Locally advanced non–small cell lung cancer: What is the optimal concurrent chemoradiation regimen?
ABSTRACTThe optimal chemoradiation regimen for patients with locally advanced non–small cell lung cancer (NSCLC) has yet to be defined. Disease and patient heterogeneity prevent a “one size fits all” approach to treatment. Concurrent chemoradiation up front is the definitive strategy for patients with unresectable stage III NSCLC; the addition of consolidation chemotherapy following definitive treatment has produced conflicting results with respect to overall survival. Biologic therapies have yet to show value as add-on treatment to chemoradiation.
The population of patients with stage III non–small cell lung cancer (NSCLC) presents a management challenge for clinicians. The standard of care for locally advanced NSCLC is chemotherapy plus radiation, but the optimal chemoradiation regimen is a work in progress, building upon decades of clinical trial research. Optimal therapy may require patient participation in a current phase 3 clinical trial.
Understanding the background behind the design of phase 3 clinical trials may permit better understanding of optimal chemoradiation. Most recent research has focused on optimization of chemotherapy with less attention paid to radiation dose and technique, the use of targeted agents, and imaging and planning.
A dilemma in the management of stage III NSCLC is how best to combine the correct treatments in the right sequence to achieve simultaneous local, regional, and distant control, as the disease occurs at multiple levels and cure is not possible without local disease control. Another dilemma concerns administration of radiation therapy when the lung, heart, esophagus, or spinal cord may impede delivery of treatment. Additionally, patients may not present with symptoms until an advanced stage of disease, and their performance status is frequently impaired and often influenced by comorbidities such as smoking.
FACTORS RELATED TO PROGNOSIS AND CHOICE OF TREATMENT
Most potentially curable patients with NSCLC present with locally advanced mediastinal disease. Despite improvements in staging procedures and therapy, however, the prognosis of locally advanced NSCLC remains poor with a survival rate of less than 20% at 5 years.
Prognostic indicators
Factors that affect treatment choice
Clinical and patient factors can influence the choice of concurrent chemoradiation therapy. Weight loss, performance status, comorbidity, and pulmonary reserve influence survival and patient outcome. Comorbidities are frequently observed in elderly patients and smokers. More than one-half of patients with stage III NSCLC are currently thought to be ineligible for concurrent regimens if inclusion is restricted to patients younger than 75 years and those with fewer than two serious comorbidities. The exact contribution of comorbidity, age, and other clinical parameters to the reported toxicity is unclear.
Tumor biology
The biology of different types of NSCLC can vary considerably (eg, bronchoalveolar vs squamous cell vs adenocarcinoma). Sometimes cancer grows indolently, even with nodal presentations. Molecular profiling to understand this phenomenon is still in its infancy.
CURRENT APPROACHES TO CHEMORADIATION
Treatment of unresectable stage III NSCLC requires control of local disease and distant metastases. Much work has been undertaken to determine the safety and efficacy of sequential chemoradiation (chemotherapy followed by radiation therapy) and concurrent chemoradiation (chemotherapy during radiation therapy).
Sequential chemoradiation
Dillman et al2,3 ushered in an era of combined modality therapy when in 1990 they demonstrated that a 5-week course of induction chemotherapy followed by radiotherapy in stage III NSCLC resulted in improved median survival compared with radiotherapy alone (13.8 months vs 9.7 months) in a randomized trial.
Sause et al4,5 later showed that in “good risk” patients (Karnofsky Performance Status > 70) with surgically unresectable NSCLC, induction chemotherapy followed by radiation therapy produced superior short-term survival compared with hyperfractionated radiation therapy or standard radiation therapy alone.
Concurrent chemoradiation
The next step in the search for optimal sequencing was the study of concurrent chemotherapy and radiation. In phase 3 studies that compared sequential chemoradiation with concurrent chemoradiation, a consistent advantage in overall survival was conferred by concurrent chemoradiation therapy. Even with concurrent chemoradiation, however, survival was still modest (16% and 21% to 5 years in the two largest comparisons), and median survival improved only from 14.5 months with sequential therapy to 17.1 months with concurrent therapy in the largest comparison.6
Further support for concurrent chemoradiation on the end point of overall survival comes from two meta-analyses. A Cochrane meta-analysis demonstrated a significant 14% reduction in the risk of death with concurrent chemoradiation compared with sequential treatment.7 The NSCLC Collaborative Group discovered a significant survival advantage with concurrent chemoradiation compared with sequential treatment (hazard ratio: 0.84) with an absolute benefit of 5.7% at 3 years (3-year survival of 18.1% with sequential chemoradiation vs 23.8% with concurrent chemoradiation).8
Applying the results of clinical trials to appropriate patients offers the best chance to improve outcomes. The heterogeneity of the NSCLC population makes application of therapeutic advances challenging. One must consider that the selection criteria used in clinical trials, including performance status, weight loss, disease stage, and volume of disease have a great bearing on the results achieved.
When toxicity between the two multimodality approaches was compared, the risk of grade 3 or 4 acute esophagitis was found to increase from 4% with sequential chemoradiation therapy to 18% with concurrent treatment, but no difference in acute pulmonary toxicity has been observed.8
Some investigators used lower doses of chemotherapy in the concurrent chemoradiation arms to minimize radiation toxicity. However, the dose intensity in sequential treatment should be maintained so that the advantage of controlling micrometastatic disease is not lost.
These clinical trials highlight that timing of chemoradiation precludes a significant proportion of patients from receiving uninterrupted radiation therapy, either because of toxicity from chemotherapy, leading to a reduction in performance status, or disease progression during sequential chemotherapy.
