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

• T1, N2, M0
• T2, N2, M0
• T3, N1, M0
• T3, N2, M0

Patients with clinical stage IIIA N2 disease have a 5-year survival rate of 10% to 15% overall; however, patients with bulky mediastinal involvement (i.e., visible on chest radiograph) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities. Although most patients do not achieve a complete response to radiation therapy, a reproducible long-term survival benefit in 5% to 10% of patients treated with standard fractionation to 60 Gy occurs, and significant palliation often results. Patients with excellent performance status (PS) and those who require a thoracotomy to prove that a surgically unresectable tumor is present are most likely to benefit from radiation therapy.[1]

Because of the poor long-term results, all patients with stage IIIA NSCLC are candidates for treatment on clinical trials. Trials examining fractionation schedules, brachytherapy, and combined modality approaches may lead to improvement in the control of this disease.[2] One prospective randomized clinical study showed that radiation therapy given as three daily fractions improved OS compared with radiation therapy given as one daily fraction.[3][Level of evidence: 1iiA]

The addition of chemotherapy to radiation therapy has been reported to improve survival in prospective clinical studies, including the RTOG-8808 and ECOG-4588 trials, for example, that have used modern cisplatin-based chemotherapy regimens.[4-7] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[8] The optimal sequencing of modalities and schedule of drug administration is yet to be determined and is under study in ongoing clinical trials such as the RTOG-9410 trial, for example.

The use of preoperative (i.e., neoadjuvant) chemotherapy has been effective in two small randomized studies of a total of 120 patients with stage IIIA NSCLC.[9,10] In both studies, the 58 patients randomized to three cycles of cisplatin-based chemotherapy before surgery had a median survival more than three times as long as patients treated with surgery but no chemotherapy. Two additional single-arm studies, including SWOG-8805, have evaluated either two to four cycles of combination chemotherapy or combination chemotherapy plus chest radiation therapy for 211 patients with histologically confirmed N2 stage IIIA NSCLC.[11] In these studies, 65% to 75% of patients had a resection of their cancers, and 27% to 28% of patients were alive 3 years later. These results are encouraging, and combined-modality therapy with neoadjuvant chemotherapy with surgery and/or chest radiation therapy should be considered for patients with good PS who have stage IIIA NSCLC.

After surgery, many patients develop regional or distant metastases.[12] Patients with resected stage IIIA NSCLC may benefit from adjuvant cisplatin combination chemotherapy, as evidenced in the (INT- JBR-10) and CALGB-9633 trials, for example.[13-18] Prospective randomized trials evaluating the role of postoperative adjuvant chemotherapy in patients with NSCLC have been performed for decades. A meta-analysis of adjuvant chemotherapy trials showed a hazard ratio (HR) for death of 0.87 for patients treated with cisplatin-based chemotherapy;[8] 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.[13] 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).[13][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.[14] OS was significantly prolonged for patients receiving chemotherapy (median 94 months vs. 73 months; HR 0.69; P = .011).[14][Level of evidence: 1iiA] Two patients died of drug-related toxic effects.

In the third trial, 344 patients with stage IB (T2, N0, M0) NSCLC were randomly assigned to four cycles of paclitaxel and carboplatin or observation.[15] 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).[15][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 (ALPI) 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.[16][Level of evidence: 1iiA] After a median follow-up time of 64.5 months, there was no statistically significant difference between the 2 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 on 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 versus 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.[17,18]

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.

Although most retrospective studies suggest that postoperative radiation therapy can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival.[19,20] One controlled trial of patients with completely resected stage II or stage III squamous cell lung cancer failed to demonstrate a survival benefit for patients who received postoperative radiation therapy, but local recurrences were significantly reduced.[21] In one trial patients with completely resected stage I, stage II, or stage IIIA lung cancers were randomly assigned to resection alone or to resection plus postoperative radiation therapy. The addition of postoperative radiation therapy did not improve OS or local recurrence either for the whole group or for the subset of patients with stage IIIA disease.[22][Level of evidence: 1iiA] An intergroup trial comparing postoperative radiation therapy alone to postoperative radiation therapy with concurrent cisplatin and etoposide did not demonstrate either a disease-free survival or OS advantage with the combined therapy.[23][Level of evidence: 1iiA] A meta-analysis of nine randomized trials that evaluated postoperative radiation therapy versus surgery alone showed no difference in OS for the entire postoperative radiation therapy group or for the subset of N2 patients.[24][Level of evidence: 1iiA] Further analysis is needed to determine whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

No consistent benefit from any form of immunotherapy has been demonstrated thus far in the treatment of NSCLC.

Treatment options:

1. Surgery alone in patients with operable tumors without bulky lymphadenopathy.[25-27]



2. Radiation therapy alone, for patients who are not suitable for neoadjuvant chemotherapy plus surgery.[1,2,28]



3. Chemotherapy combined with other modalities, as evidenced in the SWOG-8805 trial, for example.[4-6,11]

Superior sulcus tumor (T3, N0 or N1, M0)

A special approach is also merited for treatment of superior sulcus tumors. These are a locally invasive problem and usually have a reduced tendency for distant metastases; consequently, local therapy has curative potential, especially in patients with T3, N0 disease. Radiation therapy alone, radiation therapy preceded or followed by surgery, or surgery alone (in highly selected cases) may be curative in some patients, with a 5-year survival rate of more than 20% in some studies.[29] Patients with more invasive tumors of this area, or true Pancoast tumors, have a worse prognosis and generally do not benefit from primary surgical management. Follow-up surgery may be used to verify complete response in the radiation therapy field and to resect necrotic tissue. Concurrent chemotherapy and radiation therapy followed by surgery may provide the best outcome, particularly for patients with T4, N0, or N1 disease, as evidenced in the SWOG-9416 trial, for example.[30][Level of evidence: 3iiiDii]

Treatment options:

1. Radiation therapy and surgery.



2. Radiation therapy alone.



3. Surgery alone (selected cases).



4. Chemotherapy combined with other modalities.



5. Clinical trials of combined modality therapy.

Chest wall tumor (T3, N0 or N1, M0)

Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.

Treatment options:

1. Surgery.[27,31]



2. Surgery and radiation therapy.



3. Radiation therapy alone.



4. Chemotherapy combined with other modalities.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IIIA 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

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15. 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. 
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. Emami B, Kaiser L, Simpson J, et al.: Postoperative radiation therapy in non-small cell lung cancer. Am J Clin Oncol 20 (5): 441-8, 1997.  [PUBMED Abstract]
    
    
20. Sawyer TE, Bonner JA, Gould PM, et al.: Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks. Ann Thorac Surg 64 (5): 1402-7; discussion 1407-8, 1997.  [PUBMED Abstract]
    
    
21. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. The Lung Cancer Study Group. N Engl J Med 315 (22): 1377-81, 1986.  [PUBMED Abstract]
    
    
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29. Komaki R, Mountain CF, Holbert JM, et al.: Superior sulcus tumors: treatment selection and results for 85 patients without metastasis (Mo) at presentation. Int J Radiat Oncol Biol Phys 19 (1): 31-6, 1990.  [PUBMED Abstract]
    
    
30. Rusch VW, Giroux DJ, Kraut MJ, et al.: Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 121 (3): 472-83, 2001.  [PUBMED Abstract]
    
    
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