Corso Integrato di Clinica Medica ONCOLOGIA MEDICA AA LUNG CANCER. IV. THERAPY. I. NON SMALL CELL LUNG CANCER Prof.

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1 Corso Integrato di Clinica Medica ONCOLOGIA MEDICA AA LUNG CANCER. IV. THERAPY. I. NON SMALL CELL LUNG CANCER Prof. Alberto Riccardi

2 TREATMENT OF LUNG CARCINOMA * overall treatment approach to pts with LC formulated after: - histologic diagnosis, and - anatomic and physiologic staging; * pts encouraged to stop smoking (those who do fare better than those continuing to smoke)

3 SUMMARY OF TREATMENT APPROACH

4 NON SMALL CELL LUNG CARCINOMA Summary of treatment approach. I. Stages IA, IB, IIA, IIB and some IIIA * Stages IA, IB, IIA, and IIB surgical resection; - Stage IB: discussion of risk / benefits of adjuvant CT (not routinely given); - Stage II: adjuvant CT; - potential curative RT for "nonoperable" pts; * stage IIIA with "minimal N2 involvement (discovered at thoracotomy or mediastinoscopy) surgical resection with complete mediastinal lymph node dissection (also consideration of neoadjuvant CT) ; - postoperative RT for pts with N2 disease (if no neoadjuvant CT given)

5 NON SMALL CELL LUNG CARCINOMA Summary of treatment approach. II. Stage IIIA with selected types of stage T3 * tumors with chest wall invasion (T3) = en bloc resection of tumor with involved chest wall (± post - operative RT); - superior sulcus (Pancoast's, T3) tumors = preoperative RT (30-45 Gy) en bloc resection of involved lung and chest wall (± postoperative RT or intraoperative brachytherapy); * proximal airway involvement (< 2 cm from carina, T3) without mediastinal nodes = sleeve resection (preserving distal normal lung) or pneumonectomy

6 NON SMALL CELL LUNG CARCINOMA Summary of treatment approach. III. Stages IIIA "advanced, bulky, clinically evident N2" (discovered preoperatively) and IIIB disease includible in tolerable RT port * potential curative RT + CT (with reasonable good PS and general medical condition); - RT alone (if otherwise); * consider neoadjuvant CT and surgical resection for IIIA disease with advanced N2 involvement

7 NON SMALL CELL LUNG CARCINOMA Summary of treatment approach. IV. Stage IIIB with carinal invasion (T4) but no N2 involvement * consider pneumonectomy with tracheal sleeve resection with direct reanastomosis to contralateral mainstem bronchus

8 NON SMALL CELL LUNG CARCINOMA Summary of treatment approach. IV. Stage IIIB with carinal invasion (T4) but no N2 involvement * consider pneumonectomy with tracheal sleeve resection with direct reanastomosis to contralateral mainstem bronchus * carinal reconstruction with moderate amount of airway resected trachea anastomosed end to end with either right or left mainstem bronchus, with the contralateral bronchus reimplanted into side of trachea (upper right diagram = more commonly used technique)

9 NON SMALL CELL LUNG CARCINOMA Summary of treatment approach. V. More advanced stage IIIB and stage IV disease * RT to symptomatic local sites; * CT for ambulatory pts (consider CT, cetuximab and bevacizumab for selected pts); * chest tube drainage of large malignant pleural effusions; * consider resection of primary tumor and isolated brain or adrenal metastases

10 * limited stage (good performance status) = combination CT + chest RT; * extensive stage (good performance status) = combination CT; - complete responders (all stages): prophylactic cranial RT; * poor - performance - status pts (all stages): - modified - dose combination CT; - palliative RT SMALL CELL LUNG CARCINOMA Summary of treatment approach

11 LUNG CARCINOMA All pts * palliative radiotherapy for brain metastases, spinal cord compression, weight - bearing lytic bony lesions, symptomatic local lesions (nerve paralyses, obstructed airway, hemoptysis not responding to CT); * appropriate diagnosis and treatment of other medical problems and supportive care; * encouragement to stop smoking; * entrance into clinical trial

12 TREATMENT BY STAGE OF NON SMALL CELL LUNG CARCINOMA

13 TREATMENT BY STAGE OF NON SMALL CELL LUNG CARCINOMA LOCALIZED OR LOCALLY ADVANCED DISEASE (STAGES I, II and nonbulky IIIA)

14 STAGES I - II

15 STAGE I

16 STAGE I (T1a - b, N0, M0) * T1 = 3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than lobar bronchus (i.e., not in main bronchus): - T1a = 2 cm in greatest dimension; - T1b = > 2-3 cm in greatest dimension

17 STAGE I NON - SMALL CELL LUNG CANCER * stage IA = T 2 cm surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than lobar bronchus (i.e., not in main bronchus); N0; M0; * stage IB = - T > 2-3 cm + as for stage IA

18 STAGE II

19 STAGE IIA. I. T1a - T1b, N1, M0 * T1a, N1, M0 : T1a = < 2 cm, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than lobar bronchus (i.e., not in main bronchus); N1 (metastasis to ipsilateral peribronchial and / or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of primary tumor); M0 * T1b, N1, M0: T1b = > 2-3 cm + as above; N1; M0

20 STAGE IIA. II. (T2a, N1, M0; T2b, N0, M0) * T2a, N1, M0: T2a = > 3-5 cm or with any of following features: involves main bronchus 2 cm distal to carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis extended to hilar region but not involving entire lung; N1 (metastasis to ipsilateral peribronchial and / or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of primary tumor); M0 * T2b, N0, M0: T2b = > 5-7 cm + as above; N0; M0

21 STAGE IIA (T1a - T1b, N1, M0; T2a, N1, M0; T2b, N0, M0)

22 STAGE IIB (T2b, N1, M0; T3, N0, M0) * T2b, N1, M0: T2b = > 5-7 cm or with any of following: involves main bronchus; 2 cm distal to carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis not involving entire lung; N1 (metastasis to ipsilateral peribronchial and / or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of primary tumor); M0 * T3, N0, M0: T3 = > 7 cm or directly invading any of following: parietal pleural (PL3), chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura or parietal pericardium; tumor in main bronchus (< 2 cm from carina but without involvement of carina); associated atelectasis or obstructive pneumonitis of entire lung or separate tumor nodules in same lobe; N0; M0

23 STAGE IIB (T2b, N1, M0; T3, N0, M0)

24 STAGE II NON - SMALL CELL LUNG CANCER *e.g., stage IIA = T1b, N1, M0: T1b = > 2-3 cm; N1 (metastasis to ipsilateral peribronchial and / or ipsilateral hilar lymph nodes); M0); * e.g., stage IIB = T3, N0, M0: T3 = > 7 cm or directly invading any of following: parietal pleural / chest wall (a), diaphragm (b), phrenic nerve, mediastinal pleura (c) or parietal pericardium (d); tumor in main bronchus (< 2 cm from carina but without involvement of carina) (e); associated atelectasis or obstructive pneumonitis of entire lung or separate tumor nodules in same lobe; N0; M0

25 TREATMENT BY STAGE STAGES I - II NSCLC. I. Surgery * pulmonary resection (pneunomectomy, lobectomy or segmental, wedge or sleeve resection) = treatment of choice for pts who can tolerate operation; - with complete resection possible, 5 - yr survival for N0 disease ~ 60-80% (depending on size of tumor) and ~ 50% for N1 disease (hilar node involvement); * adjuvant chemotherapy after curative surgery for Stage II disease; - clinical trials of radiation therapy after curative surgery for Stage II disease

26 TREATMENT BY STAGE STAGES I - II NSCLC. II. Surgery * extent of resection = surgical judgment based on findings at exploration; - in general, conservative resection encompassing all known tumor survival = that obtained with more extensive procedures; - lobectomy preferred to pneumonectomy [and to wedge resections and segmentectomies ( rate of local relapse)]

27 TREATMENT BY STAGE STAGES I - II NSCLC. III. Surgery * pneumonectomy reserved for pts with tumors involving multiple lobes (T3A) or very central tumors and only be performed in pts with excellent pulmonary reserve; - in addition, pts undergoing right - sided pneumonectomy after induction chemotherapy and radiation therapy high mortality rate = be carefully selected before surgery; - wedge resection and segmentectomy (potentially by video assisted thoracic surgery, VATS) reserved for pts with poor pulmonary reserve and small peripheral lesions

28 RIGHT PNEUMONECTOMY

29 RIGHT PNEUMONECTOMY

30 RIGHT LOBECTOMY

31 TREATMENT BY STAGE STAGES I - II NSCLC. IV. Surgery Lobectomy vs limited resection * in local recurrence for pts treated with lobectomy compared with pts treated with limited excision but no significant difference in overall survival (Ginsberg RJ & Rubinstein LV Ann Thorac Surg 95)

32 TREATMENT BY STAGE STAGES I - II NSCLC. V. Surgery Surgery for localized disease (stages I - IIIa) * from Cochrane Collaboration group review, including 11 randomized trials of pts who underwent surgical interventions for early stage (I - IIIA) NSCLC, 4 - yr survival superior in pts with resectable stage I - IIIA who underwent resection and Complete ipsilateral Mediastinal Lymph Node Dissection (CMLND) compared with those who underwent resection and lymph node sampling (3 hilar + 3 mediastinal nodes) (p =.005) * disease - free survival with lymph node sampling vs systematic sampling (CMLND) (Gajra A et al JCO 21; 1029, 2003)

33 WEDGE RESECTION OF LUNG CANCER * part of lung lobe containing cancer and small amount of healthy tissue around removed

34 WEDGE RESECTION OF LUNG CANCER * wedge resections and segmentectomies, potentially by VATS (Video - Assisted Thoracic Surgery via thoracoscopy, not usually used for curative LC resection) for pts with poor pulmonary reserve and small peripheral lesions

35 VIDEO - ASSISTED THORACIC SURGERY - video - assisted thoracic surgery (VATS) via thoracoscopy not usually used for curative lung cancer resection, but useful for peripheral lung nodules in pts with stage I disease and poor lung function; - VATS advocated to postoperative impairment of lung function, pain, length of hospital stay and recovery time (but randomized, controlled trials not confirm advantages) open thoracotomy still preferred surgical approach to curative resection of lung cancer

36 VIDEO - ASSISTED THORACIC SURGERY * for peripheral lung nodules in pts with stage I disease and poor lung function

37 VIDEO - ASSISTED THORACIC SURGERY * also used for diagnostic purposes to examine pleural surface and cavity and biopsy peripheral lung nodules or accessible mediastinal nodes (and to drain and treat large malignant effusions)

38 OVERALL OUTCOME OF SURGERY IN NSCLC. I. (STAGES I, II and nonbulky IIIA) * overall, complete pulmonary resection = treatment of choice in pts with: - stages IA, IB, IIA and IIB (T1-2, N0-1) disease; - stage IIIA (T3, N0-1 + T1-3, N2) with favorable age, cardiopulmonary function and anatomy (from team approach, involving pulmonary medicine, thoracic surgery, medical and radiation oncology); [- neoadjuvant chemotherapy ± radiotherapy shrinks local tumor and treats micrometastases surgical resection safer and more effective in selected pts ]

39 OVERALL OUTCOME OF SURGERY IN NSCLC. II. (STAGES I, II and nonbulky IIIA) * 43% (43 / 100) of pts with NSCLC undergo thoracotomy: - 76% (= 33 / 43 pts): curative resection ; - 12%: explored only for disease extent, and - 12%: palliative procedure with known disease left behind; * 30 - day hospital mortality = 3 and 6% for lobectomy and pneumonectomy, respectively

40 OVERALL OUTCOME OF SURGERY IN NSCLC. III. (STAGES I, II and nonbulky IIIA) * overall, ~ 30% of pts (~ 10 / 33 pts) treated with curative resection survive 5 yrs [~ 15% (5 pts) survive for 10 yrs]; - most pts ultimately die of metastatic disease (usually within 5 yrs from surgery)

41 OVERALL OUTCOME OF SURGERY IN NSCLC. IV. (STAGES I, II and nonbulky IIIA) * for stage IIIA, 5 - yr survival for N1 and N2 disease = ~ 50% and 20%, respectively; * however, technically resectable only 20% of pts with N2 disease (most pts discovered with N2 disease at thoracotomy)

42 TREATMENT BY STAGE STAGES I - II NSCLC. VI. Radiotherapy with curative intent * pts with stage I or II disease refusing surgery or not candidates for pulmonary resection considered for radiation therapy with curative intent (based on extent of disease and volume of chest requiring irradiation); * pts with malignant pleural effusion or cardiac involvement not candidates for curative radiation treatment; - long - term survival for pts with all stages of LC who receive radiation with curative intent ~ 20%

43 TREATMENT BY STAGE STAGES I - II NSCLC. VII. Radiotherapy with curative intent * usually midplane doses of mgy ( rad, either split course or continuous fraction radiotherapy); - major concern: amount of lung parenchyma and other thoracic organs (spinal cord, heart and esophagus) included in treatment plan; * deleterious effects of radiation on pulmonary function often hampers treatment in pts with major underlying pulmonary disease

44 TREATMENT BY STAGE STAGES I - II NSCLC. VIII. Radiotherapy with curative intent: side effects Esophagitis * most common side effect of curative thoracic radiation = acute radiation esophagitis during treatment, usually self - limited

45 TREATMENT BY STAGE STAGES I - II NSCLC. IX. Radiotherapy with curative intent: side effects * other side effects include fatigue, radiation myelitis (spinal cord injury may be permanent, but usually avoided by careful treatment planning) and radiation pneumonitis (sometimes progressing to pulmonary fibrosis)

46 TREATMENT BY STAGE STAGES I - II NSCLC. X. Radiotherapy with curative intent: side effects Radiation pneumonitis * risk proportional to dose of radiation and volume of lung within radiation field; - full clinical syndrome (dyspnea, fever, and radiographic infiltrate corresponding to treatment port) in 5% of cases and treated with glucocorticoids

47 RADIATION PNEUMONITIS

48 RADIATION PNEUMONITIS * CT findings: a) homogeneous slight increase in attenuation (2-4 mos after therapy); b) patchy consolidation (1-12 mos after therapy); c) non - uniform discrete consolidation (most common; 3 mos to 10 yrs after therapy)

49 TREATMENT BY STAGE STAGES I - II NSCLC. XI. Radiotherapy with curative intent * Continuous Hyperfractionated, Accelerated RT (CHART) = delivery of 36 treatments of 1.5 Gy 3 times / day for 12 consecutive days (total dose of 54 Gy); yr survival rate > 20-30% (with more esophagites); * brachytherapy (local radiotherapy delivered by placing radioactive "seeds" in catheter into tumor bed) delivers local dose with sparing surrounding normal tissue

50 TREATMENT BY STAGE STAGES I - II NSCLC. XII. Radiotherapy with curative intent * beside potentially curative, radiotherapy may control primary tumor and preventing symptoms related to local spreading and increase quality and length of life of non - cured pts

51 TREATMENT BY STAGE STAGES I - II NSCLC. XIII. * pts with resected stage IA NSCLC receive no other therapy but are at high risk of recurrence (~ 2-3% / yr) or developing second primary lung cancer follow these pts with CT scans for first 5 yrs and consider entering onto early detection and chemoprevention studies

52 TREATMENT BY STAGE STAGES I - II NSCLC. XIV. Adjuvant chemotherapy. I. * meta - analysis of > 4300 pts trend toward survival of ~ 5% at 5 yrs with cisplatin - based adjuvant therapy (p =.08); - however, from 3 subsequent randomized studies no significant survival advantage despite addition of more "modern" postoperative adjuvant chemotherapy regimens; - still however, since then at least 5 additional randomized trials and two meta - analyses survival benefit in response to postoperative adjuvant - based therapy adjuvant chemotherapy now routinely recommended in NSCLC pts with good performance status and stage IIA - B disease (though with modest beneficial effects)

53 Randomized studies of adjuvant chemotherapy in NSCLC Study Treatment No. of pts 5-Year Survival (%) ECOG 3590 (II IIIA) Surgery RT vs. Surgery + post- op concurrent RT + cis / etoposide % 33% Median Survival 39 mos vs. 38 mos p Value 0.56 ALPI (I IIIA) Surgery alone vs. Surgery + post- op mitomycin / vindesine / cisplatin % 43% NR 0.59 Big Lung Trial (I IIIB) Surgery alone vs. Surgery + post- op chemotherapy a NR 33 mos 34 mos 0.90 IALT (IB IIIA) Surgery alone vs. Surgery + post- op Cis + VP16 / vinca % 44.5% NR < 0.03 UFT (IA IB) Surgery alone vs. Surgery + post- op UFT % 88% NR 0.04 CALGB IB (ASCO 06) Surgery alone vs. Surgery + post- op carbo / paclitaxel % 59% 78 mos 95 mos 0.10 NCI-C (IB II) Surgery alone vs. Surgery + post- op Cis / vinorelbine % 69% 73 mos 94 mos 0.04 ANITA (IB, - IIIA) Surgery alone vs. Surgery + post- op Cis / vinorelbine % 51% 44 mos 66 mos 0.017

54 TREATMENT BY STAGE STAGES I - II NSCLC. XV. Adjuvant chemotherapy. II. * role of adjuvant chemotherapy for stage IB disease undefined; - subset analysis of randomized studies no benefit in pts with stage IB; - one trial focusing on IB disease and using carboplatin and paclitaxel (one of most commonly used regimens for advanced disease) 20% in death (ns) pts with stage IB (T1b N0, M0) NSCLC not routinely given adjuvant therapy

55 Adjuvant chemotherapy Postoperative UFT (uracil - tegafur) in stage I adenocarcinoma Nakagawa M et al Ann Oncol 16; 75, 2005 * post - operative UFT does not significantly survival of pathological stage I NSCLC [UFT survival of pt1 pts (T1a - b, N0, M0, p =.036), but not of pt2 pts]

56 Adjuvant chemotherapy. IIter. Postoperative UFT (uracil - tegafur) in stage I adenocarcinoma * 999 pts with completely resected T1-2 N0M0 adenocarcinoma randomized ( ) between oral UFT for 2 yrs and no CT; yr OS in UFT with respect to control - arm due to greatly OS of pts with T2 disease (T2, N0, M0) in UFT arm (84.9 vs 73.5%) (p =.005) (no # among pts with T1 disease) Kato H et al NEJM 2004

57 TREATMENT BY STAGE STAGES I - II NSCLC. XVI. Neodjuvant chemotherapy * no evidence of # in overall survival with neo - adjuvant chemotherapy

58 TREATMENT BY STAGE. STAGE I - IIIA NSCLC. XVIbis. NEOADJUVANT CHEMOTHERAPY Preoperative chemotherapy in pts with resectable NSCLC: results of the MRC LU22 / NVALT 2 / EORTC multicentre randomised trial and update of systematic review (International Standard Randomised Controlled Trial, no. ISRCTN ). I. Gilligan D et al Lancet 2007; 369: 1929 Background: although surgery is best chance of cure for pts with NSCLC, overall 5 - yr survival modest improvements; - in 1990s, from small trials reporting striking results with neo - adjuvant chemotherapy randomised trial designed to investigate whether, in pts with operable NSCLC of any stage, outcomes be by platinum - based chemotherapy before surgery Methods: pts randomised to surgery alone (S) or 3 cycles of platinum - based chemotherapy surgery (CT - S); - primary outcome = overall survival, analysed on an intention - to - treat basis

59 idem. II. Gilligan D et al Lancet 2007; 369: 1929 Results. I.: 519 pts randomised (S: 261, CT - S: 258) from 70 centres in UK, Netherlands, Germany and Belgium (61% = clinical stage I, 31% = stage II and 7% = stage III); - neo - adjuvant chemotherapy feasible (75% of pts had all 3 cycles of chemotherapy), resulted in good response rate (49%) and downstaging in 31% of pts and did not alter type or completeness of surgery (lobectomy: S : 56%, CT - S: 60%, complete resection: S: 80%, CT - S: 82%), with post - operative complications not in CT - S group and no impairment of quality of life

60 idem. III. Gilligan D et al Lancet 2007; 369: Results. II.: however, no benefit in overall survival (p =.86) - Interpretation: no evidence of # in overall survival with neo - adjuvant chemotherapy

61 TREATMENT BY STAGE STAGES I - II NSCLC. XVII. Adjuvant radiotherapy * after apparent complete resection, postoperative adjuvant radiation therapy not survival (and actually detrimental to survival in N0 and N1 disease)

62 TREATMENT BY STAGE. XVIII. Superior sulcus or Pancoast tumors. I. * NSCLC of superior pulmonary sulcus (producing Pancoast's syndrome) behave # than LC at other sites and usually treated with combined radiotherapy and surgery

63 TREATMENT BY STAGE. XIX. Superior sulcus or Pancoast tumors. II. * usual preoperative staging procedures (including mediastinoscopy and CT and PET scans) for tumor extent and neurologic examination (and sometimes nerve conduction studies) to document involvement or impingement of nerves in region; - with mediastinoscopy negative curative approaches be used in treating Pancoast's syndrome despite its apparent locally invasive nature

64 TREATMENT BY STAGE. XX. Superior sulcus or Pancoast tumors. III. * best results with employing concurrent preoperative irradiation [30 Gy in 10 treatments] and cisplatin and etoposide en bloc resection of tumor and involved chest wall 3-6 wks later (65% of thoracotomy specimens complete response or minimal residual microscopic disease on pathologic evaluation); yr survival = 55% for all eligible pts and = 70% for pts with complete resection

65 TREATMENT BY STAGE. XXI. Superior sulcus or Pancoast tumors. IV. * as alternatives (as needed from pt conditions): - radiation therapy alone; - surgery alone (selected cases); - clinical trials of combined modality therapy

66 TREATMENT BY STAGE. XXII. NSCLC with T3, N0 Disease (Stage IIB) * subset of T3, N0 disease not presenting as Pancoast tumor (initially considered stage III disease, but with # natural history and treatment strategy than stage III N2 disease) now considered as stage IIB; - pts with peripheral chest wall invasion resection of involved ribs and underlying lung (chest wall defects then repaired with chest wall musculature or Marlex mesh and methylmethacrylate); yr survival = 35-50% (adjuvant chemotherapy usually recommended)

67 STAGE III

68 TREATMENT BY STAGE. XXIII. STAGE III NSCLC. I. * treatment of still locally advanced NSCLC (with involvement of mediastinal lymph nodes, N2 - N3) = one of most controversial issues in management of LC; - treatment options include local therapy (surgery or radiation therapy) combined with systemic chemotherapy to control micrometastases

69 TREATMENT BY STAGE. XXIV. STAGE III NSCLC. II. * interpretation of results clouded by a no. of issues, including changing diagnostic techniques, variation of staging systems and # pt populations, with tumors ranging from nonbulky stage IIIA (clinical N1 nodes, with N2 nodes discovered only at time of surgery, despite negative mediastinoscopy) to bulky N2 stage IIIA (enlarged adenopathy clearly visible on chest x - rays or multiple nodal level involvement) to clearly inoperable stage IIIB disease team approach involving pulmonary medicine, thoracic surgery and medical and radiation oncology essential for management of these pts

70 STAGE IIIA

71 STAGE IIIA. I. (T1a, N2, M0; T1b, N2, M0) * T1a, N2, M0: T1a = < 2 cm, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in main bronchus); N2 (metastasis to ipsilateral mediastinal and / or subcarinal lymph nodes); M0 * T1b, N2, M0: T1b = > 2-3 cm + as above; N2; M0

72 STAGE IIIA. II. T3, N1, M0; T3, N2, M0 * T3, N1, M0: T3 = > 7 cm or directly invading any of following: parietal pleural (PL3), chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura or parietal pericardium; tumor in main bronchus < cm from carina but without involvement of carina); associated atelectasis or obstructive pneumonitis of entire lung or separate tumor nodule(s) in same lobe; N1 (metastasis to ipsilateral peribronchial and / or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of primary tumor); M0 * T3, N2, M0: T3 = as above; N2 (metastasis to ipsilateral mediastinal and / or subcarinal lymph nodes(s); M0

73 STAGE IIIA. IV. (T4, N0, M0; T4, N1, M0) * T4, N0, M0: T4 = any size invading any of following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina or separate tumor nodule(s) in different ipsilateral lobe; N0; M0 * T4, N1, M0: T4 = as above; N1 (metastasis to ipsilateral peribronchial and / or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of primary tumor); M0

74 STAGE IIIA (T1a - T1b, N2, M0; T3, N1 - N2 M0; T4, N0 - N1, M0)

75 STAGE IIIA NON - SMALL CELL LUNG CANCER * e.g., Stage III A: T3, N1, M0: T3 = > 7 cm or directly invading any of following: tumor in main bronchus (< 2 cm from carina but without involvement of carina) (a); parietal pleura / chest wall (b); diaphragm (c); mediastinal pleura or parietal pericardium (e); phrenic nerve; associated atelectasis or obstructive pneumonitis of entire lung or separate tumor nodule(s) in same lobe; N1 (metastasis to ipsilateral peribronchial and / or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of primary tumor); M0

76 TREATMENT BY STAGE. XXV. STAGE IIIA NSCLC. I. Options * options: - resection postoperative radiation + chemotherapy for N2 disease; - neoadjuvant chemotherapy resection, or - neoadjuvant chemo - radiotherapy resection

77 TREATMENT BY STAGE. XXVI. Stage IIIA (N2 disease) NSCLC. II. Surgery * surgery for Stage IIIA (N2 disease) controversial; - for pts with N2 disease with "minimal disease" (involvement of only 1 node with microscopic foci, usually discovered at thoracotomy or mediastinoscopy) and? for more common pts with "advanced bulky disease (preoperatively obvious on CT scan); [- pts with incidental finding of N2 disease at time of resection need adjuvant chemotherapy]

78 TREATMENT BY STAGE. XXVII. STAGE II - IIIA NSCLC. III. ADJUVANT CHEMOTHERAPY * overall, possible, modest survival with adjuvant chemotherapy after apparently complete resection

79 TREATMENT BY STAGE. XXVIII. STAGE I - IIIA NSCLC. IV. ADJUVANT THERAPY Cisplatin - based adjuvant CT in resected stage I - IIIA LC * 1867 radically operated pts (36% stage I, 25% stage II, 39% stage IIIA) randomized between receiving or not receiving adjuvant cisplatin - based CT; and 5 - yr disease - free survival = 61 and 39% in CT arm vs 55 and 34% in control arm, respectively (p<. 003); and 5 - yr survival = 70 and 45% in CT arm vs 67 and 40% in control arm, respectively (p <.03); - benefits more evident in stage III disease 2004

80 TREATMENT BY STAGE. XXIX. STAGE I - IIIA NSCLC. V. ADJUVANT THERAPY Cisplatin - based adjuvant CT in resected stage I - IIIA LC Pignon JP et al JCO 28; 3552, 2008 * from meta - analysis (5 large trials, 4,584 pts) on cisplatin - based chemotherapy in pts with completely resected NSCLC (stages IA = 8%, IB = 30%; II = 35%; IIIA = 27%) 5 - yr absolute benefit = 5.4%, mainly in stage IIIA pts

81 Postoperative radio ± chemotherapy (cisplatin + etoposide) in resected stage II - IIIA NSCLC Keller S et al (for Eastern Cooperative Oncology Group) NEJM 343, 1217, 2000

82 TREATMENT BY STAGE. XXX. STAGE IIIA NSCLC. III. NEOADJUVANT CHEMO RADIOTHERAPY * no clear evidence suggests survival in pts with "bulky" multilevel ipsilateral mediastinal nodes (N2) with surgery and either pre - or post - operative chemotherapy compared with chemotherapy plus radiation therapy

83 NEOADJUVANT CHEMOTHERAPY IN STAGES IB - IIIA * randomized trial of neoadjuvant CT (mitomycin, ifosfamide and cisplatin) vs surgery alone in 355 pts with stages IB (37%) - II (16%) - IIIA (47%) NSCLC; - responders received two postoperative cycles (and pt3 or pn2 pts RT too); * at a median follow up of 80 mos, benefit of neoadjuvant therapy confined to pts with N0 - N1 disease A = PCT = primary CT + surgery B = PRS = surgery alone p ns p =.02 Depierre A et al JCO 2002

84 TREATMENT BY STAGE. XXXI. STAGE IIIA NSCLC. IV. NEOADJUVANT CHEMO - RADIOTHERAPY Improved results of induction chemoradiation before surgical intervention for selected pts with stage IIIA - N2 NSCLC Karl L et al J Thorac Cardiovasc Surg 134; 188, 2007 * Objective: optimal management of stage IIIA - N2 NSCLC controversial chemoradiation before surgical intervention for selected pts with stage IIIA - N2 NSCLC results after 7 yrs of reported Methods: retrospective study of 40 pts (25% T1, 62.5% T2, 7.5% T3, and 5% T4) with biopsy - proved T1-3 N2 M0 lung cancer and good performance status who underwent concurrent induction chemoradiation (radiation therapy + 2 cycles of cisplatin and etoposide) lung resection 2 further cycles of consolidation chemotherapy

85 TREATMENT BY STAGE. XXXIbis. STAGE IIIA NSCLC. IVbis. NEOADJUVANT CHEMO - RADIOTHERAPY Improved results of induction chemoradiation before surgical intervention for selected pts with stage IIIA - N2 NSCLC Karl L et al J Thorac Cardiovasc Surg 134; 188, 2007 * Results: overall and disease - free median survivals = 40 and 37.1 mos, respectively (overall and disease - free 3 - yr survivals = 51.7% and 52.3%, respectively) - trend for overall survival in pts with single node at mediastinoscopy; Conclusion: chemoradiation before pulmonary resection in carefully selected pts with surgically resectable stage IIIA (N2) NSCLC can lead to overall survival

86 TREATMENT BY STAGE. XXXII. STAGE IIIA NSCLC. V. NEOADJUVANT CHEMO - RADIOTHERAPY Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced NSCLC: a randomized study. I. Zatloukal P et al Lung Cancer 46; 87, 2004 * Purpose: relative merits of concurrent chemoradiotherapy (CRT) schedule vs sequential administration unclear; - Pts and methods: 102 previously untreated pts with locally advanced, stage IIIA (n = 15) or IIIB (n = 87) NSCLC randomized between concurrent (arm A) or sequential (arm B) CRT (cisplatin and vinorelbine + 60 Gy / 30 fractions for 6 wks)

87 TREATMENT BY STAGE. XXXIIbis STAGE IIIA NSCLC. Vbis. NEOADJUVANT CHEMO - RADIOTHERAPY Idem. II. Zatloukal P et al Lung Cancer 46; 87, Results: overall survival significantly longer in arm A vs B (median survival = 11.9 vs 8.5 mos) (p =.024), as well as time to progression (TTP) (16.6 vs 12.9 mos) and overall RR (80 vs 47%, p = 0.001); - WHO G3-4 toxicity (leucopenia and nausea / vomiting) more frequent in arm A than in B; - Conclusion: concurrent CRT significantly benefits for response rate, overall survival and time to progression over sequential CRT; - concurrent CRT associated with higher toxicity

88 TREATMENT BY STAGE. XXXIII. STAGE IIIA NSCLC. VI. NEOADJUVANT CHEMO - RADIOTHERAPY Radiotherapy plus chemotherapy ± surgical resection for stage III NSCLC: a phase III randomised controlled trial. I. Albain KS et al Lancet 374; 379, 2009 * Background: phase II studies in pts with stage IIIA NSCLC with ipsilateral mediastinal nodal metastases (N2) feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival phase III trial comparing concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection - Methods: pts with stage T1-3pN2 M0 NSCLC randomly assigned to concurrent induction chemotherapy (2 cycles of cisplatin and etoposide + radiotherapy; - with no progression, pts in group 1 resection and pts in group 2 continued radiotherapy ; - 2 additional cycles of cisplatin and etoposide given in both groups; - primary endpoint = overall survival (OS), on intention to treat (ClinicalTrials.gov, no. NCT )

89 Idem. II Albain KS et al Lancet 374; 379, 2009 * Findings: 202 pts (median age = 59 yrs) assigned to group 1 and 194 (median age = 61 yrs) to group 2; - median OS (below) = 23,6 vs 22,2 mos in groups 1 and 2 (p =.24), with pts alive at 5 yrs = 37 and 24% in group 1 and 2, respectively (p =.10); - with N0 status at thoracotomy, median OS = 34,4 mos; - progression - free survival (PFS) (above) better in group 1 (resection) than in 2 (continue radiotherapy) (median = 12,8 vs 10,5 mos; p =.017, with pts without disease progression at 5 yrs = 32 vs 13 %, respectively)

90 Idem. III. Albain KS et al Lancet 374; 379, G3-4 neutropenia and oesophagitis greater in group A than in B (38 and 10% and 41 and 23%, respectively, with treatment related deaths = 8 and 2%, respectively); - OS for pts on lobectomy, but not pneumonectomy, vs chemotherapy plus radiotherapy * Interpretation: chemotherapy + radiotherapy ± resection (preferably lobectomy: be considered, since treatment - related mortality greater in surgery arm (8 vs. 2%), with majority of deaths in pts undergoing pneumonectomy) options for pts with stage IIIA (N2) NSCLC

91 TREATMENT BY STAGE. XXXIV. STAGE IIIA NSCLC. VI. Bulky IIIA. I. * pts with persistent histologic N2 disease following neoadjuvant chemotherapy do particularly poorly, with some oncologists concluding that surgery for bulky IIIA disease be conducted only in pts with clearing of mediastinal nodes following neoadjuvant therapy; - main role of neoadjuvant chemotherapy = to control micrometastatic disease; - if macroscopically mediastinal disease still evident = disease not sensitive to chemotherapy unlikely that microscopic disease will be controlled surgical removal of primary tumor after chemotherapy probably fruitless; [- likewise, neoadjuvant chemotherapy generally not be used to render inoperable disease operable]

92 TREATMENT BY STAGE. XXV. STAGE IIIA NSCLC. IV. Bulky IIIA. II. * exception to this approach = T4, N0 or T4, N1 (stage IIIB) disease for which preoperative chemotherapy provides enough tumor debulking to allow otherwise unresectable disease to be resected (chemotherapy may allow chest wall resection for direct extension of tumor, tracheal sleeve pneumonectomy and sleeve lobectomy for lesions near carina)