lung cancer r. zenhäusern. lung cancer: epidemiology n most common cancer in the world –2./ 3....
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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 RATESEVOLUTION OF CANCER DEATH RATES
1930 1940 1950 1960 1970 1980 1990
US data/Adapted from Cancer Journal for Clinicians, 1994.
MalesMales80
70
60
50
40
30
20
10
0
Year
ProstateProstateColon and rectumColon and rectum
PancreasPancreasStomachStomachEsophagusEsophagusBladderBladder
LungLung
Rat
e pe
r 10
0,00
0 M
ale
Pop
ulat
ion
EVOLUTION OF CANCER DEATH RATESEVOLUTION OF CANCER DEATH RATES
19301930 19401940 19501950 19601960 19701970 19801980 19901990
US data/Adapted from Cancer Journal for Clinicians, 1994.
FemalesFemales8080
7070
6060
5050
4040
3030
2020
1010
00
YearYear
LungLungBreastBreast
Colon and rectumColon and rectum
OvaryOvaryPancreasPancreasUterusUterusStomachStomach
Rat
e pe
r 10
0,0
00 F
emal
e P
opul
atio
nR
ate
per 1
00,
000
Fem
ale
Pop
ulat
ion
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 SURVIVALBy stage and histologic type
LUNG CANCER: 2-YEAR SURVIVALBy stage and histologic type
SquamousSquamous cell cell AdenocarcinomaAdenocarcinoma Large cellLarge cell Small cellSmall cell
47%47%
40%40%
12%12%
46%46%
14%14%
8%8%
43%43%
13%13% 13%13%
6%6% 5%5% 4%4%
Stage IStage I
Stage IIStage II
Stage IIIStage III
Adapted from Rosenow and Carr
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 PETneg. 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 TNM 1y OS 5y OSLocal
I A T1 No Mo 94% 67%I B T2 No Mo 87% 57%
I I A T1 N1 Mo 89% 55%Locally advanced
I I B T2-3 No-1 Mo 73% 39%I I I A T1-2 N2 Mo 64% 23%
T3 N1-2 MoI I I B AnyT N3 Mo 32% 3%
AdvancedI I I B T4 any N Mo 37% 7%I V M1 20% 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 39 vs 38 months (ns) TRM 1.2 vs 1.6% Local recurrence 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
The International Adjuvant Lung Cancer Trial Collaborative Group, N Engl J Med 2004;350:351-360
Overall Survival (Panel A) and Disease-free Survival (Panel B)
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 years2% after 5 years
NSCLC Collaborative Group. BMJ 1995;311:899
Combined chemotherapy and radiation
Sequential strategies– Primary CT C C.. R R R R R– Primary and adjuvant CT C C.. R R R R R C C
Concomitant Strategies– Daily CT C C C C C C C C C C
R R R R R R R R R R– Intermittent CT C.. C..
R R R R R R R R R R Combined Strategies
– Primary and concomitant CT 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)
RRT (60 Gy/6 w)
Results: Sequential CT and RT
Med. S 2y-S 3y-S 7y-S (%)
CT-RT14 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
MS (mo) 5y-S (%)RT 11.4 52x Cis/Vbl 13.2 8hyper RT 12 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: 13% RT + daily cisplatin: 26% RT + weekly cisplatin: 18%
Schaake-Koning C. NEJM 1992;326:524
INOPERABLE NSCLCSurvival after radiotherapy and cisplatin
INOPERABLE NSCLCSurvival after radiotherapy and cisplatin
100100
9090
8080
7070
6060
5050
4040
3030
2020
1010
00
Su
rviv
al (
%)
Su
rviv
al (
%)
RadiotherapyRadiotherapy
Radiotherapy + cisplatin weeklyRadiotherapy + cisplatin weekly
Radiotherapy + cisplatin dailyRadiotherapy + cisplatin daily
00 11 22 33 44Year of StudyYear of Study
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: Curran WJ. ASCO 2003;22:a621
n=6112xCVRT(60Gy) vs CV/RT 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
Metastasis40-50% at diagnosis
70% during follow-up
Chremotherapy for NSCLC
Old agents
– Cisplatin
– Carboplatin
– Etoposid
– Vinblastin
New agents
– Docetaxel
– Paclitaxel
– Vinorelbine
– Gemcitabine
– Irinotecan
NSCLC: chemotherapy combinations
Regimes
– Cisplatin+Paclitaxel
– Cisplatin+Gemcitabine
– Cisplatin+Docetaxel
– Carboplatin+paclitaxel
Results (n=1155 pts.)
Response rate 19%
Median survival 8 months
1-year survival 33% 2-year survival 11%
Schiller et al. NEJM 2002;346:92
New agents: Induction CT followed by concomitant CT-RT
Induction (2 cycles)Concomitant (2 cycles)
Vinorelbine 25 mg/m2 D1,8,(15) 15 mg/m2 D1,8Cisplatin 80 mg/m2 D1 80 mg/m2 D1
Paclitaxel 225 mg/m2 D1 135 mg/m2 D1Cisplatin 80 mg/m2 D1 80 mg/m2 D1
Gemcitabine 1250 mg/m2 D1,8 600 mg/m2 D1,8Cisplatin 80 mg/m2 D1 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
Confined to:
– One hemithorax– Mediastinum– Ipislateral hilar
and supraclavicular nodes
Extensive Disease
– 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 80-90%– CR 50-60%– Median Survival 18-20
months– 2-year Survival 40%– 5-year Survival 15-25%
SCLC Results
Extensive Disease:
– Remission rate 70-80%– CR 20-30%– Median Survival 8-10
months– 2-year Survival < 10%
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