Lung cancer update 2007

Transcription

1 Lung cancer update 2007 HARMESH R NAIK, MD. January 24, 2007

2 Epidemiology (world) Estimated 1.35 million new cases in world in 2002 Estimated million deaths in world in 2002 Common cancer diagnosis Common cause of cancer death A significant disease burden

3 US Cancer statistics 2006 Cancer incidence mortality Lung Colo-rectal Breast Prostate Cancer statistics CA Cancer J. Clin 56: , 2006.

4 US cancer mortality lung colon breast pancrease prostate Mortality

5 Histology in lung cancer SCLC NSCLC SCLC NSCLC

6 Subtypes of NSCLC other large cell adeno adeno squamous large cell other squamous

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

8 Five year survival by stage-nsclc IA IB II IIIA IIIB-IV 10 0

9 Prognostic factors Stage-most important factor Performance status Weight loss Molecular factors 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 Diagnosis/Staging History and Physical exam, PS CBC, chemistry profile Chest x-ray, CT chest with liver & adrenals Large nodes: over 70% positive for cancer Normal size nodes: less than 15% chance of cancer. Routine CT or MRI brain:? cost-effectiveness Routine Bone scan:? cost-effectiveness

12 Diagnosis/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 Mediastinotom y Thoracotomy Newer methods PET scan Mediastinal FNA Bronchoscopic ultrasound FNA Esophageal ultrasound FNA

14 PET scan in staging Sensitivity, specificity and predictive value in 90% range. CT-PET provides additional information in over 40% cases Over 1 cm nodes with negative PET: Mediastinoscopy is advisable Negative predictive value of over 90%

15 Physiological evaluation Smoking cessation Nutritional status Age over 70 Sprirometry and PFTS FEV1 is independent prognostic marker from surgery Cardio-pulmonary exercise testing Quantitative perfusion study ABGs

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

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19 Definitive Surgery Mainstay of therapy for stage I, II and IIIA disease. Nodal status a very important predictor of survivor Surgery alone Mediastinoscopy +N2: 9% Incidental N2: 24%

20 Post surg recurrence risk by stage local distant 10 0 IA IB II IIIA Pisters KM et al. JCO 23: 3270, 2005.

21 Survival (%) following surgical resection NCDB yr 3 yr 5 yr 0 I II IIIA Betticher DC et al: Lung cancer, 50:59-516, 2005

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24 Adjuvant chemotherapy Prior to 2003: No trial showed survival advantage in conclusive manner Meta-analysis 1995: Non significant 5% survival advantage at 5 years with Cisplatin containing chemotherapy

25 Post Operative adjuvant radiation No survival benefit May worsen survival Decreases local recurrence

26 Recent adjuvant trials Surgery chemotherapy Newer trials (post 2003): 4-15% improvement in 5 yr survival Stages II and IIIA: benefit is more definite. Stage IB: Benefit remains inconsistent (see CALGB 9633 results)

27 CALGB 9633 Post surgery IB PC x 4 cycles OBV

28 CALGB yr West chemo no chemo 12% improvement at 4 years (first analysis)

29 CALGB 9633 First analysis (2004): 12% survival improvement at 4 years Second analysis (2006): Failure free survival is still favoring chemotherapy arm. Overall survival not significant. Only pts with size more than 4 cm seems to benefit Struass et al. ASCO 2006, Abstract 7007.

30 What is next.ecog 1505 IIIA resected NSCLC Chemotherapy Chemo + BEV

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32 Neo-adjuvant (Induction) therapy Treats the micro-mets earlier Potential for down staging disease Higher compliance rate Better tolerated However, delays surgery Less accurate staging

33 Neo-adjuvant (Induction) therapy Trials so far has shown potential benefit Survival benefit is not evident yet Ongoing studies may clarify role of this approach Phase II data is promising (BLOT trial). Direct comparison of neo-adjuvant and adjuvant therapy will be needed.

34 SWOG 9900 randomize TC X 2 Surgery Surgery

35 SWOG 9900 Closed early when a adjuvant results became available. The differences are not statistically significant. Med PFS: 29 months vs 20 months favoring neo-adjuvant therapy Ongoing trials may clarify its role.

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37 Stage III-locally advanced lung cancer Stage III: 50,000 new cases every year One third of the total lung cancer cases Few patients are cured with single modality Majority requires multi-modality therapy. Includes: IIIA: T3N1 or T1-3N2 IIIB: T4 and N3 to T any N3 Wet IIIB (pleural effusion): Poor prognosis.

38 Historical therapy for stage III Up to 1990s: Radiation alone was standard.

39 Post Radiation survival (Historical) yr 2 yr 5 yr 5

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

42 Combined chemo-radiation in stage III NSCLC Cisplatinum based chemotherapy with RT is associated with reduction in mortality at 1 and 2 years Early 1990's: Standard of care shifted to combined chemo-radiation.

43 Multi-modality options Definitive chemo-rt Sequential: C RT + CT Concurrent: C-RT Induction-Concurrent: C CT/RT Concurrent-consolidation: CT/RT CT

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45 Induction chemotherapy Radiation Improved survival when added to RT Meta-analysis confirmed the advantage Most positive studies used platinum agent PS and Weight loss are important in selection of patients

46 CALGB-8433 (Seq Chemo RT) randomize RT 60 GY PV RT 60 GY

47 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.

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

49 French trial: RT vs. Chemo RT: Incidence of distant mets % RT Chemo-RT distant mets

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51 Chemotherapy chemo-rt Studies so far do not support use of induction therapy prior to concurrent chemotherapy - radiation (CALGB trial, LAMP trial)

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53 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.)

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55 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.

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

57 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 LAMP: Belani CP et al: JCO 2005: 23:

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

59 RTOG 9410: CT RT vs. CT/RT vs. CT/HFRT sequential concurrent conc-hfrt MST (mo) Langer C. et al.

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62 SWOG 9019 Cisplat-VP16 Cisplat-VP 16 SWOG 9019: Albain K et al: JCO: 2002: 20:

63 SWOG 9504 Cisplat-VP16 Docetaxel SWOG 9504: Gandara DR eta al: JCO: 2003: 21:

64 Chemo-RT followed by Chemotherapy- SWOG 9504 CR: 4 %, PR : 59 % Overall response: 63 % Stable disease: 28 % Median overall survival: 26 months Aggressive surgical staging was done 3 yr survival 40% 5 yr survival 29%

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

66 Overall Survival- SWOG 9019 and y 2 y 3 y 5 yr SWOG 9019 SWOG 9504

67 Intergroup trial (S 0023) Chemo-RT SWOG 9504 randomize ZD 1839 Placebo No benefit of targeted therapy

68 SWOG 9429-poor risk patients Carboplatin - VP16

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

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

71 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 in poor risk patients

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

73 Conclusion: combined chemo-rt Concurrent chemo-rt followed by consolidation chemotherapy appears to offer best outcome so far (SWOG 9019, SWOG 9504 and LAMP trials). Optmal chemotherapy regimen, dose and schedule: Unclear Platinum based doublet used most frequently.

74 New trends in stage III Targeted therapy: Gefitinib-EGFR blocker: No survival benefit (SWOG 0023) Cetiximab: Ongoing trial RTOG 0324 Erlotinib: Ongoing studies Utility of PET scan: Ongoing 4-D radiation: Ongoing Toxicity modulation: Ongoing

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76 Summary: Stage IA Stage IA: Surgery: Adjuvant chemotherapy: No proven benefit Post operative adjuvant radiation : No proven benefit My choice: Surgical resection No adjuvant Rx

77 ASCO WEBSITE

78 Summary: Stage IB Surgery: Adjuvant chemotherapy: controversial (non significant improvement): Discuss risks and benefits with individual patient Post operative adjuvant radiation : No proven benefit My choice: Stage IB: Surgical resection consider adjuvant Rx for over 4 cm

79 ASCO WEBSITE

80 Summary: Stage II Surgery: Adjuvant chemotherapy: Strong evidence for benefit fro good PS patient. Neo-adjuvant therapy: Under investigation. Post operative adjuvant radiation : No prospective data to support routine use My choice: Surgical resection adjuvant chemotherapy

81 ASCO WEBSITE

82 Summary: Stage IIIA Surgery if feasible Adjuvant chemotherapy: Strong evidence for beneficial for good PS patient. Neo-adjuvant therapy: Consider for known N2 preoperatively (chemo or chemo-rt) Post operative adjuvant radiation : No prospective data to support routine use, however may consider in high risk N2 or positive margin patients.

83 My choice Stage III (unresectable) : Definitive chemo-rt (in order of preference) 1. Concurrent-consolidation: CT/RT CT 2. Concurrent: C-RT 3. Sequential: C RT

84 My choice: Concurrent-consolidation: CT/RT CT Etoposide-Cisplatin Chemotherapy Docetaxel Chemotherapy for 3 cycles Etoposide-Cisplatin with Radiation (SWOG 9504)

85 My choice: Concurrent-consolidation: CT/RT CT Paclitaxel-Carboplatin Chemotherapy Paclitaxel-Carboplatin or Docetaxel Chemotherapy For 2-3 cycles Paclitaxel-Carboplatin with Radiation and Post Chemo-RT therapy

86 My choice I do not routinely use (awaiting more data ) Induction therapy (Neo-adjuvant - chemo + RT ) Surgery Induction-Concurrent: C CT/RT

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88 Chemotherapy Vs BSC BSC Cisplatin based MST 1 yr (%)

89 Modern platinum doublets Med survival 8-10 months 1 yr survival over 30% RR: average 30% or so. Paclitaxel-cisplatin Paclitaxel-carboplatin Gemcitabine-cisplatin Vinorelbine-cisplatin Docetaxel-cisplatin

90 Modern doublets MST 1 yr (%) 5 0 BSC cisplat based mod doublets

91 Non platinum doublets Might be littlebit less effective Might be littlebit better tolerated No survival advantage Paclitaxel-Gemcitabine Docetaxel-Gemcitabine Docetaxel-Vinorelbine Gemcitabine-Vinorelbine

92 Triplets vs doublets No consistent survival benefit More toxic Can not be recommended outside of clinical trial

93 Duration of therapy Paclitaxel-Carboplatin 4 cycles vs continuous till progression No benefit of continuous therapy Most benefits seen in first few cycles Socinski et al.

94 Elderly patients over 70 Clinical trial: Median age yrs Real life: Over 50% are over 70. Single agent vs BSC: Vinorelbine alone vsc BSC: ELVIS study: better quality of life 1 yr survival 32% vs 14% Med surv 7 months vs 5 months MILES study: Italian study V vs G vs VG 1 yr survival 30%-non significant

95 Elderly patients over 70 retrospective data analysis: ECOG 5592: EP vs PC 15% pts over 70 No diff in survival between over or under 70 ECOG % pts over 70 No diff in survival PS 0-1 elderly Platinum based regimen can be offered (?carbolpaltin)

96 POOR PS patients ECOG 2 or worse, Karnofsky 70 or below Controversial therapy PS 2 may have some benefit of chemotherapy Less toxic chemotherapy needed Poor PS: med surv 4.9 mo, 1 yr 21% with platinum based therapy Good PS: med surv 8.4 mo, 1 yr rate 31% Stinchecombe et al: Lung cancer: 2006: 51:

97 EGFR inhibitors Gefitinib Chemo+ Gefitinib vs chemo: No survival benefit IMPACT I and II trials med survival 10 months Erlotinib TRIBUTE and TALEVT trials No survival benefit of adding Erlotinib to chemotherapy Med survival 10 months

98 Clinical predictors of EGFR inhibitors (single agent trials) Women, non smokers Adenocarcinoma bronchoalveoplar carcinoma (BAC) Skin rash is a predictor of better outcomes mutations in tyrosine binding domain of EGFR

99 PC vs PC-Bevacizumab PC PC-B RR 15% 35% PFS 4.5 m 6.2 m Med surv 10.3 mo 12.3 mo Bleeding 0.7% 4.4% Sandler A. et al. NEJM: December 14, 2006, 355:

100 Vascular growth factor inhibitors Bevacizumab life threatening hemorrhage in squamous histology use limited to non-squamous histology 15 treatment related deaths: Five hemoptysis related death, 5 febrile neutropenic deaths, two each to GI hemorrhage and CVA, 1 Pulmonary embolism

101 Targeted therapy in first line Bev study: only positive study so far Negative studies when added to CT retinoids matrix metalloproteases EGFR TK1 inhibitors

102 Second line chemotherapy Few patients are candidates overall First trial: Doc vs BSC: Med surv: 7 vs 4.6 mo, 1 yr: 29% vs 19% Shepherd et al: NEJM: 2005, 353:

103 Second line chemotherapy Alimta vs Doc RR: 9.1 vs 8.8% PFS 2.9 mon with both 1 yr: 29.7 with both median: 8.3 mo vs 7.9 mo Alimta has less alopecia,, less neutropenia, less hospitalizations higher elevations of liver enzymes

104 EGFR inhibitors in second and third line Cetiximab: Under evaluation Erlotinib: Erl vs placebo: 1 yr survival: 31% vs 21% med surv 6.7 mo vs 4.7 mo RR: 9 vs 1% Cough, dyspnea and pain improved Never smokers had better benefit Erlotinib+Bevacizumab: ongoing trial

105 Supportive care: Anti-emetics Anemia treatments Respiratory supportive care, Oxygen Smoking cessation Bis-phosphnate for bone mets Pain control Anti-depressants and anti-anxiety drugs Palliative care-hospice care

106 Balancing act Lung cancer therapy is all about balancing act Individualized patient decision after carefully reviewing Risk and benefit of therapy Quality of life and quantity of life issues Constant re-evaluation and course correction

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108 Clinical trials All patients with good PS and organ functions: Potential clinical trial candidates

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

110 Slow progress decade Improvements in 5-year lung cancer survival

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112 Broncho-alveolar carcinoma

113 Adrenal met Seen in 7% asymptomatic pts

114 Stage I lung cancer

115 Pleural effusion

116 Lung cancer-stage 4