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

• T1, N1, M0
• T2, N1, M0
• T3, N0, M0

Surgery is the treatment of choice for patients with stage II 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. Despite the immediate and age-related postoperative mortality rate, a 5% to 8% mortality rate with pneumonectomy or a 3% to 5% mortality rate with lobectomy can be expected.

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.[1] 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).[1][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 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% CI, 0.66–0.95; P = .01) that appeared mainly due to 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.[1][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.[2]

The value of postoperative radiation therapy (PORT) has been evaluated.[3] 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.[3][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 inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent.[4] Among patients with excellent performance status (PS) , a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC, who were treated with definitive radiation therapy, achieved a 5-year OS rate of 10%; however, the 44 patients with T1 tumors achieved an actuarial disease-free survival (DFS) rate of 60%. This retrospective study also suggested that improved DFS was obtained with radiation therapy doses larger than 60 Gy.[5] Primary radiation therapy should consist of approximately 60 Gy delivered with megavoltage equipment to the midplane of the volume of the known tumor 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.

After surgery, many patients develop regional or distant metastases.[6] Several randomized controlled trials and meta-analyses have evaluated the use of adjuvant chemotherapy in patients with stage I, II, and IIIA NSCLC.[7-13] 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.[9] 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 greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted with caution as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine. However, the meta-analysis as well as the individual studies [7,14] support the administration of adjuvant cisplatin-based chemotherapy in combination with vinorelbine. For these studies, the LACE pooled analysis (NCT00576914), ANITA (NCT00238849), and NCIC-CTG JBR.10 (CAN-NCIC-BR10) trials all reported superior OS for the trial population as well as for the patients with stage II disease (pooled HR = 0.83, 95% CI, 0.73–0.95; HR = 0.71, 95% CI, 0.49–1.03; HR = 0.59, 95% CI, 0.42–0.85, respectively). Chemotherapy effect was higher in patients with better PS.

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.

In a retrospective analysis of a phase III trial of adjuvant cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment. Chemotherapy significantly prolonged OS for elderly patients (HR = 0.61; 95% CI, 0.38–0.98; P = .04). There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although elder patients received less treatment.[15] Based on these data, patients with completed resected stage II lung cancer may benefit from adjuvant cisplatin-based chemotherapy.[15][Level of evidence: 1iiA]

The role of chemotherapy prior to surgery has been tested in clinical trials. The proposed benefits of preoperative chemotherapy are a reduction in tumor size that may facilitate surgical resection, early eradication of micrometastases, and better tolerability. Preoperative chemotherapy may, however, delay potentially curative surgery. The Cochrane Collaboration Review group reported a systematic review and meta-analysis of seven randomized controlled trials including 988 patients evaluating the addition of preoperative chemotherapy to surgery versus surgery alone. Included trials evaluated patients with stages I, II, and IIIa NSCLC.[16] Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease from 14% to 20% at 5 years (HR = 0.82; 95% CI, 0.69–0.97; P = .022).[16][Level of evidence: 1iiA] This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.

Although the Cochrane Collaboration group's analysis indicates an OS advantage for preoperative chemotherapy, in the largest trial reported to date, no survival advantage was seen.[17] In that trial, 519 patients were randomized to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery. Most patients (61%) had clinical stage I disease; 31% had stage II disease, and 7% had stage III disease. Postoperative complications were similar between groups, and no impairment of quality of life was observed. There was no evidence of a benefit in terms of OS (HR = 1.02; 95% CI, 0.80–1.31, P = .86). Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant chemotherapy (1,507 patients; HR = 0.88, 95% CI, 0.76–1.01, P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.

In summary, the preponderance of evidence indicates that adjuvant cisplatin combination chemotherapy provides a significant survival advantage to patients with resected stage II NSCLC. Preoperative chemotherapy may also provide survival benefit. The optimal sequence of surgery and chemotherapy and the benefits and risks of adjuvant radiation therapy in patients with resectable NSCLC remain to be determined.

Treatment options:

1. Lobectomy; pneumonectomy; or segmental, wedge, or sleeve resection as appropriate.
2. Radiation therapy with curative intent (for potentially operable tumors in patients with medical contraindications to surgery).
3. Adjuvant chemotherapy after curative surgery.
4. Clinical trials of radiation therapy after curative surgery.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II 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. 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]
   
   
2. 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]
   
   
3. PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.  [PUBMED Abstract]
   
   
4. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. Douillard JY, Rosell R, De Lena M, et al.: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7 (9): 719-27, 2006.  [PUBMED Abstract]
    
    
15. Pepe C, Hasan B, Winton TL, et al.: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25 (12): 1553-61, 2007.  [PUBMED Abstract]
    
    
16. Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev (3): CD006157, 2007.  [PUBMED Abstract]
    
    
17. Gilligan D, Nicolson M, Smith I, et al.: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369 (9577): 1929-37, 2007.  [PUBMED Abstract]
    
    

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