Updated February 2008

Guideline: Stage III patients with good performance status (ECOG 0 to 1), minimal weight loss (less than 5% in the preceding 3 months) and suitable distribution of intrathoracic disease have been shown to have a survival benefit from treatment with cisplatin-based chemotherapy combined with definitive local therapy (thoracic irradiation and/or surgical resection).1 Such patients should be considered for a combined modality treatment approach. A full discussion should occur between the patient and physician concerning the benefits, limitations and toxicities of therapy. Patients not fitting the above criteria are not candidates for combined modality treatment and should be evaluated for palliative radiotherapy or chemotherapy.

Level of Evidence: I

Grade of Recommendation: A

Until recently, the generally accepted standard therapy for patients with locally advanced, unresectable NSCLC was radiation therapy. Radiotherapy commonly relieves symptoms resultant from locally advanced NSCLC and there is a small percentage (approximately 5%) of long-term survivors following radical radiotherapy. The use of systemic treatment in combination with radiation (and/or surgery) was investigated because of evidence of tumour regression and a small survival benefit in metastatic NSCLC with chemotherapy. Several studies, but not all, have demonstrated a survival benefit for patients treated with combined modality therapy. However, much of the evidence supporting the use of aggressive regimens is based on patients selected by virtue of better performance status, minimal or no weight loss, favourable distribution of disease and/or other factors, and thus may not be representative of many patients seen in a typical clinical practice. The recommendations provided must be interpreted in this context.

The strongest evidence regarding combined modality therapy is derived from a meta-analysis of 52 randomized trials conducted by the Non-small Cell Lung Cancer Collaborative Group.1 Twenty-two trials were identified that compared radical radiation to radical radiation plus chemotherapy, of which eleven employed chemotherapy regimens including cisplatin. The addition of cisplatin-based chemotherapy to thoracic irradiation led to a 13% reduction in the risk of death, although the absolute survival advantage at 2 years was a modest 4%.

In an influential randomized trial performed in the early 1980's by the Cancer and Leukemia Group B, thoracic irradiation alone (60 Gy) was compared to two cycles of neoadjuvant chemotherapy with cisplatin plus vinblastine followed by the same thoracic irradiation.2   Median survival for stage III patients increased from 9 mos to 14 mos. More importantly, three times as many patients were alive at 5 years on the sequential chemoradiation arm (17% versus 6%). However, because the study was closed early before full planned accrual, the actual number of long-term survivors was small. Furuse et al conducted a randomized phase III study of concurrent versus sequential radiotherapy in combination with mitomycin, vindesine and cisplatin that also demonstrated an improvement in median survival, 16.5 versus 13.3 months.3  A larger study by the Radiation Therapy Oncology Group was designed to confirm the CALGB results.  RTOG trial 94-10 compared sequential treatment using cisplatin and vinblastine to concurrent treatment and the same chemotherapy program.4  A significantly improved overall survival was demonstrated with a median survival difference of 2.4 months and 5-year survival difference was 9%.

Concurrent chemoradiotherapy has become the standard for fit patients with unresectable stage III NSCLC. Trials have been conducted to evaluate the role of consolidation chemotherapy in this setting.  Gandara et al conducted the influential SWOG 9504 phase II trial of concurrent chemoradiotherapy with cisplatin and etoposide followed by consolidation docetaxel.5  The median survival from this trial was 26 months, an impressive improvement and this strategy was widely adopted in the USA, in spite of this being a phase II data only. This approach was recently evaluated by the Hoosier Oncology Group and US Oncology. This phase III trial, HOG LUN 01-24, assessed outcomes after two cycles of cisplatin and etoposide with concurrent radiotherapy with or without consolidation docetaxel.  The median survival was not different in the two groups, observation 24.1 months, docetaxel 21.5 months (p=0.94).6 As a result, the use of consolidation docetaxel has fallen out of favor and this trial raises the questions whether two cycles of platinum base chemotherapy is sufficient in this setting.

References: 

1. Anonymous: 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. 311:899-909, 1995

2. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial.[see comment]. Journal of the National Cancer Institute. 88:1210-5, 1996

3. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. Journal of Clinical Oncology. 17:2692-9, 1999

4. Curran W, Jr.; Scott, C. B.; Langer, C.; Komaki, R.; Lee, J.; Hauser, B.; Movsas, T.; Sause, W.; Cox, J.D.: Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with recurrent unresected stage III NSCLC: RTOG 9410, ASCO. Chicago, 2003

5. Gandara DR, Chansky K, Albain KS, et al: Consolidation Docetaxel After Concurrent Chemoradiotherapy in Stage IIIB Non-Small-Cell Lung Cancer: Phase II Southwest Oncology Group Study S9504. J Clin Oncol 21:2004-2010, 2003

6. Hanna NH, Neubauer M, Ansari R, et al: Phase III trial of cisplatin (P) plus etoposide (E) plus concurrent chest radiation (XRT) with or without consolidation docetaxel (D) in patients (pts) with inoperable stage III non-small cell lung cancer (NSCLC): HOG LUN 01-24/USO-023. ASCO Meeting Abstracts 25:7512-, 2007