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FRACP teaching 2007
• 50 year old man with 50 pack year
smoking. PS is normal (ECOG 1).
Investigations show he has a non-small
cell carcinoma stage T2N1M0. His
exercise tolerance is unrestricted and his
bloods are normal. What would be
considered the most appropriate treatment
for him?
•
•
•
•
A.
B.
C.
D.
Surgery
Radical radiotherapy
Combined chemo/RT
Surgery followed by adjuvant
chemotherapy
• E. Downstaging with (neoadjuvant) chemo
followed by surgery
NSCLC – Staging
NSCLC – Staging
•
•
•
•
A.
B.
C.
D.
Surgery
Radical radiotherapy
Combined chemo/RT
Surgery followed by adjuvant
chemotherapy
• E. Downstaging with (neoadjuvant) chemo
followed by surgery
Answer
• D. Resection followed by adjuvant
chemotherapy
Chemotherapy in NSCLC: A Meta-analysis using updated
data on individual patients from 52 randomised clinical trials.
Early Disease: Surgery versus Surgery plus Chemotherapy
Cisplatin-based
Alkylating agents
Other agents
• 5% improvement in survival at 5 years (P=0.08)
with cisplatin-based postoperative chemotherapy
Cisplatin-based
Overall
NSCLC Collaborative Group BMJ 1995; 311: 899-909
Cisplatin-Based Adjuvant Chemotherapy in
Patients with Completely Resected NSCLC:
The IALT Trial
• Observation
• (post-operative thoracic
radiotherapy given to 28% of pts)
• 1867 pts
• Complete resection
• Pathological Stage I, II
or IIIA NSCLC
• Cisplatin 80-100 mg/m2 for 3-4 doses
• Given with etoposide (57% of pts) or
vinorelbine (27% of pts)
• (post-operative thoracic radiotherapy
given to 23% of pts)
The International Adjuvant Lung Cancer Trial Collaborative Group.
New England Journal of Medicine 2004; 350:4 351-360.
Cisplatin-Based Adjuvant Chemotherapy in
Patients with Completely Resected NSCLC:
The IALT Trial
• Absolute 5-year
survival benefit was
4.1% (P = 0.03)
• RT given to <25% pts
• Compliance achieved
in 74% pts
• Chemo mortality <1%
The International Adjuvant Lung Cancer Trial Collaborative Group.
New England Journal of Medicine 2004; 350:4 351-360.
Is this therapy proven?
• Efficacy
– 5% improvement in 5 yr survival demonstrated in
stage II and III by independent studies, JBR10 and
ANITA (platinum and vineralbine) but also LACE
metanalysis pooled data from 5 adjuvant cisplatin
trials
– Evidence in stage I is lacking and not currently
recommeded
• Safety
– Treatment regimens are well established
– <1% treatment-related mortality in postoperative
NSCLC patients
• Statistics
– Conventional levels of significance now achieved
Are the benefits clinically significant?
• Cisplatin-based Postoperative Adjuvant Chemotherapy
in NSCLC
– Absolute survival increased by 5% at 5 years
– NNT, 25 pts treated to prevent 1 death
– Estimated to prevent >7,000 deaths/year worldwide
• Postoperative Adjuvant Breast Cancer Chemo
– Absolute survival increased by 3.3% at 5 years and 6.3% at 10
years
• Thoracic radiotherapy and PCI for SCLC
– Absolute survival benefit of 5.4% at 3 years
Review
Sashidharan et al NZ Med J 2006 119 1245
• A 53 year with a 45 pack year smoking
history presents with haemoptysis and wt
loss of 2%. A CT scan shows a RLL
tumour with mediastinal nodes and 2
lesions in the liver. ECOG PS = 0-1. The
patient is offered palliative chemotherapy
in the for of Carboplatin/paclitaxel. Which
of the following statements about chemo in
NSCLC are true.
• The likely response rate is 50% with
median survival 18 months
• The likely response rate is 20-30% with
median survival 7-9 months
• The response rate is in the order of 1015% and med survival 5 months
• There is no role for chemotherapy for
NSCLC (and all Oncologists who offer this
type of therapy are mad).
Chemotherapy in NSCLC: A Meta-analysis using data from
52 RCTs. Extensive disease. Chemotherapy v Best
Supportive Care
NSCLC Collaborative Group BMJ 1995; 311:
899-908
Alkylating agents
Other agents
Cisplatin based
Chemotherapy
Cisplatin
overall
Median survival improvement 6 weeks
p < 0.001
ECOG 1594: A randomised, phase III
four arm trial in advanced NSCLC
(Shepard et al ASCO 2000)
RR(%)
Pac/Cis
Gem/Cis
Doc/Cis
Pac/Carbo
21
21
17.3
15.3
Med
7.8
8.1
7.4
8.2
1 yr(%)
31
36
31
35
Ist law of Oncology
“Tumour must shrink faster than patient”
All studies tend to be in “fit” patients PS 0-1 with
generally improvement in survival and QOL
PS > 2 very few trials
Elderly patients only single agent vineralbine
assessed and tolerated well “ELVIS” study
Role second and 3rd line chemo
NSCLC response rates decrease with
subsequent regimens of chemotherapy
Objective 25
response
rate (%) 20
20.9
16.3
15
10
5
2.3
2.3
0.0
0
1st
2nd
3rd
4th
Last
Line of therapy
Massarelli et al 2003
Lung Cancer Screening
•
Which of the following statements on
screening for lung cancer in an at risk smoking
group is correct
A.
CT screening is no more sensitive than CXR or sputum
analysis
CT screening shown to improve survival and reduce
mortality from lung cancer in smokers
CT screening shown to improve survival but not
mortality
Screening for lung cancer is now well established and
recommended
B.
C.
D.
Answer
• B
CT screening has been shown to improve
survival but not evidence reduce mortality from
lung cancer in smokers
Lung Cancer Screening
• CT screening more sensitive than CXR (ELCAP I)
detection rate 2.7% v 0.7% Henscke et al lancet
1999;345:99-105
• Improved survival but not mortality (ELCAP I)
• Result however may be due to over diagnosis and lead
time bias
• ELCAP II international study screened 31,567 at risk
individuals NEJM 2006: 355:1763-71
• Estimated 10 yr survival of 302 who were resected 92%
compared with 80% for all 484 patients
ELCAP CT screening
Henschke et al NEMJ 2006; 355:1763-71
Combined Results from 3 centres of Lung Cancer Screening With Computed Tomography
Bach, P. B. et al. JAMA 2007;297:953-961.
Copyright restrictions may apply.
• Screening not currently standard practice
• Early detection may alter survival but not
mortality
• Mayo data suggests good survival of screened
individuals may be due to over diagnosis
(picking up good prognosis tumours) and lead
time bias (earlier detection but not alter
outcome)
• Awaiting results of large RCTs of CT v CXR
• A 42 non smoking asian woman presents
with wt loss and coughing a CXR shows a
4 cm RUL lesion and liver mets. An FNA
shows a NSCLC with the profile of a lung
primary
Which of the following are correct?
1) The cytological profile is likely to be that of an
adenocarcinoma
2) The tumour is likely to respond to an EGFRI
(erlotinib, gefitinib) if there is evidence of EGFR
mutation
3) The correct treatment would be a combination
of EGFR and chemo concurrently
4) Standard treatment would be platinum based
chemo (and consider 2nd line EGFRI)
• Correct answers are 1 ,2 and 4
Responsiveness to EGFR inhibitors
(gefitinb (Iressa) and erlotinib (tarceva)
correlates with
– female gender,
– non smoker,
– adenocarcinoma histology,
– Asian ethnicity
– Mutations in the EGFR gene
Paez et al, Science. 2004 304: 1497-1500
Franklin et al, ASCO 2004
EGFR-TK mutations
and response to gefitinib (IRESSA)
• 8/9 (89%) of patients with striking responses to
IRESSA (>50% tumour shrinkage) had tumours with
EGFR-TK mutations compared to none in 7 who did
not respond
• Over 30 somatic mutations in the EGFR-TK domain
(exons 18-24) have been observed in primary tumour
biopsies from patients with NSCLC
Lynch et al, NEJM 2004
Paez et al, Science 2004
Activating Mutations in the Epidermal
Growth Factor Receptor Underlies the
Responsiveness of NSCLC to Gefitinib
Lynch TJ et al. New England Journal of Medical 2004 350; 21 (20 May 2004)
Paez et al Science 2004 online; Marx J Science 2004 ; 304: 658-9
EGFR mutations
• Activation Mutated EGFR is more intense
and prolonged than wild type
• stabilise interaction between EGFR-TK
and ATP (or competitive inhibitor gefitinib)
• Lower concentration gefitinib will
completely inhibit mutant receptor cf wild
type
Paez et al, science 2004; 304, 1497-1500
Lynch et al, NEJM; 2004; 101, 2129-2139
Combination therapies
Phase III RCT
Chemo ± EGFR TKI stage III or stage IV disease
• INTACT I
Gefitinib ± Gem/cis
• INTACT II
Gefitinib ± Carbo/taxol
• TRIBUTE
Erlotinib ±Carbo/taxol
• TALENT
Erlotinib ± Gem/cis
• Conclusion: no increase in survival in patients
receiving combination treatment
Combination therapy
Why did the combination (INTACT) trials fail?
• Chemo and EGFR-TKI may be antagonistic
(Similar to antagonism demonstrated with
tamoxifen and chemo in breast cancer)
• EGFR-TKI have antiproliferative effects with
p27-mediated G1 cell-cycle arrest of EGFR
which could render tumour cells less sensitive to
cytotoxic agents
BR.21 Study Design
Previously Treated
NSCLC
Stratified by:
Centre
PS, 0/1 vs 2/3
Response to prior Rx
(CR/PR:SD:PD)
Prior regimens,
(1 vs 2)
Prior platinum,
(Yes vs no)
R
A
N
D
O
M
I
S
E
Erlotinib*
150 mg daily
Placebo
“150 mg” daily
*2:1
Randomization
BR.21 Study Endpoints and Statistical
Considerations
• Primary endpoint survival
• Median survival of untreated patients was
estimated to be 4 months
• Goal: detect an improvement in median survival
of 33% (HR 0.75)
• 90% power and a 2-sided 5% level test
• 700 patients required to enter the study over 14
months with 6 months follow-up; 582 events
required
BR.21 Overall Survival
1.00
42.5% improvement in median survival
Survival distribution function
TM
Tarceva
(n=488)
Placebo
(n=243)
Median survival (months)
6.7
4.7
1-year survival (%)
31
21
0.75
0.50
HR* = 0.73, p<0.001
0.25
erlotinb
Placebo
0
0
5
10
15
20
25
30
Survival time (months)
*HR and p-value adjusted for stratification factors at randomisation + HER1/EGFR status
Survival benefit with Tarceva according
to EGFR biomarker status
n
HR
CI
177
0.75
0.53–1.07
p value*
p value†
EGFR mutation status
Wild-type‡
Mutant§
0.11
24
0.52
0.21–1.31
0.16
IHC +ve
184
0.68
0.49–0.95
0.02
IHC –ve
141
0.93
0.63–1.36
0.70
0.45
EGFR expression (IHC)
0.25
Gene copy number (FISH)
Low
69
0.86
0.48–1.51
0.59
High
56
0.44
0.2–0.82
0.008
0.10
*p value for subgroup compared with placebo
†p value for interaction
‡Includes indeterminate variants
Tsao M-S, et al. N Engl J Med 2005;353:133–44
§Exon 19 deletions and L858R
Tsao M-S, et al. N Engl J Med 2006;354:527–8
Responsiveness to EGFR inhibitors
(gefitinb (Iressa) and erlotinib (tarceva)
correlates with
– female gender, non smoker,
adenocarcinoma histology, Asian
ethnicity, Mutations in the EGFR gene
– Effective following chemotherapy as 2nd
line therapy and no benefit concurrently
Paez et al, Science. 2004 304: 1497-1500
Franklin et al, ASCO 2004
Which of the following is not correct
1. This CT is most compatible with
mesothelioma?
2. This could represent other pleural malignancy
such as metastatic adenocarcinoma
3. The cells are cytokeratin and EMA positive but
TTF-1 negative is this compatible with the
diagnosis?
4. There is no standard treatment for this tumour
5. Treatment requires the addition of B12 and
folate
The Gemcitabine/Cisplatin
Combination in Mesothelioma
Byrne1
Nowak2
Van
Haarst3
SWOG4
21
53
25
44
1000
1000
1250
1000
d 1,8,15
d 1,8,15
d 1,8
d 1,8,15
CDDP mg/m2
100d1
100 d1
q21D
q28D
Schedule
q28D
q28D
q21D
q28D
Response
48%
33%
16%
9%
9.5 mo
11.2 mo
9.6 mo
NA
Author
Patients
Gemcitabine
mg/m2
Survival
1
Byrne, JCO 1999; 17:25 2Nowak, Br J Ca 2002; 87:491 3van Harrst, Br J Ca 2002:
86:342 4K Antman, personal communication
Phase II Trial of Pemetrexed in MM
Dose 500mg/m²
Patients:
Partial Response Rate:
Median time to progression:
Median survival:
months
1 year survival:
Grade 3/4 neutopenia:
64
14%
4.7 months
10.7
47.8%
23%
Scagliotti JOC 2003
pemetrexed and platinum
• Pemetrexed 600mg/m²and cisplatin
75mg/m²
• 11 patients
• RR 5/11 45%
• 7 gd 3/4 neutropenia
Calvert et al, 2000
Treatment for MM
• Largest contolled study in treatment of MM
• Cis/pemetrexed currently the most active
combination trialed for MMshowing a
survival advantage
• Cis/pemetrexed new standard treatment
for MM in many countries
• Needs addition folate and B12 in view
toxicity