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

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

2 TREATMENT OF NON SMALL CELL LUNG CARCINOMA LOCALLY ADVANCED DISEASE (STAGES BULKY IIIA AND IIIB)

3 STAGE IIIB

4 STAGE IIIB. I. (T1a, N3, M0; T1b, N3, M0) * T1a, N3, 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); N3 (metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes; M0 * T1b, N3, M0: T1b = > 2-3 cm + as above

5 STAGE IIIB. II. (T2a, N3, M0; T2b, N3, M0) * T2a, N3, M0: T2a = > 3 cm but 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; N3 (metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes; M0 * T2b, N3, M0: T2b = > 5 cm as above

6 STAGE IIIB. III. (T3, N3, M0) * T3, N3, M0: T3 = > 7 cm or directly invading any of following: parietal pleura (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 nodule(s) in same lobe; N3 (metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes; M0

7 STAGE IIIB. IV. (T4, N2, M0; T4, N3, M0) * T4, N2, 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; N2 (metastasis to ipsilateral mediastinal and / or subcarinal lymph nodes(s); M0 * T4, N3, M0: T4 = as above; N3 (metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes; M0

8 STAGE IIIB (T2a - T2b; N3, M0; T3, N3, M0; T4, N2 - N3, M0)

9 STAGE IIIB NON - SMALL CELL LUNG CANCER * e.g., stage IIIb: T4, N2, M0: T4 (a) = any size invading any of following: mediastinum / heart (b), great vessels (c), vertebral body (d), diaphragm (e); trachea (f), recurrent laryngeal nerve, sternum / esophagus (g), carina or separate tumor nodule(s) in different ipsilateral lobe; N3 (metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes; M0

10 TREATMENT BY STAGE. XXXVI. Stage IIIB (Any T, N3, M0; T4, any N, M0). I. * Stage IIIB for N3 disease = pts with contralateral+ or bilateral+ mediastinal (N3) nodes or fixed nodes and bulky Stage IIIa disease (preoperatively obvious on CT scan: pathologically involved N2 nodes be confirmed histologically because enlarged nodes detected by CT negative for cancer in ~ 30% of pts) not candidates for conventional resection

11 TREATMENT BY STAGE. XXXVII Stage IIIB (Any T, N3, M0; T4, any N, M0). II. * chemotherapy plus radiation therapy = treatment of choice for pts with bulky stage IIIA or IIIB disease without pleural effusion (referred to as "dry IIIB ); - radiation therapy alone for pts medically unfit for combined modality therapy

12 TREATMENT BY STAGE. XXXVIII. Stage IIIB (T4, N0-1, M0). III. * exception to this approach = stage IIIB for T4, N0-1 disease = new surgical approaches making resection possible include chest wall resection (for direct extension of tumor) and tracheal sleeve pneumonectomy and sleeve lobectomy (for lesions near carina)

13 TREATMENT OF NON SMALL CELL CARCINOMA LOCALLY ADVANCED DISEASE COMBINED MODALITY THERAPY

14 TREATMENT BY STAGE. XXXIX. Stage IIIB (Any T, N3, M0; T4, any N, M0). IV. Combined modality therapy. I. * chemotherapy + radiation therapy = treatment of choice for pts with bulky stage IIIA or dry IIIB disease; - from randomized studies in median and long - term survival with chemotherapy followed by radiation therapy, compared with radiation therapy alone

15 TREATMENT BY STAGE. XXXX. Stage IIIB (Any T, N3, M0; T4, any N, M0). V. Combined modality therapy. III. Concomitant radio - chemotherapy based on platin compounds in pts with locally advanced NSCLC: a meta - analysis of individual data from 1764 pts Aupérin A et al Ann Oncol 17; 473, 2006 * overall, from meta - analysis, concomitant chemo (based on platin compounds) - radiotherapy (RT + CT) improves survival over radiotherapy alone (RT)

16 TREATMENT BY STAGE. XXXXI. Stage IIIB (Any T, N3, M0; T4, any N, M0). I. Combined modality therapy. VI. * concurrent chemotherapy and radiation therapy survival compared to sequential chemotherapy and radiation therapy (albeit with more side effects, e.g, fatigue, esophagitis and neutropenia)

17 TREATMENT BY STAGE. XXXXII. Stage IIIB (Any T, N3, M0; T4, any N, M0). II. Combined modality therapy. II. * meta - analysis (O'Rourke N et al Cochrane Database Syst Rev 2010) of concurrent (cisplatin - based regimens + once / d radiation therapy) vs sequential treatment (711 pts) significant benefit of concurrent over sequential treatment (p =.003); - all used cisplatin - based regimens and once - daily radiation therapy; - more acute G3-4 esophagitis with concurrent treatment compared to sequential treatment (p =.001) and similar G3-4 neutropenia similar in both arms; - more deaths (3% overall) in concurrent arm, without statistical significance (p =.2)

18 TREATMENT BY STAGE. XXXXIII. STAGE IIIB NSCLC. III. 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 (no. = 15) or IIIB (no. = 87) NSCLC randomized between concurrent (arm A) or sequential (arm B) CRT (cisplatin and vinorelbine + 60 Gy / 30 fractions for 6 wks)

19 TREATMENT BY STAGE. XXXXIIIbis. STAGE IIIB NSCLC. III. I. NEOADJUVANT CHEMO - RADIOTHERAPY Idem. II. Zatloukal P et al Lung Cancer 46; 87, 2004 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 significant benefits response rate, overall survival and time to progression over sequential CRT; - concurrent CRT schedule associated with higher toxicity (but adverse event profile acceptable in both arms)

20 TREATMENT BY STAGE. XXXXIV. Stage IIIB (Any T, N3, M0; T4, any N, M0). III. * frequently, additional 2-3 cycles of chemotherapy also given, but unclear whether additional cycles be administered before (as neoadjuvant, widely used for stage IIIA disease) or after chemoradiation, what optimal drugs, or whether doses be attenuated during radiation but given more frequently (lower doses of drugs "sensitizes tumor to radiation therapy but may not by themselves remove other microscopic disease)

21 TREATMENT BY STAGE. XXXXV. Stage IIIB (Any T, N3, M0; T4, any N, M0). IV. Combined modality therapy for locally advanced disease. VI. Neoadjuvant chemo - radiotherapy plus surgery * preoperative combined modality therapy surgical resection promising results (whether surgery adds benefit after chemo - radiotherapy not fully defined); - therapy given in non - investigational setting after risk / benefit ratio of using chemo - radiotherapy discussed appropriately with pt

22 TREATMENT BY STAGE. XXXXVI. Stage IIIB (Any T, N3, M0; T4, any N, M0). V. Combined modality therapy for locally advanced disease. VII. New chemotherapic agents * randomized clinical phase III trials still needed on usefulness of new agents effective against NSCLC [including taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and camptotecins (topotecan and irinotecan)] in both adjuvant and neoadjuvant settings

23 TREATMENT OF NON SMALL CELL LUNG CARCINOMA LOCALLY ADVANCED DISEASE RADIOTHERAPY

24 TREATMENT BY STAGE. XXXXVII. Radiotherapy with curative intent for locally advanced (stage IIIB) disease. I. - stage IIIB pts (T4 or N3, M0, as stages I - II - IIIA refusing surgery or poor candidates for medical reasons) high - dose radiation therapy with curative intent (decision based on extent of disease and volume of chest requiring irradiation); - not candidate for curative radiation pts with supraclavicular nodes+ or pleural effusion or cardiac involvement; * median survival for unresectable NSCLC localized to chest < 1 yr (6% alive at 5 yrs and possibly cured)

25 TREATMENT OF NON SMALL CELL LUNG CARCINOMA DISSEMINATED DISEASE

26 STAGE IV

27 STAGE IV NON - SMALL CELL LUNG CANCER * cancer has spread to another lobe of same lung, to other lung, and / or to one or more other parts of body

28 STAGE IV. (Any T, Any N, M1a; Any T, Any N, M1b) * Any T, Any N, M1a = separate tumor nodule(s) in contralateral lobe or tumor with pleural nodules or malignant pleural (or pericardial) effusion * Any T, Any N, M1b = distant metastasis

29 STAGE IV NON - SMALL CELL LUNG CANCER * Any T, Any N, M1a = separate tumor nodule(s) in a contralateral lobe or tumor with pleural nodules or malignant pleural (or pericardial) effusion Any T, Any N, M1b = distant metastasis

30 STAGE IV M1a NON - SMALL CELL LUNG CANCER

31 STAGE IV M1b NON - SMALL CELL LUNG CANCER

32 TREATMENT BY STAGE. I. Stage IV. Symptomatic management of metastatic disease * pts who present with or progress to metastatic NSCLC (as well as pts with pleural effusions) poor prognosis; - when untreated, median survival of these pt groups (often treated in same way) ~ 4-6 mos; * standard medical management, judicious use of pain medications, appropriate use of radiotherapy and of outpatient chemotherapy = cornerstone of management

33 TREATMENT BY STAGE. II. Stage IV. I. Overall options * external beam radiotherapy for palliative relief of local symptomatic tumor growth; - endobronchial laser therapy and / or brachytherapy for obstructing lesions - doublets of chemotherapy with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan and pemetrexed; - paclitaxel, carboplatin and bevacizumab for pts with nonsquamous histology, no brain metastases or no hemoptysis; - EGFR tyrosine kinase inhibitors in pts with EGFR mutations; - cisplatin, vinorelbine and cetuximab for pts with NSCLC expressing EGFR; - maintenance pemetrexed or erlotinib in pts with stable or responding disease following 4 cycles of (non - pemetrexed) platinum combination chemotherapy; * clinical trials evaluating role of new chemotherapy regimens and other systemic agents

34 TREATMENT BY STAGE. III. Stage IV. II. External beam radiotherapy. I. * primarily for palliative relief of local symptomatic tumor growth

35 TREATMENT BY STAGE. IV. Stage IV. III. External beam radiotherapy. II. * primarily for palliative relief of local symptomatic tumor growth; * usually, Gy over 2-4 wks to primary tumor for pts urgent with symptoms (e.g., bronchial obstruction with pneumonitis, hemoptysis or upper airway or superior vena cava obstruction); - frequencies of relief = hemoptysis, 84%; superior vena cava syndrome, 80%; dyspnea, 60%; cough, 60%; atelectasis, 23%, and vocal cord paralysis, 6%; * with closely followed pt, radiation deferred until symptoms, rather than given prophylactically as prevention

36 TREATMENT BY STAGE. V. Stage IV. IV. External beam radiotherapy. III. * cardiac tamponade (pericardiocentesis + radiation therapy to entire cardiac silhouette); * painful bony metastases (relief in 66% of pts), and - brachial plexus involvement

37 TREATMENT BY STAGE. VI. Stage IV. V. External beam radiotherapy. IV. * brain metastases (often isolated relapse in adenocarcinoma, otherwise controlled by surgery or radiotherapy) usually treated with radiation therapy and, in highly selected cases, with surgical resection; - no proven value for CT scan of brain or prophylactic cranial irradiation in NSCLC asymptomatic pts; - with proven brain or spinal cord compression radiotherapy + dexamethasone ( mg / day in 4 divided doses, rapidly tapered to lowest dosage which relieves neurologic symptoms)

38 TREATMENT BY STAGE. VII. Stage IV. VI. Pleural effusions * common and usually treated with thoracentesis; * if recurring and symptomatic, chest tube drainage with a sclerosing agent (doxyciclin and bleomicin by chest tube and talc via thorascopic insufflation); - in former case, chest cavity first completely drained xylocaine 1% instilled (15 ml), followed by 50 ml normal saline sclerosing agent dissolved in 100 ml normal saline (this solution injected through chest tube); - chest tube clamped for 4 hrs if tolerated, an pt rotated onto different sides to distribute sclerosing agent chest tube removed h later, after drainage becomes slight (usually < 100 ml / 24 h) - with sclerosing agents widely used, indwelling pleurex catheter equivalent to chest tube drainage and better tolerated by pts (pleurex catheter is tunneled under the and remains in place for wks and pt periodically drains catheter into specially designed bag)

39 TREATMENT BY STAGE. VIII. Stage IV. VII. VATS for pleural effusions - video - assisted thoracic surgery (VATS) via thoracoscopy used to drain and treat large malignant effusions (better tolerated by pt)

40 TREATMENT BY STAGE. IX. Stage IV. VIII. Recurring symptomatic endobronchial lesions * other possibilities: - brachytherapy; - photodynamic therapy (PDT, using a photosensitizing agent) and - endobronchial stents

41 TREATMENT BY STAGE. X. Stage IV. IX. Recurring symptomatic endobronchial lesions. Neodynium - YAG laser therapy * symptomatic endobronchial lesions recurring after surgery or radiotherapy or developing in pts with severely compromised pulmonary function difficult to treat with conventional therapy; * neodynium - YAG (yttrium - aluminum - garnet) laser therapy through flexible fiberoptic bronchoscope (general anesthesia) palliation in 80-90% of pts (even when tumor relapsed after radiotherapy)

42 TREATMENT BY STAGE. XI. Stage IV. X. Recurring symptomatic endobronchial lesions Brachytherapy * brachytherapy

43 TREATMENT BY STAGE. XII. Stage IV. XI. Recurring symptomatic endobronchial lesions. Photodynamic therapy (PDT). I. * photodynamic therapy (PDT) = with endoscopes and fiber optic catheters to deliver light and intravenously - administered photosensitizers photodynamic therapy

44 TREATMENT BY STAGE. XIII. Stage IV. XII. Recurring symptomatic endobronchial lesions. Photodynamic therapy (PDT). II. * PDT uses drug (called photosensitiser, e.g., Tookad, bacterio - chlorophyll derivative absorbing light at 763 nm) activated by light, usually from laser; - activated drug kills cells around light fibre, by producing Reactive Oxygen Species (ROS), powerful forms of oxygen which can either kill cells directly or attack blood vessels which supply cells; - in photochemical terms, photosensitiser energy levels (from ground low energy at higher energy state, when activated by laser light)

45 TREATMENT BY STAGE. XIV. Stage IV. XIII. Recurring symptomatic endobronchial lesions. Endobronchial stents * above) expandable metallic stent; - right) three - dimensional reconstruction of thoracic CT scan demonstrating tracheal stent (large white arrow), right mainstem stent (1), left mainstem stent (2) and bronchus intermedius stent (3)

46 TREATMENT BY STAGE. XV. Stage IV. XIV. Chemotherapy. I. * doublets of chemotherapy with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan and pemetrexed

47 TREATMENT BY STAGE. XVI. Stage IV. XV. Chemotherapy. II. * careful judgment to balance potential benefits and toxicity; - chemotherapy cost - effective palliation of symptoms, quality of life and survival in newly diagnosed pts, particularly in pts with good performance status; * combination chemotherapy: - objective response in ~ 20-30% of pts (complete in < 5%); - median survival = 8-10 mos (vs 4-6 mos with supportive care alone) and yr survival = 30-35% (vs 5-10% with supportive care alone) and 2 - year survival = 10-15%

48 TREATMENT BY STAGE. XVII. Stage IV. XVI. Chemotherapy. III. Indications of chemotherapy * reasonable if pt is ambulatory (improved antiemetics allows treatment be tolerable on outpt basis), did not receive prior CT, desires to be treated and is able to understand and accept risk / benefit ratio; - chemotherapy for previously untreated, good - PS pats typically consists of two drugs ("doublets"); - "doublets contain cisplatin or carboplatin + another drugs with proven activity, including taxanes (paclitaxel or docetaxel), gemcitabine, vinca alkaloid (e.g., vinorelbine) and pemetrexed; - no major # in outcome between standard chemotherapy doublets (although they # in terms of schedule, side effects and cost

49 TREATMENT BY STAGE. XVIII. Stage IV. XVII. Chemotherapy. IV. Outlines for chemotherapy * first - line chemotherapy typically administered for 4-6 cycles, with no benefit for continuing same chemotherapy beyond that point; - chemotherapy then usually stopped and pt observed closely for tumor progression (at which point second - line chemotherapy started if pt's performance status still good)

50 TREATMENT BY STAGE. XIX. Stage IV. XVIII. Chemotherapy. V. Outlines for chemotherapy * nausea with typical first - line regimens usually mild, particularly with 5 - HT3 serotonin antagonists used as antiemetics; - hair loss depends on choice of regimen and be discussed with pt; - all regimens cause myelosuppression (but low incidence of neutropenic fevers, bleeding episodes or anemia requiring transfusions, with growth - factor support rarely needed); * elderly pts without significant comorbid conditions benefit from and tolerate chemotherapy ~ as younger pts; - pts with poorer PS obtain less benefit; * all eligible pts encouraged to enter clinical studies designed to determine benefits and toxicities of new treatments

51 TREATMENT BY STAGE. XX. Stage IV. XIX. Chemotherapy. VI. Outlines for chemotherapy * docetaxel and pemetrexed = second - line agents for pts with progressive disease on first - line chemotherapy and still good performance PS; - docetaxel progression - free and overall survival compared to best supportive care (pemetrexed ~ same efficacy as docetaxel, with fewer side effects)

52 TREATMENT BY STAGE. XXI. Stage IV. XX. Chemotherapy. VII. Pemtrexed * pemetrexed = novel, "multitargeted" folate - directed antimetabolite = activity of several enzymes, including dihydrofolate reductase, thymidylate synthetase and glycinamide ribonucleotide formyltransferase affects synthesis of both purine and pyrimidine nucleic acid precursors of both RNA and DNA; - to avoid significant toxicity to normal tissues, pts receive low - dose folate and vitamin B12 supplementation; * activity against certain lung cancers and, in combination with cisplatin, also against mesotheliomas

53 Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first - line chemotherapy in advanced non - small - cell lung cancer Grønberg BH et al JCO 27; 3217, 2009 * Purpose: to compare pemetrexed / carboplatin with standard regimen as 1st line therapy in advanced NSCLC Pts and methods: pts with stage IIIB - IV NSCLC and performance status 0-2 randomly assigned to pemetrexed plus carboplatin or gemcitabine plus carboplatin; - primary end point = health - related quality of life (HRQoL) defined as global quality of life, nausea / vomiting, dyspnea, and fatigue (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and lung cancer - specific module LC13) during the first 20 weeks; - secondary end points = overall survival and toxicity

54 Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first - line chemotherapy in advanced non - small - cell lung cancer Grønberg BH et al JCO 27; 3217, 2009 * Results. I.: 436 pts enrolled (April, July 2006) pts completed baseline questionnaire and analyzed for HRQoL, with compliance of HRQoL questionnaires = 87% no significant differences for primary HRQoL

55 Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first - line chemotherapy in advanced non - small - cell lung cancer Grønberg BH et al JCO 27; 3217, 2009 * Results. II: 423 pts received 1 cycle of chemotherapy overall survival no # between two treatment arms (pemetrexed / carboplatin, PC, 7.3 mos; gemcitabine / carboplatin, GC, 7.0 months; p =.63) - (A) all pts; (B) pts with nonsquamous histology (adenocarcinoma and large - cell carcinoma); (C) females; (D) males; (E) pts with performance status of 0-1, and (F) pts with performance status of 2

56 Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first - line chemotherapy in advanced non - small - cell lung cancer Grønberg BH et al JCO 27; 3217, 2009 * Results. III: pts on gemcitabine / carboplatin more G3-4 hematologic toxicity than pts on pemetrexed / carboplatin, including leukopenia (46 vs 23%, respectively; p <.001), neutropenia (51 vs 40%, respectively; p =.024), and thrombocytopenia (56 vs 24%, respectively; p <.001).. - Conclusion: pemetrexed / carboplatin provides similar health - related quality of life (HRQoL) and survival when compared with gemcitabine / carboplatin with less hematologic toxicity and less need for supportive care

57 Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy - naive pts with advanced - stage non - small - cell lung cancer Scagliotti GV JCO 26: 3543, 2008 * Purpose: cisplatin plus gemcitabine = standard regimen for 1st - line treatment of advanced NSCLC, with phase II studies of pemetrexed plus platinum compounds show activity in this setting; - Pts and methods: noninferiority, phase III, randomized study compared overall survival between treatment arms in 1,725 chemotherapy - naive pts with stage IIIB - IV NSCLC and Eastern Cooperative Oncology Group performance status of pts received cisplatin and gemcitabine (no = 863) or cisplatin and pemetrexed (no. = 862) / 3 wks for up to six cycles

58 Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy - naive pts with advanced - stage non - small - cell lung cancer Scagliotti GV JCO 26: 3543, 2008 Results. I.: overall survival for cisplatin / pemetrexed noninferior to cisplatin / gemcitabine (median survival, 10.3 v 10.3 mos, respectively)

59 Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy - naive pts with advanced - stage non - small - cell lung cancer Scagliotti GV JCO 26: 3543, 2008 Results. II.: overall survival statistically superior for cisplatin / pemetrexed vs cisplatin / gemcitabine in adenocarcinoma (no. = 847; 12.6 v 10.9 months, respectively) and large - cell carcinoma (no. = 153; 10.4 vs 6.7 mos, respectively)

60 Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy - naive pts with advanced - stage non - small - cell lung cancer Scagliotti GV JCO 26: 3543, 2008 Results. III.: #, in pts with squamous cell histology, significant in survival with cisplatin / gemcitabine vs cisplatin / pemetrexed (no. = 473; 10.8 vs 9.4 months, respectively);

61 Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy - naive pts with advanced - stage non - small - cell lung cancer Scagliotti GV JCO 26: 3543, for cisplatin / pemetrexed, G 3-4 neutropenia, anemia and thrombocytopenia (p.001), febrile neutropenia (p =.002) and alopecia (p <.001) significantly lower, whereas G 3-4 nausea (p =. 004) more common Conclusion: in advanced NSCLC, cisplatin / pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin / gemcitabine in adeno - and large cell - carcinoma (first prospective phase III study showing survival # based on histologic type)

62 TREATMENT BY STAGE. XXII. Stage IV. XXI. Chemotherapy. VIII. Response by histology Comparison of pt outcomes according to histology among pemetrexed - treated pts with stage IIIB / IV non - small - cell lung cancer in two phase II trials Zinner RG et al Clinical Lung Cancer 11; 126, 2010 * in pts treated with pemetrexed / platinum doublets, nonsquamous histology associated with better outcome (consistent with results reported from previous studies)

63 TREATMENT BY STAGE. XXIII. Stage IV. XXII. Chemotherapy. VIII. * paclitaxel, carboplatin and bevacizumab for pts with nonsquamous histology, no brain metastases and no hemoptysis

64 TREATMENT BY STAGE. XXIV. Stage IV. XXIII. VEGF targeted therapy. I. * bevacizumab (MoAb to VEGF) response rate, progression - free and overall survival of pts with advanced disease when combined with chemotherapy (paclitaxel / carboplatin); - median 1 - and 2 - yr survival with chemotherapy + bevacizumab (15 mg / kg IV / 3 wks) = 12.3 mos, 51 and 23% vs, respectively, to 10.3 mos, 44%, and 15% with chemotherapy alone (hazard ratio 0.79, p =.003; 1 - yr survival > 50% and 2 - yr survival > 20% = significant improvement in long - term prognosis)

65 TREATMENT BY STAGE. XXV. Stage IV. XXIV VEGF targeted therapy. II. * bevacizumab side effects include bleeding, hypertension and proteinuria, with hemorrhagic side effects making this agent risky to use; - pts with squamous cancer do not receive bevacizumab because of their tendency toward serious hemorrhagic; - pts with brain metastases, hemoptysis, bleeding disorders or needing anticoagulation also not eligible to bevacizumab; - despite these restrictions and careful pt selection, significant bleeding in ~ 4% of pts

66 TREATMENT BY STAGE. XXVI. Stage IV. XXV EGFR targeted therapy. I. * EGFR tyrosine kinase inhibitors in pts with EGFR mutations; - cisplatin, vinorelbine and cetuximab for pts with NSCLC expressing EGFR

67 TREATMENT BY STAGE. XXVII. Stage IV. XXVI EGFR targeted therapy. II. * erlotinib (oral inhibitor of EGFR kinase) used in second - and third - line therapy of NSCLC; - clinical responses in large fraction of small subset of pts with tumors bearing mutations in EGFR; - prolonged survival with EGFR TKI treatment also in some pts with tumors bearing amplification of EGFR gene or overexpression of receptor = substantial clinical benefit for pts whose tumors respond to EGFR TKI therapy; * side effects of erlotinib include acneiform skin rash and diarrhea

68 TREATMENT BY STAGE. XXVIII. Stage IV. XXVII Maintenance therapy * maintenance with pemetrexed or erlotinib in pts with stable or responding disease following 4 cycles of (non - pemetrexed) platinum combination chemotherapy

69 Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non - small - cell lung cancer: a randomised, double - blind, phase III study. I. Ciuleanu T et al Lancet 374: 1432, 2009 BACKGROUND: from several studies efficacy, tolerability and ease of administration of pemetrexed (antifolate antineoplastic agent) in pts with advanced NSCLC assessing pemetrexed as maintenance therapy METHODS: randomised double - blind study (83 centres in 20 countries) including 663 pts with stage IIIB - IV disease not progressing on 4 cycles of platinum - based chemotherapy randomized (2 : 1 ratio) to pemetrexed plus best supportive care (no. = 441) or placebo plus best supportive care (no. = 222) in 21 - day cycles until disease progression (pts and investigators masked to treatment); - pts received vitamin B12, folic acid and dexamethasone; - primary endpoint = progression - free survival and secondary endpoint = overall survival (by intention to treat) (Clinical Trials.gov, no. NCT )

70 Idem. II Ciuleanu T et al Lancet 374: 1432, 2009 FINDINGS. I.: pemetrexed significantly progression - free survival (4.3 vs 2.6 mos p <.0001) and overall survival (13.4 vs 10.6 mos; p =.012) compared with placebo; (A) progression - free survival (PFS), as assessed by investigators (intention - to - treat population, 663 randomly assigned pts; (B) PFS from independent, central review of scans available (581 randomly assigned pts; (C) overall survival (intention - to - treat population, 663 randomly assigned pts) progression - free survival overall survival

71 progression - free survival Idem II Ciuleanu T et al Lancet 374: 1432, 2009 * progression - free survival (A) and overall survival (B) in non - squamous NSCLC overall survival

72 Idem. III. Ciuleanu T et al Lancet 374: 1432, 2009 FINDINGS. II.: treatment discontinuations higher in pemetrexed than in placebo group (5 vs 1%), due to drug - related G3 toxic effects INTERPRETATION: maintenance therapy with pemetrexed well tolerated, with progression - free and overall survival compared with placebo in pts with advanced NSCLC

73 TREATMENT BY STAGE. XXIX. Stage IV. XXVIII Clinical trials * clinical trials evaluating role of new chemotherapy regimens and other systemic agents