How To Know If You Have Small Cell Lung Cancer

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1 Lung cancer

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3 Lung cancer

4 TABLE MALIGNANT PULMONARY NEOPLASMS INCIDENCE (%) Common 99 Non small cell lung cancer ~75 Adenocarcinoma ~35 Squamous cell carcinoma ~30 Large cell carcinoma ~10 Small cell lung cancer ~20 Carcinoids ~5 Rare <1 Lymphoma, carcinosarcoma, mucoepidermoid carcinoma, malignant fibrous histiocytoma, melanoma, sarcoma, blastoma University of Milano

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6 TABLE CHARACTERISTIC CHROMOSOMAL DELETIONS COMMON IN LUNG CANCER CHROMOSOMAL REGION DELETED 3p14-25 Unknown, probably multiple,?fhit 5q 9p21 13q14 17p13?APC, MCC TUMOR SUPPRESSOR GENES INACTIVATED CDKN2A, CDKN2B, possibly others Rb (~100% SCLC, ~20% NSCLC) p53 (~90% SCLC, ~60% NSCLC) FHIT = fragile histidine triad; APC = adenomatous polyposis coli; MCC = mutated in colon carcinoma; Rb = retinoblastoma; SCLC = small cell lung cancer; NSCLC = non-sclc (see Chapter 191). University of Milano

7 TABLE ONCOGENE ABNORMALITIES ABNORMALITY ONCOGENE SCLC NSCLC Ki-ras % of adenocarcinomas (activating mutation) H-ras 0 Rare mutation; overexpression occurs N-ras 0 Rare mutation; overexpression occurs myc (c, L, N) Majority Gene amplification and overexpression her2/neu 30% (overexpression) c-kit Overexpression bcl-2? Overexpression cyclin D1 (prad) Overexpression SCLC = small cell lung cancer; NSCLC = non-sclc. University of Milano

8 Sintomi e Segni

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12 TABLE STAGING OF SMALL CELL LUNG CANCER Limited Tumor confined to chest plus supraclavicular nodes, but excluding cervical, axillary nodes Extensive Tumor outside of above confines University of Milano

13 FARMACI UTILIZZATI University of Milano

14 NSCLC. A number of drugs are frequently used: cisplatin, carboplatin, paclitaxel, mitomycin, vinca alkaloids, ifosfamide, and etoposide. Newer regimens, such as carboplatin and paclitaxel, have improved activity over the regimens with which most controlled trials have been performed. Trials comparing chemotherapy with best supportive care for stage IV NSCLC have yielded conflicting results; however, several recent trials and meta-analyses suggest a small (several weeks to months increased survival) benefit from chemotherapy, and the costs of the chemotherapy option are less than the best supportive care because of lower utilization of palliative treatments. Several trials treating stage IIIB patients with chemotherapy plus radiation have demonstrated a longer survival with chemoradiotherapy than with radiation alone. Further trials are under way. University of Milano

15 Terapia adiuvante

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18 Terapia malattia avanzata University of Milano

19 Table Single-Agent Activity of New Chemotherapeutic Agents for Non-Small Cell Lung Cancer Agent No. of Studies**a No. of Patients Total CR + PR Median No. of 1-Y Survival No. of Survival**b Studies**c (%) Studies**d Paclitaxel**e (26%) 37 (24-56) Docetaxel**f (26%) 41 (27-48) Vinorelbine (20%) 33 (29-40) Gemcitabine**g (21%) 41 (31-49) Irinotecan (27%) 35 (27-42) 2 NR NR Topotecan (13%) 38 (33-40) CR, complete response; NR, not reported; PR, partial response. **anumber of studies reporting results. **baverage median survival in weeks (range). **cnumber of studies with median survival data. **dnumber of studies with 1-year survival data. **eincludes both short (1- to 3-hour) and long (24-hour) infusion schedules. There were no differences in response or survival based on infusion duration. **fincludes doses of mg/m**2. The response rates were 23% at 60 mg/m**2 and 29% at 100 mg/m**2. Survival data were similar. **gincludes doses of 800 mg/m**2 given on days 1, 8, and 15 of a 28-day cycle. At doses >1000 mg/m**2, there were no obvious dose responses. University of Milano

20 Table Randomized Trials Study Chemotherapy No. of Patients Median Survival P Value BSC/Chemo (wk) BSC/Chemo Cormier [ref: 507] MACC 19/20 9/ Rapp [ref: 508] CAP/VP 50/43/44 17/25/33.05/.01 Cartei [ref: 509] CCM 50/52 17/ Quoix [ref: 510] VP 10/28 17/27.33 Ganz [ref: 511] VibP 26/22 14/19.26 Woods [ref: 512] VP 91/97 17/27.33 Cellerino [ref: 513] CEP/MEC 57/58 21/ Kassa [ref: 514] VP 43/44 17/22.28 ELVIS [ref: 515] VNR 81/80 21/28.03 Cullen [ref: 516] MIC 176/175 21/ BSC, best supportive care; CAP/VP, cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), cisplatin (platinum)/vinblastine, cisplatin; CCM, cisplatin, cyclophosphamide-mytomycin; CEP/MEC, cyclophosphamide, etoposide + platinum/mito, etoposide + cisplatin; MACC, methotroxate, doxorubicin (Adriamycin), cyclophosphamide, lomustine (CCNU); MIC, mitomycin, ifosfamide, cisplatin; VibP, vinblastine-platinum; VNR, vinorelbine; VP, vindesine-platinum. University of Milano

21 Table Metaanalysis of Best Supportive Care versus Chemotherapy Study No. of Studies Results Conclusion Souquet [ref: 513] 7 Reduced mortality at 3 CT to be offered and 6 mo. Grilli [ref: 519] 6 6-wk gain in survival CT for selected patients (24% reduction in probability of death). Marino [ref: 519a] 8 Median survival, 3.9 vs. CT to be offered 6.7 mo (20% more at 6 mo). NSCLC Collaborative 11 (8 cisplatin-based) Median survival 6 vs. 8 CT improves survival Group [ref: 352] mo; 1-y survival: 16% vs. 26%. Data best for cisplatin-based therapy CT, chemotherapy; NSCLC, non-small cell lung cancer. University of Milano

22 SCLC. Chemotherapy is the cornerstone of treatment for both limitedand extensive-stage SCLC. A variety of agents have activity. Many experts believe that regimens containing etoposide, an anthracycline and either carboplatin or cisplatin offer the best combination of efficacy. University of Milano

23 Table Effect of Treatment on Survival in Small Cell Lung Cancer According to Extent of Disease Median Survival (mo) 2- to 3-Y Survival Rate (%) Therapy Limited Extensive Limited Extensive Disease**a Disease Disease Disease Supportive care Surgery 5-6**a **a -- 11**b **b -- Thoracic radiotherapy 10**a -- 10**a Single-agent chemotherapy Combination chemotherapy Combination chemotherapy with chest irradiation **aoperable patients in prechemotherapy era. **bselected, carefully evaluated, pathologically staged patients. Modified from Morstyn G, Ihde DC, Lichter AS, et al. Small cell lung cancer : early progress and recent obstacles. Int J Radiat Oncol Biol Phys 1984;10:51, and from ref. 69, with permission.) University of Milano

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32 TABLE ONCOGENE ABNORMALITIES ABNORMALITY ONCOGENE SCLC NSCLC Ki-ras % of adenocarcinomas (activating mutation) H-ras 0 Rare mutation; overexpression occurs N-ras 0 Rare mutation; overexpression occurs myc (c, L, N) Majority Gene amplification and overexpression her2/neu 30% (overexpression) c-kit Overexpression bcl-2? Overexpression cyclin D1 (prad) Overexpression SCLC = small cell lung cancer; NSCLC = non-sclc. University of Milano

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37 ALK + NSCLC Shinmura et al EML4-ALK is detected in about 3% of NSCLC tumours (incidence x 10E- 5/year) and cell lines The fusion gene comprises portions of the EML4 gene and the ALK gene that resulted from a small inversion in chromosome 2p Fusion transcripts was detected in two (2.6%) of the 77 NSCLCs cases Mouse 3T3 fibroblasts forced to express this EML4-ALK fusion generate transformed foci in culture and subcutaneous tumours in nude mice University of Milano TAE684 has an inhibitory effect on ALK activation in cells and mice

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39 NSCLC Tumor Responses with Crizotinib Best tumor response* Number of responses (N=105) CR 2 PR 57 SD 33 PD 6 Not evaluable 7 OR rate, % (95% CI) 56 (46 66) Disease control rate at Week 8, % 88 *as assessed by RECIST: CR, complete response; PR, partial response; SD, stable disease Including patients who experienced abrupt clinical deterioration and those who could not be radiographically assessed Sum of CR, PR and SD Solomon B et al. Poster 369 presented at 22nd EORTC-NCI-AACR, 2010

40 1. Camidge R et al. Poster 366 presented at the 35th ESMO, Solomon B et al. Poster 369 presented at 22 nd EORTC-NCI-AACR, 2010 Response to Crizotinib Occurs Rapidly Case 1: Response within 14 days 1 Case 2: Response within 28 days 2 Baseline End of cycle 1

41 Progression Free Survival for Patients with NSCLC Receiving Crizotinib Median PFS 9.2 months (95% CI 7.6, 10.3; N=113) 48% of patients in follow-up for PFS Median follow-up for PFS: 8.0 months PFS probability % Hall-Wellner Band No. at risk Time (months) Camidge R et al. Poster 366 presented at the 35 th ESMO, 2010

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45 X University of Milano

46 T = Clusters#/Tile x Tile/Lane# x Lanes# x Seq_Length x 2 T = * 120 * 8 * 76 * 2 = ~ 30Gb

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49 WHOLE EXOME SEQUENCING

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