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ADVANCED NSCLC

ADVANCED NSCLC. Special Populations PS 2 Elderly. Corey J. Langer, M.D. Co-Director, Thoracic Oncology Fox Chase Cancer Center Philadelphia, PA 19111. PS 2 and Elderly NSCLC. NEGLECTED SUBSETS BASIC UNADDRESSED QUESTIONS CONSTITUTE > 2/3 OF NEWLY DX’D ADVANCED NSCLC.

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ADVANCED NSCLC

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  1. ADVANCED NSCLC • Special Populations • PS 2 • Elderly Corey J. Langer, M.D. Co-Director, Thoracic Oncology Fox Chase Cancer Center Philadelphia, PA 19111

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

  3. IS THERE OPTIMAL TXFOR 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 65 years 300 250 Number of persons (in millions) 200 150 100 20.0% 50 12.7% 8.1% 0 1950 1990 2030 Yancik R, et al. Hematol Oncol Clin North Am. 2000;14:17–23.

  6. Cancer Risk Increases With Age 50 Male Female 40 33.7 30 Risk (%) 22.2 20 9.2 8.2 10 1.9 1.6 0 0–39 40–59 60–79 Age American Cancer Society. Cancer Facts & Figures 2000. 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) 400 300 200 100 0 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 E5592 15% S9509/9305 19% E5594 20% CALGB 9730 27% UNC 29%

  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 (%) <70 488 21.5 4.37 9.05 38 14 70 86 23.3 4.30 8.53 28 12 P value 0.666 0.294 Log rank 0.2857 •  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): 173-181, 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 9308Karen 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) 0 - 1 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 SWOG 9509 Paclitaxel + Carboplatin versus Vinorelbine + Cisplatin SWOG 9308 Vinorelbine + Cisplatin versus Cisplatin A retrospective analysis was conducted on two recent SWOG trials in advanced NSCLC:

  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 0 178 (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 (n=491) (n=117) p-value TTP (mo) 4.2 3.9 .62 Median Survival (mo) 8.6 6.9 .06 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 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. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 DocetaxelCisplatin Vinorelbine Cisplatin P = 0.044(adjusted log-rank) Cumulative Probability 0 3 6 9 12 15 18 21 24 27 30 33 Survival Time (Mos.) TAX326 SURVIVAL All patients D+CIS VS. V+CIS: Non-inferiority vs improved survival

  26. Tax 326 Elderly SubanalysisDocetaxel-Cisplatin

  27. Tax 326 Elderly SubanalysisDocetaxel-Carboplatin

  28. Tax 326 Elderly SubanalysisVinorelbine-Cisplatin

  29. Age <65 Age 65 No. 287 114 N/V 13 12 Asthenia 11 14 Infection 7 12 Diarrhea 6 8 Neurotoxicity 9 16 % Grade 3/4 Nonhematologic Toxicity: Docetaxel/Cisplatin

  30. Age <65 Age 65 No. 288 114 N/V 9 3 Asthenia 10 13 Infection 8 18 Diarrhea 6 4 Neurotoxicity 7 11 % Grade 3/4 Nonhematologic Toxicity: Docetaxel/Carboplatin

  31. Age <65 Age 65 No. 268 128 N/V 18 26 Asthenia 13 17 Infection 7 10 Diarrhea 3 3 Neurotoxicity 14 16 % Grade 3/4 Nonhematologic Toxicity: Vinorelbine/Cisplatin

  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 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 3-week cycle Arm D: Carboplatin + Paclitaxel Paclitaxel: 225 mg/m2 over 3 hours, day 1 Carboplatin: AUC 6.0 day 1 3-week cycle R A N D O M I Z E 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

  34. 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)

  35. ECOG 1594: Outcome Based on Age Age Cohort <70 yrs 70 yrs p value No. 912 227 Completion of 6 cycles 34% 30% 0.36 Gr 4 toxicity 66% 71.2% 0.04 Median no. of cycles 4 3 0.24 OR(%) 22.1 24.5 0.76 PFS (mo) PS 0-1 3.71 3.75 PFS 1yr (%) 6.5 8.6 0.37 PFS 2yr (%) 0.5 2.2 0.04 MS (mo) 8.15 8.25 1yr OS(%) 32.8 35.2 0.53 2yr OS(%) 10.6 13.7 0.24

  36. Outcome in Patients 80 Years of Age: E1594 Age range 70-79 80 p value No. 215 9 Tx completion (6 cycles) 32.5 0* OR (%) 21.5 0 0.16 PFS (mo) 3.7 2.2 0.16 MS (mo) 8.2 4.2 0.09 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

  37. 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) 7.8 7.1 1-Year Survival (%) 30 34 2-Year Survival (%) 15 9 …Hensing, Socinski et al., Proc ASCO 2001, A-1382

  38. CALGB 9730: CbT v T R A N D Carboplatin AUC 6 Q 3 wk Paclitaxel 225 mg/m2 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

  39. 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

  40. CALGB 9730 *p=0.1014

  41. Role of SchedulePaclitaxel-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

  42. Response Rates at 8 Week Follow-up Arm 1 Arm 2 Arm 3 Week 8 CR-PR (%) 35 38 31 Week 16 CR-PR (%) 32 24 18 Median survival (wks) 49 30 40

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

  44. Phase III Scheduling Trial R A N D 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

  45. NON-PLATINUM TXIN ELDERLY WITH NSCLC

  46. 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

  47. 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 78 20 6.5 32% BSC 76 - 4.9 14% • Statistically significant QoL benefit for patients receiving VNR …Gridelli, JCNI 1999; 85: 365-376

  48. 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

  49. Gemcitabine in Advanced NSCLC • Phase II trials • RR 21% - 26% • Median survival 7 - 12.3 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

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