In the present study, the median TTF and MST of patients with mutated EGFR
(treated with gefitinib) were 9.7
months and 27.9
months, respectively, which were comparable to the results of two recent trials. The North East Japan 002 Gefitinib Study Group conducted a phase III trial comparing an EGFR
mutation-positive group of patients receiving gefitinib with carboplatin plus paclitaxel [21
]. In the planned interim analysis, the PFS was significantly longer in the gefitinib group and the study was terminated. The gefitinib group had a significantly longer PFS compared with the chemotherapy group (10.8
months vs. 5.4
months, respectively; hazard ratio, 0.30; P
<0.001). The MST for the gefitinib group was 30.5
months. Mitsudomi et al.
, from the West Japan Thoracic Oncology Group, compared gefitinib with cisplatin plus docetaxel as the first-line treatment for advanced NSCLC with EGFR
]. The gefitinib group had a significantly longer PFS compared with the cisplatin plus docetaxel group, with a median PFS of 9.2
months vs. 6.3
months, respectively (hazard ratio, 0.489; P
<0.0001). These results represent a milestone toward “tailor-made” therapy for NSCLC and gefitinib has been recently registered as the first-line treatment for NSCLC patients with EGFR
activating mutations in Europe. Elderly patients have less of a chance of receiving second-line chemotherapy compared with their younger counterparts, due to poor organ function and/or comorbidities [28
], and many elderly patients with relapsed or refractory NSCLC after first-line chemotherapy are deemed unfit for second-line chemotherapy [29
]. Upfront administration of the most effective regimen (i.e., a regimen that is expected to have the longest PFS) is needed for these patients. The use of first-line gefitinib is valuable for elderly patients with EGFR
No significant unexpected toxicity was found in the gefitinib group. Similar to other EGFR-targeted agents, skin-related AEs were the most common toxicity observed. No interstitial lung disease was reported. The Grade 3 to 4 elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was observed in 22.7% and 13.6% of patients who received gefitinib, respectively. This result was comparable to previous studies conducted in Japan. The most common toxicity criteria (CTC)-AE grade 3 or 4 toxicity reported in the gefitinib group of the North East Japan 002 trial was aminotransferase elevation (26.3%) [21
]. In the West Japan Thoracic Oncology Group 3405 trial, 14 of 87 patients (16.1%) experienced CTC-AE grade 3 or 4 AST elevation, and grade 3 or 4 ALT elevation was observed in 24 of 87 patients (27.6%) [22
]. This liver enzyme elevation is almost always reversible; however, it may cause a decrease in dose intensity and may lessen efficacy.
The ORR in the gefitinib group was 45%, which seemed to be low compared with that reported in the literature [12
]. One cause may be the high drug-discontinuation rate due to AEs. In the gefitinib group, 11 patients (50%) had drug discontinuation and dose intensity was lessened, which explains the low ORR in the gefitinib group. In the present study, all participants were aged 70
years or older, and the median age of the enrolled patients was 80 in the entire treatment population. Age-related decreases in organ function have the potential to increase drug-related toxicity in the elderly, although chronological age itself should not preclude appropriate treatment. Given the favorable TTF and OS in the gefitinib group, gefitinib was just as effective in the elderly with mutated EGFR
compared with their younger counterparts. A comprehensive guide on dose adjustments in this population is mandatory, even for this recently developed, molecular-targeted agent.
Monotherapy with vinorelbine, gemcitabine, or docetaxel is still reasonable for patients with NSCLC of unknown EGFR
mutation status (i.e.
, both EGFR
mutation-positive and -negative groups combined). In the key phase III study ELVIS (the Elderly Lung Cancer Vinorelbine Italian Study) [30
], 161 chemotherapy-naïve patients (≥ 70
years old) were randomized to receive vinorelbine or best supportive care. The ORR was 20% and 1-year survival rate was 32% for patients receiving vinorelbine, and a significant survival benefit was recorded compared with the control group. In another key phase III study, the Multicenter Italian Lung Cancer in the Elderly Study, 700 patients were randomized to receive single-agent chemotherapy with vinorelbine or gemcitabine, or combination therapy with vinorelbine plus gemcitabine [32
]. Combination treatment had no advantage regarding ORR, time to progression (TTP), or survival over single-agent therapy. The ORR was 18%, 16%, and 21% for vinorelbine, gemcitabine, and vinorelbine plus gemcitabine, respectively; the median TTP was 4.5, 4.3, and 4.8
months and MST was 9.0, 7.0, and 7.5
months, respectively. A phase III trial (West Japan Thoracic Oncology Group 9904), which compared docetaxel with vinorelbine for the treatment of elderly patients with advanced NSCLC, demonstrated a statistically significant improvement in median PFS (5.5
months vs. 3.1
months, respectively) and ORR (22.7% vs. 9.9%, respectively; P
0.019), but no statistical difference was found regarding the MST (14.3
months vs. 9.9
months, respectively; P
]. Recently, the IFCT-0501 phase III study demonstrated an improved OS of a platinum-based combination regimen (carboplatin plus paclitaxel) compared with single-agent chemotherapy; however, toxicity was an issue, as 9 of 143 (6.3%) patients died due to treatment-related AEs [33
]. While the survival benefit with doublet chemotherapy is impressive, accompanying toxicity is a concern with this regimen.
In our study, single-agent chemotherapy was effective and feasible for the elderly patients with NSCLC who were wild type for EGFR
. The ORR of 18.8% and MST of 14.9
months observed in the single agent chemotherapy group were compatible to the results of the previous clinical trials mentioned above. The major AEs were related to myelosuppression, were clinically manageable, and included no treatment-related deaths. Given the favorable results, we suggest that cytotoxic agent monotherapy should be considered to be the treatment for elderly patients with NSCLC who are wild type for EGFR
At first, we planned a subsequent phase III study to evaluate the customized treatment based on EGFR mutation status, with patients randomized to either a control (conventional cytotoxic chemotherapy) arm or experimental (customized treatment) arm. In June 2007, however, outsourcing of EGFR genetic testing was fully covered by the health-insurance system in Japan, and customized treatment based on EGFR mutation status is a part of the practice for the treatment of NSCLC. Advanced-generation analytical methods, including highly-specific, rapid PCR techniques, allow us to detect EGFR mutations from fluid specimens, such as malignant effusion or aspiration-needle fluid, with satisfactory sensitivity and specificity. Most of patients with NSCLC have their tumor analyzed when the pathological diagnosis is confirmed, and the results of EGFR mutational analysis are usually available at the beginning of the first-line chemotherapy. Results of the present study represent outcomes of the current standard therapy for elderly patients with NSCLC in Japan, although the number of enrolled patients was small.