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Lung Cancer

Lung Cancer. Remains the leading cause of cancer deaths in the United States. Surgery is still the standard of care for early stage NSCLC and represents the best chance for cure . Unfortunately, only approximately one-third of patients present with potentially resectable disease.

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Lung Cancer

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  1. Lung Cancer Remains the leading cause of cancer deaths in the United States. Surgery is still the standard of care for early stage NSCLC and represents the best chance for cure. Unfortunately, only approximately one-third of patients present with potentially resectable disease. Since prognosis is closely linked to pathologic stage, it is of utmost importance that thorough intra-operative staging, including adequate lymph node sampling, be performed.

  2. Lung Cancer However, surgery is an imperfect therapy and 5-year survival rates have been disappointing because of distant and local recurrences. There have been a number of trials using adjuvant chemotherapy and/or postoperative radiation therapy in an attempt to improve cure rates.

  3. What is the rationale for addingadjuvant chemotherapyafter complete resection in early-stage NSCLC ?

  4. Disease recurrence post-surgery • Majority of post-surgical relapses are due to distant metastases • <25% of first recurrences are in regional sites alone • Micrometastatic cancer cells are often present in the bone marrow of patients with NSCLC Ohgami A, et al. Ann Thorac Surg 1997;64:363–7

  5. 1,000,000 new lung cancers yearly 80% NSCLC 33% resectable NSCLC 75% candidates to adjuvant chemotherapy 180,000 patients candidates to adjuvant chemotherapy 4.5% increase in survival 7,000 deaths could be avoided

  6. Early Adjuvant Trials Adjuvant chemotherapy after primary surgical resection would appear to be the logical approach in order to reduce disease recurrence and improve survival. There were a number of trials conducted in the 1960s and 1970s that involved immunotherapy or alkylating agents as adjuvant therapy, and/or radiotherapy for the treatment of lung cancer after surgery. These trials were plagued by inadequate surgical staging, inferior chemotherapy, and insufficient patient numbers.

  7. A 1995 meta-analysis • A 1995 meta-analysis examined the results of randomized trials of surgery compared with surgery plus chemotherapy conducted between 1965 and 1991. • In this analysis, the overall hazard ratio was 0.87(p=0.08) with a 13% reduction in death favoring cisplatin-based adjuvant chemotherapy. • This translated into an absolute benefit of 5% at 5 years. Although adjuvant chemotherapy did not become the standard of care after this analysis, there was a renewed interest in pursuing adjuvant trials using cisplatin-based chemotherapy.

  8. Recent Platin-based Adjuvant Trials • Another generation of trials utilizing platin-based chemotherapy have been conducted . • In general these trials had more consistent surgical staging, larger patient samples, and employed newer chemotherapeutic agents in combination with a platinum.

  9. Recent Platin-based Adjuvant Trials • The North American Intergroup Trial INT0 115 randomly assigned patients with stages II and IIIA NSCLC to receive radiotherapy or concurrent chemoradiotherapy after surgery. There was no difference between the patient groups with regard to survival and patterns of recurrence. • This is really the only trial in which all patients received postoperative radiotherapy. There was more toxicity on the concurrent arm of the study, which may have accounted for the lack of efficacy on this trial, particularly for stage II patients.

  10. The Adjuvant Lung Project Italy (ALPI) • ALPI trial enrolled 1,209 patients with stages I - IIIA NSCLC and randomly assigned them to receive mitomycin, vindesine, and cisplatin (MVP) or observation. • Patients received radiotherapy as determined by the participating institution. • There was no significant difference in overall survival between the study arms. Only 69% of patients completed three cycles of chemotherapy with many requiring dose reductions possibly accounting for the poor results in the chemotherapy study arm.

  11. Adjuvant Lung Project Italy (ALPI) • Mitomycin C, vindesine plus cisplatin (MVP) in 1,209 patients with resected stage I, II and IIIA NSCLC • Failed to confirm effectiveness of adjuvant MVP (no difference in OS [p=0.589] or PFS [p=0.128]) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 HR=0.96 (0.81, 1.13); p=0.589 Overall survival Events Total MVP 279 548 Control 289 540 0 1 2 3 4 5 Years from randomisation Scagliotti GV, et al. JNCI 2003;95:1453–61

  12. The Big Lung Trial (BLT) • BLT from Great Britain examined the role of cisplatin-based chemotherapy in NSCLC. • There was no survival advantage for chemotherapy in the postoperative group, but this study was not designed to specifically study adjuvant chemotherapy; therefore, it was under-powered to detect a significant difference.

  13. HR= 0.72 [0.59-0.89]p=0.003 Control Chemotherapy Years 737 171 932 424 291 583 At risk 935 556 401 265 150 719 Incidence of local relapse observation

  14. HR= 0.84 [0.72-0.98]p=0.03 Control Chemotherapy Years 702 165 932 412 285 568 At risk 935 538 388 262 154 695 Incidence of metastasis observation

  15. HR= 1.07 [0.82-1.39] p=0.61 Control Chemotherapy Years 702 165 932 412 285 568 At risk 538 388 262 154 935 695 Incidence of brain metastasis as first metastasis

  16. IALT (International Adjuvant Lung Trial) • n=1,867 patients (1995–2000) • Stage I, II and IIIA • Treatment: surgery ±platin based chemotherapy. RT optional • Results: • 5-year survival rates: 45% vs 40% • HR 0.86 (95% CI: 0.76, 0.98; p<0.03) • 69% completed chemotherapy • 73.8% received ≥240mg CDDP The IALT Collaborative Group, N Engl J Med 2004;350:351–60

  17. Post - IALT • Since the report of the IALT trial there have been three large randomized trials using platin new generation chemotherapy, and all have demonstrated a survival advantage for postoperative treatment.

  18. Adjuvant Vinorelbine/ Cisplatin Prolongs Survival in Patients With Early-Stage Non-Small Cell Lung Cancer (JBR.10) Slideset on: Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;352:2589-2597.

  19. Background and Rationale • Observation considered standard treatment after complete resection of stage IB/II non-small cell lung cancer (NSCLC) • Adjuvant chemotherapy trials in this population have failed to show significant survival gains • Newer agents, including vinorelbine, show improved efficacy vs older regimens in treating advanced NSCLC • Current randomized, multicenter, phase 3 trial evaluates efficacy of adjuvant therapy with vinorelbine and cisplatin Winton T, et al. N Engl J Med. 2005;352:2589-2597.

  20. Study Design Vinorelbine 25 mg/m2* weekly for 16 weeks, and Cisplatin 50 mg/m2 Days 1 and 8 every 4 weeks for 4 cycles (n = 242) Median follow-up, 5.1 yrs Patients with completely resected T2N0, T1N1, or T2N1 NSCLC ECOG PS 0/1 (N = 482) Observation (n = 240) Median follow-up, 5.3 yrs ECOG,Eastern Cooperative Oncology Group; PS, Performance Status *Dose of 30 mg/m2 for first 18 patients; reduced due to hematologic toxicity Winton T, et al. N Engl J Med. 2005;352:2589-2597.

  21. Survival Outcomes • 5-year survival • Higher in vinorelbine/cisplatin vs observation arm • 69% vs 54% (P = .03) • Median survival • 94 months in chemotherapy group vs 73 months in observation group; P =.009 • After adjustment for interim analysis, P = .4 Winton T, et al. N Engl J Med. 2005;352:2589-2597.

  22. Other Outcomes • Chemotherapy-related toxicity • 43 hospital admissions due to toxicity (1 death) • Grade 3/4 neutropenia, 73% • Grade 3/4 anemia, 7% • Older age, pneumonectomy linked to shorter survival • Squamous features associated with improved survival vs adenocarcinoma • Ras mutationalstatus did not predict survival Winton T, et al. N Engl J Med. 2005;352:2589-2597.

  23. Key Conclusions • Combination of vinorelbine and cisplatin significantly improves disease-free and OS following complete resection of stage IB or stage II NSCLC • Investigators suggest adjuvant chemotherapy should become standard of care Winton T, et al. N Engl J Med. 2005;352:2589-2597.

  24. Adjuvant therapy with vinorelbine / cisplatin: JBR-10 trial • 482 patients with completely resected stage IB or II NSCLC • Overall and 5-year survival were significantly improved by chemotherapy Winton T, et al. N Engl J Med 2005;352:2589–97

  25. 100 80 e g a 60 t n e c r 40 e P 20 0 0.0 2.0 4.0 6.0 8.0 10.0 239 182 94 47 13 0 243 193 121 51 10 0 Observation Vinorelbine Log-Rank test for equality of groups: p=0.0164 Wilcoxon test for equality of groups: p=0.0100 Survival rate at 5 years for Observation: 54% - % C.I. ( 48%, 61%) Survival rate at 5 years for Vinorelbine: 69% - % C.I. ( 62%, 75%) JBR.10 - Overall Survival P = 0.012 69% 69% 54% 54% Vinorelbine _____ Observation _____ Years Time (years)

  26. JBR.10 Overall survival Overall survival All Stages Stage IB (+7%) 100 80 60 40 20 0 100 80 60 40 20 0 Vinorelbine + cisplatin Observation Probability (%) Probability (%) Vinorelbine + cisplatin Observation p=0.009 p=0.79 0 2 4 6 8 10 0 2 4 6 8 10 Years Years Recurrence-free survival Overall survival All Stages Stage II (+20%) 100 80 60 40 20 0 100 80 60 40 20 0 Vinorelbine + cisplatin Vinorelbine + cisplatin Probability (%) Probability (%) Observation Observation p=0.004 p=0.001 0 2 4 6 8 10 0 2 4 6 8 10 Years Years Winton TL, et al. N Engl J Med 2005;352:2589–97

  27. Cancer and Leukemia Group B Protocol 9633 CALGB 9633 randomly assigned patients with stage IB to receive carboplatin/paclitaxel compared with surgery alone. Overall survival benefit at 4 years was 12%, with a reduction of lung cancer mortality from 26% to 15% favoring chemotherapy.

  28. Schematic Study Design Schematic of Study Design

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