Lung Cancer

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Lung Cancer

• R. Zenhäusern

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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

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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

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Non-Small-Cell Lung Cancer

• 75 of all lung cancers
• Majority of patients present with stage III and IV

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NSCLC Histology

• Squamos-cell carcinoma 20-25
• Adenocarcinoma 40
• Large cell carcinoma 10

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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 gt 1.0 cm or positive on PET
• neg. PET scanning does not preclude biopsy
• ASCO Guideline 200422330

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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 200422330

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Staging of Lung Cancer
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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 ?

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Adjuvant Radiotherapy

• Port meta-analysis Trialist Group. Lancet
  1998352257
• 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

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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.

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Adjuvant Chemotherapy

• Undetectable microscopic metastasis at diagnosis
• Individual trials have not shown a significant
  benefit
• Meta-analysis BMJ 1995311899
• Alkylating agents had an adverse effect
• Cisplatin-based therapy
• 13 reduction in risk of death (not significant)

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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 20003431217

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Cisplatin-based Adjuvant Chemotherapy(Internation
al 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 lt0.03
• 5-y. OS 44.5 40.4 p lt0.03
• IALT. NEJM 2004350351

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Overall Survival (Panel A) and Disease-free
Survival (Panel B)
The International Adjuvant Lung Cancer Trial
Collaborative Group, N Engl J Med
2004350351-360
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Adjuvant Chemotherapy

• Conclusion
• One should consider the use of adjuvant
  platinum-based chemotherapy in patients with
  stage I,II or IIA NSCLC

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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

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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 1995311899

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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

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Therapeutic Strategies

• Sequential CTRT
• 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

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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 1990329940
• Sause et al. JNCI 199587198
• Le Chevalier et al. JNCI 1992858

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Sequential chemo- and radiotherapy

• Dillman etal. NEJM 1990329940 (CALGB 8433)
• 2 cycles of Cis / Vbl ? RT (60 Gy/6 w)
• R
• RT (60 Gy/6 w)

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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 1990329940
• Dillman et al. JNCI 1996881210

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Results Sequential CT and RT

• US intergroup trial Sause W. JNCI 199587198
• n458 Sause W. Chest 2000117351
• MS (mo) 5y-S ()
• RT 11.4 5
• 2x Cis/Vbl 13.2 8
• hyper RT 12 6
• French trial Le Chevalier JNCI 1992858
• N353
• 3x CT ? RT vs RT 3y-S 12 vs 4

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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

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Concomitant CT-RT EORTC Trial

• Schaake-Koning C. NEJM 1992326524
• 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)

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EORTC Trial Results

• 2-year Survival
• RT alone 13
• RT daily cisplatin 26
• RT weekly cisplatin 18
• Schaake-Koning C. NEJM 1992326524

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Sequential versus concomitant CT-RT

• Japanese study Furuse K et al. JCO 1999172692
• 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 200322a621
• n611
• 2xCV?RT(60Gy) vs CV/RT OS 4 vs 25 p 0.046

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Neoadjuvant Therapy

• Pancoasts 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 199486673
• Phase II trials report good results of
  neoadjuvant CT

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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

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Metastasis
40-50 at diagnosis 70 during follow-up
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Chremotherapy for NSCLC

• Old agents
• Cisplatin
• Carboplatin
• Etoposid
• Vinblastin

• New agents
• Docetaxel
• Paclitaxel
• Vinorelbine
• Gemcitabine
• Irinotecan

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NSCLC chemotherapy combinations

• Regimes
• CisplatinPaclitaxel
• CisplatinGemcitabine
• CisplatinDocetaxel
• Carboplatinpaclitaxel

• Results (n1155 pts.)
• Response rate 19
• Median survival 8 months
• 1-year survival 33
• 2-year survival 11
• Schiller et al. NEJM 200234692

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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 D1,8
• Cisplatin 80 mg/m2 D1 80 mg/m2 D1
• Paclitaxel 225 mg/m2 D1 135 mg/m2 D1
• Cisplatin 80 mg/m2 D1 80 mg/m2 D1
• Gemcitabine 1250 mg/m2 D1,8 600 mg/m2 D1,8
• Cisplatin 80 mg/m2 D1 80 mg/m2 D1
• CALGB study 9431 Vokes et al. JCO 2002204191

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New agents Induction CT followed by
concomitant CT-RT

• RR(CT) RR(CT-RT) 1yS 2yS 3yS
• ()
• VC 44 73 65 40 23
• PC 33 67 62 29 19
• GC 40 74 68 37 28
• CALGB study 9431 Vokes et al. JCO 2002204191

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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

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Small-cell Lung Cancer (SCLC)

• 15-20 of all lung cancer
• Incidence 15/100000/year
• Men women 5 1

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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

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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

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SCLC Therapy

• No surgery SCLC is a systemic disease
• Chemotherapy is the standard of care
• CisplatinEtoposid
• Limited stage SCLC Bimodality therapy with
  chemotherapy and radiotherapy

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SCLC Therapy

• The addition of thoracic RT significantly
  improves survival in patients with LS-SCLC
• Meta-analysis. Pignon et al. NEJM 19923271618
• 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

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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. NEJM1999341475
• PCI 5.4 greater absolute survival at 3 years

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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

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SCLC Results

• Extensive Disease
• Remission rate 70-80
• CR 20-30
• Median Survival 8-10 months
• 2-year Survival lt 10