Innovative Treatment Strategies in Non-Small Cell Lung Cancer
Background: While small improvements in outcome have occurred for patients with locally advanced non-small cell lung cancer (NSCLC), 5-year survival results remain low, ranging from 5% to 20%. Distant metastases and local-regional progression remain significant patterns of failure.
Methods: Trials investigating innovative treatment strategies for patients with locally advanced and/or unresectable NSCLC are reviewed, including altered radiation fractionation schema, conformal 3-dimensional radiotherapy, and combined chemoradiotherapy regimens.
Results: Whereas hyperfractionated radiation therapy (HFRT) alone does not appear to be beneficial, combined HFRT and chemotherapy appears promising in several trials. Patients treated with accelerated RT compared with standard RT have an improved survival. As higher radiation doses appear to enhance local tumor control, strategies involving 3-dimensional conformal radiotherapy merit further investigation. RT plus chemotherapy is superior to RT alone, albeit with greater toxicity. Amifostine is currently being investigated as a radioprotector. The optimal chemotherapy agents and their integration with radiotherapy are the subject of randomized trials.
Conclusions: Ongoing investigations are warranted to combat both local-regional and systemic failures for patients with locally advanced NSCLC. Treatment strategies need to consider not only the traditional endpoints of survival and local control, but also quality of life.
Lung cancer is far and away the leading cause of cancer mortality in the United States for both men and women. The number of deaths secondary to lung cancer exceeds the combined total deaths from the second (colon), third (breast), and fourth (prostate) leading causes of cancer deaths combined. Non-small cell lung cancer (NSCLC) comprises the vast majority (75% to 80%) of all lung cancers, with approximately 40% of patients presenting with locally advanced and/or unresectable disease. This group typically includes those with bulky stage IIIA and IIIB disease, excluding malignant pleural effusions.
Up until only a decade ago, the standard nonoperative management for this group of patients was conventional external beam thoracic radiotherapy (RT) alone -- 60 Gy over 6 weeks, administered once per day. While this dose of radiation was shown in a randomized trial by the Radiation Therapy Oncology Group (RTOG trial 73-01) to enhance short-term (3-year) survival compared to lower doses, the 5-year survival was disappointingly low (5%). In RTOG 73-01, the local control rate at 3 years appeared reasonable at approximately 70% for patients treated with 60 Gy. Yet, in a more recent study employing even higher radiation doses (up to 70 Gy), Hazuka et al reported local tumor progression as the first site of failure in 50% of patients. Part of this discrepancy in local control rates may reflect the difficulty in defining local failure; it is challenging to distinguish radiographically between fibrosis and local progression. While most studies have used clinical and radiographic criteria to define local control, Le Chevalier et al also employed serial bronchoscopic biopsies. They reported that less than 20% of patients achieved a "histologically" confirmed local control whether they received RT alone (65 Gy) or sequential chemotherapy and RT. Although nests of histologically viable cells may not necessarily translate into local progression, this study suggests that clinically and radiographically determined local control rates are substantially overestimated when strict criteria for local control are applied.
While local therapy will have no influence on survival if cells resistant to chemotherapy have escaped from the primary site, local control is still a prerequisite for cure. Indeed, failure pattern analyses in NSCLC demonstrate that both locally persistent (or recurrent) disease and distant metastases are significant problems. Even in small cell lung cancer (SCLC), in which the rate of distant metastases is higher than that in NSCLC, the addition of local therapy (thoracic radiation) to chemotherapy resulted in improved survival. A recent randomized study in SCLC demonstrates that the very type of local therapy employed (hyperfractionated vs standard radiation) can have a dramatic impact on survival. This article reviews several innovative treatment strategies to improve outcome in locally advanced NSCLC, with a particular focus on the "local issues." These strategies include altered radiation fractionation schemes, radiation dose escalation via 3-dimensional conformal RT, and combined chemoradiotherapy regimens.
Background: While small improvements in outcome have occurred for patients with locally advanced non-small cell lung cancer (NSCLC), 5-year survival results remain low, ranging from 5% to 20%. Distant metastases and local-regional progression remain significant patterns of failure.
Methods: Trials investigating innovative treatment strategies for patients with locally advanced and/or unresectable NSCLC are reviewed, including altered radiation fractionation schema, conformal 3-dimensional radiotherapy, and combined chemoradiotherapy regimens.
Results: Whereas hyperfractionated radiation therapy (HFRT) alone does not appear to be beneficial, combined HFRT and chemotherapy appears promising in several trials. Patients treated with accelerated RT compared with standard RT have an improved survival. As higher radiation doses appear to enhance local tumor control, strategies involving 3-dimensional conformal radiotherapy merit further investigation. RT plus chemotherapy is superior to RT alone, albeit with greater toxicity. Amifostine is currently being investigated as a radioprotector. The optimal chemotherapy agents and their integration with radiotherapy are the subject of randomized trials.
Conclusions: Ongoing investigations are warranted to combat both local-regional and systemic failures for patients with locally advanced NSCLC. Treatment strategies need to consider not only the traditional endpoints of survival and local control, but also quality of life.
Lung cancer is far and away the leading cause of cancer mortality in the United States for both men and women. The number of deaths secondary to lung cancer exceeds the combined total deaths from the second (colon), third (breast), and fourth (prostate) leading causes of cancer deaths combined. Non-small cell lung cancer (NSCLC) comprises the vast majority (75% to 80%) of all lung cancers, with approximately 40% of patients presenting with locally advanced and/or unresectable disease. This group typically includes those with bulky stage IIIA and IIIB disease, excluding malignant pleural effusions.
Up until only a decade ago, the standard nonoperative management for this group of patients was conventional external beam thoracic radiotherapy (RT) alone -- 60 Gy over 6 weeks, administered once per day. While this dose of radiation was shown in a randomized trial by the Radiation Therapy Oncology Group (RTOG trial 73-01) to enhance short-term (3-year) survival compared to lower doses, the 5-year survival was disappointingly low (5%). In RTOG 73-01, the local control rate at 3 years appeared reasonable at approximately 70% for patients treated with 60 Gy. Yet, in a more recent study employing even higher radiation doses (up to 70 Gy), Hazuka et al reported local tumor progression as the first site of failure in 50% of patients. Part of this discrepancy in local control rates may reflect the difficulty in defining local failure; it is challenging to distinguish radiographically between fibrosis and local progression. While most studies have used clinical and radiographic criteria to define local control, Le Chevalier et al also employed serial bronchoscopic biopsies. They reported that less than 20% of patients achieved a "histologically" confirmed local control whether they received RT alone (65 Gy) or sequential chemotherapy and RT. Although nests of histologically viable cells may not necessarily translate into local progression, this study suggests that clinically and radiographically determined local control rates are substantially overestimated when strict criteria for local control are applied.
While local therapy will have no influence on survival if cells resistant to chemotherapy have escaped from the primary site, local control is still a prerequisite for cure. Indeed, failure pattern analyses in NSCLC demonstrate that both locally persistent (or recurrent) disease and distant metastases are significant problems. Even in small cell lung cancer (SCLC), in which the rate of distant metastases is higher than that in NSCLC, the addition of local therapy (thoracic radiation) to chemotherapy resulted in improved survival. A recent randomized study in SCLC demonstrates that the very type of local therapy employed (hyperfractionated vs standard radiation) can have a dramatic impact on survival. This article reviews several innovative treatment strategies to improve outcome in locally advanced NSCLC, with a particular focus on the "local issues." These strategies include altered radiation fractionation schemes, radiation dose escalation via 3-dimensional conformal RT, and combined chemoradiotherapy regimens.
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