Locally Advanced, Unresectable Non–Small-Cell Lung Cancer Recent Phase III Trials Undermine the Dogma of Consolidation and Maintenance Treatment

Introduction

A significant proportion of patients with non-small cell lung cancer (NSCLC) present with locally advanced, unresectable disease. For the most part, fit patients with this diagnosis are treated with combined-modality therapy. Relatively few are rendered resectable. Over the past two decades, combination chemotherapy and radiation, preferably concurrent chemoradiation, has emerged as the standard of care. However, survival gains have been offset, to some extent, by local, normal-tissue, in-field toxicity, particularly esophagitis and pneumonitis.

Over the past 5 years, based on a single-arm phase II trial, consolidative therapy with docetaxel (Taxotere) became increasingly popular. The Southwest Oncology Group (SWOG) 9504, which featured a platform regimen of etoposide, cisplatin, and radiation therapy (RT) followed by 3 cycles of docetaxel (EP/RT → Doc), yielded a median survival of 27 months, and a 5-year survival rate of 29%, results unprecedented in the treatment of locally advanced NSCLC. However, the results of a phase III trial orchestrated by the Hoosier Oncology Group (HOG) proved sobering, with no obvious survival advantage for consolidative docetaxel versus standard observation in patients who received concurrent EP/RT alone. Moreover, the use of maintenance therapy with gefitinib (Iressa), a prototypic EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor, after EP/RT → Doc not only failed to evince a survival advantage but resulted in an unanticipated survival decrement.

Consequently, the routine use of consolidative or maintenance therapy in this setting has been undermined. Future strategies will incorporate the testing of three-dimensional (3D) conformal RT with escalated RT doses, using modern imaging techniques including 3D conformal RT to limit the field size. In addition, the role of other cytotoxics, such as pemetrexed (Alimta), and selected targeted agents, such as cetuximab (Erbitux) and bevacizumab (Avastin), are being explored. Finally, we need to conquer the typical toxicities associated with concurrent chemoradiation, most notably esophagitis and pneumonitis; a relative paucity of studies address this ubiquitous issue. 

The Modern Era of Combined-Modality Therapy

In 2007, 35,000 to 40,000 people in the United States will be diagnosed with locally advanced NSCLC.¹ Relatively few are candidates for surgical resection, and likely little more than half are good candidates for combined-modality therapy, based on performance status and recent weight loss. The presentation of CALGB (Cancer and Leukemia Group B) 8433 in 1990 ushered in the modern era with respect to combined-modality therapy.² This relatively small trial, which accrued just over 150 patients, demonstrated a conclusive survival advantage for induction chemotherapy (5 weeks of cisplatin and vinblastine) followed by definitive RT (60 Gy) versus RT alone. The median survival improved by 4 months (14 vs 10 months; P = 0.0066), with persistent, consistent improvement in long-term survival rates. At 6 years, the overall survival was more than double in the combined-modality arm (13%) than in the control group (6%).³

Much larger studies by the Radiation Therapy Oncology Group (RTOG)^4,5 and by French investigators⁶ (Le Chevalier et al) confirmed these results, though long-term survival figures in both efforts were a bit less impressive for sequential chemotherapy followed by RT than in the CALGB study (Table 1). Chemotherapy produced a systemic effect with reduction in distant failure, which translated into a survival benefit. A recent meta-analysis reported by Le Chevalier and colleagues on behalf of the NSCLC Collaborative Group confirmed the survival advantage for sequential chemoradiation compared with radiation alone.⁷ A total of 22 trials testing this concept, with 3,839 patients enrolled and follow-up of nearly 7 years, demonstrated a statistically significant survival benefit: an increase from 8.7% to 11.3% at 3 years (hazard ratio [HR] = 0.88; 95% confidence interval [CI], 0.82−0.94; P = 0.0001). There was no clear evidence of difference in effect by the type or timing of chemotherapy, or in any particular subgroup, defined by age, gender, performance status, histology, or stage.

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At the same time, sequential chemoradiation became the standard; several trials reported a therapeutic benefit for concurrent chemoradiation compared with RT alone. A landmark effort by Schaake-Koning et al of the European Organization for Research and Treatment of Cancer (EORTC) showed a clear-cut survival advantage for daily cisplatin (6 mg/m²) during split-course RT over split-course RT alone.⁸ At 2 years, 26% of those receiving concurrent daily chemotherapy and radiation were alive, compared with 13% in the control arm and 19% in a separate group receiving weekly cisplatin and RT (P = 0.04).

Two additional efforts from Jeremic and colleagues evaluating twice-daily RT, first in combination with weekly carboplatin and etoposide, the second in combination with daily carboplatin/etoposide, yielded a clear-cut advantage over RT alone.^9,10 The benefits were due to enhanced local control, presumably radiosensitization. There was no systemic benefit.

A companion meta-analysis of 21 separate trials⁷ reported by Le Chevalier et al reinforced these results. Individual patient data (IPD) were obtained from 15 randomized controlled trials (RCTs) with 2,733 patients accrued, with survival from 1 additional RCT without IPD also included. Among 2,910 eligible patients with a median follow-up of 5.3 years, a significant benefit was observed for concomitant chemoradiation, with a 3.2% improvement in 3-year survival rate: 16.6% versus 13.4% (HR = 0.88; 95% CI, 0.81−0.95; P = 0.0008). Whether these patients truly reflect the types of individuals typically seen in North America is open to question, since 82% were male and more than 50% had squamous cell histology. Nevertheless, both meta-analyses, as proof of principle, confirmed the primacy of combined chemoradiation versus RT alone.