Loading...
Despite undergoing complete resection surgery, many patients with stage I and II non–small-cell lung cancer (NSCLC) experience relapse. To determine whether preoperative or adjuvant therapy would reduce risk for disease recurrence, investigators in the NATCH study randomized 582 patients to surgery alone, preoperative chemotherapy followed by surgery, or surgery followed by adjuvant chemotherapy. Preliminary analysis (median follow-up, 43 months) showed a trend toward higher rates of 5-year disease-free survival (DFS) among patients in the preoperative chemotherapy group compared with those who underwent surgery alone. However, this improvement might be partially explained by the fact that 90% of patients in the preoperative group received the planned 3 cycles of chemotherapy, whereas only 66% of patients in the postoperative adjuvant group did so. No difference in overall survival (OS) was observed. Given these results, the benefits of adjuvant versus neoadjuvant chemotherapy remain unanswered.
The JBR.10 trial was one of the pivotal phase III trials that established the benefit of adjuvant cisplatin-based chemotherapy in resected stage IB/II NSCLC. Updated analysis of the JBR.10 trial at median follow-up of >9 years showed that this regimen was associated with prolonged relapse-free survival (RFS) and OS (hazard ratios, 0.60 and 0.69, respectively). Further analysis identified survival benefits primarily in patients with Stage II tumors or Stage IB with tumors >4 cm.
Cisplatin and etoposide with concurrent thoracic radiation therapy is the standard treatment for locally advanced unresectable NSCLC. Taxanes are also commonly used, albeit at lower doses because of adverse effects. Investigators in the phase II CALGB 30407 trial evaluated systemically active doses of carboplatin, pemetrexed (with or without cetuximab) plus radiation therapy. The study met its primary endpoint of increased survival greater than 18 months. However, the contribution of cetuximab seems to be minimal.
Central nervous system (CNS) metastases are common in patients with locally advanced NSCLC. Prophylactic cranial irradiation (PCI) prevents CNS relapses and prolongs survival in patients with small-cell lung cancer. To further investigate the effects of PCI in NSCLC patients, investigators in the RTOG 0214 trial randomized individuals with stage III NSCLC without disease progression after locoregional treatment (surgery, radiation therapy, or both, with or without chemotherapy) to PCI or observation. The study was terminated early because of slow accrual, and only 340 patients were evaluable. No between-group differences in OS or DFS were observed. However, the rates of CNS failure were lower in the PCI group than in the observation group (7.7% vs. 18.0%; P=0.004). Data on PCI’s effects on quality of life and neuropsychological functioning are pending.
Patients with stage IIIB/IV NSCLC are typically treated with 4 to 6 cycles of chemotherapy and followed closely until disease progression, at which time treatment is reinstituted. Docetaxel, pemetrexed, and erlotinib are approved for patients at disease progression after first-line therapy. However, the optimal time to administer these agents is currently under investigation. Trial results presented 1 year ago at ASCO 2008 suggested that early second-line (maintenance) therapy with erlotinib resulted in prolonged PFS and that maintenance therapy with docetaxel prolonged OS. Now, in a trial designed to evaluate maintenance pemetrexed, 663 patients with stage IIIB/IV NSCLC who did not have disease progression on initial therapy were randomized 2:1 to receive pemetrexed or placebo. Those who received pemetrexed achieved longer PFS (4.3 months vs. 2.6 months; P<0.0001) and longer OS (13.4 months vs. 10.6 months; P=0.012). Benefits were achieved primarily in patients with non-squamous cell histology (15.5 months vs. 10.3 months; HR, 0.70; P=0.002).
In the SATURN trial, researchers randomized 889 nonprogressing patients with advanced NSCLC to erlotinib versus placebo. Patients who received erlotinib had lower risk for disease progression (HR, 0.71); this benefit was achieved in patients with squamous cell histology or adenocarcinomas. OS data are pending.
In the ATLAS trial, 768 nonprogressing patients with advanced NSCLC after bevacizumab and platinum chemotherapy were randomized to bevacizumab with or without erlotinib. Patients who received bevacizumab plus erlotinib achieved longer PFS (4.76 months vs. 3.75 months; HR, 0.722; P=0.0012). OS data are not yet reported.
These trials all suggest that maintenance therapy after first-line platinum chemotherapy has benefits in nonprogressing patients with stage IIIB/IV NSCLC. However, modest gains in PFS come at the price of adverse events. Data from quality-of-life questionnaires as well as OS data from the SATURN and ATLAS trials might help determine which patients will benefit.
The phase II ZODIAC trial was designed to assess the efficacy of vandetanib, an oral inhibitor of the vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and RET pathways, in patients with previously untreated NSCLC. A total of 1391 patients were randomized to docetaxel with or without vandetanib. At median follow-up of 12.8 months, those who received vandetanib achieved modestly longer PFS (4.0 months vs. 3.2 months; HR, 0.79; P<0.001); however, OS was not improved.
Histone deacetylase (HDAC) inhibitors have been shown to enhance the efficacy of taxanes. In a randomized phase II trial of HDAC inhibitor vorinostat (Zolinza), 94 patients with stage IIIB/IV NSCLC were treated with first-line carboplatin and paclitaxel with or without vorinostat. Patients who received vorinostat achieved higher response rates (RRs) than those who did not (34% vs. 12.5%; P=0.02) and a longer median OS (13 months vs. 9.7 months).
The COX-2 enzyme is overexpressed in approximately 75% of NSCLC tumors and adversely affects patient survival. To test the hypothesis that inhibition of COX-2 would disrupt proliferation and angiogenesis in cancer cells and improve survival, investigators in the phase III NVALT-4 trial randomized 561 patients to receive carboplatin and docetaxel with or without the COX-2 inhibitor celecoxib (Celebrex). At median follow-up of 36 months, the RR was higher in patients who received celecoxib than in those who did not (P=0.05); however, PFS and OS were similar in both study groups.
Epidermal growth factor receptor (EGFR) inhibitors are used in NSCLC with dramatic results in some individuals. Identification of markers predictive of response would help treatment decisions. Researchers for the IPASS trial selected a population of stage IIIB/IV NSCLC patients in Asia who were highly likely to respond to oral EGFR tyrosine kinase inhibitors (TKIs). Tissue samples from 683 study participants were assessed for gene mutations, copy number, and expression; results showed that the presence of EGFR mutations strongly predicted likelihood of response.
At ASCO 2008, authors of the FLEX trial demonstrated that NSCLC patients treated with first-line cetuximab plus chemotherapy versus chemotherapy alone achieved survival benefits irrespective of tumor histology. Given the accumulating data about prediction of treatment responses based on KRAS-mutation status in colorectal cancer, investigators conducted further analysis of FLEX study data to identify factors predictive of responses to cetuximab in patients with NSCLC. Of the factors assessed, development of a facial rash during the first treatment cycle was predictive of response, but KRAS or EGFR mutation status was not.