Most clinical trials of NSCLC therapies have excluded elderly patients (typically described as those ≥70 years of age) and patients with borderline or poor performance status (ECOG ≥2) even though these patients comprise a significant proportion of typical lung cancer populations.
Elderly patients or those with decreased performance status with a sensitizing EGFR mutation are usually considered for EGFR TKI therapy even though studies done in similar patients whose cancers were unselected for EGFR mutation status did not show an advantage for these agents over chemotherapy or placebo.52 These patients are also underrepresented in the large phase III studies of EGFR TKIs versus chemotherapy in EGFRm+ patients. For example, 10% of the patients in the IPASS study were ECOG 2 and the median age was 57 in both treatment arms.4These agents, however, are generally thought to be well-tolerated in this group of patients although toxicities must be followed closely. Similarly, large trials of ALK TKIs versus chemotherapy in patients with ALK rearrangements did not include many elderly patients or patients with decreased PS but these agents also appear to be well tolerated and would be favored over chemotherapy in such patients.
For patients with advanced NSCLC without EGFR mutations or ALK rearrangements or those with such mutations who have progressed on targeted therapies, the decision to proceed with cytotoxic chemotherapy is a challenging one. Retrospective reviews of first-line combination studies have been undertaken. Studies of single agent chemotherapy regimens have been done. More recent studies have looked at combination chemotherapy regimens versus single agent regimens in these patients. It is important to note that elderly patients with good performance status cannot be considered analogous to younger patients with poor performance status.
In the Italian ELVIS trial 161 patients with advanced NSCLC ≥70 years old were randomized to vinorelbine plus BSC versus BSC alone. After adjusting for stage and ECOG PS the vinorelbine arm had improved mOS (28 versus 21 weeks, HR 0.65, 95% CI 0.45-0.93) as well as QOL compared to BSC. 24% of patients in both arms were ECOG 2 but there was no analysis of benefit specifically in these patients.53 In the West Japan Thoracic Oncology Trial 9904 182 patients with advanced NSCLC ≥70 years old were randomized to either docetaxel or vinorelbine. The docetaxel appeared to be at least as effective as the vinorelbine although the toxicity profiles were different. Well over 90% of the patients in both arms were ECOG 0 or 1 so this trial also did not address the value of single agent chemotherapy in elderly patients with decreased performance status.54Vinorelbine remains the BCCA standard for single agent chemotherapy in elderly patients with advanced NSCLC who cannot tolerate or do not want platin-based combination chemotherapy.
Several trials have compared combination chemotherapy regimens to single agents in older patients. The largest, the Italian MILES study, randomized 698 patients ≥70 years of age to single agent gemcitabine or vinorelbine versus the non-platin doublet of gemcitabine plus vinorelbine at combination doses tested in a previous multi-arm phase I/II study. The primary endpoint of mOS and additional endpoints of QOL and toxicity did not favor the combination in this population.55 A French intergroup trial randomized 451 patients aged 70-89 to vinorelbine or gemcitabine monotherapy versus the combination of carboplatin plus paclitaxel. The study was stopped at the first interim analysis. The primary endpoint of mOS was 10.3 months in the combination group and 6.2 months in the monotherapy group (HR 0.64, 95% CI 0.52-0.78; p<0.0001). Hematologic toxicities were higher in the combination arm but QOL was similar in the 2 groups.56
The management of patients with advanced NSCLC with ECOG PS 2 is less clear than the management of well elderly patients with this disease. Little prospective data has been gathered. In a multicenter phase III trial 205 patients with advanced NSCLC patients with PS ECOG 2 were randomized to either single agent pemetrexed or the combination of carboplatin and pemetrexed. Initially patients with all histologies were invited to participate but later the protocol was amended to include only those with nonsquamous histologies. Over 80% of the patients in each arm had adenocarcinoma. Analyses were done ITT as well as in the nonsquamous patients only and were similar. The mPFS was 2.8 months for the single agent regimen and 5.8 months for the combination (HR 0.46; 95% CI 0.35 to 0.63; p<0.001). The primary endpoint of mOS was 5.3 months for the pemetrexed and 9.3 months for the carboplatin plus pemetrexed (HR 0.62; 95% CI 0.46-0.83; p=0.001). Hematologic toxicities were greater in the combination arm and there were 4 treatment related deaths compared to none in the single agent arm. QOL data was not collected.57
Chemotherapy, either platin-doublet or single agent, may be considered for appropriate elderly patients and/or patients with PS ECOG 2 as long as they have acceptable organ function and bone marrow reserve and are aware of the potential for greater toxicities and uncertain overall benefit. The roles of bevacizumab, which is not included in standard BCCA chemotherapy regimens, as well as maintenance therapy in these patients are even far less certain and are not routinely recommended.