Concurrent Chemoradiotherapy Followed by Consolidation Docetaxel in Stage IIIB Non–Small-Cell Lung Cancer

r nb Rationale

• The poor long-term outcome for patients with stage III unresectable non– small-cell lung cancer (NSCLC) led to the SWOG 8805 trial, which found concurrent chemotherapy (cisplatin/etoposide) and irradiation followed by surgery to be feasible but with significant morbidity and mortality in these patients.1 • More recently, in the SWOG 9019 trial, the same stage IIIB subsets were studied to examine whether surgery after induction chemoradiotherapy was more of a risk than a benefit.2 This trial used the same induction chemotherapy and radiotherapy (RT) regimen and followed that with continued RT and 2 additional cycles of cisplatin/etoposide (PE). The survival results (median survival of 15 months and 2-year survival of 34%) were similar to those from SWOG 8805. • Docetaxel is active as second-line treatment of NSCLC.3 There are potential mechanisms of action which favor taxane sequencing.4 This, along with results from S8805 and S9019, led Dr. Gandara and colleagues to conduct a phase II study (SWOG 9504) of concurrent PE/RT followed by consolidation docetaxel in patients with pathologically confirmed stage IIIB NSCLC. Results of this trial, presented at the 2000 American Society of Clinical Oncology Meeting in New Orleans, LA, are discussed below.

Trial Design This SWOG trial (S9504), led by Dr. Gandara, was conducted to evaluate docetaxel consolidation following concurrent chemoradiotherapy (XRT) in patients with stage IIIB NSCLC. The primary endpoint was survival. Patients were required to have stage IIIB NSCLC with biopsy-confirmed T4 (no pleural effusion) or N3 status. The staging requirements are outlined in Table 1. Ninety-seven patients were registered for this trial (S9504). Fourteen patients were ineligible, seven due to inadequate staging and seven because they had stage IV disease. The 83 eligible patients were given cisplatin 50 mg/m2 days 1, 8, 29, and 36 and etoposide 50 mg/m2 days 1-5 and 29-33. Concurrent RT (45 Gy + 16 Gy boost, 1.8-2.0 Gy/day) was started on day 1. Consolidation docetaxel followed every 21 days for 3 cycles (75 mg/m2 cycle 1, 100 mg/m2 cycles 2-3). The treatment schema is shown in Figure 1.

Results The median age of patients was 60 years. Most (73%) patients were male and 78 (94%) had a good performance status. TNM staging was as follows: 37% T4 N0-1; 27% T4 N2; 36% N3. These values were similar to those in S9019. Patient characteristics are summarized in Table 2.

• N3: Documentation by FNA, mediastinoscopy, or thoracotomy • T4: Documentation by FNA, attending surgeon, or bronchoscopy; involvement of heart, esophagus, vertebrae, or great vessels with mediastinal mass by CT or MRI • If pleural effusion: Cytology negative Abbreviations: CT = computed tomography; FNA = fine-needle aspiration; MRI = magnetic resonance imaging

Age Median

60 years

Range

34-80 years

Gender Male

73%

Female

27%

Performance Status 0-1

94%

Tumor Characteristics

Treatment Schedule

Table 1: Staging Requirements

Table 2: Patient Characteristics (n = 83)

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Concurrent Chemoradiotherapy Followed by Consolidation Docetaxel in Stage IIIB Non–Small-Cell Lung Cancer (SWOG 9504)

T4 N0-1

37%

T4 N2

27%

N3

36%

Efficacy The radiographic response rates are shown in Table 3. The complete response rate was 4%. There were 49 patients (59%) with a partial response, for an encouraging overall response rate of 63%. Twenty-three patients (28%) had stable disease and eight (9%) had disease progression. The survival data are encouraging and represent an improvement of consolidation docetaxel (S9504) in comparison to continued cisplatin/etoposide (S9019). Progression-free survival was 13 months. Median survival was 22 months. The 1year and 2-year survival rates were 78% and 50%, respectively. Each of these compared favorably with results from S9019. A comparison of survival results

Figure 1: Treatment Schema PE x 2/RT

Docetaxel x 3

• Cisplatin/Etoposide Cisplatin 50 mg/m2 days 1, 8, 29, and 36; Etoposide 50 mg/m2 days 1-5, 29-33 • Concurrent RT (starting day 1) 45 Gy (1.8 Gy/fraction), 16 Gy boost (2 Gy/fraction) • Consolidation Docetaxel 75 mg/m2 cycle 1 ➝ 100 mg/m2 cycles 2-3 Abbreviations: PE = cisplatin/etoposide; RT = radiotherapy

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Table 3: Response Data Radiographic Response

(n = 83)

Complete Response (CR)

4%

Partial Response (PR)

59%

Overall Response (CR + PR)

63%

Stable Disease (SD)

28%

CR + PR + SD

91%

from both trials is shown in Figure 2.

Toxicity Consolidation docetaxel was generally well tolerated in these patients. The main Figure 2: Results at a Glance S9504

S9019

toxicity arising from consolidation docetaxel was grade 3/4 neutropenia (75%). Nonhematologic adverse events were primarily due to pneumonitis (7% grade 3, 4% grade 5). Three patients died from pulmonary complications. Toxicity data are summarized in Table 4.

Conclusion Cisplatin/etoposide with concurrent radiotherapy followed by consolidation docetaxel is a viable and tolerable regimen in patients with pathologic stage IIIB NSCLC. The survival results are encouraging (Figure 2) and compare well with previous studies with similar patients. These results merit further study of this regimen. The recommended dose for consolidation docetaxel is 75 mg/m2/cycle.

Table 4: Major Toxicities Toxicities with Concurrent Chemoradiotherapy (n = 83) Hematologic Grade 3/4 neutropenia

42%

Febrile neutropenia

2%

Nonhematologic Grade 3/4 esophagitis Toxicities with Consolidation Docetaxel (n = 69) Hematologic Grade 3/4 neutropenia

75%

Febrile neutropenia

9%

Nonhematologic Grade 3/5 pneumonitis

References

Median Survival 22 months 15 months 1-Year Survival 78% 58% 2-Year Survival 50% 34% S9504: SWOG 9504, current study = PE/RT➝ docetaxel S9019: SWOG 9019, previous study = PE/RT➝ PE Abbreviations: PE = cisplatin/etoposide; RT = radiotherapy

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11%

Deaths*

12% 6%

1. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radio* There was one infection-related death. Three patients therapy followed by surgery for stages IIIA (N2) died due to pulmonary complications. and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995; 13:1880-1892. dynamics. Urology 1999; 54:22-29. 2. Albain KS, Crowley JJ, Turrisi III AT, et al. Concurrent 5. Gandara DR, Lovato LC, Albain KS, et al. Prolonged cisplatin/etoposide plus radiotherapy (PE +RT) for survival in pathologic stage IIIB non-small cell lung pathologic stage (pathTN) IIIB non-small cell lung cancancer (NSCLC) with concurrent chemoradiotherapy cer (NSCLC): a Southwest Oncology Group (SWOG) followed by consolidation docetaxel: a phase II study phase II study (S9019). Proc Am Soc Clin Oncol 1997; (S9504) of the Southwest Oncology Group (SWOG). 16:446a (Abstract #1600). Proc Am Soc Clin Oncol 2000; 19:490a (Abstract #1916). 3. Fossella FV, DeVore R, Kerr RN et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000; 18:2354-2362 4. Vaishampayan U, Parchment RE, Jasti BR, et al. Taxanes: an overview of the pharmacokinetics and pharmaco-