Transcript Bronchuskarzinom
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 – Women 1965-: 5
70/100000/J 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%
80 70 60 50 40 30 20 10 0 1930 1940 1950 1960 Year 1970 1980 1990 US data/Adapted from
Cancer Journal for Clinicians
, 1994.
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%
Squamous cell
Adapted fr om 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
IA IB IIA
Locally advanced
IIB IIIA IIIB
Advanced
IIIB IV
TNM
T1 No Mo T2 No Mo T1 N1 Mo T2-3 No-1 Mo T1-2 N2 Mo T3 N1-2 Mo AnyT N3 Mo T4 any N Mo M1
1y OS 5y OS
94% 87% 89% 73% 64% 32% 37% 20%
67% 57% 55% 39% 23% 3% 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 1.2 vs 1.6% 13 vs 12% (ns) 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 5-Y. DFS 5-y. OS
CT
39.4%
44.5% no CT
34.3%
40.4%
p <0.03
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;350:351 360
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
Concomitant Strategies
– Daily CT – Intermittent CT
Combined Strategies
– Primary and concomitant CT
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Therapeutic Strategies
Sequential CT–RT
Concomittant C-RT +
CT in standard dose of micrometastasis volume of primary tumor
+
Improvement of local control (radiosensitisation)
-
longer treatment time delay of RT
-
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) R 2 cycles of Cis / Vbl RT (60 Gy/6 w) RT (60 Gy/6 w)
Results: Sequential CT and RT
CT-RT RT Med. S 14 mo 10 mo 2y-S 3y-S 7y-S (%) 26 23 17 13 11 6 Dillman etal. NEJM 1990;329:940 Dillman et al. JNCI 1996;88:1210
Results: Sequential CT and RT
US intergroup trial
n=458
RT 2x Cis/Vbl hyper RT
Sause W. JNCI 1995;87:198 Sause W. Chest 2000;117:351
MS (mo) 11.4
13.2
12 5y-S (%) 5 8 6
French trial
N=353
3x CT
RT vs RT
Le Chevalier JNCI 1992;8:58
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/m 2 – 30 mg/m 2 daily weekly – 70 mg/m 2 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/m 2 ) – RT + weekly cisplatin (30 mg/m 2 )
EORTC Trial: Results
RT alone: RT + daily cisplatin: RT + weekly cisplatin: 2-year Survival 13% 26% 18% Schaake-Koning C. NEJM 1992;326:524
Adapted from
NEJM.
1992;326:524-530.
Sequential versus concomitant CT-RT
Japanese study:
n= 320
2 cycles MVC
Furuse K et al. JCO 1999;17:2692
RT 56 Gy MS (mo) 5y-DFS 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
– 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 2-year survival 33% 11%
Schiller et al. NEJM 2002;346:92
New agents: Induction CT followed by concomitant CT-RT Vinorelbine Cisplatin Paclitaxel Cisplatin Gemcitabine Cisplatin Induction
(2 cycles)
Concomitant
(2 cycles) 25 mg/m 2 D1,8,(15) 80 mg/m 2 D1 225 mg/m 2 D1 80 mg/m 2 D1 1250 mg/m 2 D1,8 80 mg/m 2 D1 15 mg/m 2 D1,8 80 mg/m 2 D1 135 mg/m 2 D1 80 mg/m 2 D1 600 mg/m 2 D1,8 80 mg/m 2 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 P+C G+C 44% 73% 33% 67% 40% 74% 65 62 68 40 29 37 23 19 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 – 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%