Overview of Lung Cancer

1
Overview of Lung Cancer

• Nevin Murray, MD FRCPC
• BC Cancer Agency Lung Tumour Group

2
Incidence and Mortality Rates for Lung Cancer in
Canadian Men and Women
National Cancer Institute of Canada Canadian
cancer statistics 2004
3
Estimated Incidence and Mortality for Cancer in
Canada, 2004
National Cancer Institute of Canada Canadian
Cancer Statistics 2004
4
Histological Types of Lung Cancer
Adenocarcinoma
75
Squamous cell
50
BAC
Percent
Large cell
25
Other
0
Gazdar and Linnoila, Seminars Oncol 1988 15(3)
215
5
NSCLC Treatment and Outcomes
NSCLC Treatment and outcomes according to stage
Stages IIIa resectable
Stages IIIa/b unresectable
Stages IIIb / IV
Stages I II
Surgery CHT
Surgery /- pre-operative CHT, RT/- CHT
CHT with 2 agents for 3-4 cycles
CHT RT or CHT followed by RT
40-70 5 yr survival
15-30 5 yr survival
30 35 1 yr survival
10-20 5 yr survival
CHT chemotherapy RT radiotherapy
Spira and Ettinger, New Engl J Med 2004 350 379
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Lung Case 1

• 60 year old former smoker with completely
  resected T2N0M0 large cell anaplastic carcinoma
  of RUL.
• Appropriate preoperative work-up.
• 3 weeks post-op. No complications.
• No co-morbidity. CrCl 75 cc/min.
• Performance status 0. Hematology and
  biochemistry normal. Somewhat intimidated by
  prospect of chemotherapy.

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Adjuvant Chemotherapy Rationale
Surgical Survival Relapse () Stage 5 yr
() Local Distant IA T1NOMO 67 10 15 IB T2NOMO
57 10 30 IIA T1N1MO 55 IIB T2N1MO 39 12 4
0 T3NOMO 38 IIIA T3N1MO 25 15 60 T1-3N2MO
23

Mountain 1997 Feld 1984 Pairolero 1984 Martini
1980 Thomas 1990
8
Adjuvant Therapy

• Administered following definitive local therapy
  with the intent to improve outcome
• Overall survival
• Disease-free survival
• Local recurrence rate

9
Adjuvant Therapy

• General principles
• Occult, viable cancer cells present following
  surgery account for risk of disease relapse
• Treatments with proven effectiveness against the
  cancer are available
• Risk-benefit ratio for therapy must be favourable
  for individuals who may remain asymptomatic for
  their natural life expectancy after tumour
  resection

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PORT Meta-analysis
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NSCLC Collaborative Group Meta-analysis
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IALT - Overall Survival NEJM 2004
___ Chemotherapy
___ Control
240 mg/m2 - 74 PORT - 27
Yrs
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IALT Conclusions

• Overall survival
• Five-year survival with chemotherapy 44.5 versus
  40.4 in the control arm (? 4.1)
• Hazard ratio for death 0.86 (95 CI 0.76-0.98, p
  lt0.03)
• Treatment related mortality 0.8
• Disease-free survival
• 39.4 with chemotherapy versus 34.3 in the
  control arm at five years (? 5.1)
• Hazard ratio 0.83 (95 CI 0.74-0.94, plt0.003)

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IALT

• Number Needed to Treat
• 24
• Number Needed to Harm
• 122

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JBR.10 - Study Design Winton, NEJM 2005
RANDOM I ZE
STRATIFIED Nodal N0 N1 ras Neg
Pos UNK
ELIGIBLE T2N0, T1-2N1 ? Lobectomy N2
sampling
No Chemotherapy
Chemotherapy VbP x 4 cycles
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JBR.10 - Overall SurvivalWinton, NEJM 2005
____ VbP ____ Observation
HR 0.696 .524-.923 p0.012
3 cycles - 59 PORT - No
69 54
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JBR.10 - ConclusionsAdjuvant VbP in Stage IB/II
NSCLC

• Adjuvant VbP safe (59 3 cycles)
• Absolute benefit 15 at 5 years, p0.0022
• 30 reduction risk of death, p0.012
• Subgroup analysis stage IB, p0.79
• no effect of stage by treatment, p0.13
• events less than planned

Winton, NEJM 2005
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CALGB 9633 - Overall SurvivalStrauss, ASCO
237019, 2004
----- Chemotherapy ----- Observation
HR 0.62 0.41-0.95 p0.028
4 cycles - 85 PORT - No
71 59
4 yr
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CALGB 9633 - ConclusionsAdjuvant PacCb in Stage
IB NSCLC

• Adjuvant PacCb safe (85 4 cycles)
• Overall Survival
• Absolute benefit 12 at 4 years
• 38 reduction risk of death, p0.028
• Lung Cancer Specific Mortality
• Absolute reduction 11 at 4 years
• 49 reduction risk of death, p0.018

Strauss, ASCO 237019, 2004
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Adjuvant Chemotherapy

• Why are the NCIC/CALGB results better?
• Patient Selection
• Earlier stage disease
• Uniform patient population
• ? More women, more adenocarcinoma
• Therapy
• 2 drug regimen
• Inclusion of 3rd generation agent no
  pneumotoxins
• Better compliance (CALGB)
• Lack of radiation

21
Current BC Cancer Agency Recommendations

• PORT
• Not considered routine
• Discussion with patients with N2 disease or close
  margins
• Adjuvant chemotherapy
• Routine recommendation to appropriate
  post-thoracotomy patients
• Eligibility
• Completely resected stage IB to IIIA disease
• Lobectomy or pneumonectomy preferred
• ECOG performance status 0-1
• Able to start chemotherapy within 2 months of
  surgery
• No upper limit age restriction

22
Lung Case 2

• A 53 year old woman presents with persistent
  cough.
• Chest X-ray a right upper lobe (RUL) mass.
• 30 pack-year smoking history.
• Fully functional, excellent performance status
  (PS1)
• No weight loss.

23
Lung Case 2

• Subsequent CT scan reveals a 2.8 cm RUL mass and
  a 2 cm precarinal (N2) lymph node.
• No other enlarged mediastinal nodes and no
  evidence of distant metastases.
• Fine needle aspiration (FNA) of the RUL mass
  discloses poorly differentiated adenocarcinoma.
• Bronchoscopy no other lesions.
• Volumes allow radical thoracic irradiation. 

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PET for NSCLC
PET image courtesy of Dr Nevin Murray, BC Cancer
Agency
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A) Proceed to Surgical ResectionB) Radical
radiotherapyC)     Preoperative Chemotherapy
D)    Preoperative ChemoradiotherapyE)
Sequential Chemotherapy followed by
Radiotherapy without SurgeryF)    Concurrent
Chemoradiotherapy without Surgery
Lung Case 2 Recommendation
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Sequential Chemo and RT

• CALGB 8433 - Dillman

Chemo and RT
23
RT alone
11
27
Concurrent Chemoradiation

• Theoretically improves local control by
  sensitizing the tumour to radiation, while
  treating systemic disease
• Early definitive local therapy potential benefits
• Decrease metastatic events
• Decrease accelerated repopulation
• Decrease emergence and spread of chemotherapy
  resistance elements.
• Decrease radiotherapy resistance
• Destroy as much cancer as quickly as possible

28
Long Term Survival Comparison between Sequential
and Concurrent Chemoradiation Therapy
29
Chemotherapy and Surgery

• Depierre, JCO 20(1)247, 2002

355 stage I (except T1N0), II, IIIA PS 0-1, age
lt75
Chemo
Surgery
mitomycin 6mg/m2 d 1, ifosfamide 1.5 g/m2 d 1-3,
cisplatin 30mg/m2 d1-3 q 21d x 2 cycles
Surgery
Chemo responders
60Gy over 7 weeks pT3 or pN2 disease and/or those
with incomplete surgery
Chemo
Radiation
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Intergroup 0139/RTOG 9309
Albain, World Conference on Lung Cancer 2003,
Abstract PL-4
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Intergroup 0139/RTOG 9309
Albain, World Conference on Lung Cancer 2003,
Abstract PL-4
32
Intergroup 0139/RTOG 9309
Albain, World Conference on Lung Cancer 2003,
Abstract PL-4
33
Survival
34
Survival
35
Survival
36
Trimodality Perioperative complications

• No patients
• Deaths 0 0
• Complications
• Post-thoracotomy pain 1 4
• Empyema 1 4

37
Lung Case 3

• A 50 year old female presents with stage IV
  adenocarcinoma of the lung.
• Staging demonstrates an adrenal lesion and
  several small liver metastases.
• Brain scan is negative.
• Biochemistry and hematology are normal.
• Performance status is 1.
• Weight loss lt5.

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Treatment Regimens for NSCLC Historical Context
1-Yr Survival
New Single Agents
Cis NVB/Txtr/Gem Carbo Txl3
CDDP-combos Pre-1995
Supportive Care
39
Newer 2-agent Platinum-basedCombination Therapies

• Docetaxel
• Gemcitabine
• Irinotecan
• Paclitaxel
• Topotecan
• Vinorelbine

• Cisplatin
• Carboplatin

Haura E Cancer Control 2001 8(4)326-36.
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Survival ECOG 1594
Schiller et al. ASCO, 2000.
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Issues in the 90s

• New Drugs vs Old?
• New vs New?
• Cis vs Carbo?
• 1 vs 2 vs 3?
• Platin vs Non-platin-containing?
• Maintenance therapy?

42
Doublets vs. Doublet Targeted Therapy

• Chemo /- prinomastat (MMPI)
• Carbo/paclitaxel /- gefitinib
• Gem/cis /- gefitinib
• Carbo/paclitaxel /- erlotinib
• Gem/cis /- erlotinib
• Carbo/paclitaxel /- ISIS 3521 (anti-sense raf
  kinase)
• Chemo /- lonifarnib (FTI)

NEGATIVE
43
Lung Case 4

• A 55 year old male caucasian smoker received
  first-line chemotherapy with cisplatin/gemcitabine
  for stage IV squamous cell carcinoma of the
  lung.
• Bone lesions responded to chemotherapy and there
  was no evidence of progression until a liver
  lesion developed 8 months later.
• Patient is ambulatory but has lost 7 body weight
  and albumin is 29 grams per liter.
• He continues to be keen for additional active
  therapy.
• Management?

44
Retrospective Analysis of Response Rates in NSCLC
Massarelli, et al., ASCO abstract 2002
45
Second-line Docetaxel in Advanced NSCLC
Cumulative probability
1.0
Docetaxel 75 mg/m2 (n55) Best supportive care
(n49)
0.8
Doc 67.5 37
BSC 4.6 12
Response() Median survival
(months) 1-year-survival ()
0.6
0.4
0.2
p0.01 (log rank)
0.0
0
3
6
9
12
15
18
21
Survival time (months)
Shepherd FA et al. J Clin Oncol 2000 18
2095-2103
46
BR.21 schema
RANDOM I ZE

• Stratified by
• Center
• Performance status
• (0/1 vs 2/3)
• Response to prior Rx
• (CR/PRSDPD)
• Prior regimens
• (1 vs 2)
• Prior platinum
• (Yes vs no)

TarcevaTM150 mg daily
Placebo150 mg daily
SDstable disease PDprogressive disease 21
randomization.
47
Overall Survival All Patients
1.00 0.75 0.50 0.25 0
42.5 improvement in median survival
HR0.73, Plt0.001
31
Survival distribution function
TarcevaTM Placebo
21
0 5 10 15 20 25 30
Survival time (months)
HR and P-value adjusted for stratification
factors at randomization plus HER1/EGFR status.
48
Clinical Predictors of EGFR Tyrosine Kinase
Inhibitors

• Adenocarcinoma with BAC Features
• Lifetime non-smoking status
• Females
• Southeast Asian Origin

49
Survival Improvement in Stage III NSCLC since
1980s
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CXR Screening

• Three studies in the 1970s
• Memorial Sloan Kettering, Johns Hopkins and Mayo
  Clinic
• 1980s Czechoslovakian study
• No mortality difference screened vs. control
  group with CxR

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Automated Quantitative Cytology System
5 of smokers with 5 non-diploid sputum cells
developed lung cancer within 5 years
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CIS in Trachea Detected By Onco-LIFE
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Baseline CT scan
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12 month Follow-up CTStage IA Squamous Cell
Carcinoma
55
3,356 Nodules (n1,118 74)

• 96 Benign
• False positives
• gt100 million lung nodules in high-risk Americans

Benign nodules
Lung cancers
56
79
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Definition Well Person

• Some one who has not ..
• had a screening CT

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ELCAP

• 1000 baseline exams
• 27 CT detected cancers
• 7 CxR detected cancers
• 85 stage I

Henschke, et al, Lancet 351 1998
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What we do know

• CT gt CXR
• ? More early stage
• Ancillary findings
• False positives

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What we dont know

• Saving lives?
• Same advanced stage?
• QOL?
• Good gt Harm?
• Cost Effectiveness?

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