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Lung Cancer
R. Zenhäusern
Lung cancer: Epidemiology

Most common cancer in the world
– 2./ 3. most cancer in men / women

1.2 million new cases / year

1.1 million deaths / year

Incidence
– Men 1940-80: 10  70/100000/J
– Women 1965-: 5  30/100000/J
Lung cancer: Epidemiology

13% of cancers,
18% of cancer deaths
Switzerland 3500 new cases / year
80% die during the first year

Prognosis remains dismal:



– five-year survival 10-14%
EVOLUTION OF CANCER DEATH RATES
80
Lung
Males
Rate per 100,000 Male Population
70
60
50
40
30
Prostate
Colon and rectum
20
Pancreas
Stomach
Esophagus
Bladder
10
0
1930
1940
1950
1960
1970
1980
1990
Year
US data/Adapted from Cancer Journal for Clinicians, 1994.
EVOLUTION OF CANCER DEATH RATES
Rate pe r 10 0,0 00 Female Pop ulation
80
Females
70
60
50
40
30
Lung
Bre ast
20
Colon and rectum
Ova ry
Pancreas
Uterus
Stoma ch
10
0
193 0
194 0
195 0
196 0
197 0
198 0
199 0
Yea r
US data/Adapted from Cancer Journal for Clinicians, 1994.
Non-Small-Cell Lung Cancer


75 % of all lung cancers
Majority of patients present with
stage III and IV
NSCLC: Histology

Squamos-cell carcinoma
20-25%

Adenocarcinoma
40%

Large cell carcinoma
10%
LUNG CANCER: 2-YEAR SURVIVAL
By stage and histologic type
47%
46%
43%
40%
Stage I
Stage II
Stage III
14%
12%
13% 13%
8%
6% 5%
Squamous cell
Adenocarcinoma
Large cell
4%
Small cell
Adapted from Rosenow and C arr
NSCLC: Staging

Staging Locoregional Disease:
– Chest x-ray and chest CT scan
(including liver and adrenal glands)
– No evidence of distant metastatic disease:
FDG-PET ist recommended
– Biopsy of mediastinal LN ist recommended:
CT-scan > 1.0 cm or positive on PET
neg. PET scanning does not preclude biopsy
ASCO Guideline 2004;22:330
NSCLC: Staging

Staging Distant Metastatic Disease:
– No evidence of distant metastatic disease on
CT scan of the chest: PET ist recommended
– A bone scan is optional
– Resectable primary lung lesion and bone lesion
on PET/bone scan: MRI/CT and biopsy
– Brain: CT or MRI if symptoms, patients with
stage III considered for aggressive local Th.
– Isolated adrenal mass: biopsy
– Isolated liver mass: biopsy
ASCO Guideline 2004;22:330
Staging of Lung Cancer
Stage
Local
TNM
IA
T1 No Mo
IB
T2 No Mo
IIA
T1 N1 Mo
Locally advanced
IIB
T2-3 No-1 Mo
IIIA
T1-2 N2 Mo
T3 N1-2 Mo
IIIB
AnyT N3 Mo
Advanced
IIIB
T4 any N Mo
IV
M1
1y OS
5y OS
94%
87%
89%
67%
57%
55%
73%
64%
39%
23%
32%
3%
37%
20%
7%
1%
Local NSCLC: Stage I, II





Standard of care = Surgery
Relapse rate
35%-50% in St. I
Relapse rate
40%-60% in St. II
Adjuvant radiotherapy ?
Adjuvant chemotherapy ?
Adjuvant Radiotherapy

Port meta-analysis Trialist Group. Lancet 1998;352:257
– 9 randomised trials of postoperative RT versus surgery
(2128 patients)
–
–
–
–
21% relative increase in the risk of death with RT
Reduction of OS from 55% to 48% (at 2 years)
Adverse effect was greatest for Stage I,II
St.III (N2): no clear evidence of an adverse effect
Adjuvant Radiotherapy

Conclusion
– Postoperative RT should not be used outside of a
clinical trial in Stage I, II lung cancer, unless
surgical margins are positive and repeated
resection is not feasible.
Adjuvant Chemotherapy



Undetectable microscopic metastasis at diagnosis
Individual trials have not shown a significant benefit
Meta-analysis BMJ 1995;311:899:
– Alkylating agents had an adverse effect
– Cisplatin-based therapy:
13% reduction in risk of death (not significant)
Postoperative Chemo- and Radiotherapy





ECOG-Trial: 488 patients with stage II, IIIA
RT alone (50.4 Gy) versus
RT + 4x Cisplatin/Etoposid
Median survival
TRM
Local recurrence
39 vs 38 months (ns)
1.2 vs 1.6%
13 vs 12%
Keller et al. NEJM 2000;343:1217
Cisplatin-based Adjuvant Chemotherapy
(International Adjuvant Lung Cancer Trial Collaboratvie Group)

Randomised trial of 3-4 cycles of cisplatin-based
CT vs observation in patients with St. II, III LC
CT
no CT
5-Y. DFS
39.4%
34.3%
p <0.03
5-y. OS
44.5%
40.4%
p <0.03
IALT. NEJM 2004;350:351
Overall Survival (Panel A) and Disease-free Survival (Panel B)
The International Adjuvant Lung Cancer Trial Collaborative Group, N Engl J Med 2004;350:351360
Adjuvant Chemotherapy

Conclusion:
– One should consider the use of adjuvant
platinum-based chemotherapy in patients with
stage I,II or IIA NSCLC
Locally advanced NSCLC


Thoracic irradiation is the mainstay of
treatment for inoperable stage III disease
Its curative potential is extremely poor
5-year survival rates 3-5%
Locally advanced NSCLC

A meta-analysis of 22 randomised studies
showed a beneficial effect of CT added to
RT
– 10% reduction in risk of death per year
– Small absolute survival benefit:
4% after 2 years
2% after 5 years
NSCLC Collaborative Group. BMJ 1995;311:899
Combined chemotherapy and radiation


Sequential strategies
– Primary CT
– Primary and adjuvant CT
C C.. R R R R R
C C.. R R R R R C C
– Daily CT
C C C C C
R R R R R
C..
R R R R R
Concomitant Strategies
– Intermittent CT

Combined Strategies
– Primary and concomitant CT
C C C C C
R R R R R
C..
R R R R R
C...
C C.. R R R R R
Therapeutic Strategies

Sequential CT–RT
+ CT in standard dose
 of micrometastasis
 volume of primary tumor
- longer treatment time
delay of RT

Concomittant C-RT
+ Improvement of local
control
(radiosensitisation)
- greater toxic effects
Reduced dose of CT
Sequential chemo- and radiotherapy


Studies performed in the 1980s did not show an
advantage
Three large phase III trials gave pos. Results
– Dillman etal. NEJM 1990;329:940
– Sause et al. JNCI 1995;87:198
– Le Chevalier et al. JNCI 1992;8:58
Sequential chemo- and radiotherapy
Dillman etal. NEJM 1990;329:940 (CALGB 8433)
2 cycles of Cis / Vbl  RT (60 Gy/6 w)
R
RT (60 Gy/6 w)
Results: Sequential CT and RT
Med. S
2y-S 3y-S 7y-S (%)
CT-RT
14 mo
26
23
17
RT
10 mo
13
11
6
Dillman etal. NEJM 1990;329:940
Dillman et al. JNCI 1996;88:1210
Results: Sequential CT and RT

US intergroup trial
Sause W. JNCI 1995;87:198
n=458
Sause W. Chest 2000;117:351
RT
2x Cis/Vbl
hyper RT

MS (mo)
11.4
13.2
12
5y-S (%)
5
8
6
French trial
Le Chevalier JNCI 1992;8:58
N=353
3x CT  RT vs RT
3y-S
12% vs 4%
Concomitant Chemo- and Radiotherapy

Simultaneous CT / RT
is beneficial in:
– Head and neck cancer
– Anal cancer
– Cervical cancer

Cisplatin is effective
as a radiosensitiser
– 6-8 mg/m2 daily
– 30 mg/m2 weekly
– 70 mg/m2 3-weekly
Concomitant CT-RT: EORTC Trial

Schaake-Koning C. NEJM 1992;326:524
331 patients randomised to one of three regimens:
– RT alone: 30 Gy in 10 fractions, 3-week rest period,
25 Gy in 10 fractions
– RT + daily cisplatin (6-8 mg/m2)
– RT + weekly cisplatin (30 mg/m2)
EORTC Trial: Results
2-year Survival



RT alone:
RT + daily cisplatin:
RT + weekly cisplatin:
13%
26%
18%
Schaake-Koning C. NEJM 1992;326:524
INOPERABLE NSCLC
Survival after radiotherapy and cisplatin
100
Radiotherapy
90
Radiotherapy + cisplatin weekly
80
Radiotherapy + cisplatin daily
Survival (%)
70
60
50
40
30
20
10
0
0
1
2
Year of Study
3
4
Adapted from NEJM.1992;326:524-530.
Sequential versus concomitant CT-RT

Japanese study:
Furuse K et al. JCO 1999;17:2692
n= 320

MS (mo)
5y-DFS
-2 cycles MVC  RT 56 Gy
13.3
19%
-MCV/RT-10 days rest-MVC/RT
16.5
27%
RTOG 9410:
n=611
2xCVRT(60Gy) vs CV/RT
Curran WJ. ASCO 2003;22:a621
OS:
4 vs 25%
p= 0.046
Neoadjuvant Therapy

Pancoast`s tumor, vertebral invasion
– Combined neoadjuvant CT-RT should be considered

Tumors with ipsilateral mediastinal spread (N2)
– Poor survival with surgery alone
– 2 small randomised trials showed a benefit of
neoadjuvant combined CT-RT
– Roth et al. JNCI 1994;86:673
– Phase II trials report good results of neoadjuvant CT§
SAKK Studies

SAKK 16/00
– Preoperative CRT vs CT in NSCLC stage IIIA
– CT: 3 cycles docetaxel and cisplatin (D1,22,43)
– RT: 3 weeks of RT (44 Gy in 22 fractions)

SAKK 16/01
– Preoperative CRT in NSCLC pts with operable
stage IIIB disease
– The same regimen as 16/00
Metastasis
40-50% at diagnosis
70% during follow-up
Chremotherapy for NSCLC

Old agents

New agents
– Cisplatin
– Docetaxel
– Carboplatin
– Paclitaxel
– Etoposid
– Vinorelbine
– Vinblastin
– Gemcitabine
– Irinotecan
NSCLC: chemotherapy combinations

Regimes

Results

Response rate 19%
– Cisplatin+Gemcitabine

Median survival 8 months
– Cisplatin+Docetaxel

– Cisplatin+Paclitaxel

– Carboplatin+paclitaxel
(n=1155 pts.)
1-year survival
2-year survival
33%
11%
Schiller et al. NEJM 2002;346:92
New agents:
Induction CT followed by
concomitant CT-RT
Induction
(2 cycles)
Concomitant
Vinorelbine
Cisplatin
25 mg/m2 D1,8,(15)
80 mg/m2 D1
Paclitaxel
Cisplatin
225 mg/m2 D1
80 mg/m2 D1
135 mg/m2 D1
80 mg/m2 D1
Gemcitabine
Cisplatin
1250 mg/m2 D1,8
80 mg/m2 D1
600 mg/m2 D1,8
80 mg/m2 D1
(2 cycles)
15 mg/m2 D1,8
80 mg/m2 D1
CALGB study 9431: Vokes et al. JCO 2002;20:4191
New agents:
Induction CT followed by
concomitant CT-RT
RR(CT) RR(CT-RT)
1yS
2yS
3yS
(%)
V+C
44% 73%
65
40
23
P+C
33% 67%
62
29
19
G+C
40% 74%
68
37
28
CALGB study 9431: Vokes et al. JCO 2002;20:4191
Conclusion: Combined-Modality Therapy for
Stage III Disease


Adding CT to radiation therapy improves survival and alters
the course of this disease
Phase III studies suggest improvement in both local control
and survival with concomitant CT-RT

Combined CT-RT should be the standard of care of patients
with good PS and minimal weight loss

The absolute gain from combined CT-RT is still modest

The role of surgery following induction CT-RT is for patients
with unresectable Cancer is being explored
Small-cell Lung Cancer
(SCLC)

15-20% of all lung cancer

Incidence: 15/100000/year

Men : women = 5 : 1
SCLC





Rapid local and metastatic spread
Mediastinal lymph node metastasis in most
cases
Median Survival in untreated patients 2-3
months
Superior vena caval obstruction and
paraneoplastic syndromes (SIADH, Cushing)
Association with smoking
SCLC Staging

Limited Disease

Extensive Disease
Confined to:
– One hemithorax
– Mediastinum
– Ipislateral hilar
and supraclavicular
nodes
– Malignant pleura
and pericard
effusion
– Contralateral hilar
and supraclavicular
nodes
SCLC Therapy

No surgery; SCLC is a systemic disease

Chemotherapy is the standard of care
– Cisplatin+Etoposid

Limited stage SCLC: Bimodality therapy
with chemotherapy and radiotherapy
SCLC Therapy

The addition of thoracic RT significantly improves
survival in patients with LS-SCLC
– Meta-analysis. Pignon et al. NEJM 1992;327:1618
– 14% reduction in the mortality rate
– 5.4% benefit in terms of OS at 3 years

Early use of RT with CT improves cure rates
SCLC Therapy


The actuarial risk of CNS metastasis developing
2 years after CR of SCLC is 35%-60%
Prophylactic cranial Irradiation is recommended
for pts. With LS-SCLC in CR
– Meta-analysis:
Auperin et al. NEJM;1999:341:475
– PCI: 5.4% greater absolute survival at 3 years
SCLC Results

Limited Disease:
–
–
–
–
–
Remission rate
CR
Median Survival
2-year Survival
5-year Survival
80-90%
50-60%
18-20 months
40%
15-25%
SCLC Results

Extensive Disease:
–
–
–
–
Remission rate
CR
Median Survival
2-year Survival
70-80%
20-30%
8-10 months
< 10%