Transcript HER Education Network

Challenging Cases in Cancer:
Integration of Findings from ASCO 2007
into Clinical Practice
Lung Cancer
Corey J. Langer, MD, FACP
Medical Director, Thoracic Oncology
Fox Chase Cancer Center
Philadelphia, PA
Extensive Stage Small Cell Lung Cancer
Case 1
Extensive Stage SCLC
• 72-year-old WM former smoker (50 pack-years) presents
with cough, DOE and hoarseness over a 6-week course
• CXR suggests a (L) para-hilar infiltrate
• He initially receives antibiotics, but symptoms worsen
• PE is notable for a (L) SCN measuring 2 cm, with focal
wheezing in the (L) mid-lung field
• Liver edge extends 3 cm below the RCM with focal
tenderness
Case 1
Extensive Stage SCLC
• Follow-up CXR demonstrates worsening infiltrate
• CT shows a dense, coalescent mass in the (L) hilar
area measuring 9 x 8 cm with prominent hilar and
mediastinal adenopathy; multiple, bilateral pulmonary
nodules; and hepatic masses ranging between 2-3 cm
in size and occupying 15% of the hepatic volume
• FNA of an anterior hepatic mass demonstrates classical
SCLC
• PS is 1
• CBC and chemistries are WNL
Case 1
Extensive Stage SCLC
Which of the following is appropriate therapy for this
patient?
1. Irinotecan + cisplatin
2. Etoposide + cisplatin
3. Irinotecan + carboplatin
4. Etoposide + carboplatin
5. All of the above
Case 1
Extensive Stage SCLC
Which of the following is appropriate therapy for this
patient?
1. Irinotecan + cisplatin
2. Etoposide + cisplatin
3. Irinotecan + carboplatin
4. Etoposide + carboplatin
5. All of the above
Recommended Approach:
 All of the options above are appropriate for this patient.
Case 1
Extensive Stage SCLC
Bevacizumab has been proven in phase III trials to
enhance therapeutic outcome in patients receiving
cisplatin in combination with either irinotecan or etoposide
1. True
2. False
Case 1
Extensive Stage SCLC
Bevacizumab has been proven in phase III trials to
enhance therapeutic outcome in patients receiving
cisplatin in combination with either irinotecan or etoposide
1. True
2. False
Answer:
 False, bevacizumab has not been proven in phase III trials to
enhance outcomes.
Lung Cancer
Incidence and 5-Year Survival in the U.S.
2006-2007
> 175,000
NSCLC
139,000
STAGE I-III STAGE IV
78,500
60,500
STAGE I/II STAGE III
39,250
39,250
5-Year Survival (%) Goal
SCLC
36,000
EXT
24,000
LTD
12,000
• LTD SCLC
• EXT SCLC
• ST IA
• ST IB
• ST IIA
• ST IIB
• ST IIIA
• ST IIIB
• ST IV NSCLC
15-25
<1
70-85
60-70
35-45
25-35
5-20
3-7
<1
25-30
2-5
85-95
70-85
45-60
35-45
20-30
10-20
2-5
Small Cell Lung Cancer
Epidemiology & Biology
•
•
•
•
170,000 new cases of lung cancer/year in USA
Decreasing proportion of SCLC: 30%  15%
Nearly all cases of SCLC associated with smoking
Distinct molecular profile & biologic behavior
Molecular Profile
Biologic Behavior
• 3p (del)
• High cellular proliferation
• p53 mutations: 80%
• Short cell cycle time
• Rb abnormalities: 100%
• Rapid doubling time
• High Expression of myc
• Central presentation
• High Expression of c-Kit
• Early metastases
• Chemo-Radiation Sensitivity
Small Cell Lung Cancer
Standard Therapy
Limited Stage
• EP – 4-cycles
Extensive Stage
• Concurrent chest XRT
• EP (IP) or EP/CAV x 4-6
cycles
• PCI for CR
• CNS mets: chemo or XRT
• Clinical trials: consolidation
or maintenance for CR
• XRT: bone metastasis or
obstructive lesions
• Window of opportunity for
clinical trials
EP vs. ECarb in Extensive Disease SCLC
Hellenic Co-operative Oncology Group
• Treatment was with EP or ECarb in ED or LD SCLC
• No difference in response or survival was seen between treatments
• EP was more toxic, with a higher incidence of leukopenia (P = 0.09),
infection (P = 0.05), nausea and vomiting (P = 0.0001), neurotoxicity
(P = 0.0002), and hyperergic reactions (P = 0.001) in this treatment
arm
RANDOMIZATION
N = 143
E: 300 mg/m2 days 1 to 3
P: 50 mg/m2 days 1 and 2
q3 weeks x 6
E: 300 mg/m2 days 1 to 3
Carb: 300 mg/m2 day 1
q3 weeks x 6
Responding
patients
PCI
and TRT
in third
cycle
EP = etoposide, cisplatin; ED = extensive-disease; LD = limited-disease;
PCI = prophylactic cranial irradiation; TRT = thoracic radiotherapy.
Skarlos DV et al. Ann Oncol. 1994;5:601-607.
Phase III Extensive Disease SCLC Trial
Design
Stratify
PS (0, 1, 2)
R
A
N
D
O
M
I
Z
E
CPT-11 60 mg/m2 d1,8,15
Cisplatin 60 mg/m2 d1
Q4wk x 4
Etoposide 100 mg/m2 d1-3
Cisplatin 80 mg/m2 d1
Q3wk x 4
• First-line extensive disease SCLC
• Primary endpoint: survival
• Secondary endpoints: response, response duration,
mode of recurrence, TTP, toxicity, QOL
Noda et al. Proc Am Soc Clin Oncol. 2000;19. Abstract 1887; NEJM 1/2002; 346: 85-91.
Irinotecan/Cisplatin (PI) vs. Etoposide/Cisplatin (PE)
in Extensive SCLC (JCOG 9511)
Survival
PI
PE
Median (95% CI)
12.8 mos. (11.7-15.2)
9.4 mos. (8.1-10.8)
1-year (%)
58.4%
37.7%
2-year (%)
19.5%
5.2%
Noda et al., NEJM 1/2002; 346: 85-91.
Irinotecan/Cisplatin vs. Etoposide/Cisplatin
U.S. Randomized Trials
PFIZER
SWOG
Arm 1 q 3w
Arm 2 q 3w
Arm 1 q 4w
Arm 2 q 3w
CPT-11
Cisplatin
CPT-11
Cisplatin
65 mg/m2
60 mg/m2
65 mg/m2
60 mg/m2
d 1, 8
d1
d 1, 8, 15
d1
+
+
+
+
Cisplatin
VP-16
Cisplatin
VP-16
30 mg/m2
120 mg/m2
60 mg/m2
100 mg/m2
d1, 8
d 1-3
d1
d 1-3
N = 331
N = 670 (03/07)
Irinotecan/Cisplatin vs. Etoposide/Cisplatin
Tumor Response Rate
Intent-to-Treat Population
(ITT)
Complete response
Partial response
Overall response
Stable disease
Progressive disease
Not evaluable
IP
(N = 221)
%
EP
(N = 110)
%
3.6
44.3
48.0
2.7
40.9
43.6
4.1
7.3
20.0
28.1
20.0
29.1
Hermes et al., ASCO 2005, Abstract 7004.
Irinotecan/Cisplatin vs. Etoposide/Cisplatin
Time to Disease Progression (ITT)
1.0
IP (N = 219)
EP (N = 109)
0.9
0.8
Probability
0.7
0.6
0.5
IP: median 4.1 mo (0.1-31.1)
EP: median 4.6 mo (0.3-18.4)
0.4
P = 0.2522
0.3
0.2
0.1
0
0
3
6
9
12
15
18
21
24
27
30
Months
Hermes et al., ASCO 2005, Abstract 7004.
Irinotecan/Cisplatin vs. Etoposide/Cisplatin
Overall Survival (ITT)
IP (N = 221)
EP (N = 110)
1.0
0.9
IP: median 9.3 mos. (0.1-32.6) 1-yr 35.4%, 2-yr 8.0%
EP: median 10.2 mos. (0.3-44.6) 1-yr 36.7%, 2-yr 7.9%
0.8
Probability
0.7
0.6
P = 0.6226
0.5
0.4
0.3
0.2
0.1
0
0
10
20
30
40
Months
Hermes et al., ASCO 2005, Abstract 7004.
Irinotecan/Cisplatin vs. Etoposide/Cisplatin
Hematological Toxicities
Grade 3 or 4 Toxicity
IP
EP
(N = 210)
%
(N = 104)
%
P-value
Neutropenia
36.2
86.5
< 0.0001
Anemia
4.8
11.5
< 0.0268
Thrombocytopenia
4.3
19.2
< 0.0001
Hermes et al., ASCO 2005, Abstract 7004.
Irinotecan/Cisplatin vs. Etoposide/Cisplatin
Non-Hematological Toxicities
Grade 3 or 4 Toxicity
IP
(N = 216)
%
Febrile Neutropenia
Dehydration
Vomiting
Diarrhea
Alopecia*
Infection
Nausea
Fatigue
Asthenia
Dyspnea
Anorexia
3.7
13.0
12.5
21.3
6.9
7.4
13.0
11.6
6.0
5.1
5.6
*Grade 2
EP
(N = 106)
%
10.4
2.8
3.8
0
32.1
11.3
5.7
6.6
5.7
5.7
1.9
P-value
0.0577
0.015
0.0445
0.0001
0.0001
0.5027
0.1343
0.3748
0.9918
0.9773
0.3164
Hermes et al., ASCO 2005, Abstract 7004.
Irinotecan/Cisplatin vs. Etoposide/Cisplatin
Conclusions
• Treatment with this regimen of IP results in similar efficacy
outcomes when compared with EP
– Response Rates
– Time to Progression
– Overall Survival
• IP results in statistically significant lower rates of
– Neutropenia and neutropenic fever
– Anemia and thrombocytopenia
• IP results in statistically significant higher rates of
– Diarrhea, vomiting and dehydration
Hermes et al., ASCO 2005, Abstract 7004.
Irinotecan/Cisplatin vs. Etoposide/Cisplatin
Conclusions (cont.)
• The dose intensity of Irinotecan delivered on this trial
was higher compared to the JCOG trial
• The explanation(s) for the differences in outcomes
between this effort and the JCOG trial remain
speculative; they may be accounted for by:
– Pharmacogenomic disparities
– Platinum dose and schedule changes
– Patient characteristic differences in the study populations
Hermes et al., ASCO 2005, Abstract 7004.
Irinotecan/Cisplatin vs. Etoposide/Cisplatin
U.S. Randomized Trials
PFIZER
SWOG
Arm 1 q 3w
Arm 2 q 3w
Arm 1 q 4w
Arm 2 q 3w
CPT-11
Cisplatin
CPT-11
Cisplatin
65 mg/m2
60 mg/m2
65 mg/m2
60 mg/m2
d 1, 8
d1
d 1, 8, 15
d1
Negative
Cisplatin
VP-16
Cisplatin
VP-16
30 mg/m2
120 mg/m2
60 mg/m2
100 mg/m2
d1, 8
d 1-3
d1
d 1-3
+
+
N = 331
+
+
N = 670 (07/06)
Resuscitating Irinotecan?
Eligibility:
• Ext SCLC
• PS 0-4
• No upper age limit
Stratifications:
• PS: 0-1, 2, 3-4
• Age: < 70 vs. ≥ 70
• Center
R
A
N
D
O
M
I
Z
E
Irinotecan 175 mg/m2 q 3 wk
Carboplatin AUC 4 (Chatelut)
Etoposide 120 mg/m2 po q d X 5
Carboplatin AUC 4 (Chatelut)
Hermes et al., ASCO 2007, Abstract 7523.
Resuscitating Irinotecan?
• 220 patients randomized, 210 eligible
• PS 0: 20; PS 1: 91; PS 2: 61; PS 3: 29, PS 4: 8
• Significant benefit for IC
Arm
EC
IC
67 (39-62)
67 (46-81)
Male
65%
63%
PS ≥ 2
50%
56%
> 70 yrs
40%
31%
MS* (mos)
7.1
8.5
1 yr OS* ( %)
24
34
Med age
* P = 0.04, HR = 1.34 (1.01-1.79)
• No significant difference with respect to QoL, grade 3 and 4
toxicities
Hermes et al., ASCO 2007, Abstract 7523.
CALGB 30306: Phase II Trial of
Cisplatin/Irinotecan and Bevacizumab in
Extensive Stage SCLC
Extensive Stage SCLC
• Treatment-naïve
• PS 0-2
Irinotecan 65 mg/m2 d 1, 8 q 3wk
Cisplatin 30 mg/m2 d 1, 8 q 3wk
Bevacizumab 15 mg/kg q 3wk
Continues for 1-yr or PD
• Targeted 72 patients for enrollment
• Activated 12/04; Completed accrual 4/16/06
• Data presented at ASCO 2007
Ready et al., ASCO 2007, Abstract 7563.
E3501: Phase II Trial in Extensive SCLC
Cisplatin/Etoposide and Bevacizumab
Cis/etoposide x 4 +
Bev 15 mg/kg q 3 wk
•
•
•
•
Bevacizumab q 3 wks
Continues for 1-yr or PD
Rationale: SCLC is a highly vascularized tumor which metastasizes quickly
Objectives: Improvement in PFS from 16% to 33% at 6 months
Number of patients: 66
Laboratory Endpoints: VEGF levels
• Passed interim analysis; re-opened 12/05
• 66 patients entered through summer ‘06
• No bleeding thus far
Sandler et al., ASCO 2007, Abstract 7564.
Integrating Bevacizumab into
First-Line ED-SCLC: Phase II Trials
Ready, CALGB 30306, Abs#7563
Cisplatin 30 mg/m2 IV d1,8
Irinotecan 65 mg/m2 IV d1,8
Bevacizumab 15 mg/kg d1
q 21 days x 6 cycles
No Maintenance Bev
Sandler, ECOG 3501, Abs#7564
Cisplatin 60 mg/m2 IV d1
Etoposide 120 mg/m2 IV d1-3
Bevacizumab 15 mg/kg d1
q 21 days x 4 cycles
then Bevacizumab until PD
• No brain metastases; no recent hemoptysis
Ready, CALGB 30306
Sandler, ECOG 3501
68
61
51:49
46:54
Age, median
62 (36-81)
65 (45-83)
PS 0/1:2 (%)
90:10
92:8
Pl. Effusion (%)
35%
22%
N
F:M (%)
Ready et al., ASCO 2007, Abstract 7563.
Sandler et al., ASCO 2007, Abstract 7564.
Integrating Bevacizumab into
First-Line ED-SCLC: Phase II Trials
Toxicity Results
• Ready et al., CALGB 30306
– No grade 3-5 hemoptysis
– One patient died w/thromboembolic CVA, secondary bleeding
– Other treatment-related mortality due to FN, sepsis or PNA
• Sandler et al., ECOG 3501
– No serious hemoptysis reported
– Two treatment related deaths
• Mutli-organ failure
• Infection with grade 3/4 neutropenia
• Grade 5 toxicities seen at similar or higher rate with chemo alone as
well (e.g., Noda, NEJM 2002 & Hanna JCO 2006)
• Central location does not appear to be correlated with bleeding risk
on bevacizumab in Tx of SCLC (vs. squamous histology)
Ready et al., ASCO 2007, Abstract 7563.
Sandler et al., ASCO 2007, Abstract 7564.
Chemotherapy with Bevacizumab
in First-Line ED-SCLC
Efficacy Results
Ready, IPB
CALGB 30306
IP, Hanna
JCO 2006
Sandler, EPB
ECOG 3501
EP, Hanna
JCO 2006
CR, %
4
4*
6
3**
PR, %
71
44*
63
41**
DCR (ORR+SD), %
91
52*
86
51**
Med PFS, mo.
7.1
4.1
4.7
4.6
Med OS, mo.
11.7
9.3
11.1
10.2
49
35
N.R.
35
One-year OS, %
*28% non-evaluable
**29% non-evaluable
Chemo with Bevacizumab in ED-SCLC
Conclusions
• Neither trial reached the median survival of 12.8 months
for cisplatin-irinotecan in Noda, NEJM 2002
• Results of SWOG 0124 still pending
• Both regimens are feasible, with few treatment-related
deaths and no evidence of serious hemoptysis
• Encouraging results with bevacizumab vs. US-based
historical controls, but phase II trials typically exceed
broader experience
• Phase III study of chemo ± bevacizumab is an
appropriate consideration
Case 1
Extensive Stage SCLC
• Patient receives 4 cycles of systemic therapy with
etoposide 100 mg/m2 days 1, 2, and 3 along with
carboplatin (AUC 5) every three weeks
– Enters a near CR with complete resolution of the hepatic and
pulmonary metastases and SCN
– 80% regression of the primary lung mass and mediastinal
adenopathy
• You elect to radiate the remaining volume of tumor in
the chest
Case 1
Extensive Stage SCLC
Is there a role for PCI in this patient?
1. Yes
2. No
Case 1
Extensive Stage SCLC
Is there a role for PCI in this patient?
1. Yes
2. No
Recommended Approach:
 Yes, this patient should be treated with PCI to improve
outcomes.
Prophylactic Cranial Irradiation (PCI)
• Decreases brain relapse
– Dose related
• Survival advantage of 5%*
– Does not appear dose related
• Neurotoxicity < 10 %
– Found pre-Rx; ± PCI in 50% !
• Timing and dose less certain
*Auperin et al. NEJM(1999) 341: 476-84.
PCI Survival
Auperin et al. NEJM(1999) 341: 476-84.
PCI in ED-SCLC
EORTC 08993-22993
Chemotherapy
(4-6 cycles)
No response
Any response
R
A
N
D
O
M
I
Z
E
PCI
20-30 Gy in
5-12 fractions
No PCI
< 5 weeks
4-6 weeks
Stratify:
• Institution
• PS
Slotman et al., ASCO 2007, Abstract 4
PCI in ED-SCLC
Efficacy
PCI
No PCI
HR
P-value
1-year OS
27%
13%
0.68
.003
6-month FFS
23%
15.5%
0.76
.02
Symptomatic brain
metastases at 1-year
15%
40%
0.27
< .001
-
-
-
.2699
Extracranial progression
Slotman et al., ASCO 2007, Abstract 4
Late Radiation Reactions With PCI
N (%)
No change from baseline
87 (65%)
Grade 1: Mild headache, slight lethargy
29 (22%)
Grade 2: Moderate headache, great lethargy
15 (11%)
Grade 3: Severe headache, severe CNS
dysfunction
3 (2%)
Slotman et al., ASCO 2007, Abstract 4.
Case 1
Extensive Stage SCLC
• Patient receives PCI and does well
• After 9 months, he ultimately relapses in the chest and
liver
Case 1
Extensive Stage SCLC
Which of the following agents is FDA-approved for
chemo-sensitive relapse of SCLC?
1. Oral topotecan
2. Intravenous topotecan
3. Oral etoposide
4. Intravenous etoposide
5. Paclitaxel
Case 1
Extensive Stage SCLC
Which of the following agents is FDA-approved for
chemo-sensitive relapse of SCLC?
1. Oral topotecan
2. Intravenous topotecan
3. Oral etoposide
4. Intravenous etoposide
5. Paclitaxel
Answer:
 Intravenous topotecan is the only FDA-approved agent for
second-line SCLC.
Salvage Therapy for SCLC
• Topotecan: de facto standard
– Not very popular (in US)
• Other options
– Taxanes
– Gemcitabine
– Oral etoposide
– Phase I approaches
SCLC: Outcome Contingent on Status
at Time of Relapse
Time to relapse
Response (%)
Med Survival (mos.)
> 2 years
60-80
8-10
> 10 wks
20-40
5-6
< 10 wks
10-15
<4
Topotecan (T) vs. CAV
Chemosensitive Relapse
T
CAV
107
104
OR (%)
24.3*
18.3
NSS
TTP (wk)
13.3
12.3
0.552
MS (wk)
25
24.2
0.795
14.2
14.4
0.955
N
1-yr Surv. (%)
P-value
*statistically significant  LCSS
Schiller et al., J Clin Onc 17: 2, 1999.
Oral vs. IV Topotecan
Study Results
PO
IV
153
151
≥ 65 yrs
43
42
PS 2
13
12
4
4
N
Med # cyc
Range
1-14
RDI (%)
97.6
1-19
92.4
PO
IV
OR (%)
18
22
TTP (wks)
11.9
14.6
MS ( wk)
33
35
1-Yr OS
33%
29%
ANC
47
64
Plts
29
18
H/H
23
31
36
20
Toxicity (Gr ≥ 3)
Diarrhea (AE)
QoL, TOI, Sx Scores: No difference between PO and IV
Conclusion: Oral topotecan offers activity and tolerability comparable to
IV topotecan, more convenient alternative
Oral Topotecan vs. BSC
Study Design
Open-Label, Randomized, Multicenter Phase III Trial
Stratification
• Gender
• PS (0/1 or 2)
• Presence of liver
metastases at baseline
• TTP from end of prior
chemo (≤ 60 or > 60 days)
R
A
N
D
O
M
I
ZE
Topotecan 2.3 mg/m2/day
PO days 1–5 + BSC
BSC alone
Cycles repeated q 21 d
O`Brien et al J Clin Oncol 2006;24:5441-5447.
Oral Topotecan vs. BSC
Overall Survival (ITT)
Cumulative Proportion Alive
1.0
0.9
Topo + BSC
BSC alone
0.8
0.7
0.6
0.5
HR = 0.64 (0.45, 0.90)
Log-rank P = .0104
0.4
0.3
0.2
0.1
0.0
0
12
24
36
48
60
72
84
96
108 120
132
Time (weeks)
O`Brien et al J Clin Oncol 2006;24:5441-5447.
Relapsed SCLC
Randomized Trial BSC vs. BSC + Oral Topotecan
N = 141 pts
BSC
OR
Oral Topotecan
7%
MS wks
14
26
6 mos. (%)
26
49
Sepsis
QOL
P = 0.01
4%
Faster 
O`Brien et al J Clin Oncol 2006;24:5441-5447.
ASCO 2007 – SCLC
Commentary