Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage I non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

• T1, N0, M0
• T2, N0, M0

Surgery is the treatment of choice for patients with stage I NSCLC. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age-related, but 3% mortality to 5% mortality with lobectomy can be expected.[1] Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. The Lung Cancer Study Group conducted a randomized study (LCSG-821) to compare lobectomy with limited resection for patients with stage I lung cancer. Results of the study showed a reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision, but the outcome showed no significant difference in overall survival (OS).[2] Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.[3] A survival advantage was noted with lobectomy for patients with tumors more than 3 cm but not for those with tumors less than 3 cm; however, the rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size.

Another study of stage I patients showed that those treated with wedge or segment resections had a local recurrence rate of 50% (i.e., 31 recurrences out of 62 patients) despite having undergone complete resections.[4] Exercise testing may aid in the selection of patients with impaired pulmonary function who can tolerate lung resection.[5] The availability of video-assisted thoracoscopic wedge resection permits limited resections in patients with poor pulmonary function who are not usually candidates for lobectomy.[6]

Patients with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent. In a single report of patients older than 70 years who had resectable lesions smaller than 4 cm but who had medically inoperable disease or who refused surgery, survival at 5 years after radiation therapy with curative intent was comparable with an historical control group of patients of similar age who were resected with curative intent.[7] In the two largest retrospective radiation therapy series, patients with inoperable disease treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%.[8,9] Both series found that patients with T1, N0 tumors had better outcomes, and 5-year survival rates of 60% and 32% were found in this subgroup.

Primary radiation therapy should consist of approximately 60 Gy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results; this requires the use of a simulator.

Many patients treated surgically subsequently develop regional or distant metastases.[4] Such patients are candidates for entry into clinical trials evaluating adjuvant treatment with chemotherapy or radiation therapy following surgery. A meta-analysis of nine randomized trials evaluating postoperative radiation versus surgery alone showed a 7% reduction in OS with adjuvant radiation in patients with stage I or stage II disease.[10][Level of evidence: 1iiA] Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

Patients with stage IB disease may benefit from adjuvant platinum-based combination chemotherapy, as evidenced in the INT- JBR-10 and the CALGB-9633 trials, for example.[11-15] A meta-analysis of adjuvant chemotherapy trials showed a hazard ratio (HR) for death of 0.87 for patients treated with cisplatin-based chemotherapy;[16] however, this result was not statistically significant. Four large randomized trials and an additional meta-analysis evaluating the benefit of adjuvant cisplatin combination chemotherapy have also been reported. Three of the trials and the meta-analysis have shown that adjuvant cisplatin-based chemotherapy improves OS in selected NSCLC patients.

In the largest trial, the International Adjuvant Lung Cancer Trial (IALT), 1,867 patients with resected stage I, stage II, or stage III NSCLC were randomly assigned to cisplatin combination chemotherapy or follow-up.[12] Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (5-year survival, 44.5% vs. 40.4%; HR for death = 0.86; 95% confidence interval [CI], 0.76–0.98; P < .03).[12][Level of evidence: 1iiA] Seven patients (0.8%) died of chemotherapy-induced toxic effects.

In the second trial, 482 patients with completely resected stage I (T2, N0) or stage II (excluding T3, N0) NSCLC were randomly assigned to receive four cycles of vinorelbine and cisplatin or observation.[11] OS was significantly prolonged for patients receiving chemotherapy (median survival, 94 months vs. 73 months; HR = 0.69; P = .011).[11][Level of evidence: 1iiA] Two patients died of drug-related toxicity.

In the third trial, 344 patients with stage IB (T2, N0, M0) NSCLC were randomized to four cycles of paclitaxel and carboplatin or observation.[13] There were no chemotherapy-related toxic deaths. The hazard ratio for death was significantly lower among patients receiving adjuvant chemotherapy (HR = 0.62; 95% CI, 0.41–0.95; P = .028).[13][Level of evidence: 1iiA] OS at 4 years was 71% (95% CI, 62%–81%) in the chemotherapy group and 59% (95% CI, 50%–69%) in the observation group.

In the fourth trial, the Adjuvant Lung Project Italy trial, 1,209 patients with stage I, stage II, or stage IIIA NSCLC were randomly assigned to receive mitomycin C, vindesine, and cisplatin every 3 weeks or no treatment after complete resection.[14][Level of evidence: 1iiA] After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in OS (HR = 0.96; 95% CI, 0.81–1.13; P = .589) or progression-free survival (HR = 0.89; 95% CI, 0.76–1.03; P = .128).

The literature-based meta-analysis of randomized trials identified 11 trials conducted with a total of 5,716 patients. This analysis includes the IALT and ALPI trials noted above. In this analysis, HR estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR = 0.872; 95% CI, 0.805–0.944; P = .001). In a subset analysis, both cisplatin-based chemotherapy (HR = 0.891; 95% CI, 0.815–0.975; P = .012) and single-agent therapy with tegafur and uracil (UFT) (HR = 0.799; 95% CI, 0.668–0.957; P = .015) were found to yield a significant survival benefit.[15,17]

In summary, the preponderance of evidence indicates that adjuvant cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC. The optimal sequence of surgery and chemotherapy and the benefits and risks of adjuvant radiation therapy in patients with resectable NSCLC are yet to be determined.

A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers.[18] Others have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.[4] A randomized trial of vitamin A versus observation in patients with resected stage I disease showed a trend toward decreased second primary cancers in the vitamin A arm and no difference in OS rates;[19] however, a large randomized study of beta-carotene and retinol supplements used in the primary prevention of lung cancer showed an increase in mortality and lung cancer incidence.[20][Level of evidence: 1iA]

An intergroup trial evaluated the role of isotretinoin in the chemoprevention of second cancers in patients with resected stage I NSCLC. In the trial, 1,116 patients were randomly assigned to receive isotretinoin (30 mg/day) for 3 years or a placebo.[21][Level of evidence: 1iiA] (Refer to the PDQ summary on Lung Cancer Prevention for more information.) After a median follow-up of 3.5 years, no differences existed between the arms in time to development of second primary tumors, disease recurrence, or survival.

Treatment options:

1. Lobectomy or segmental, wedge, or sleeve resection as appropriate.



2. Radiation therapy with curative intent (for potentially resectable tumors in patients with medical contraindications to surgery).



3. Adjuvant chemotherapy after resection.



4. Clinical trials of adjuvant chemoprevention , as evidenced in the ECOG-5597 trial, for example.



5. Endoscopic photodynamic therapy (under clinical evaluation in highly selected patients with T1, N0, M0 tumors).[22]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Ginsberg RJ, Hill LD, Eagan RT, et al.: Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 86 (5): 654-8, 1983.  [PUBMED Abstract]
   
   
2. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60 (3): 615-22; discussion 622-3, 1995.  [PUBMED Abstract]
   
   
3. Warren WH, Faber LP: Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg 107 (4): 1087-93; discussion 1093-4, 1994.  [PUBMED Abstract]
   
   
4. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.  [PUBMED Abstract]
   
   
5. Morice RC, Peters EJ, Ryan MB, et al.: Exercise testing in the evaluation of patients at high risk for complications from lung resection. Chest 101 (2): 356-61, 1992.  [PUBMED Abstract]
   
   
6. Shennib HA, Landreneau R, Mulder DS, et al.: Video-assisted thoracoscopic wedge resection of T1 lung cancer in high-risk patients. Ann Surg 218 (4): 555-8; discussion 558-60, 1993.  [PUBMED Abstract]
   
   
7. Noordijk EM, vd Poest Clement E, Hermans J, et al.: Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol 13 (2): 83-9, 1988.  [PUBMED Abstract]
   
   
8. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992.  [PUBMED Abstract]
   
   
9. Gauden S, Ramsay J, Tripcony L: The curative treatment by radiotherapy alone of stage I non-small cell carcinoma of the lung. Chest 108 (5): 1278-82, 1995.  [PUBMED Abstract]
   
   
10. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 352 (9124): 257-63, 1998.  [PUBMED Abstract]
    
    
11. Winton TL, Livingston R, Johnson D, et al.: A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer (NSCLC) Intergroup JBR.10. [Abstract] J Clin Oncol 22 (Suppl 14): A-7018, 621s, 2004. 
    
    
12. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004.  [PUBMED Abstract]
    
    
13. Strauss GM, Herndon J, Maddaus MA, et al.: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) protocol 9633. [Abstract] J Clin Oncol 22 (Suppl 14): A-7019, 621s, 2004. 
    
    
14. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003.  [PUBMED Abstract]
    
    
15. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004.  [PUBMED Abstract]
    
    
16. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.  [PUBMED Abstract]
    
    
17. Kato H, Ichinose Y, Ohta M, et al.: A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350 (17): 1713-21, 2004.  [PUBMED Abstract]
    
    
18. Thomas P, Rubinstein L: Cancer recurrence after resection: T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 49 (2): 242-6; discussion 246-7, 1990.  [PUBMED Abstract]
    
    
19. Pastorino U, Infante M, Maioli M, et al.: Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 11 (7): 1216-22, 1993.  [PUBMED Abstract]
    
    
20. Goodman GE, Thornquist MD, Balmes J, et al.: The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst 96 (23): 1743-50, 2004.  [PUBMED Abstract]
    
    
21. Lippman SM, Lee JJ, Karp DD, et al.: Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 93 (8): 605-18, 2001.  [PUBMED Abstract]
    
    
22. Furuse K, Fukuoka M, Kato H, et al.: A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan Lung Cancer Photodynamic Therapy Study Group. J Clin Oncol 11 (10): 1852-7, 1993.  [PUBMED Abstract]
    
    

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