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

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ale

Pop

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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

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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

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Su

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Su

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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%