Non–small cell lung cancer (NSCLC) is diagnosed at an early stage, when it is amenable to surgical resection in approximately 20% to 25% of cases.1
Surgical resection is standard treatment for early-stage NSCLC. Approximately 40% of patients with early-stage NSCLC are unable to undergo surgery due to comorbid medical conditions. Of patients who undergo surgery, 60% to 70% experience recurrences at systemic sites and 20% to 40% suffer local failures. Recurrence of disease is attributed to micrometastatic disease present at the time of diagnosis. Adjuvant chemotherapy is administered postoperatively with the goal of eradicating micrometastatic disease and improving long-term disease-free survival (DFS) and overall survival (OS).
Although a number of clinical trials conducted over the years suggested a survival benefit with adjuvant chemotherapy, the evidence was not conclusive. The outlook on adjuvant chemotherapy started to change after data were published from a meta-analysis conducted by the Non–Small Cell Lung Cancer Collaborative Group in 1995, which reviewed 14 trials of adjuvant lung cancer therapy (N = 4357).2
The analysis included 8 trials involving cisplatin-based chemotherapy (n = 1394). The analysis reported a 5% reduction (95% confidence interval [CI], –0.5%-7%) in the absolute risk of death at 5 years (hazard ratio [HR], 0.87; P
= .08) with cisplatin-based chemotherapy. This finding led to large prospective clinical trials that demonstrated benefits with adjuvant chemotherapy.
Since platinum-based chemotherapy regimens have been established as the standard for the treatment of advanced NSCLC,3
they have also become the mainstay of therapy in the adjuvant setting. In this review, we summarize the current evidence regarding the role of chemotherapy for NSCLC in the adjuvant setting and provide recommendations for routine clinical practice.PHASE III CLINICAL TRIALS OF ADJUVANT CHEMOTHERAPY FOR RESECTED NSCLC
A number of phase III studies have been conducted in the past 2 decades to evaluate the role of postoperative chemotherapy in early-stage NSCLC. These trials differ from each other in distribution of tumor stage, chemotherapy regimen, and use of postoperative radiotherapy (PORT). As a result, some studies showed a survival benefit with adjuvant therapy, while others noted no improvement in outcomes (Table
).Eastern Cooperative Oncology Group 3590
The Eastern Cooperative Oncology Group (ECOG) 3590 study randomized 488 patients with resected stage II or IIIA NSCLC to receive PORT alone (n = 242) or combined with 4 cycles of cisplatin and etoposide (n = 246).4
This phase III trial is unique among the recent adjuvant chemotherapy trials in that it included PORT as a standard part of therapy. Only 69% of patients in the combination therapy arm received all 4 cycles of chemotherapy. This is in keeping with other NSCLC trials of adjuvant chemotherapy, in which a significant number of patients did not receive all planned cycles of chemotherapy. The planned total dose of radiotherapy (50.4 Gy) was delivered to 82% of patients in the combined therapy arm and 84% of those in the radiation-only arm.
The addition of chemotherapy to thoracic radiation offered no survival benefit, with a median OS of 38 months in the combination arm versus 39 months in the PORT-only group (P
= .56). Patterns of recurrence did not differ significantly between the groups.Big Lung Trial
In an effort to assess the value of cisplatin-based chemotherapy in NSCLC, British researchers for BLT (Big Lung Trial) randomized patients with stage I-III NSCLC to receive 3 cycles of chemotherapy or no chemotherapy in conjunction with their primary treatment (ie, surgery, radiotherapy, or best supportive care), which was determined by disease stage.5
Of the 381 patients who underwent surgery, 192 were randomized to chemotherapy; 3% of patients received neoadjuvant chemotherapy and 97% had adjuvant chemotherapy. The 189 patients in the control arm did not receive any chemotherapy. The treating physician had the discretion to select from among 4 cisplatin-based chemotherapy regimens: cisplatin plus mitomycin and ifosfamide; cisplatin plus mitomycin and vinblastine; cisplatin and vindesine; or cisplatin and vinorelbine (Navelbine). Chemotherapy and PORT were administered sequentially for those patients in the surgery arm who received adjuvant PORT.
The primary endpoint of OS was not improved with adjuvant chemotherapy (HR, 1.02; P
= .90). More than 75% of patients treated in this trial received a 3-drug regimen; triplet regimens are known to have an inferior therapeutic index compared with standard doublet regimens. The majority of patients in this study had stage I NSCLC, a setting in which adjuvant chemotherapy appears to be least beneficial.Adjuvant Lung Cancer Project Italy