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

• Any T, N3, M0
• T4, any N, M0

Based on the Surveillance, Epidemiology, and End registry the estimated incidence of stage IIIB NSCLC is 17.6%.[1] The anticipated 5-year survival for the vast majority of patients who present with clinical stage IIIB NSCLC is 3% to 7%.[2] In general, patients with stage IIIB NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on the sites of tumor involvement and the performance status (PS) of the patient. In small case series, selected patients with T4, N0-1 solely due to satellite tumor nodule(s) within the primary lobe have been reported to have 5-year survival rates of 20%.[3,4][Level of evidence: 3iiiA] Selected patients with T4 N0 disease may be treated with combined modality therapy and surgery similar to patients with superior sulcus tumors. Patients with T4 disease caused by malignant pleural effusions are treated similarly to patients with stage 4 disease. With the above exceptions, most patients with excellent PS are candidates for combined modality chemotherapy and radiation therapy. Many randomized studies of patients with unresectable stage III NSCLC show that treatment with neoadjuvant or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. 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.

Patients with stage IIIB disease with poor PS are candidates for chest radiation therapy to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain).[5][Level of evidence: 3iiiC] (Refer to the Cardiopulmonary Syndromes summary [for information on cough] and the Pain summary.)

T4 or N3, M0

Radiation therapy alone, administered sequentially or concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC. However, combination chemoradiation therapy delivered concurrently provides the greatest benefit in survival with increase in toxic effects. Radiation therapy with traditional dose and fractionation schedules (1.8 Gy–2.0 Gy per fraction per day to 60 Gy–70 Gy in 6 to 7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[5] 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.[6][Level of evidence: 1iiA] Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

Although patients with unresectable stage IIIB disease may benefit from radiation therapy, long-term outcomes have generally been poor, often due to local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials. 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.[7][Level of evidence: 1iiA] A meta-analysis of the 13 trials (based on 2,214 evaluable patients) showed that the addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR] = 0.93; 95% confidence interval [CI], 0.88–0.98, P = .01). For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99, P = .02).[8]

In a meta-analysis of individual data from 1,764 patients, based on nine trials, the hazard ratio of death among patients treated with radiation chemotherapy compared to radiation therapy alone was 0.89 (95% confidence interval, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. The combination of platinum with etoposide seemed more effective than platinum alone. Concomitant platinum-based radiation chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[9]

The results of two randomized trials (including RTOG-9410) and a meta-analysis ( NPC 95-01) indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit albeit with more toxic effects than sequential chemotherapy and radiation therapy.[10-12][Level of evidence: 1iiA] In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared to chemotherapy followed by continuous daily radiation therapy to 56 Gy. Five-year OS favored concurrent therapy (27% vs. 9%). Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[10]

In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy, or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiotherapy. Median and 4-year survival were superior in the concurrent chemotherapy with daily radiation therapy (17 mo vs. 14.6 mo and 21% vs. 12% for sequential regimen [P = .046). Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[12][Level of evidence: 1iiA]

Meta-analysis of three trials of concurrent versus sequential treatment (711 patients) indicated a significant benefit of concurrent over sequential treatment (RR = 0.86; 95% CI, 0.78–0.95; P = .003). All used cisplatin-based regimens and once-daily radiation therapy.[8,13] More deaths (3% overall) were reported in the concurrent arm but this did not reach statistical significance (RR = 1.60; CI, 0.75–3.44; P = .2).There was more acute esophagitis (grade 3 or worse with concurrent treatment [range = 17%–26%] compared to sequential treatment (range = 0%–4%; RR = 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.

Several small series have reported that reduction in fluorodeoxyglucose-positron emission tomography (FDG-PET) after chemotherapy, radiation therapy, or chemoradiation therapy predict for pathological complete response and favorable prognosis.[8,11-17] Studies have used different timing of assessments, positron emission tomography (PET) parameters, and cutpoints to define PET response. Reduction in maximum standardized uptake value (SUV) of more than 80% predicted for complete pathological response with a sensitivity of 90%, specificity of 100%, and accuracy of 96%.[14] Median survival after resection was greater for patients with tumor SUV values of less than 4 (56 mo vs. 19 mo).[17] Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.[18]. PET may be more sensitive and specific than the CT scan in assessing response to induction therapy. Optimal timing imaging remains to be defined; however, one study suggests that greater sensitivity and specificity of PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.[19]

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as tracheal, esophageal, or bronchial compression; pain; vocal cord paralysis; hemoptysis; or superior vena cava syndrome (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information). In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[20] A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[21] Better overall symptom palliation and fewer retreatments were required in previously untreated patients using EBRT alone.[21][Level of evidence: 1iiC]. HDREB did provide palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, providing it is technically feasible. Although EBRT is frequently proscribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief, [22-27] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCIC Clinical Trials' Group trial NCIC-CTG-SC15.[24][Level of evidence: 1iiC] Evidence is available of a modest increase in survival in patients with better PS given high-dose radiation therapy.[22,23][Level of evidence: 1iiA]

Because of the poor overall results, these patients are candidates for clinical trials that examine new fractionation schedules, radiosensitizers, and combined modality approaches, which may lead to improvement in the control of disease. Information about ongoing clinical trials is available from the NCI Web site.

Treatment options:

1. Chemotherapy combined with radiation therapy.
2. Radiation therapy alone.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IIIB 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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11. Curran WJ, Scott CB, Langer CJ, et al.: Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III nsclc: RTOG 9410. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2499, 2003. 
    
    
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15. Pöttgen C, Levegrün S, Theegarten D, et al.: Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res 12 (1): 97-106, 2006.  [PUBMED Abstract]
    
    
16. Eschmann SM, Friedel G, Paulsen F, et al.: 18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer. Eur J Nucl Med Mol Imaging 34 (4): 463-71, 2007.  [PUBMED Abstract]
    
    
17. Hellwig D, Graeter TP, Ukena D, et al.: Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma. J Thorac Cardiovasc Surg 128 (6): 892-9, 2004.  [PUBMED Abstract]
    
    
18. Mac Manus MP, Hicks RJ, Matthews JP, et al.: Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 21 (7): 1285-92, 2003.  [PUBMED Abstract]
    
    
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24. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.  [PUBMED Abstract]
    
    
25. Erridge SC, Gaze MN, Price A, et al.: Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol) 17 (1): 61-7, 2005.  [PUBMED Abstract]
    
    
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27. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Młyński E, et al.: A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 92 (6): 1038-45, 2005.  [PUBMED Abstract]
    
    

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