneIIIB(except wet T4)DefinitiveCCRT or RTaloneN1 IIIA (T3N1)N2IIIAPreop. CCRT + Op + RTDefinitive CCRT or RT aloneN3
Stage I/II• Whenever possible, surgery is recommendedfirst.• After surgery, CTx and/or RT may berecommended to decrease recurrence risk.• RT alone is recommended if surgery is notfeasible due to severe lung disease or otherunderlying medical problems.• A few individualized RT techniques and doseschedules are used.
Stage III• There is no one “best” treatment for stage IIINSCLC.– Choice of Tx modality depends upon several factorsincluding size and location of tumor, N stage, andphysiologic status of patient.• Whenever possible, combination of RT and CTx(CCRT) is recommended first.• Either RT or CTx alone is considered ifaggressive CCRT is not feasible.
How radiation kills cancer? Ionization --> Damage to DNA or membrane--> Mutation, Cell death metabolically active for the time-being die out at time of cell division due to aberrantreproduction takes time before cancer cells disappear
Preparation for Radiation Therapy• Acquisition of CT (MR, PET-CT)• Contouring:– Targets (GTV, CTV, ITV)– Organs at risk• Determination of beam arrangement, intensityto achieve the most optimal plan among rivalplans• Quality assurance
Image Guided RT• RT procedure using image guidance at variousstages of its process (patient data acquisition,treatment planning, treatment simulation,patient setup, and target localization beforeand during treatment)
To identify and correct problemsarising from inter- and intra-fractional variations in patient setupand anatomy
Stereotactic Body RT• High ablative dose• To small tumor (usually <3~4 cm)• Within a few fractions• Using multiple non-coplanar beams• With adequate immobilization and motioncontrol
SBRT• One of the state-of-the-art RT techniques– Highly conformal and accurate radiation delivery• Conformal high dose• Compact intermediate dose• Very large low dose volume– High fractional dose (10~20 Gy * ≤4 fractions)– Within short period of time (within 1 week)– Patient-specific Tx planning
Conventional RT SBRTDose/fraction 1.8~3.0 Gy 10~20 GyFraction number 10~30 fractions 1~5 fractionsTarget delineation GTV, CTV, (ITV), PTVGTV, CTV, ITV, PTV(GTV CTV)Margins cm range mm rangeNeed for mechanicalaccuracyLow to medium Very highNeed for respiratorymotion controlModerate HighRadiobiologyModerately wellunderstoodStill poorly understoodInteraction withsystemic therapyCurrently active Will become active
Toxicities of SBRT• Acute:– Fatigue, anorexia, nausea– Pulmonary– Skin• Late:– Pulmonary– Chest wall• Unknown:– Heart– Large vessel– Etc
Rationale of SBRT in Stage I NSCLC• RT is better than doing nothing.• (+) dose-response relationship has beenconfirmed with respect to local control.• The smaller the tumor, the higher the localcontrol and survival by RT.• Incidence of lymphatic metastasis is known to bevery low.• Shorter RT duration is better than protracted RTschedule in survival.
Importance of tumor size Importance of RT duration
SBRT Indications at SMC• cT1-2,N0• Single metastasis or recurrence• ≤ 5 cm in size (preferably ≤ 3 cm)• Location (peripheral > central, upper > lower)
Pinnacle®Heterogeneity correctionRespiratory training for imaging & SBRT4D CT; CTV-ITV (1.2+ cm margin around GTC-ITV)CBCT for target localization
Respiratory Training(Respiratory Signal Analysis Program)
Summary• SBRT to lung cancer at SMC:– High local control (90%)– Favorable 5 year survival (primary/metastatic –66.4%/53.8%)– Very low risk of complication (Grade 2/3 –3.4%/1.7%)– Highly effective and curative modality to patientswho are unfit for surgery.JTO, 2010
Conclusion• SBRT for single or oligo-metastasis seemsquite effective and safe.• Tumor size, disease-free interval, and presenceof extrathoracic disease are prognosticators forsurvival.Acta Oncologica, 2012
Introduction• Remarkable improvements in diagnosis of N2disease -- CT, FDG PET-CT, mediastinoscopy,VATS, and EBUS• A few different ways of classifying N2 disease --clinical vs surgical, minimal vs bulky etc…• N2 disease is a very important prognosticfactor in NSCLC.• There is no single answer that defines the besttreatment option for N2(+) NSCLC.
Trimodality for N2 Disease @ SMC• TRT– 45 Gy/25 Fx’s (’97~Sep ’09)– 44 Gy/22 Fx’s (Oct ’09~)• CTx– EP #2 q 4 weeks (’97~Apr ’01)– Weekly DP #5 (Mar ’01~)• Surgery in 3-4 weeks• Optional postop TRT (18~20 Gy/2 weeks)• Optional CTx (usually sequential)
Summary (Acta Oncol, 2001)• Preoperative CCRT resulted in fair pathologicresponse, down-staging (68.2%), less radicalsurgery, and 2-year OS with tolerablemorbidity.• Surgery added to CCRT did not affect OS, butaltered failure pattern only.Acta Oncol, 2001
Preop CCRT(N=410)Patients (June ’97~Aug ’11)Surgical resection(N=396)Postop TRT (+)(N=228)Postop TRT (-)(N=144)Incomplete Tx,progression, refusal (14)Periop deaths (19)Systemic progression (5)Presented at ACOS, KOSRO, ASTRO meetings in 2012
Patients’ Characteristics (N=396)Age Median 59 (18-76) yearsGender MaleFemale310 (78.3%)86 (21.7%)Histology AdenocaSquamous cell caLarge cell caNon-small cell ca, NOS213 (53.8%)157 (39.6%)11 (2.8%)15 (3.8%)cT stage cT1cT2cT399 (25.0%)239 (60.4%)62 (15.6%)Tumor size Mean 33 (9-128) mmcN2 status (CT and/or PET-CT) BulkyMinimal276 (69.7%)120 (30.3%)Pathologic confirmation of N2 NoYes41 (10.4%)355 (89.6%)Number of (+) nodal station SingleMultiple250 (63.1%)146 (36.9%)
Preop TxTRT 45 Gy in 25 Fx’s (1997’ ~ Oct 2009’)44 Gy in 22 Fx’s (Sep 2009’ ~ )293 (74.0%)103 (26.0%)CTx EP q 3 weeks (1997’ ~ Jul 2001’)Weekly DP (Jul 2001’ ~ )48 (12.1%)348 (87.9%)SurgerySublobar resection(Bi-)LobectomyPneumonectomy2 ( 0.5%)335 (84.6%)59 (14.9%)Postop TxTRT No or incompleteYes (18-20 Gy in 10 Fx’s)177 (44.7%)219 (55.3%)CTx NoYes301 (76.0%)95 (24.0%)Treatment Characteristics (N=396)
Median 3-year 5-yearOS 46 (35-58) mo 56.9% 44.2%PFS 21 (16-26) mo 37.5% 33.3%LRC Not reached 76.2% 71.6%DMFS 28 (21-34) mo 42.1% 37.7%Survival Outcomes (N=396) Median F/U = 33 (4-156) months
Prognostic Factors – Multivariate analysisP valueFactors LRC PFS OSAge < 60 vs. ≥ 60 years 0.174 0.389 0.002Gender Female vs. Male 1.000 0.578 0.291Histology Adenoca vs. non-Adenoca 0.629 0.009 0.662cT stage cT1-2 vs. cT3 0.847 0.847 0.481Chemo regimen EP q 3 weeks vs. weekly DP 0.243 0.092 0.009Op. type Lobectomy vs. Pneumonectomy 0.070 0.001 0.004ypT stage ypT0-2 vs. ypT3-4 0.284 0.182 0.064ypN stage ypN0 vs. ypN1-3 0.001 <0.001 <0.001Resection margin Negative vs. Close/positive 0.294 0.380 0.811Postop TRT No/incomplete vs. Yes 0.163 0.198 0.003Postop chemo No vs. Yes 0.291 0.600 0.050
SummaryExcellent clinical outcomes (Median survival =46 months; 5-year OS = 44.2%) with trimodalitytherapy.Pathologic nodal down-staging was the mostimportant prognostic factor.SWOG 8805 RTOG 0229 INT 0139 SMCMedian 13 months 26.6 months 23.6 months 46 monthsOS 27% (3-Yr) 54% (2-Yr) 27% (5-Yr) 44.2% (5-Yr)
Conclusions• There definitely is positive role of surgical resectionfollowing preoperative CCRT in cN2 disease.• Benefit of surgery is summarized as improved loco-regional control at no excess morbidity.• Without loco-regional control,real cure cannot be expected,and surgery remains essentialunder multi-disciplinary spirit.