Introduction

The addition of systemic chemotherapy for patients with N2 disease, either before surgery or after surgery, is the new ‘standard’ for locally advanced non-small cell lung cancer (NSCLC). Thus, research reported at the 2004 meeting of the American Society of Clinical Oncology evaluated systemic therapies in locally advanced NSCLC. Researchers reported that the addition of induction chemotherapy prior to definitive chemoradiation did not provide a survival advantage over chemoradiation alone. However, early studies with the EGFR-inhibitor gefitinib (Iressa®) produced encouraging results. Two studies demonstrated the feasibility of combining Iressa® with external beam radiation and recommended doses of weekly paclitaxel and Paraplatin®.

Background

A multi-modality approach consisting of chemotherapy and radiation is superior to radiation alone for the treatment of patients with surgically unresectable, locally advanced NSCLC. Large randomized studies have demonstrated significant survival benefit for concurrent administration of chemotherapy and radiation over the sequential approach.^[1],[2] With the concurrent chemoradiation schedule, the median survival has improved to 16-17 months for this subset of patients. In fact, it appears that about 20-30% of locally advanced NSCLC patients will experience long-term survival with the combined modality approach.^[3] Therefore, the concurrent administration of chemotherapy and radiation is widely used for the treatment of patients with locally advanced NSCLC.

Despite effective control of localized disease with the combined modality approach, systemic recurrence continues to be a problem following definitive chemoradiotherapy for locally advanced NSCLC. 

Early-phase research evaluating consolidation chemotherapy has produced promising results. A phase II study conducted by the Southwest Oncology Group (SWOG 9504) demonstrated a median survival of 26 months, with a 3-year survival rate of 37% with consolidation chemotherapy following chemoradiaition. This study evaluated 3 cycles of single-agent docetaxel (Taxotere®) following definitive chemoradiation for patients with stage IIIB NSCLC (no pleural or pericardial effusion).^[4] A confirmatory trial to prove the benefit from consolidation Taxotere® after definitive cisplatin (Platinol®)/etoposide/RT is currently underway by the Hoosier Oncology Group. The CALGB has evaluated a strategy of induction chemotherapy prior to chemoradiation to eradicate micrometastatic disease.^[5] 

Induction Chemotherapy

At the 2004 ASCO meeting, investigators from the CALGB reported data from a phase III trial that failed to support the strategy of induction chemotherapy prior to definitive chemoradiation for patients with locally advanced NSCLC.^[6]

In this phase III trial (CALGB 39801), patients with surgically unresectable locally advanced NSCLC were randomized to:

• Two cycles of induction chemotherapy consisting of carboplatin (Paraplatin®) plus paclitaxel (Taxol®) followed by concurrent weekly carboplatin, paclitaxel and external beam TRT, or
• The same concurrent chemoradiation alone.

Patients in both groups received Paraplatin® (AUC=2) and paclitaxel (50 mg/m2) on a weekly basis with radiation (66Gy, one fraction per day) during the concurrent phase. For patients in the induction arm, Paraplatin® and paclitaxel were administered at a dose of AUC=6 and 200 mg/m2 respectively. The study was designed to detect a 40% improvement in median survival with the induction strategy versus chemoradiation without the induction strategy.

A total of 366 patients were enrolled in the study over four years. The median survival was 11.4 months for the standard arm and 13.7 months for the induction therapy arm. The overall response rate was similar for the 2 arms of the study (66% vs. 61%). The 3-year survival favored the induction arm (24% vs. 18%), though it did not reach statistical significance (p=0.138).  There were no differences in the incidence of local and distant recurrences between the 2 arms of the study.

The incidence of grades 3 & 4 neutropenia was higher with the induction arm (28% vs. 15%). However, the frequency of grades 3 & 4 esophagitis was similar between the 2 arms of the study (31% vs. 29%).

There is continued controversy regarding the use of full doses of Platinol®/etoposide or Platinol®/vinblastine with TRT versus weekly radiosensitizing doses of Paraplatin® and a taxane with TRT. Despite the lack of phase III data, community oncologists in the United States favor the combination of weekly Paraplatin® and paclitaxel or Taxotere®.

Chemotherapy plus Iressa®

At ASCO 2004, two small studies reported on the safety of combining Iressa®, an inhibitor of the epidermal growth factor receptor, with chemotherapy and radiation for the treatment of locally advanced NSCLC. Both of these studies demonstrate the feasibility of combining Iressa® with external beam radiation and recommended doses of weekly paclitaxel and Paraplatin®.

An Australian study reported by Rischin and colleagues showed that chemotherapy and external beam radiation therapy (EBRT), plus Iressa® was well tolerated without excessive toxicity, and reported a promising response rate of 91%. Fifteen patients with locally advanced NSCLC were treated with Paraplatin® (AUC=2/week), paclitaxel (at 3 dose-levels of 25mg/m2. 35 mg/m2 and 45 mg/m2/week respectively) and daily doses of Iressa® (250 mg PO). External beam radiation was administered once a day to a total of 60 Gy.^[7]

A CALGB pilot study of Iressa® with chemoradiation for locally advanced NSCLC demonstrated that treatment was well-tolerated without excessive toxicity.^[8] In their study, all patients received two cycles of induction chemotherapy with Paraplatin® and paclitaxel. Patients were then stratified into two groups. The first group included PS 2 patients who were treated with external beam radiation (66 Gy) with daily doses of Iressa® (250 mg QD). The second group, with PS less than 2, received radiation (66Gy), Iressa® (250 mg QD) with weekly doses of Paraplatin® (AUC=2) and paclitaxel (50 mg/m2). This study is ongoing.

Conclusions

In summary, the paradigm for the treatment of early stage NSCLC has changed considerably. Surgical resection alone can no longer be considered standard therapy for patients with stages IB, II or IIIA NSCLC. Addition of systemic chemotherapy for patients with N2 disease, either before surgery or after surgery, is the new ‘standard’.

Currently, chemoradiotherapy followed by 3 cycles of consolidation chemotherapy appears to be the most efficacious regimen for the treatment of locally advanced NSCLC. Integration of targeted agents into the treatment paradigms and development of newer chemotherapy platforms are essential to improve the outcome.

The encouraging results presented at ASCO 2004 strongly suggest areas for future clinical trials such as:

• randomized comparisons between neoadjuvant and adjuvant chemotherapy,
• research aimed at establishing optimal chemotherapy schedules and custom therapies based on patient and tumor characteristics, and
• further investigation of targeted molecular agents.

Efficacy studies are warranted to define the role of Iressa® in locally advanced NSCLC. Furthermore, a two-fold improvement in median survival has been demonstrated by a randomized phase III study in which cetuximab (Erbitux®), a monoclonal antibody against the EGFR, was combined with radiation in patients with head and neck cancer. We believe this treatment strategy should be evaluated for locally advanced NSCLC.

References