Non small cell Lung Cancer

Transcription

1 Non small cell Lung Cancer The 13th refresher course for residents in radiation oncology Jiraporn Setakornnukul, M.D. Radiation oncology division, Radiology department Siriraj Hospital, Mahidol University

2 Outline Screening Staging and investigation Management by stages (NSCLC) ES-NSCLC LA-NSCLC Radiation techniques

3 Screening for lung cancer Why? High morbidity and mortality identified risk factors allowing targeted screening for high risk therapy is more effective in early stage disease J Thorac Oncol 2007; 2:706

4 Screening for lung cancer Annual chest X-ray Biannual chest X-ray Annual chest X-ray plus sputum cytology No benefit to reduce mortality rate in lung cancer

5 Screening for lung cancer National Lung Screening Trial: low-dose chest CT scanning VS. chest x-ray for 3 years High risk population: age years with history of at least 30 pack-years of smoking included current smokers and discontinued smoking within 15 years of enrollment Low dose CT Chest X-ray Positive test 24.2% 6.9% False positive 96.4% 94.5% Death (per 100,000 person-yr) Relative reduction in mortality 20.0% (95% CI, 6.8 to 26.7; P=0.004) N Engl J Med. 2011;365(5):395.

6 Pretreatment evaluation Complete blood count Serum electrolytes, calcium LFT: alkaline phosphatase, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin Creatinine Pulmonary function test (PFT) Counseling smoking cessation

7 Staging for lung cancer CT chest (including liver and adrenal glands) with contrast Tumor: tumor size, separated nodules, atelectasis, invasion adjacent structure Mediastinal LN: sensitivity 51% specificity 86% Most area: normal mediastinal LN size < 10 mm. but subcarinal LN size mm. Rare area: retrocrural region, para-aortic region, or pericardial fat If LN. > 8 mm. suspected pathologic nodes Chest. 2007;132(3 Suppl):178S.

8 Staging for lung cancer Positron emission tomography/ct (PET/CT) sensitivity 91%, specificity 86 % (Petterman RM, NEJM 2000) Good negative predictive value PET/CT for contouring change radiation portal 35-62% (most mediastinum LN) False negative: Lesion less than 1 cm, DM, During 1st week after chemotherapy

9 Staging for lung cancer Bone scan Imaging brain: MRI or CT Suspected mediastinal LN from imaging Mediatinoscopy Mediastinotomy EBUS with biopsy

10 Mediastinal LN: Station J Thorac Oncol. 2007;2:

11 Update 8 th edition AJCC 7 th edition T0 : No evidence of primary tumor Tis : Carcinoma in situ T1 : Tumor 3 cm, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus T1a : Tumor 2 cm T1b : Tumor 2- (<) 3 cm 8 th edition o T0: No evidence of primary tumor o Tis: Carcinoma in situ o T1 : Tumor 3 cm, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus o T1a(mi): Minimally invasive adenocarcinoma** o T1a : Tumor 1 cm o T1b : Tumor 1- (<) 2 cm o T1c : Tumor 2- (<) 3 cm **Solitary adenocarcinoma, < 3cm with a predominately lepidic pattern and < 5mm invasion in any one focus

12 Update 8 th edition AJCC 7 th edition T2 : Tumor 3 (<) 7 cm with involves main bronchus, > 2 cm distal to the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung T2a : Tumor 3 - (<) 5 cm T2b : Tumor 5 - (<) 7 cm 8 th edition o T2 : Tumor 3 (<) 5 cm with involves main bronchus not carina, > 2 cm distal to the carina; invades visceral pleura (PL1 or PL2); Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung o T2a : Tumor 3 - (<) 4 cm o T2b : Tumor 4 - (<) 5 cm

13 Update 8 th edition AJCC T2 7 th edition T3 : Tumor > 7 cm or one that directly invades any of the following: parietal pleural (PL3), chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; tumor in the main bronchus < 2 cm distal to the carina but without involvement of the carina associated atelectasis or obstructive pneumonitis of the entire lung separate tumor nodule(s) in the same lobe 8 th edition o T3: Tumor 5 (<) 7 cm or associated with o directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve,parietal pericardium o separate tumor nodule(s) in the same lobe as the primary tumor

14 Update 8 th edition AJCC 7 th edition T4 : Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus vertebral body Carina separate tumor nodule(s) in a different ipsilateral lobe 8 th edition o T4: Tumor > 7 cm or associated with o separate tumor nodule(s) in a different ipsilateral lobe than that of the primary tumor o invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina

15 Update 8 th edition AJCC 7 th edition No changes 8 th edition NX : Regional lymph nodes cannot be assessed N0 : No regional lymph node metastases N1 : Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 : Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 : Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) o o o o o NX : Regional lymph nodes cannot be assessed N0 : No regional lymph node metastases N1 : Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 : Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 : Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

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17 Update 8 th edition AJCC 7 th edition M0 : No distant metastasis M1 : Distant metastasis M1a : Separate tumor nodule(s) in a contralateral lobe, tumor with pleural nodules or malignant pleural (or pericardial) effusion M1b : Distant metastasis (in extrathoracic organs) 8 th edition o M0: No distant metastasis o M1: Distant metastasis present o M1a: Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodule(s)or malignant pleural or pericardial effusion o M1b: Single extrathoracic metastasis o M1c: Multiple extrathoracic metastases in one or more organs

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19 Treatment of Non-small cell lung cancer - ES-NSCLC - LA-NSCLC

20 Treatment of Non-small cell lung cancer - ES-NSCLC: Surgical candidate case Medically inoperable case

21 Early stages: stage I or II Surgery is standard treatment for patients with clinical stage I and II Primary Lung mass Lobectomy: Standard procedure Open thoracotomy Video-assisted thoracoscopic surgery (VATS) Sublobar resection: Segmentectomy or wedge resection Compromised pulmonary function, advanced age, extensive comorbidity Limited tumor < 3 cm.

22 Early stages: Lobectomy VS. Sublobar resection Loco-regional free survival Increased50% 5 yrs OS Lobectomy 65% VS. Sublobar resection 45% Ongoing study: CALGB (NCT ) Lobectomy VS. Sublobar resection in peripheral tumors 2 cm (stage IA) Ann Thorac Surg 1995;60:615-23

23 Early stages: stage I or II Mediastinal LN surgery Systemic mediastinal lymph node dissection Sampling mediastinal lymph node Right: 2R, 4R, 7, and 10R Cochrane meta-analysis Left: 5, 6, 7, and 10L European Society of Thoracic Surgeons guidelines recommended systematic lymph node dissection in all cases T h e Cochran e Li brar y 2010, Issue 4

24 Complete resection from NCCN Complete resection requires: free resection margins + Systematic node dissection or sampling + highest mediastinal node negative for tumor

25 Treatment of Non-small cell lung cancer - ES-NSCLC: Surgical candidate case Medically inoperable case

26 Stereotactic Body RadioTherapy (SBRT) Stereotactic ABlative Radiotherapy (SABR) = high dose radiation per day (> 10 Gy) = small number of fraction (< 5 fractions)

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28 Medically inoperable stage I non-small cell lung cancer

29 Outcome: SBRT/SABR Authors Patient Dose(Gy) Stage 3 yr Local Control (%) Prospective SBRT trials 3 yr Overall Survival (%) 5 yr OS 5 yr LC Baumann Gy x 3F IA/B %, 79% Fakiris Gy x 3F IA/B Koto Gy x 3F 7.5 Gy x 8F IA/B/IIA T1: 78 T2: 40 Systematic review: 5-yr OS 40% (17-83%) 5-yr LC 90% (83-95%) Ricardi 15 Gy x 3F IA/B Timmerman Gy x 3F IA/B/IIA %, 62% Nagata Gy x 4F IA/B Retrospective SBRT studies Nyman Gy x 3F IA/B Onishi Gy x 1- IA/B F Timmerman Gy x 3F IA/B 95 (2 yr) 55 (2yr) Uematsu Gy x 10F IA/B 94 (2 yr) 66 (2 yr) 72

30 Peripheral location Central location Radiotherapy dose 18 Gy x 3 fractions

31 70 patients treated with SBRT: develop five (7%) grade 5 toxicity (3 pneumonia, 1 hemoptysis, 1 respiratory failure)

32 ASCO recommendation Delivery of SBRT in more than 3 (ie, 4 or 5 ) fractions may reduce the risk of severe toxicity. For central tumors for which SBRT is deemed too high-risk (eg, tumors directly abutting or invading the esophagus or proximal bronchial tree), hypofractionated radiotherapy utilizing 6-15 fractions or conventionally fractionated radiotherapy may be considered.

33 Medically operable ESNSCLC - Standard operative risk - High operative risk

34 Criticize Under power to test benefit of SBRT Thoracotomy surgery Chang 2015

35 Overall survival Lobectomy SBRT 59% 29% SBRT: excluded medically inoperative patients Rosen 2016

36 ASCO recommendation Standard operative risk and stage I NSCLC, SBRT is not recommended as an alternative to surgery outside of a clinical trial. For this population, lobectomy with systematic mediastinal/hilar lymph node evaluation remains the recommended treatment, though a sublobar resection may be considered in select clinical scenarios.

37 Median FU: 2.9 yr SBRT Surgery HR: 1.92 ( ), P,.001 OS: video-assisted thoracoscopic resection vs SBRT Paul 2016

38 ASCO recommendation High operative risk: cannot tolerate lobectomy, but are candidates for sublobar resection SBRT as a potential alternative to surgery are encouraged within the multidisciplinary cancer care team. In cases where SBRT is offered, patients should be informed that while SBRT may have decreased risks from treatment in the short term, the longer-term outcomes > 3 years are not wellestablished.

39 Summary1: role of SBRT in ES-NSCLC Medically inoperable ES-NSCLC SBRT as standard of care Medically operable ES-NSCLC: high risk patient SBRT as alternative treatment to surgery Medically operable ES-NSCLC: standard risk patient SBRT is not recommended

40 Postoperative RT

41 Retrospective ANITA trial N1 N2 Median OS (yr) No CMT CMT No RT RT Median OS (yr) No CMT CMT No RT RT Int. J. Radiation Oncology Biol. Phys., 2008

42 Criticize for PORT meta-analysis 25% patients had T1N0 disease Initial staging inadequate by today s standards Cobalt 60 used in 4 trial (5 yr survival Co-60 8% vs 30% for Mev) Conventional RT High dose (60Gy) and fractionation (up to 3.0 Gy/Fx) PORT meta-analysis 2005

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44 Complete resected N2 Lymph node sampling or systematic dissection of lymph nodes RUL/RML: levels 2, 4 and 7 RLL: levels 4, 7, 8 and 9 LUL: levels 5, 6 and 7 LLL: levels 7, 8 and 9 3 intrapulmonary and hilar nodes at least 3 nodes from mediastinal nodes

45 Summary 2: PORT Complete node resection N0-1: no role of PORT N2: controversy Incomplete resection R1/2: PORT

46 Treatment of Non-small cell lung cancer - LA-NSCLC

47 LA-NSCLC: operable case - Trimodality - Definite CCRT

48 Induction CCRT+Sx VS CCRT Intergroup INT-0139 (RTOG 93-09, SWOG 93-36) stage IIIA (pn2) NSCLC Cisplatin/Etoposide +RT 45Gy/25F Radical surgery Consolidation CMT Cis+Eto 396 patients Cisplatin/Etoposide +RT 61Gy Consolidation CMT Cis+Eto Pattern Failure PFS Preop CCRT Definite OS CCRT Primary tumor 2% 14% Regional LN 7% 3% Brain metastasis 11% 15% Distant metastasis 37% 42% Albain KS, The Lancet 2009

49 Induction CCRT+Sx VS CCRT Intergroup INT-0139 (RTOG 93-09, SWOG 93-36) Lobectomy Pneumonectomy Pathological N0 surrogate for better 5 yr OS Albain KS, The Lancet 2009

50 German GLCCG Stage IIIA-B NSCLC 524 patients Cisplatin+Etoposide 3 cycle Cisplatin+Etoposide 3 cycle RT 45Gy/30 F bid plus carboplatin Surgery surgery Postoperative RT Overall survival and Progression free survival: not difference Pneumonectomy after induction treatment increase mortality Thomas M, Lancet Oncol. 2008

51 Summary 3: Operable LA-NSCLC Trimodality Preoperative CCRT Lobectomy + node dissection Preoperative CMT Lobectomy + node dissection PORT Definitive CCRT

52 Inoperable LA-NSCLC

53 Concurrent CMT-RT VS Sequential CMT RT

54 RTOG 9410 Medically or surgically inoperable AJCC stage II, IIIA, or IIIB 595 pts Arm I 2 cycles of CDDP + VBL Arm II CMT-RT63 Gy, 2 Gy/F Arm III CMT-RT69.6 Gy, 1.2 Gy/f, bid RT 63 Gy, 2 Gy/F Median OS 17 mo 5 yr OS 16% Median OS 15.6 mo 5 yr OS 13% Median OS 14.6 mo 5 yr OS 10% Curran W et al. J Natl Cancer Inst. 2011

55 NSCLC Collaborative Group Meta-analysis: individual patients data of 6 trials (CALGB 8831, WJLCG, RTOG 9410, GMMA Ankara, GLOT-GFPC NPC 95-01, EORTC 08972) OS absolute benefit at 3-years of 5.7% (18% to 24%), 5-years 4.5% (11% to 15%) Auperin A, J Clin Oncol 2010

56 Concurrent CMT-RT + Induction CMT

57 Vokes EE, J Clin Oncol. 2007

58 CALGB B39801 Conclusion: addition of induction chemo added toxicity without survival benefit

59 RT alone

60 Very accelerated RT: shortening of the total duration > 50% Moderately accelerated RT: shortening of the total duration 15-50% Hyperfractionated RT with identical total dose Hyperfractionated RT with increased total dose.

61 absolute benefit of 2.5% (8.3% to 10.8%) at 5 years

62 Toxicity

63 Summary 4: Inoperable LA-NSCLC Definitive CCRT Sequential CMT RT RT alone: Conventional fraction, altered/hyperfractionation

64 Radiation Technique - Volume - Dose - Technique

65 Volume of RT Recommended Involve-field radiotherapy RCTs from Shangdong et al IFRT ENI RT dose Gy Gy Local control 51% 36% RP 17% 29% ENF 7% 4% MSKCC: evaluated 524 pts. Elective node failure (ENF) 6% Lung Cancer Aug;41(2):

66 Radiation dose Recommended dose: Gy RTOG 7301 (Conventional RT): randomly escalated dose 40, 50, 60 Gy Local control 52%, 62%, 73% Standard dose: 60 Gy Michigan escalated dose: RT alone with 3D-CRT/ IFRT 5-yr OS 4% (63-69 Gy), 22% (74-84 Gy), and 28% ( Gy). 5-yr LRC 12%, 35%, and 49% Int J Radiat Oncol Biol Phys. 1986;12(4):539.

67 Stage IIIA: 60% AdenoCA ~ SCC 58% 44%

68 Local failure and Distant metastasis

69 Treatment related death

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71 Lung Heart

72 G3 Radiation pneumonitis Local failure G3 RP IMRT 6.5% vs PSPT 10.5%

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74 Q & A