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HIGHLIGHTS IN THE MANAGEMENT OF LUNG CANCER Developments in multimodality treatment of SCLC

Università degli Studi di Palermo Facoltà di Medicina e Chirurgia Dipartimento di Oncologia Cattedra di Oncologia Medica UO Terapie Oncologiche Innovative Prof. S. Palmeri. HIGHLIGHTS IN THE MANAGEMENT OF LUNG CANCER Developments in multimodality treatment of SCLC.

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HIGHLIGHTS IN THE MANAGEMENT OF LUNG CANCER Developments in multimodality treatment of SCLC

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  1. Università degli Studi di PalermoFacoltà di Medicina e Chirurgia Dipartimento di Oncologia Cattedra di Oncologia Medica UO Terapie Oncologiche Innovative Prof. S. Palmeri HIGHLIGHTS IN THE MANAGEMENT OF LUNG CANCERDevelopments in multimodality treatment of SCLC CINBO Mediterranean School of Oncology Roma 15 may 2009

  2. Routine staging of SCLC does not include: • CT of the chest • Bone scan • PET • CT of the brain • Physical examination Cross-tablabel 20 / 30

  3. PCI is recommended in: • Pts with limited-stage SCLC achieving major clinical response • Pts with limited-stage SCLC • Pts with extensive- stage SCLC achieving any clinical response • Pts with limited-stage SCLC even if non-responders • All SCLC pts Cross-tab label 14 / 30

  4. Which of the following biologic agents is approved for the treatment of SCLC: • Bevacizumab • Imatinib • Sorafenib • Gefitinib • No targeted therapy is approved for SCLC Cross-tablabel 20 / 30

  5. Lung cancer-Epidemiology • Lung cancer in Italy: ~ 37.000 new cases/year ~ 32.000 deaths in 2002 •  incidence and mortality in males,  among females • SCLC: 9-13% of all newly diagnosed lung cancers (~ 3.330 new cases/year) APC=AnnualPercentageChange

  6. SCLC • Predominant risk factor: cigarette smoking (0-3% in non smokers) •  smoking   incidence (in US) • Rapid doubling time and high growth fraction • Neuroendocrine derivation

  7. SCLC • Tends to present with a large central lung mass and associated extensive hilar and mediastinal lymphoadenopathy • Clinically evident distant mts in ~ 66% of pts at diagnosis • Micrometastatic disease in 63% of pts died within 30 days of attempted curative resection (data from autopsy examination) systemic disease at presentation in > of pts • Frequently associated with paraneoplastic syndromes

  8. The distinction of SCLC from the more common NSCLC is of paramount importance because treatment paradigms differ significantly

  9. SCLC-Staging • TNM staging system does not predict well for survival in SCLC  rarely used, except for surgical staging • Veterans Administration Lung Study Group (VALSG) system: - limited-stage disease (30%) - extensive disease (70%)

  10. SCLC-Staging • - limited-stage disease : tumor confined to one hemithorax with or without omolateral nodes/pleural effusion that can be encompassed within a single tolerable radiation therapy port - areas of controversy: contralateral hilar or supraclavicular nodes or malignant pleural or pericardial effusions - extensive disease: presence of metastatic disease

  11. SCLC

  12. SCLC-Staging • History and physical examination • Routine hematologic and serum chemistry tests, LDH • Chest radiographs • Chest + (upper) abdomen CT scan • Bone scan • CT with contrast or MRI of the brain • PET :  invasive procedures/better definition of irradiation field, possible future role for better pt staging • OMB (controversial)

  13. SCLC-Prognostic factors • Stage • PS • Sex (unfavourable: male) • LDH • Weight loss (> 10% of body weight)

  14. SCLC-Treatment Decreased frequency and difficulty in conducting large trials  lack of studies • Extensive-Stage (ES) SCLC • Second-line chemotherapy • Limited stage (LS) SCLC • Surgery • PCI • Novel and Targeted therapy in SCLC

  15. SCLC-Treatment • Extensive-Stage (ES) SCLC • Second-line chemotherapy • Limited stage (LS) SCLC • Surgery • PCI • Novel and Targeted therapy in SCLC

  16. ES-SCLC Treatment • For more than 3 decades combination CT  the cornerstone of SCLC therapy • 1978: CAV/CAE • 1985: EP • 1998-2000: - cisplatin-based > non- cisplatin-based regimens   OR and OS with Cisplatin - carboplatin = cisplatin (less toxic) 19 trials ,4054 pt Mortality at 1 yr, Pujol 2000

  17. ES-SCLC Treatment 1998-2000: CDDP > and CBCA=CDDP 1985: EP 1978: CAV/CAE

  18. ES-SCLC Treatment • EPwidely regarded as the gold standard but the optimal dose and scheduling of these agents are not well defined • (little impact on survival at least in ES-SCLC) Death rate < 2%

  19. ES-SCLC Treatment • Attempts to enhance the therapeutic efficacy of the EP regimen: - addition of a third active agent - substitution of etoposide with a newer active agent - dose intensification - use of maintenance or consolidation chemotherapy

  20. ES-SCLC Treatment MultidrugCisplatin + EtoposideCombinations in SmallCellLungCancer [*]Toxicity-relateddeath rate = 9% Addition of a third (or more) active agent to EP ineffective (OS) and generally associated with  tox. Outside of a clinical trial setting, such an approach is to be discouraged.

  21. Phase II trials including oral topotecanin SCLC Author Phase Dose No.pts %OR MS % G3+4 (wks) Neut. Von Pawel, II rand. 2.3 mg/m²/d x5 p.o. 52 23 32 35.3 2001 vs 1.5 mg/m²/d x5 i.v. 54 15 25 67.3 Eckardt, II 1.7-2.0 mg/m²/d x5 41 (I line) 30 37.3 57(1.7) 2001 80(2.0) Molina, II 1.75 mg/m2/d x5 + 38 (I line) 45 37 40 2006 TAX 175/3h/d5+G-CSF

  22. ES-SCLC Treatment EtoposideDrugSubstitutionPhase III Trialsin SmallCellLungCancer

  23. Pemetrexed 500 mg/m2 + CDDP 75 mg/m2 d1 every 21 days Results OR=35% MTTP= 4.9 mo MST=7. 6 mo R A N D O M I Z E 78 untreated ES-SCLC pts Results OR=39.5% MTTP= 4.5 mo MST= 10.4 mo Pemetrexed 500 mg/m2 + CBDCA AUC 5 d1 every 21 days Socinski , 2006

  24. ES-SCLC Treatment Dose intensification • 1991 (Klasa et al) “Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung”  No direct correlation between DI and clinical outcome • 1994 (Ihde et al): standard dose EP vs high-dose EP  no difference in terms of RR and OS • 2005 (Lorigan et al): ICE dose-dense q14 (plus G-CSF and BPCS*) vs ICE  no difference in terms of RR and OS *BPCS=Blood- Progenitor-CellSupport

  25. ES-SCLC Treatment Maintenance treatment • 1998, review Sculier et al: - 1 study   OS (maintenance) - 5 studies   OS (maintenance) in subgroups - 1 study   OS (maintenance) - 6 studies  no difference • 2005, meta-analysis Bozcuk et al: 14 trials, 2550 pts   OS (maintenance) but the clinical relevance of this report is questionable (old trials, IPD not used)

  26. SCLC-Treatment • Extensive-Stage (ES) SCLC • Second-line chemotherapy • Limited stage (LS) SCLC • Surgery • PCI • Novel and Targeted therapy in SCLC

  27. SCLC: second-linechemotherapy • Despite high initial response to CT (45-75% CRs in LS and 20-30%v in ES) short response duration (MPFS = 4 mo) • Pts who relapse < 3 mo after 1° line CT = refractory

  28. Best Supportive care Oral topotecan 2.3 mg/m2/day for 5 consecutive days R A N D O M I Z E Patients with relapsed SCLC not considered as candidates for intravenous therapy Cycles repeated q21 days M O’Brien et al, JCO 2006

  29. 26 vs 14 weeks (p=.0104)  QoL M O’Brien et al, JCO 2006

  30. IV topotecan 1.5 mg/m2/day as a 30-minute IV infusion for 5 consecutive days Oral topotecan 2.3 mg/m2/day for 5 consecutive days R A N D O M I Z E • Stratification • Response duration to prior chemotherapy(3–6 months vs> 6 months) • Gender • Liver metastasispresent or absent Cycles repeated q21 days Eckardt et al, JCO 2007

  31. Oral Topotecan (n=153) IV Topotecan (n=151) Overall Survival (ITT population) 1.0 0.9 309 pts 0.8 • Median Survival (weeks) • oral=33, IV=35 • 1-year survival (95% CI) • oral=32% (24.6,39.4) • IV=29% (21.6, 36.3) • Post study chemotherapy oral=33% IV=35% 0.7 0.6 Cumulative Proportion Alive 0.5 0.4 0.3 0.2 0.1 0.0 0 24 48 72 96 120 144 168 192 Time (weeks) Conclusion: no statistical difference between oral and IV Eckardt et al, JCO 2007

  32. SCLC-Treatment • Extensive-Stage (ES) SCLC • Second-line chemotherapy • Limited stage (LS) SCLC • Surgery • PCI • Novel and Targeted therapy in SCLC

  33. LS-SCLC Treatment • 1992: 2 meta-analyses (Pignon and Warde) addition of RT to CT in LS-SCLC statistically improved survival The debateshifted: whethertouse RT how best to integrate itwith CT From Pignon J et al A metaanalysis of thoracic radiotherapy for SCLC. N Engl J Med 1992

  34. LS-SCLC Treatment Which CT with RT? • 436 pts LS and ES-SCLC PE vs CEV (+RT in LS) • OS =14.5 mo (EP) 9.7 mo (CEV) in LS-SCLC 10.2 mo (EP) 7.8 mo (CEV) In all SCLC pts Sundstrom 2002

  35. 2007 New chemotherapyapproaches in LS-SCLC

  36. LS-SCLC Treatment • Many issues remain unresolved regarding the optimal chemoradiotherapy approach - dose of RT - timing of RT - RT volumes Fried 2004

  37. SCLC-Treatment • Extensive-Stage (ES) SCLC • Second-line chemotherapy • Limited stage (LS) SCLC • Surgery • PCI • Novel and Targeted therapy in SCLC

  38. Surgery in SCLC • Surgery  abandoned after the results of the British Medical Council study (1973) comparing RT vs S in pts with resectable SCLC • Surgery for early-stage SCLC (i.e small single pulmonary nodules) may be more appropriate (possible biological difference from more advanced disease) • Resected T1N0M0 tumors: 50-80% 5-year survival rate (Shepherd 1991) • T1*N0 tumors • Even though the role of adjuvant therapy has not been evaluated in prospective randomized trials, there are several reports, suggesting benefit for adjuvant chemotherapy even in the earliest stages of the disease. *T1 < 3 cm

  39. Surgery in SCLC N° % INCIDENTAL % % SURVIVAL ANY LOCAL STUDY RESECTED TREATMENT SCLC p CR R0 MST % 2y % 5y RECURRENCE (mo) % Merkle et al 170 Various - - - - - 18 - Rea et al 104 Various - - - 28 - 32 24 Prasad et al 97 Various 27 - - 12 37 17 - Massen et al 94 Various - - 86 - - 15 - Hage et al 74 Various 43 - - 17 35 25 - --------------------------------------------------------------------------------------------------------------------------------------------------------------------- Davis et al 118 S - - - 18 39 20 - Sorensen et al 71 S - - - - - 12 - Shore et al 40 S 57 - - - - 27 20 Shah et al 28 S 36 - 93 34 55 43 - --------------------------------------------------------------------------------------------------------------------------------------------------------------------- Shields et al 132 S--->Chemo RT - - - 11 33 23 - Karrer et al 112 S--->Chemo 58 - - 37 60 51 11 Lucchi et al 92 S--->Chemo 31 - 99 24 50 32 16 Shepherd et al 63 S--->Chemo RT 64 - 90 19 45 31 11 -------------------------------------------------------------------------------------------------------------------------------------------------------------------- Lad et al 70 Chemo--->S –RT+PCI - 19 77 15 20 10 - Shepherd et al 38 Chemo--->S- RT - 8 87 21 47 36 18 Eherhart et al 32 Chemo-RT---->S - 34 72 36 - 46 - Holoye et al 22 Chemo--->S - 19 - 25 54 33 14 Wiliams et al 21 Chemo--->S - 16 84 - - - 28 -------------------------------------------------------------------------------------------------------------------------------------------------------------------- Shepherd et al 28 Salvage * - - 82 24 48 23 - -------------------------------------------------------------------------------------------------------------------------------------------------------------------- Average 81 22 44 28 19  * Resection of residual disease after CT +/- RT

  40. Surgery in SCLC In these trials (1980-1998): • Median OS  2 yrs • 5-year survival  26% • Heterogeneity in disease extent (limited disease) • Adjuvant CT  no randomized studies

  41. SCLC-Treatment • Extensive-Stage (ES) SCLC • Second-line chemotherapy • Limited stage (LS) SCLC • Surgery • PCI • Novel and Targeted therapy in SCLC

  42. SCLC-Treatment PCI (Prophylactic Cranial Irradiation) • Pts with CR to induction therapy: 50-60% CNS mts over the next 2 ys • The need for PCI = area of controversy (CNS=sanctuary and common site of mts)

  43. SCLC-TreatmentPCI (Prophylactic Cranial Irradiation) Meta-analysis: • in 987 pts (86% LS) with CR - 5.4% OS benefit at 3 years with PCI - > DFS e < brain mts Auperin NEJM 1999

  44. SCLC-TreatmentPCI (Prophylactic Cranial Irradiation) • EORTC study: 286 ES-SCLC pts randomized to PCI or no PCI: -  risk of symptomatic brain metastases -  in median DFS from 12 to 14.7 weeks and in median OS from 5.4 to 6.7 months - 1-year survival rate = 27.1% vs 13.3% in the control group Slotman, NEJM 2007

  45. Global health status Hair loss Short-term results up to 3 months: • negative impact of PCI on selected HRQOL scale (the largest mean difference for fatigue and hair loss) Fatigue Rolefunctioning Cognitive functioning Emotionalfunctioning Slotman, JCO 2009

  46. SCLC-Treatment • Extensive-Stage (ES) SCLC • Second-line chemotherapy • Limited stage (LS) SCLC • Surgery • PCI • Novel and Targeted therapy in SCLC

  47. 2008 Mainnovelbiologicagentsinvestigated in the treatment ofptswith SCLC mTOR

  48. 2008

  49. 2008

  50. 2008

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