screening and early diagnosis in lung cancer.ppt
TRANSCRIPT
Epidemiology of lung cancer
• 1912 - 374 cases worldwide (Adler I. Primary malignant growths of the lungs and bronchi. New York: Longmans, Green, and Company; 1912)
• 20th century– 100 million tobacco-related deaths
• 21st century– expected 1 billion deaths; 1/3 due to lung cancer!!
Smoking and smoking cessation
• Smoking is and will remain the leading cause of cancer death (Jemal A et al. Ca Cancer J Clin 2002; 52: 23-47)
• Smoking is increasing among young people and women (Tickle JJ et al. Favorite movie stars, their tobacco use in contemporary movies, and its association with adolescent smoking. Tob Control 2001; 10: 16-22)
Cessation:• Reduces death rate to non-cancer causes immediately (Barone-
Adesi F et al. Short-term effects of Italian smoking regulation on rates of hospital admission for acute myocardial infarction. Eur Heart J 2006; 27:2468.)
• Very limited effect on lung cancer death rate(Enstrom JE et al. Smoking cessation and mortality trends among 118,000 Californians, 1960-1997. Epidemiology 1999, 100: 500-512)
Lung cancer classification based on:
• TNM-staging (revision due early 2009)• histology (SCLC versus NSCLC)• further histological description: squamous,
adeno, large cell• location in thorax: central versus peripheral
Lung cancer outcome• Strongly related to size and stage: small tumors
do better!
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0 5 10 15Years After Enrollment
Deaths / N MST 5-YearcT1, <=2cm 217/ 423 68 53%cT1, >2-3 cm 248/ 445 52 47%cT2, <=5 cm 787/ 1345 43 43%cT2, >5-7 cm 272/ 411 30 36%cT2, > 7 cm 127/ 173 17 26%cT3 354/ 486 19 29%
After stereotactic radiotherapy (Lagerwaard FJ et al. Int J Radiation Oncology Biol Phys 2008; 70: 685-692)
After surgery (Rami-Porta R et al. Journal of Thoracic Oncology. 2007; 2:593-602)
How to improve the outcome of lung cancer?
• Improve systemic therapy (may take decades)
• detect tumors at a curable stage
►try to find lung cancer at an earlier stage: screen the high risk group
However……..
• This is only effective if the outcome of the screen-detected tumors is identical to the outcome of the clinically found tumors…..
How can we screen?• Investigation of patient tissue or cells: sputum cytology ►mainly larger airways; squamous, SCLC
• Radiological imaging: chest X-ray; spiral CT►mainly lung parenchyma; adenoca, large cell
• Endoscopic imaging (bronchoscopy)►only larger airways; squamous, SCLC
• Metabolic imaging (FDG-PET)►size limit > 8 mm
Chest X-ray screening improved outcome for detected lung cancer,
Marcus P et al. Lung Cancer Mortality in the Mayo Lung Project:Impact of Extended Follow-up J Natl Cancer Inst 2000; 92: 1308-1316
Especially in resected early stage but …….
Marcus P et al. Lung Cancer Mortality in the Mayo Lung Project:Impact of Extended Follow-up J Natl Cancer Inst 2000; 92: 1308-1316
Marcus P et al. Lung Cancer Mortality in the Mayo Lung Project:Impact of Extended Follow-up J Natl Cancer Inst 2000; 92: 1308-1316
Chest X-ray studies: no effect on survival
Number of lung cancer deaths
In the example shown, the diagnosis of disease is made earlier in the screened group, resulting in an apparent increase in survival time (lead-time bias), although the time of death is the same in both groups.
Patz EF et al, NEJM 2000; 343: 1627
Potential biases in screening studies: Lead-time bias
The probability of detecting disease is related to the growth rate of the tumor. Aggressive, rapidly growing tumors have a short potential screening period (the interval between possible detection and the occurrence of symptoms). Thus, unless the screening test is repeated frequently, patients with aggressive tumors are more likely to present with symptoms. More slowly growing tumors have a longer potential screening period and are more likely to be detected when they are asymptomatic. As a result, a higher proportion of indolent tumors is found in the screened group, causing an apparent improvement in survival.
Potential biases in screening studies: Length-time bias
Overdiagnosis bias is an extreme form of length-time bias. The detection of very indolent tumors in the screened group produces apparent increases in the number of cases of lung cancer (three in the screened group in the figure and one in the control group) and in survival (two of three patients in the screened group were treated and died of natural causes, without evidence of disease [66 percent survival], and the one patient in the control group did not survive [0 percent survival]), with no effect on mortality (one death from lung cancer in each group). Two patients in the control group died with undiagnosed lung cancer that did not affect their natural life span.
Potential biases in screening studies: Overdiagnosis bias
Other problems with screening studies for lung cancer
• What type of tumors will be found: by CT-screening only parenchymal lesions• If there is no reduction in detection of late stages it will never effect survival
• Crossoverof patients due to availability of screening instruments outside the study
• Sticky-diagnosis bias. Because the target cancer in a screening trial is more likely to be diagnosed in the screened group than in the control group, deaths are more likely to be attributed to the target cancer in the screened group.
• Slippery-linkage bias. Death due to a procedure related to the study but not perse in a case with the target cancer (for instance benign tumor), is often not scored appropriate
Baseline Annual repeat
Total scans 13,122 10,245Number of Tumors 112 55
Stage I (%) 55-85 60-100Stage III,IV (%) 3-36 0-36Rate of Cancer (%) 0.4-2.7 0.07-1.1Mean diameter (mm) 14-21 10-16Invasive procedures for benign lesions (%) 4-22 14-15Interval cancers (%) NA 0-22
Low dose spiral-CTScreening results from 5 large
observational studies
ALCA: anti lung cancer association, JapanELCAP: Early Lung Cancer Action Project, USAMayo Clinic Study, USALung Cancer Screening study, Milan, ItalyHitachi Health Center, Japan
Mulshine J, NEJM, 2005
I-ELCAP results
• 31,567 baseline and 27,456 repeat scans 7-18 months after baseline
• 484 reviewed LC cancer cases detected
• All cases: 10-yr survival 80%• Stage I resected cases (85%): 10-yr survival
92%
• Stage I untreated cases (n=8): dead within 5-yrs
Henschke C, NEJM 2006
I-ELCAP results
Henschke C, NEJM 2006
I-ELCAP results
• Estimated 10-yr survival data• Median FU 3.3 yr, small numbers at risk after 5 yrs
(n=90) and 10 yrs (n=2)• Of all resected stage I LC cases (n=375) survival
curves of only those resected < 1 months presented (n=302).
• No lung cancer specific mortality data
Comments on ELCAP
• Length-time bias?• Overdiagnosis?• Reduction in later stages at annual
screen?• Is the population found comparable to the
normal lung cancer population?
I-ELCAP: length-time bias?
• Of 35 stage I LC cases detected at baseline in ELCAP-I and ELCAP-II 9 had > DT 400 days (26%)
• So far DT’s of all baseline cases have not been reported
• But 87% either invasive growth or DT < 400 days; according to authors overdiagnosis uncommon
• Does invasive growth exclude overdiagnosis ?Henschke C et al. J Clin Imag 2006;30:11-15.
Does invasive growth exclude overdiagnosis ?
• In retrospective study of 149 stage I LC cases 2 CT scans were made
• Median interval 130 days (range 25-2493 days)
* Jennings SG et al, Radiology 2006;241:554-563
Distribution of Doubling times
* Jennings SG et al, Radiology 2006;241:554-563
Tumor Doubling time and LC survival
• Median % volume change +54% (range -81%-10.759%)
• 48/149 (32%) proven invasive LC cases showed no growth or DT > 1 year
• Survival lower in fast growing tumors (p=0.002) also for non-adenocarcinomas/BAC (p<0.05).
• Elderly people had more slow or non-growing tumors (p = 0.047)
* Jennings SG et al, Radiology 2006;241:554-563
I-ELCAP: reduction in number of late stages?
More LN metastases: • baseline 7%• Annual repeat 11%
Different histological distribution:• baseline: adeno/BAC 76%, SCC 13%• annual repeat: 48% adeno/BAC, SCC 22%
I-ELCAP results
7% 11%
less frequent LN metastases
Henschke C et al. Arch Intern Med 2006;166:321-325
Nodule consistency and frequency of LN metastases
Henschke C et al. Arch Intern Med 2006;166:321-325
More baseline lung cancer cases found by CT screening in females
• Henschke, Miettinen (2004): higher risk (2.7) of detecting lung cancer in females than in males at the baseline CT screen
• Controlled for age and pack-years of smoking
• Confounders discussed and found unlikely to contribute (underreporting of smoking in females)
Henschke and Miettinen, Lung Cancer 2004
Effect of Gender in Mayo CT trial
• VDT of 48 cancers detected during 5 annual CT’s
• Males 38% (n=18) , Females 62% (n=30)
Lindell et al Radiology 2007
Male Female
Mean VDT (d) 234±447 688 ±1321
Median VDT (d) 92 217
Possibly Overdiagnosed cancers especially in females
• Overdiagnosed cancers are those with a VDT > 400 days
• Mayo Clinic study: 23% had VDT > 400 days; for all histological subtypes VDT was longer in females
• Hasagawa et al: 44% (27/61) VDT > 400 days
Lindell et al Radiology 2007
Hasagawa et al Br J Radiol 2000
Gender difference in tumor growth rates: females demonstrate slower
growth
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CT CXR
VDT, daysMales Females
Hasegawa et al2000 Usuda et al1994
CT Screening for Lung Cancer
in Health Examination
Toru Nakagawa MD Suzushi Kusano MD
Syuichiro Hosoda MD Syuichiro Yamamoto MD
Masataka Irokawa MD
Hitachi Health Care Center, HITACHI, Ltd., JapanE-mail::::[email protected]
• Large population study in Japan
• Baseline detection rate 0.47%, 90% stage I• Incidence detection rate 0.09%, 100% stage I
• baseline 57/60 ( 95%) adenocarcinoma !!• Incidence 20/22 (91%) adenocarcinoma !!
• Smokers and non-smokers (females)• Lower LC incidence in Japan than in US and Europe• Slow growing adenocarcinomas
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Baseline Repeat
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Repeat
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5th
00,050,10,150,20,250,30,350,40,450,5
Total of Exams. Detection Rate(%)
70%%%% 54%%%% 39%%%% 24%%%%10%%%%100%%%%
Changes of the Detection Rate of Lung Cancer during Baseline and annual Repeat Screening
“ Should Spiral CT screeningfor lung cancer screening already be introduced on a large scale ?”
What would support implementation
aLC is an important diseaseaPrimary prevention is unsuccessfulaThe consequences of LC are substantialaWe have an acceptable and feasible test
(LDCT)aLC can be detected in an early stage by
LDCT
Questions to be answered:
?Has an mortality-based survival benefit been demonstrated and what is the magnitude of lead time and overdiagnosis bias
?Are the side-effects of LC screening in balance with the amount of favourable health outcomes (test/QOL/natural history)
?Will LC screening be accepted to individuals at risk and health care providers (implementation)
? Is LC screening reasonably cost-effective
Overview RCT’s on spiral CT
• NLST: USA, n= 53,000 • NELSON: Holland-Belgium, n=16,000• Italy: n= 10.000 (Pastorino, proposal)• Denmark: n=4,000, part of NELSON• ITALUNG-CT: Italy, n= 3,000• Germany/Heidelberg: n=4,000, NELSON design
National LungScreening Trial
National Cancer Institute
National LungScreening Trial
National Cancer Institute
TSLNChristine D. Berg, MDChief, Early Detection Research GroupDivision of Cancer Prevention | NCIProject Officer, LSS-NLST
Deni R. Aberle, MDCancer Imaging Program, DCTD | NCI
David Geffen School of Medicine at UCLANational PI, ACRIN-NLST
The combat against lung cancer
A Randomised Clinical Trial for
Lung Cancer Screening in high risk subjects
2004-2009
1,019
1,889
6,814
53,476
Nr screened
31/12/05
47%NoNo4-16 detector
MSCT
3
(4 units)
ITALUNG-CT
50%YesYes16-detector
MSCT
1Denmark
76%YesYes16-detector
MSCT
4NELSON
63%NoNo4-64 detector
MSCT
46NLST
Stage I,II
Double reading
Volu-
metry
CTNumber of sites
Trial
Overview ongoing RCT’s
64%/36%2,33355-69No screening
Random sample
ITALUNG-CT
55%/45%4,10450-70No screening
MediaDenmark
85%/15%15,53050-75No screening
Random sample
NELSON
59%/41%53,47655-74CXRMediaNLST
Males / Females
NoAgeControl arm
Selection procedure
Trial
Overview ongoing RCT’s
6 yrs1 yr4<10 yrs>20 PYITALUNG-CT
5 yrs1 yr5<10 yrs> 20 PYDenmark
6 yrs1 and 2 yr3<10 yrs>30 yrs >11 cig
>26 yrs >16 cig
NELSON
2 yrs1 yr3< 15 yrs> 30 PYNLST
Follow-up period
Screening interval
Screening rounds
Ex-smokers
Smoking history
Trial
Overview ongoing RCT’s
Conclusion
• LDCT screening for lung cancer is a very promising early detection tool
• Several uncertainities make it premature to advocate Spiral CT screening on a large scale
• Spiral CT screening should not be recommended outside clinical trials
Flehinger BJ et al. The effect of surgical treatment on survival from early lung cancer. Implications for screening. Chest 1992;101;1013-1018