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 a 3% to 5% mortality rate 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 larger than 3 cm but not for those with tumors smaller than 3 cm; however, the rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size. A 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]

The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early stage (I–IIIA) lung cancer.[5] From a pooled analysis of three trials, 4-year survival was superior in patients with resectable stage I to IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND) compared with those who underwent resection and lymph node sampling; the HR was estimated to be 0.78 (95% CI, 0.65–0.93, P = .005).[5][Level of evidence: 1iiA]

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and the potential methodological weaknesses of the trials. However, there was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR] = 0.79; 95% confidence interval [CI], 0.66–0.95; P = .01) that appeared mainly because of a reduction in the number of distant recurrences (RR = 0.78; 95% CI, 0.61–1.00; P = .05). There was no difference in operative mortality. Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR = 2.94; 95% CI, 1.01–8.54; P = .05). Current evidence suggests that lung cancer resection combined with CMLND is associated with a small to modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I to IIIA NSCLC.[5][Level of evidence: 1iiA] CMLND versus lymph node sampling has been evaluated in a large randomized phase III trial (ACOSOG-Z0030). Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[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. A small case series using matched controls reported that the addition of endobronchial brachytherapy improved local disease control compared to external beam radiation therapy.[4][Level of evidence: 3iiiDiii]

Many patients treated surgically subsequently develop regional or distant metastases.[10] Such patients are candidates for entry into clinical trials evaluating adjuvant treatment with chemotherapy or radiation therapy following surgery. At present, neither chemotherapy nor radiation therapy has been found to improve the outcome of patients with stage I NSCLC that has been completely resected.

The value of postoperative radiation therapy (PORT) has been evaluated.[11] The meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported an 18% relative increase in the risk of death for patients who received PORT compared to surgery alone (hazard ratio [HR] = 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2%–9%), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0–N1 disease, whereas for stage III, N2 patients there was no clear evidence of an adverse effect. Results for local (HR = 1.13; P = .02), distant (HR = 1.14; P = .02) and overall (HR = 1.10; P = .06) recurrence-free survival similarly show a detriment of PORT.[11][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.

Several randomized controlled trials and meta-analyses have evaluated the use of adjuvant chemotherapy in patients with stage I, II, and IIIA NSCLC.[12-18] In the largest meta-analysis based on individual patient outcomes, data were collected and pooled from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[14] With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95–2.06; HR for stage IB = 0.93; 95% CI, 0.78–1.10; HR for stage II = 0.83; 95% CI, 0.73–0.95; and HR for stage III = 0.83; 95% CI, 0.72–0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80–1.07), or other (HR = 0.97; 95% CI, 0.84–1.13). The apparent greater benefit seen with vinorelbine should be interpreted cautiously as vinorelbine and cisplatin combinations generally required that a higher dose of cisplatin be given. Chemotherapy effect was higher in patients with better performance status.

There was no interaction between chemotherapy effect and any of the following:

• Sex.
• Age.
• Histology.
• Type of surgery.
• Planned radiation therapy.
• Planned total dose of cisplatin.

Based on this meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.[19,20][Level of evidence: 1iiA].

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.[21] 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.[10] (Refer to the PDQ summary on Smoking Cessation and Continued Risk in Cancer Patients for more information.)

Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials with the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.[22-26][Level of evidence: 1iiA] (Refer to the PDQ summary on Lung Cancer Prevention for more information.)

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. Clinical trials of adjuvant chemoprevention (as evidenced in the ECOG-5597 trial, for example).
4. Endoscopic photodynamic therapy and other endobronchial therapies (under clinical evaluation in highly selected patients with T1, N0, M0 tumors).

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. Mantz CA, Dosoretz DE, Rubenstein JH, et al.: Endobronchial brachytherapy and optimization of local disease control in medically inoperable non-small cell lung carcinoma: a matched-pair analysis. Brachytherapy 3 (4): 183-90, 2004.  [PUBMED Abstract]
   
   
5. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005.  [PUBMED Abstract]
   
   
6. Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006.  [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. 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]
    
    
11. PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.  [PUBMED Abstract]
    
    
12. Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005.  [PUBMED Abstract]
    
    
13. 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]
    
    
14. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008.  [PUBMED Abstract]
    
    
15. 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]
    
    
16. 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]
    
    
17. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992.  [PUBMED Abstract]
    
    
18. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007.  [PUBMED Abstract]
    
    
19. Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001.  [PUBMED Abstract]
    
    
20. van Boxem TJ, Venmans BJ, Schramel FM, et al.: Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique. Eur Respir J 11 (1): 169-72, 1998.  [PUBMED Abstract]
    
    
21. 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]
    
    
22. van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001.  [PUBMED Abstract]
    
    
23. Blumberg J, Block G: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland. Nutr Rev 52 (7): 242-5, 1994.  [PUBMED Abstract]
    
    
24. Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996.  [PUBMED Abstract]
    
    
25. 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]
    
    
26. van Zandwijk N, Dalesio O, Pastorino U, et al.: EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 92 (12): 977-86, 2000.  [PUBMED Abstract]
    
    

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