Combined Chemoradiation Therapy for Limited-Stage Small-Cell Lung Cancer

Introduction

Approximately 20% of new lung cancer cases are small-cell lung cancer,[1] composed of cells with small, round or spindle-shaped, darkly staining nuclei and scant cytoplasm. Small-cell lung cancer manifests as a central tumor with early dissemination to the regional lymph nodes and distant sites. It has a large growth fraction, grows rapidly, is associated with paraneoplastic syndromes (syndrome of inappropriate secretion of antidiuretic hormone, Cushing’s syndrome, and Eaton-Lambert syndrome), develops almost exclusively in smokers, and is sensitive to chemotherapy.[2] Even when the disease is extensive, approximately 60% of patients will respond to intensive chemotherapy. The results of initial chemotherapy trials showed median survival of patients with limited-stage disease treated with combination chemotherapy to be approximately 12 months, compared with 3 months for those receiving best supportive care.[3] Long-term survival is rare, however, with fewer than 10% of patients alive at 10 years.

The American Joint Committee on Cancer’s TNM staging system has been used to stage non–small-cell lung cancer with reasonable prognostic predictive value. The system has not been universally adopted for small-cell lung cancer because the majority of small-cell lung cancer patients present with stages beyond IIIA, and because small-cell lung cancer is considered a systemic disease characterized by rapid proliferation and early distant dissemination. Thus, clinicians have adopted the simple two-stage system of the Veterans Administration Lung Cancer Study Group, limited and extensive disease. Limited stage is defined as tumor confined to one hemithorax and the regional nodes, and is based on whether all detectable disease can be encompassed by a tolerable, single continuous therapeutic radiation port. Extensive-stage disease encompasses demonstrable extra-thoracic disease. A better understanding of the biology of small-cell lung cancer and of its patterns of failure has provided the principles for its management.[2,4] Since small-cell lung cancer is a systemic disease, current treatment of limited disease consists of chemotherapy to manage undetected micrometastases present at diagnosis and thoracic radiation therapy to improve locoregional tumor control. The presence of pleural effusions or involved supraclavicular or contralateral hilar nodes has been considered limited disease in some trials and extensive disease in others; such differences must be kept in mind when results from different institutions and cooperative groups are compared.

Impact of Thoracic Radiation on Local Control and Survival

Thoracic radiation therapy has been used to treat small-cell lung cancer since the 1960s, but surgery was the treatment of choice for patients with all types of lung cancer until approximately 25 years ago. It was abandoned following the results of a randomized trial conducted in the United Kingdom by the Medical Research Council that compared radiation therapy alone with surgery alone in patients who had limited-stage disease.[5] None of the patients were alive at 10 years in the surgery group compared with 5% alive in the radiation group. Additionally, a review of the outcome of a large number of small-cell lung cancer patients treated in the United States whose disease was thought to be surgically resectable revealed absolutely no difference in survival whether or not surgery was performed.[6]

Just as the discovery of the radiosensitivity of small-cell lung cancer shifted local management of limited disease from surgery to radiation,[5] realization of the propensity of small-cell lung cancer for early systemic metastases also led to the assessment of chemotherapy. The observation of high overall and complete response rates in limited-disease patients who received only chemotherapy initially led some to question the value of local therapy with thoracic radiation. In 1969, the Veterans Administration Lung Cancer Study Group demonstrated that cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan) treatment could double median survival in patients with extensive-stage disease—to 6 months.[7] However, the high frequency of locoregional recurrence (up to 80% of limited-stage patients) and the poor survival of patients who received only chemotherapy led to investigations of the role of thoracic radiation therapy in the management of small-cell lung cancer.

Several single-institution and cooperative group randomized trials were initiated in the United States to test the role of thoracic radiation therapy in the treatment of limited-stage small-cell lung cancer (Table 1).[8-20] The cooperative group randomized trials include those conducted by the Southeast Cancer Study Group (SECSG),[19] the National Cancer Institute,[10] the Cancer and Leukemia Group B (CALGB),[8] the Eastern Cooperative Oncology Group (ECOG),[13] and the Southwest Oncology Group (SWOG).[14] In each, patients with limited disease were randomized to chemotherapy with or without thoracic radiation. All results showed that chest radiation improved local control, and all but Osterlind,[11] LeBeau,[18] and the SWOG trial[14] reported borderline improvement or significantly improved survival with combined-modality treatment.

Two meta-analyses have also shown a small but significant improvement in survival for patients treated with chemotherapy and thoracic radiation vs those treated with chemotherapy alone.[21,22] Pignon et al obtained data on 1,862 individual patients from the American, European, and Japanese investigators who had conducted 13 randomized studies.[21] They then updated the survival rates and performed an intent-to-treat analysis that included all patients; they found that treatment with thoracic radiation was associated with a 14% reduction in the risk of death (P = .001). In addition, the 3-year survival rate improved for patients treated with chemotherapy and radiation therapy to 14.3% compared with 8.9% for patients who received chemotherapy alone. No significant survival differences emerged, however, when the timing of thoracic radiation (early vs late) and the schedule of chemotherapy and radiation (sequential vs concurrent) were evaluated.

Moreover, this intent-to-treat analysis may have underestimated the impact of radiation on improving survival. Warde and Payne analyzed 11 published trials and discovered significantly better survival for patients who received chemotherapy and radiation therapy.[22] The odds ratio was 1.56 for patients treated with chemoradiotherapy (P < .001). Comparison of the 2-year survival rates showed a 5.4% improvement for patients who received radiation therapy. The 5% increase in absolute survival in patients receiving thoracic radiation represents a more than 50% relative improvement in the survival rate observed with chemotherapy alone. Local control rates were doubled from approximately 25% with chemotherapy alone to approximately 50% with the addition of thoracic radiation. Neither study reported the “best” chemotherapy and radiation regimen. However, the use of cisplatin(Drug information on cisplatin) (Platinol) and etoposide(Drug information on etoposide) (VePesid) (PE) and concurrent thoracic radiation has been associated with the best survival results observed thus far.

Despite these findings demonstrating the benefits of thoracic radiation on local control and survival in limited-stage small-cell lung cancer, the chest relapse rate remains unacceptably high, with a 60% actuarial risk of local recurrence by 3 years. Further enhancement of locoregional control may increase the proportion of long-term survivors. Issues like the optimal integration of thoracic radiation with chemotherapy (sequential vs concurrent vs alternating), the appropriate volume, and dose/fractionation need to be explored further.