1. Co-Director, Thoracic Oncology Fox Chase Cancer Center
ADVANCED NSCLC
Special Populations
PS 2
Elderly
Corey J. Langer, M.D.
Co-Director, Thoracic Oncology
Fox Chase Cancer Center
Philadelphia, PA

2. PS 2 and Elderly NSCLC NEGLECTED SUBSETS BASIC UNADDRESSED QUESTIONS
CONSTITUTE > 2/3 OF NEWLY DX’D ADVANCED NSCLC

3. IS THERE OPTIMAL TX FOR THE ELDERLY WITH ADVANCED NSCLC?

4. Objectives Public Health Perspective
Cooperative Group Elderly NSCLC Subanalyses
Isolating role of Platinum (Carbo)
Evidence-based literature: ELVIS, SICOG, MILES, etc.
Future Directions

5. The U.S. Population Is Aging
350
65 years
300
65 years
250
Number
of persons
(in millions)
200
150
The US population is aging; the over-65 group is expanding faster than other age groups, accounting for growing percentage of total population and affecting disease demographics.
In the past, a wide base of younger people and small population of elderly; now there is a smaller ratio of younger to older.
Over-65 population accounts for growing percentage of population:1
In 1950, approximately 12.3 of 150 million (8.1%)
In 1990, approximately 34 of 260 million (12.7%)
In 2030, anticipated 70 of 350 million (20.0%)
As population ages, demographics of cancer and other diseases change.
Yancik R, Ries LAG. Aging and cancer in America: demographic and epidemiologic perspectives. Hematol Oncol Clin North Am. 2000;14:17–23.
100
20.0% 50
12.7%
8.1%
1950
1990
2030
Yancik R, et al. Hematol Oncol Clin North Am. 2000;14:17–23.

6. Cancer Risk Increases With Age50
Male
Female 40
33.7
Risk (%) 30
22.2 20
Most common types of cancer occur more frequently in older age groups, and overall incidence rises with age, especially in males.
For all types and sites of cancer combined, incidence (number of cases per population base) increases with age.1
Highest percentage of all newly diagnosed tumors occurs after age 60.
Overall lifetime risk of cancer is higher in males than in females (43.6% vs 38.1%):1
Most of the gender-related difference in cancer incidence occurs past age 60
Lifetime incidence of breast cancer in women (12.6%) is similar to lifetime incidence of prostate cancer in men (15.9%)
However, lifetime incidence of lung cancer is 40% higher in men than in women (8.1% vs 5.7%)
American Cancer Society. Cancer Facts & Figures Atlanta, GA; 2000.
9.2
8.2 10
1.6
1.9
0–39
40–59
60–79
Age
American Cancer Society. Cancer Facts & Figures Atlanta, GA; 2000.

7. Incidence of Lung Cancer Increases With Age
U.S. incidence of lung cancer by age
600
Men
500
Women
Incidence (per 100,000)
400
300
Lung cancer is the leading cause of cancer-related death in the United States, and long-term survival is still poor.
US incidence peaks at about age 70–75 in both men and women.1
Unlike many other forms of cancer, death-rates from lung cancer rising worldwide.2
Mortality and survival in US:2
Leading cause of cancer-related death in men; also in women since late 1980s (surpassing breast cancer)
Mortality rate may be levelling off in men due to decrease in smoking over previous years, but still rising in women as their smoking rates have risen
5-year survival ~14%
Survival rates have not improved significantly over past two decades3
Diagnosis typically in older patients due to long delay between onset of smoking, development of cancer, and onset of cancer symptoms.
Yancik R, Ries LA. Cancer in the older person: magnitude of the problem. In Balducci L, Lyman GH, Ershler WB (eds). Comprehensive Geriatric Oncology. Amsterdam; The Netherlands: Harwood Academic Publishers; 1998:95–104.
American Cancer Society. Cancer Facts & Figures Atlanta, GA; 2000.
Ginsburg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers. 1997;858–911.
200
100 35 40 45 50 55 60 65 70 75 80
85+
Age
Yancik R, et al. Comprehensive Geriatric Oncology. 1998:95–104.

8. Elderly Lung Cancer Patients are Under-Represented on Clinical Trials
60% of lung cancer patients are 60
35% - 40% of lung cancer patients are 70
Elderly representation on N.A. Trials
Study % 70
E %
S9509/ %
E %
CALGB %
UNC %

9. Explanations for Under-Representation on Clinical Trials
Therapeutic nihilism
Misperception
Societal pressure (UK > EUR > NA)
Increased co-morbidity or “unfitness” (??)

10. ECOG 5592: Elderly Data RANDOMIZATION cDDP 75 mg/m2 &
Etoposide 100 mg/m2 d 1-3
Paclitaxel 135 mg/m2/24o d 2
Paclitaxel 250 mg/m2/24o d 2 + G-CSF
BREAKDOWN by Elderly ( 70) v “Young” (<70)
Elderly:  cardiovascular (p=0.0089) + resp (p=0.0441) co-morbidities
Age N RR(%) TTP (mo) MS (mo) 1 YS (%) 2YS (%)
< 
P value Log rank
 leukopenia (p=0.0001) and neuropsych tox (0.0025) in  70 yrs
No difference baseline QoL, TOI, or  over time
CONCLUSION: PS trumps age; Fit elderly merit/benefit from Tx
...Langer et al., J Natl Cancer Inst. 94(3): , 2002

11. Should Older Patients Receive Combination Chemotherapy For Advanced Stage Non-Small Cell Lung Cancer (NSCLC)? An Analysis of Southwest Oncology Trials 9509 and Karen Kelly, Sheryl Giarritta, Stephen Hayes, Wallace Akerley, Paul Hesketh, Antoinette Wozniak, Kathy Albain, John Crowley, David R. Gandara

12. OBJECTIVES To determine the effect of age > 70 on
survival, toxicity, and drug delivery in
patients with a good performance status
(PS) receiving combination
chemotherapy for advanced stage NSCLC.

13. RATIONALE
1. Adults of advanced age constitute a growing proportion of patients with metastatic NSCLC.
2. Older lung cancer patients often present with a decreased PS and/or co-morbidities.
3. Appropriate treatment options must be
identified for this group of patients.

14. METHODS
A retrospective analysis was conducted on two recent SWOG trials in advanced NSCLC:
SWOG 9509
Paclitaxel + Carboplatin
versus
Vinorelbine + Cisplatin
SWOG 9308
Vinorelbine + Cisplatin
versus
Cisplatin

15. METHODS 1. The analysis identified two age groups:
patients < 70 years of age and patients
> 70 years of age.
2. The cohorts were compared for:
a) baseline characteristics
b) efficacy of treatment
c) toxicity
d) drug delivery

16. RESULTS Number of Evaluable Patients by Age and Treatment
* Total number of patients from SWOG 9509 and 9308

17. RESULTS Patient Characteristics
Variable Age <70 Age 70 Total p-value
Stage IIIB 45 (9%) 17 (15%) 62 (10%) .08
IV 446 (91%) 100 (85%) 542 (90%)
PS (37%) 37 (33%) 215 (36%) .45
1 309 (63%) 76 (67%) 385 (64%)
Weight loss <5% 261 (55%) 63 (56%) 324 (55%) .84
5% 216 (45%) 50 (44%) 266 (45%)
Patient characteristics were similar between the two groups except for stage of disease in which there was a trend toward higher stage in younger patients

18. RESULTS
Toxicity
* p-value for all grades of toxicities

19. RESULTS Drug Delivery: SWOG 9509, 9305 PCb - Paclitaxel + Carboplatin
VC - Vinorelbine + Cisplatin
* p-value for comparison by age

20. RESULTS: Elderly S9305, 9509 Efficacy <70 70
<70 70
(n=491) (n=117) p-value
TTP (mo)
Median Survival (mo)
1 Yr OS 40% 30% ----
2 Yr OS 16% 10% ----
In a multivariate analysis including age, treatment arm, stage, PS and weight loss, there was no effect of age on PFS (p=.74) or survival (p=.10) …Kelly et al., ASCO 2001, A-1313

21. CONCLUSIONS 1. Relatively few older patients (19%)
entered these cooperative group trials.
2. There was a trend toward shorter
survival in older patients (p=.06).
3. Grade 3-5 toxicities occurred more
frequently in older patients (p=.06).

22. CONCLUSIONS complete VC compared to PCb.
4. Fewer patients of any age were able to
complete VC compared to PCb.
5. A significantly larger number of older
patients discontinued VC due to toxicity
as compared to PCb.
6. Trials should be specifically designed for
this population.

23. FUTURE PLANS SWOG 0027 A phase II trial of vinorelbine followed by
docetaxel in advanced NSCLC patients with a PS of 2 or Age > 70 years old
Vinorelbine
25 mg/m2, d 1 & 8
every 3 weeks x 3
Docetaxel
35 mg/m2 weekly
3/4 weeks x 3

24. TAX326: Study Design
Docetaxel 75 mg/m2 IV + Cisplatin 75 mg/m2 IV q 3 wk
RANDOMIZE
: Stratification by
Stage (IIIB or IV)
Geographic region
Docetaxel 75 mg/m2 IV + Carboplatin AUC 6 IV q 3 wk
Vinorelbine 25 mg/m2 IV d 1, 8, 15, 22 + Cisplatin 100 mg/m2 IV d 1 q 4 wk
Premed: Dexamethasone 8 mg PO bid  6 doses (first dose 12 hours prior to Docetaxel infusion) for the Docetaxel groups.
Fossella FV. Eur J Cancer 2001;37(suppl 6):S154. (abstr & oral presentation 562)

25. TAX326 SURVIVAL All patients Cumulative Probability
D+CIS VS. V+CIS: Non-inferiority vs improved survival
Survival Time (Mos.)
Cumulative Probability
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Docetaxel Cisplatin
Vinorelbine
Cisplatin
P = (adjusted log-rank)

26. Tax 326 Elderly Subanalysis Docetaxel-Cisplatin

27. Tax 326 Elderly Subanalysis Docetaxel-Carboplatin

28. Tax 326 Elderly Subanalysis Vinorelbine-Cisplatin

29. % Grade 3/4 Nonhematologic Toxicity: Docetaxel/Cisplatin16 9
Neurotoxicity 8 6
Diarrhea 12 7
Infection 14 11
Asthenia 13
N/V
114
287
No.
Age 65
Age <65

30. % Grade 3/4 Nonhematologic Toxicity: Docetaxel/Carboplatin11 7
Neurotoxicity 4 6
Diarrhea 18 8
Infection 13 10
Asthenia 3 9
N/V
114
288
No.
Age 65
Age <65

31. % Grade 3/4 Nonhematologic Toxicity: Vinorelbine/Cisplatin16 14
Neurotoxicity 3
Diarrhea 10 7
Infection 17 13
Asthenia 26 18
N/V
128
268
No.
Age 65
Age <65

32. TAX 326 Elderly Conclusions
Survival benefit is independent of age
Modest increase in toxicity in elderly
Docetaxel/Carboplatin is well tolerated in elderly NSCLC patients

33. E1594 Schema R A N D O M I Z E Stratification
Arm A: Cisplatin + Paclitaxel
Paclitaxel: 135 mg/m2 over 24 hours, day 1
Cisplatin: 75 mg/m2 day 2
3-week cycle
Arm B: Cisplatin + Gemcitabine
Gemcitabine: 1,000 mg/m2 days 1,8,15
Cisplatin: 100 mg/m2 day 1
4-week cycle
Arm C: Cisplatin + Docetaxel
Docetaxel: 75 mg/m2 day 1
Cisplatin: 75 mg/m2 day 1
Arm D: Carboplatin + Paclitaxel
Paclitaxel: 225 mg/m2 over 3 hours, day 1
Carboplatin: AUC 6.0 day 1
Stratification
Performance status
0-1 vs. 2
Weight loss in
previous 6 months
<5% vs. 5%
Disease stage IIIB
or IV
Presence or absence of brain metastases

35. ECOG 1594 1207 pts enrolled 227 (20%) 70 years; 9 (1%)  80 yrs
Demographics similar for pts 70 yrs and <70 yrs
Septuagenarians: signif more cardiac (p<0.0001) & other non-cardiorespiratory co-morbidities (p=0.008, Fisher’s exact test)

36. ECOG 1594: Outcome Based on Age
Age Cohort <70 yrs 70 yrs p value No
Completion of 6 cycles 34% 30% 0.36
Gr 4 toxicity 66% 71.2% 0.04
Median no. of cycles
OR(%)
PFS (mo) PS
PFS 1yr (%)
PFS 2yr (%)
MS (mo)
1yr OS(%)
2yr OS(%)

37. Outcome in Patients  80 Years of Age: E1594
Age range 80 p value No
Tx completion (6 cycles) *
OR (%)
PFS (mo)
MS (mo)
CONCLUSION: Low numbers preclude broad inferences, but octogenarians with advanced NSCLC, even though fit, fared no better than PS 2 patients.
*Tx completion No.
1 cycle 2
2 cycles 3
3 cycles 3
4 cycles 1

38. Elderly Subanalysis: PCb X 4 vs PCb (indef)
AGE <70 (n=163)  70 (n=67)
Gr 2 Toxicity (%)
Neutropenia 38 35
Anemia 9 13
Thrombocytopenia 7 9
Peripheral Neuropathy 13 16
Nausea/Vomiting 14 15
Myalgia 15 9
Fatigue 8 15
Outcome
Median Survival (mos)
1-Year Survival (%) 30 34
2-Year Survival (%) 15 9
…Hensing, Socinski et al., Proc ASCO 2001, A-1382

39. CALGB 9730: CbT v T R Carboplatin AUC 6 Q 3 wk AD
Carboplatin AUC 6 Q 3 wk
Paclitaxel 225 mg/m2 Q 3 wk
N=584 Tx-naïve advanced NSCLC; accrued 10/97 - 1/01
Well balanced with respect to stage (III vs IV), gender (M v F), PS (0/1 vs 2)
Demographics: 156 (27%) >70 yrs; 399 M; 100 PS 2
…A-2 ASCO 2002, Lilenbaum

40. CALGB: Results
Response rates significantly better for carboplatin/paclitaxel vs paclitaxel (30% vs 16%, P<.0001)
Median survival after 12.5 m follow-up significantly better for carboplatin/paclitaxel vs paclitaxel (8.8 m vs 6.7 m, P<.023)
1-year survival not significantly different for carboplatin/paclitaxel (37% vs 33%)
Lilenbaum et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 2

41. CALGB 9730
*p=0.1014

42. Role of Schedule Paclitaxel-Carbo (RP2)
Arm 1) PACLITAXEL 100 mg/m2 Q wk X 3 Q 4 wk
CARBOPLATIN AUC 6 Q 4 wk
Arm 2) PACLITAXEL 100 mg/m2 Q wk X 3 Q 4 wk
CARBOPLATIN AUC 2 Q wk X 3 Q 4 wk
Arm 3) PACLITAXEL 150 mg/m2 Q wk X 6 Q 8 wk
CARBOPLATIN AUC 2 Q wk X 6 Q 8 wk R A N D
Arm 2
…Belani, ASCO 2001, A1287

43. Response Rates at 8 Week Follow-up
Arm 1 Arm 2 Arm 3
Week 8 CR-PR (%)
Week 16 CR-PR (%)
Median survival (wks)

44. Conclusion Arm 1: best Tx index
Best survival with lowest inc. of FN; gr 3 neuropathy; N/V; fewest dose reductions

45. Phase III Scheduling Trial
Carbo AUC 6 Q 4 wk
Paclitaxel 100 mg/m2 d1, 8, 15 Q 4 wk
Carbo AUC 6 Q 3 wk
Paclitaxel 225 mg/m2 Q 3 wk
PI: C. Belani

46. NON-PLATINUM TX IN ELDERLY WITH NSCLC

47. Randomized Trials in Elderly NSCLC
Trial Group Comment
V vs BSC ELVIS Completed
GV vs V SICOG Completed
G vs V vs GV ITA-MILES Completed

48. ELVIS Trial E.L.V.I.S.: Elderly Lung Vinorelbine Italian Study
Eligibility: St IIIB/IV NSCLC: PS 0-2
Outcome clearly favored vinorelbine
Arm N OR(%) MS(mo) 1y OS%
VNR %
BSC %
Statistically significant QoL benefit for patients receiving VNR
…Gridelli, JCNI 1999; 85:

49. Navelbine in the Elderly: Summary
E.L.V.I.S.: first Phase III trial demonstrating a survival advantage for single-agent chemotherapy vs BSC
Navelbine is generally well tolerated in the elderly patient
Age does not appear to change or increase toxicity
Greater sensitivity of some older individuals cannot be ruled out

50. Gemcitabine in Advanced NSCLC
Phase II trials
RR 21% - 26%
Median survival months
One-year survival of 30% - 50%
Phase III trials
Gemcitabine 1000 mg/m2 weekly in symptomatic patients vs BSC
Improvement in symptom control 93% vs 67%
Toxicities are mainly myelosuppression and fatigue
Rare pulmonary toxicity

51. Rationale for Combining Gemcitabine and Vinorelbine in NSCLC
Both drugs have activity in NSCLC
Nonoverlapping toxicities except myelosuppression
Outpatient schedule
Both drugs well tolerated by elderly

52. Gemcitabine Plus Vinorelbine vs Vinorelbine Alone in Patients with NSCLC: SICOG Study
Patients with Stage IIIB/IV NSCLC
Age  70 years at diagnosis
Randomized to:
Vinorelbine 30 mg/m2 d1, 8 q 3 weeks
vs.
Vinorelbine 30 mg/m2 d 1, 8
Gemcitabine 1250 mg/m2 d 1, d 8 administered q 3 weeks

53. Gemcitabine Plus Vinorelbine vs Vinorelbine Alone in Patients with NSCLC: SICOG Study
GV V
N 76 76
Stage IV 60% 60%
PS % 78%
OR 22% 15%
SD 27% 12%
MST 29 wks 18 wks
1-yr survival 30% 13%*
*P<.01

54. Chemotherapy in Elderly Patients with Advanced NSCLC
Author
Regimen
N Response
MS (mo)
1 YR
6.5
Gridelli*
Vinorelbine %
32%*
BSC
4.9
14% 7
Frasci‡
Gemcitabine +
Vinorelbine %
30%*
Vinorelbine %
13%
4.5
*Gridelli, J Natl Cancer Inst 1999; 85:
‡Frasci et al, Proc ASCO 2001, 19:A1895
* p<0.05

55. (N3 or pleural effusion) or IV
The MILES Phase III Trial: Gemcitabine + Vinorelbine vs Vinorelbine and vs Gemcitabine in Elderly Advanced NSCLC Patients Gridelli et al Multicenter Italian Lung Cancer in the Elderly Study
RANDOMIZE
Vinorelbine 30 mg/m2 d1,8
Q 3 weeks
NSCLC
70+ years old
Chemotherapy naïve
Stage IIIB
(N3 or pleural effusion) or IV
PS 0-2
Gemcitabine 1200 mg/m2 d1,8
Q 3 weeks
Gemcitabine 1000 mg/m2 d1,8
Vinorelbine 25 mg/m2 d1,8
Q 3 weeks
ASCO 2001 Abstract 1230

56. MILES STUDY: ELDERLY NSCLC
…Gridelli et al., ASCO 2001, A-1230

57. Baseline Quality of Life and Survival Prediction in NSCLC Elderly
Patients enrolled in MILES study
Assessment at baseline
Activities of daily living (ADL)
Instrumental ADL
EORTC C30 global (items 29-30)
Analysis using multivariate Cox model
Data on 81% (566/698) of patients
Perrone et al. Proc Am Soc Clin Oncol 2002;21. Abstract 1346

58. Baseline Quality of Life and IADL Predicted Survival in NSCLC Elderly: Results
20 (16-28)
<42%
30 (26-34)
42-67%
53 (46-76)
>67%
QOL
21 (17-27)
50%
32 (26-43)
51-99%
43 (34-49)
100%
IADL
Median Survival, weeks (95% CI)
Score
Perrone et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 1346

59. Baseline Quality of Life and Survival Prediction in NSCLC Elderly: Results
ADL has no prognostic value
IADL and QoL have prognostic value
Independently: IADL P=.0006, QoL P<.0001
Together IADL P=.051, QoL P<.0006
Perrone et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 1346

60. MILES Trial - Conclusions
Polychemotherapy with gemcitabine + vinorelbine does not improve outcomes compared to single-agent vinorelbine or gemcitabine
Single-agent chemotherapy should remain a standard for advanced NSCLC elderly patients
Baseline QoL predictive of outcome, though no difference observed in Qol or IADL between each arm
ASCO 2001 Abstract 1230 ORAL PRESENTATION

61. Elderly Patients with Advanced NSCLC
Chemotherapy in
Elderly Patients with Advanced NSCLC
Author Regimen N Response MS (mo) 1 YR
Vinorelbine % %*
BSC %
Gemcitabine +
Vinorelbine % %*
Vinorelbine % %
Vinorelbine % %
Gemcitabine % %
Vinorelbine % %
Gridelli*
Frasci‡
Gridelli
*Gridelli, J Natl Cancer Inst 1999; 85:
‡Frasci et al, Proc ASCO 2000, 19:A1895
 Gridelli, Proc ASCO 2001, 20: A-1230
* p<0.05

62. Phase II/III Trials in the Elderly
Trial Group Comment
Oral Vinorelbine (V) NCCTG Open
VX3  DX3 SWOG Closed (?)
DG v D SCCC Open
V - vinorelbine, D - docetaxel, G - gemcitabine

63. Elderly: Adv NSCLC Outstanding Issues
No elderly-specific phase III trial (yet) comparing single agent(s) +/- platinum
Comprehensive analysis of co-morbidities and their influence on toxicity, Tx tolerance, QoL and survival (CRASH score)
Sparse data for pts  80 yrs

64. Main Domains of Multidimensional Assessment in Elderly Cancer Patients
Measuring Tool
Comorbidity
Charlson comorbidity scale
CIRS-G
Functional Status
ADL
IADL
Depressive symptoms
Mental Status
Nutritional State
GDS
MMSE
Mini nutritional assessment
CIRS-G, cumulative illness rating scale-geriatric; ADL, activities of Daily living; IADL, instrumental activities of daily living; GDS, geriatric Depression scale; MMSE, mini mental state examination

65. Study Concepts: Elderly NSCLC
MONOTHERAPY VS PLATINUM COMBINATIONS: e.g.,
gemcitabine +/- cisplatin or carboplatin
vinorelbine or gemcitabine +/- oxaliplatin
COMBINATION CHEMO & TARGETED TX: e.g., vinorelbine +/- OSI-774 or other EGFr inhibitor
MONOTHERAPY COMPARISONS: e.g., weekly vinorelbine vs weekly paclitaxel or docetaxel
NESTED PHARMACOKINETIC ANALYSES

66. Randomized Trials with CT+/- Targeted Therapies
TRIAL TARGET CT GROUP COMMENT
ZD1839 EGFR GC AstraZeneca Closed, no benefit
ZD1839 EGFR TCb AstraZeneca Closed, no benefit
OSI 774 EGFR TCb Genentech/OSI Closed
ABXEGFR EGFR TCb Immunex Proposed
Herceptin Her-2/neu TCb ECOG Proposed
AG3340 MMP TCb Agouron Closed no benefit
AG3340 MMP GC Agouron Closed no benefit
BMS MMP TCb BMSO Closed
TNP-470 Angiogenesis TCb MDACC Proposed (or ditched)
rhuMabVEGF Angiogenesis TCb ECOG Open
ISIS3521 PKC TCb ISIS Closed, no benefit
Deltaparin Metastases Std NCCTG Open

67. PS 2 NSCLC What are the data?

68. Impact of PS on Outcome ECOG 1581 Performance Objective Median Toxic
Status Response (%) Survival (wks) Deaths (%)

69. ECOG Recursive Partitioning Analysis Terminal Nodes
Median Survival Months
Appetite
Intact (N) Diminished (N)
PS-0
Female (111) 8.54 (15)
Male 9.86 (219) 6.74 (50)
PS-1
Female 7.77 (214) 6.95 (102)
Male 6.70 (421) 5.08 (224)
PS-2
Female 5.31 (24) (27)
Male 4.30 (64) (100)
Jiroutek et al.

70. GEPC/98-02: Outcomes Arm CG CGV GVIV Subgroups (MST)
OR(%) * PS
TTP (wk) PS
MST (m) ST IIIB 9.4
1y OS (%) ST IV 8.1
*CG v GVIV (p=0.0003); CGV v GVIV (p=0.01)
…Alberola, ASCO 2001, A-1229

71. EORTC: TP v GP v TG Outcome Measures
T+P G+P T+G
OR%
PFS (m) (0.08)
MST (m)
1 yr OS (%) (.09)
…Van Meerbeeck et al. (EORTC), ASCO 20001, A-1228

72. EORTC: TP v GP v TG Subgroups: Median Survival
STAGE MST (m)
IIIB 9.5
IV 7.5 PS
2 3.3
p <0.0001

73. HeCOG Trials: Outcome based on PS
Tax (175 vs 225)
TTP (mo)
MS (mo)
1 y OS %
PS 0-1
6.3
11.25
N/A
PS 2
2.4
3.8
N /A
PCb vs PG
6.6
11.1
44.4
5.9 20

74. Impact of PS on Toxicity in Elderly pts
ELVIS Trial
Performance Grade 4 Grade 3/4
Status Patients Neutropenia (%) Constipation (%)
(5.7) 4 (7.5)
Perrone F. Personal Communication to P. Hesketh

75. Impact of PS on Outcome ELVIS Trial
Group Patients Response (%) MS (wks)*
Overall
BSC V
PS 2
BSC V
*P=0.03
Perrone F. Personal Communication to P. Hesketh

76. E1594 Schema R A N D O M I Z E Stratification
Arm A: Cisplatin + Paclitaxel
Paclitaxel: 135 mg/m2 over 24 hours, day 1
Cisplatin: 75 mg/m2 day 2
3-week cycle
Arm B: Cisplatin + Gemcitabine
Gemcitabine: 1,000 mg/m2 days 1,8,15
Cisplatin: 100 mg/m2 day 1
4-week cycle
Arm C: Cisplatin + Docetaxel
Docetaxel: 75 mg/m2 day 1
Cisplatin: 75 mg/m2 day 1
Arm D: Carboplatin + Paclitaxel
Paclitaxel: 225 mg/m2 over 3 hours, day 1
Carboplatin: AUC 6.0 day 1
Stratification
Performance status
0-1 vs. 2
Weight loss in
previous 6 months
<5% vs. 5%
Disease stage IIIB
or IV
Presence or absence of brain metastases

79. ECOG 1594: PS 2 Subanalysis CONCLUSIONS
68 of 1207 pts enrolled had PS 2
Accrual suspended b/o untoward inc. of Gr 4/5 AEs
Overall toxicity rate, however, did not differ significantly from that observed in PS 0-1 pts
5 deaths (7.35% Grade 5 AE), but only two were directly attributable to Tx
Med survival of 4.1 mo and 1-yr survival rate 19.1% likely 2o to disease process rather than toxicity
….Sweeney et al Cancer 2001, 92:

80. ECOG 1594: PS 2 Subanalysis % G3 Heme Tox (n=64)
PC GC DC PCb N
ANC
PLT
H/H
NF * 0
*1 gr 5
….Sweeney et al cancer 2001, 92:

81. ECOG 1594: PS 2 Subanalysis % Gr3 Non-Heme Tox (n=64)
PC GC DC PCb
Renal 6 24* 0 0
N/V
Diarrhea
Neuropathy
Allergy
Grade
*One Gr 5 toxicity
….Sweeney et al Cancer 2001, 92:

82. ECOG 1594: PS 2 Subanalysis OUTCOME
PC GC DC PCb Overall
Total
Evaluable
OR(%)
TTP (mo)
MST (mo)
1yr OS(%)
….Sweeney et al Cancer 2001, 92:

83. ECOG 1599 RP2: CbT or GC in PS 2 Adv NSCLC
CARBOPLATIN AUC 6 Q 3 wk
PACLITAXEL mg/m2 Q 3 wk
GEMCITABINE 1gm/m2 d1, 8 Q 3 wk
CISPLATIN mg/m2 Q 3 wk

84. E1599: RP2 Adv NSCLC: Status Update 8/18/01
Activated 5/31/00
Suspended 5/8/01 for interim toxicity analysis (n=47)
CbT GC
No. Evaluable (to date) 32 30
% Gr  3(4) Toxicity
ANC 44(28) 40(13)
Plt 9(0) 37(7)
H/H 9 13
N/V 6(0) 23(0)
PNS 13 0
Worst 75(29) 80(28)
Reopened 1/02; 103 accrued as of 11/15/02
2 grade 5 toxicities to date (CbT)

85. Randomized HeCOG Phase II Trial PS 2 NSCLC
Gemcitabine 1250 mg/m2 d 1 +15
Carboplatin AUC 3 d 1+ 15
Gemcitabine 1250 mg/ms2 d 1+ 15
100 pts targeted; 4 cycles of Tx projected
Endpoint: clinical benefit

86. CALGB 9730
Single agent Paclitaxel vs. combination chemotherapy Paclitaxel/Carboplatin in advanced NSCLC
Select eligibility criteria:
Stage IIIB/IV NSCLC
Chemotherapy naïve
Performance status 0-2
No CNS disease
Measurable or evaluable disease

87. CALGB: Subanalysis Elderly PS 2 P CbP P CbP All 78 77 50 49 99
31 35* 10 18 14
NA NA 0 9 5 N
OR (%)
MST (mo)
1yr OS%*
2y OS%
*Wilcoxon= log rank p=0.0123
ss (<0.0001) vs PS 0-1
Conclusion: PS 2 may benefit from combination, carboplatin-based tx
… Lillenbaum et al ASCO 2002, A-2;21

88. PS 2 NSCLC: Treatment Efficacy
Trial RR (%) TTP (mo) MS (m) 1y OS%
ECOG
HeCOG
HeCOG
CALGB
PCb P

89. Alternative Approach for PS 2 Patients with Advanced NSCLC
Use “new” active single agents
Use schedules with demonstrated favorable toxicity profiles
Use agents sequentially
Avoid cisplatin (off study) although carboplatin combinations appear reasonable
Consider formal phase III study evaluating new agent +/- carbo or new agent +/- targeted Tx
Integrate quality of life into any future efforts

90. Elderly vs “Poor Risk” Patients with Advanced NSCLC
“Healthy” elderly fare as well as younger patients with standard chemotherapy approaches
“Poor risk” patients (PS2 ± low albumin ± weight loss) fare poorly
Tolerability and potential benefits of chemotherapy in “poor risk” patients remain to be determined