Chemo-radiotherapy in non-small cell lung cancer. HARMESH R NAIK, MD. September 25, 2002

Transcription

1 Chemo-radiotherapy in non-small cell lung cancer HARMESH R NAIK, MD. September 25, 2002

2 Epidemiology Estimated new cases Estimated 157,000 deaths Second commonest cancer diagnosis in men and women Leading cause of cancer death in men and women A significant disease burden

3 Pathology Lung cancer (100%) non small cell-80% small cell-20% adenoca-40% squamous-30% large cell-10%

4 Stage at diagnosis-nsclc Most cases diagnosed at late stage Only 16% cases are localized

5 Five year survival by stage-nsclc IA IB II IIIA IIIB-IV 0

6 NSCLC-Survival data Stage 5 year survival I 55-75% II 25-50% IIIA 20-40% IIIB <5% IV <5%

7 Stage III-locally advanced lung cancer Stage III: 50,000 new cases every year 1/3 of the total lung cancer cases few patients are cured with single modality Majority requires multi-modality therapy

8 Goals of lung cancer treatment Provide palliation Improve quality of life Prolong survival Cure the disease Minimize the side effects of treatment

9 Prognostic factors Stage-most important factor Performance status Weight loss Molecular factors C-erb-2 Epidermal growth factor (EGF) Ras mutations

10 ECOG performance status scale 0: no symptoms 1: symptomatic but no extra time in bed 2: in bed <50% of the day, can care for self 3: in bed >50% of the day, minimal self care 4: completely bed ridden Good predictor of treatment tolerance

11 Staging History and Physical exam, PS CBC, chemistry Chest x-ray, CT chest with liver & adrenals 10-30% false neg. for mediastinum 25-35% false positives CT or MRI brain:? cost-effectiveness Bone scan:? cost-effectiveness

12 Staging (ct.) Bronchoscopy Mediastinoscopy: Uniform staging,? N2 or N3 low morbidity (1-2%) and mortality (<0.1%)?PET scan Thoracoscopy PFTs & Quantitative V/Q scan

13 Staging procedures Old methods CT chest Mediastinoscopy Mediastinotomy Thoracotomy Newer methods PET scan Mediastinal FNA Bronchoscopic ultrasound FNA Esophageal ultrasound FNA

14 Interpretation of data: current problems Variable staging methods CT + mediastinoscopy: IIIA or IIIB Uniform staging comparison Heterogeneity of the disease T3N0 is now IIB T4N1 and T2N3 PS and weight loss criteria

15 Interpretation of data (cont.) Endpoints: Survival: most useful, 2 or 5 years Response rate: commonly reported Down staging data CR

16 Multi-modality options Surgical resection?c +?RT (Adjuvant) Induction therapy Surgery (Neo-adjuvant) Preop-chemo + RT Definitive chemo-rt Sequential: C RT + CT Concurrent: C-RT Concurrent: C CT/RT Concurrent: CT/RT CT

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18 Summary results RT alone 5-10% 5 yr survival Surgery alone Mediastinoscopy +N2: 9% Incidental N2: 24% Induction therapy: 17-37% pre-op chemo: 17-19% pre-op chemo-rt: 22-37%

19 Adjuvant therapy for completely resected lung cancer Overall results of randomized trials remains discouraging so far. New generation of trials with newer combinations are in progress

20 SWOG 9900 randomize TC X 2 Surgery Surgery

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22 Goals of Chemo-RT Local- Regional Control Distant Micro-mets control

23 Combined chemo-radiation in stage III NSCLC Cisplatinum based chemotherapy with RT is associated with reduction in mortality at 1 and 2 years

24 Combined chemo-radiation in stage III NSCLC RT alone (historical data for comparison) CT RT CT CT/RT CT/RT CT/RT CT

25 Current status-chemo-rt results method MST(mos) 1y (%) 2y(%) Tox % RT 10 m CT RT 14 m CT/RT 17 m CT CT/RT 15 m CT/RT CT 26 m Last line is SWOG 9504 data

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27 Induction chemotherapy Radiation Improved survival when added to RT Meta-analysis confirmed the advantage Most +ve studies used platinum agent Considered standard by many PS and Weight loss are important in selection of patients

28 Definitive sequential Au. Arm Med. 2yr 5yr 7 yr Dillman CT+RT 13.7m 26% 17% 13% CALGB RT 9.5m 13% 13% 7% Le Che CT+RT 12m 21% 6% French RT 10m 14% 3%

29 CALGB-8433 randomize RT 60 GY PV RT 60 GY

30 CALGB year survival data RT vs. Sequential Chemo RT RT Chemo-RT 5 0 MST (mo) 2 yr 3 yr 5 yr 7 yr Dillman RO et al.

31 RTOG 8808: RT vs. PV RT % RT HFRT PV->RT 0 MST(mo) 2 yr 3 yr 5 yr Sause W. et al.

32 French trial: RT vs. Chemo RT % RT C->RT yr OS Arrigada R. et al.

33 French trial: RT vs. Chemo RT: Incidence of distant mets % RT C->RT 0 dist mets

34 Definitive sequential (An example) 1-1 Pre-therapy CT scan Month 0 Non-small cell lung cancer

35 Definitive sequential (An example): Paclitaxel-Carboplatin x 2 RT 1-2 Post-chemo- RT therapy CT scan Month 3

36 Definitive sequential (Case 1) 1-3 Post-therapy CT scan Month 5

37 Definitive sequential (Case 1) 1-4 Post-therapy CT scan Month 8

38 Definitive sequential (Case 1) 1-5 Post-therapy CT scan Month 13

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40 Chemotherapy chemo-rt CALGB 9431 trial Induction chemotherapy with different chemotherapy regimens x 2 cycles RT follows with concurrent chemotherapy Vinorelbine, Paclitaxel and Gemcitabine in combination with platinum agents

41 CALGB 9431 trial Chemotherapy x 2 cycles: Cisplatin with Taxol, Navelbine or Gemcitabine Concurrent chemotherapy (reduced dose)-rt

42 CALGB 9431 trial % MST (mos) PC VC GC

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44 Concurrent chemo-rt Phase II trials: Full dose RT (up to 70 Gy) Median survival months 2 year survival 24-26% Taxol-Carboplatin with RT Phase II: 39% 3 year survival (Belani et al.)

45 Concurrent TC-RT (Case 3) 3-1 Pre-therapy CT scan Month 0 Squamous cell carcinoma

46 Concurrent TC-RT (Case 3) 3-2 Post-therapy CT scan Month 3

47 Concurrent TC-RT (Case 3) 3-3 Pre-therapy CT scan Month 4

48 Concurrent EP-RT (Case 5) NSCLC-5-1 Pre-therapy Month-1 Poorly differentiated squamous cell carcinoma

49 Concurrent EP-RT (Case 5) NSCLC-5-2 Pre-therapy Month-10

50 Concurrent EP-RT (Case 5) NSCLC-5-2 Pre-therapy Month-15

51 Concurrent EP-RT (Case 5) NSCLC-5-2 Pre-therapy Month-20

52 Concurrent EP-RT (Case 5) NSCLC-5-2 Pre-therapy Month-24

53 Concurrent EP-RT (Case 5) NSCLC-5-2 Pre-therapy Month-28

54 Concurrent EP-RT (Case 5) NSCLC-5-2 Pre-therapy Month-36

55 Concurrent EP-RT (Case 5) NSCLC-5-2 Pre-therapy Month-44 Last follow-up

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57 SWOG 9019 Cisplat-VP16 Cisplat-VP 16

58 SWOG 9504 Cisplat-VP16 Docetaxel Gaspar L. et al.

59 Chemo-RT followed by Chemotherapy-SWOG 9504 CR: 4 %, PR : 59 % Overall response: 63 % Stable disease: 28 % Progression: 9 % Median overall survival: 26 months Median PFS: 16 months Aggressive surgical staging was done

60 Overall median Survival- SWOG 9504 and SWOG 9504 SWOG 9019 Med Survival

61 Overall Survival- SWOG 9504 and y 2 y 3 y SWOG 9504 SWOG 9019

62 Intergroup trial (S 0023) Chemo-RT SWOG 9504 randomize ZD 1839 Placebo

63 SWOG 9429-poor risk patients Carboplatin - VP16

64 SWOG 9429-poor risk patients Response rate: 29% Median survival: 13 months 2 year survival 21% Patients with bad heart, kidneys or poor PS

65 SWOG 9712-poor risk patients Concurrent Carboplatin-VP 16 as in SWOG 9429 Consolidation Paclitaxel x 3 cycles Davies et al.

66 SWOG 9712-poor risk patients No improvement in survival over SWOG 9429 Response rate is higher at 58% Median survival is 10.3 months 2 year survival is 27% 9.2% death rate during consolidation Paclitaxel

67 Concurrent Chemo-RT (TC+RT) Chemo (Case 2) 2-1 Pre-therapy CT scan Month 0 Poorly diff non small cell carcinoma with SVC syndrome

68 Concurrent Chemo-RT (TC+RT) Chemo (Case 2) 2-2 Post-therapy CT scan Month 3

69 Case 2 SVC syndrome from Squamous cell ca Good response to Paclitaxel-carboplatin-RT Month 4: obstructive jaundice-local RT Asymptomatic pleural effusion Month 7L Gemzar-Carboplatin x 1 Recurrent jaundice Died at months 12 past diagnosis

70 Concurrent Chemo-RT (TC+RT) Chemo (Case 4) 4-1 Pre-therapy CT scan Month 0 Non small cell lung cancer

71 Concurrent Chemo-RT (TC weekly+rt) (Case 4) 4-2 Post-therapy CT scan Month 3

72 Concurrent Chemo-RT (TC weekly+rt) (Case 4) 4-3 Post-therapy CT scan Month 6

73 Concurrent Chemo-RT (TC weekly+rt) (Case 4) 4-4 Post-therapy CT scan Month 9

74 Concurrent Chemo-RT (TC weekly+rt) (Case 4) 4-5 Post-therapy CT scan Month 13

75 Case 4 Non small cell lung cancer Palcitaxel-Carboplatin-RT Minimal response Docetaxel x 1 Navelbine-Gemzar Gemzar Alive at 13 months Pericardial effusion-non malignant

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77 Locally advance multi-modality protocol (LAMP) trial Randomize Sequential chemo RT Chemo Chemo/RT Chemo/RT Chemo

78 Locally advance multi-modality protocol (LAMP) trial RT: 6300 rads Chemotherapy with Paclitaxel and Carboplatin Toxicity : Esophagitis 28% in arm III Granulocytopenia in one third in arm I and II 70% completed therapy in arm III

79 Locally advance multi-modality protocol (LAMP) trial C-->RT C-->C/RT C/RT-->C RTOG C-->RT months ASCO 2002, abstract 1160

80 West Japan trial CT/RT vs. CT RT % CT/RT CT-->RT 0 MST (mo) 2 yr 3 yr 5 yr Furuse K. et al.

81 RTOG 9410: CT RT vs. CT/RT vs. CT/HFRT MST (mos) CT-->RT CT/RT CT/HFRT Langer C. et al. Same results for elderly and younger.

82 Questions remaining Is surgery necessary for all? Optimal Induction: C or C-RT Concurrent or sequential C-RT What chemotherapy drugs and what schedule Radiation dose and fractionization

83 What should we do until then? Aggressive staging IIIA: Induction therapy surgery Induction chemo or chemo-rt IIIB or poor risk IIIA Chemo-RT (definitive)? concurrent Negative mediastinoscopy: Surgery alone +? adjuvant therapy

84 Improvements in 5-year lung cancer survival decade

85 Thalidomide Angiogenesis Inhibitor: Angiogenesis suppression result in balancing of tumor cell proliferation and cell death resulting in dormancy of metastases in mice. Hypothesis: Any strategy promoting dormancy of micromets may add to the results of standard chemo-rt in locally advanced lung cancer

86 Pilot trial of Chemotherapy + Thalidomide University of Wisconsin trial Taxol+Carboplatin+Thalidomide Feasible ECOG 3598 is a randomized comparison of chemo-rt with or without Thalidomide

87 ECOG trial- Chemo-RT + Thalidomide randomize TC X 2, Thalidomide RT TC X 2, placebo RT

88 ZD 1839 (EGFR TKI) A novel targeted therapy for lung cancer Epidermal growth factor receptor (EGFR)- Tyrosine kinase inhibitor (TKI)

89 EGFR family erbb family of cell membrane receptors Four members erb B1 (EGFR or HER1) erb B2 (HER 2) erb B3 (HER 3) erb B4 (HER 4) Expressed in 60% lung cancers

90 Function of EGFR Ligand (eg. EGF) binding to extra-cellular domain activation Dimerization Activation of intrinsic tyrosine kinase activity Auto-phosphorylation Cellular signaling

91 EGFR activation and cancer Activation of EGFR leads to : Tumor growth Tumor proliferation Angiogenesis Invasion/metastasis Inhibition of apoptosis

92 igand Extra cellular domain ntracellular omain yrosine kinase nucleus proliferation metastasis Apoptosis inhibition

93 EGFR inhibition Antibodies directed against extra-cellular domain (IMC-C225-cetuximab in phase I trials, ABX-EGF also in phase I trials) Vaccine Conjugated toxins (with single chain antibody) Drugs-TKI (ZD 1839 and OSI-774)

94 Vaccine Toxin conjugate C225 antibody ZD 1839 nucleus proliferation metastasis Apoptosis inhibition

95 ZD-1839-IDEAL I and II trials randomize ZD mg/day ZD mg/day

96 ZD-1839-IDEAL I and II trials IDEAL-1 IDEAL II Pre-treatment 1-2, cisplatin >2, Plat and Doc # 209 (non US) 216 (US) RR 18.4% 11.8% Dis control 54.4% 42.2% MST (mos) 7.6 mos 6.1 mos

97 ZD-1839-IDEAL I and II trials Well tolerated: main side effects: Rash, nausea, diarrhea Rapid symptom improvement in 40-43% Rapid improvement within 2 weeks sometimes Oral drug Phase III trials are ongoing at current time

98 Future therapies Antiangiogenesis agents Tumor vaccines Gene replacement therapy Antisense oligonucleotides Targeted therapies?? 50% 5 year survival