The extended review by Gridelli and colleagues regarding appropriate treatment of the elderly with early-stage and locally advanced non-small-cell lung cancer (NSCLC) is welcome, and its scope is comprehensive. But a North American perspective is essential.
Over the past 3 to 4 years, adjuvant chemotherapy employing platinum-based regimens has become the standard therapeutic strategy in fit patients who have undergone resection for stage IB-IIIA NSCLC. However, many elderly patients with NSCLC—even those who appear fit—have difficulty tolerating cisplatin-based treatment, either because of hearing loss or difficulty handling obligate hydration, or because of renal insufficiency or other comorbidities.
Carboplatin is a far safer drug than cisplatin, with significantly less neurotoxicity, nephrotoxicity, and ototoxicity; and area under the concentration-time curve (AUC)-based dosing represents a logical extension of pharmacokinetics to the clinic. The Calvert formula takes age, as well as weight and renal function, into account. However, of the four studies showing a benefit for adjuvant treatment,[2-5] only one employed carboplatin, and this study was confined to patients with stage IB NSCLC. It is attractive, if not logical, to extrapolate the results observed with paclitaxel and carboplatin in stage IB NSCLC to stage II and IIIA NSCLC, but as yet, there are no concrete data demonstrating therapeutic superiority for carboplatin-based regimen in these two stages. Such an extrapolation must be tempered with caution.
Unfortunately, to date, there are no published subanalyses examining outcomes for elderly patients enrolled in the four positive adjuvant trials, two of which explicitly excluded patients over age 75.[2,3] Even in those trials without age limits, elderly patients with NSCLC were clearly underrepresented, compared to their projected proportion in the Surveillance, Epidemiology, and End Results (SEER) database. A pooled subanalysis would be greatly welcome, as would elderly-specific adjuvant trials examining less toxic third- and fourth-generation regimens (eg, pemetrexed [Alimta] and carboplatin). In addition, we need to carefully delineate the influence of comorbidities, especially baseline impaired renal function and cardiopulmonary disease, in terms of both toxicity and therapeutic effect. To date, such endeavors have not been mounted.
A landmark trial of the Lung Cancer Study Group (LCSG) showed that anatomic resection, preferably lobectomy, was superior to wedge or segmental resection in fit individuals with early-stage NSCLC. This approach yielded a significant reduction in local recurrence rates and a borderline trend toward improved survival (P = .088). However, many elderly patients have compromised pulmonary reserve, as well as other comorbidities that deter surgeons from performing resections or compel limited resections. In a review of Medicare-insured patients in Virginia, those over 65 years of age with localized lung cancer were only one-third as likely to undergo resection compared to their younger counterparts. These observations echo those cited by Gridelli and colleagues. With each decade of life after 65, the likelihood of undergoing resection declines by 65%.
Ever since Evans and colleagues found a clear relationship between increasing patient age and increased operative mortality, delineating operative risk has become key. In an LSCG review of 2,200 lung resections in the early 1980s, Ginsberg and colleagues clearly confirmed this risk: The 30-day operative mortality for patients at least 70 years old ranged from 7% to 8%. However, more recent reports have suggested no increased risk in mortality if lung-sparing operations are performed.
Under these circumstances, critical measures must be applied to determine medical operability. There are numerous challenges in the elderly, induced by age-related physiologic changes in cardiovascular and respiratory reserve.[12,13] These include decreased response to hypoxemia or hypercapnia, decreased elasticity of lung tissue, increased ventilation-perfusion mismatch, and decreased forced expiratory volume. Hence, diligent assessment of pulmonary function is mandatory; some have suggested a minimum baseline forced expiratory volume in 1 second (FEV1) of 2 L for those about to undergo pneumonectomy, and 1.5 L for those who require lobectomy. Assessment is enhanced by measurements of diffusing capacity of the lung for carbon monoxide (DLCO), pulmonary oxygen saturation, and, if necessary, quantitative ventilation perfusion (VQ) scans.
Dr. Langer receives grant/research support from Bristol-Myers Squibb, Pharmacia, Lilly, Schering-Plough Research Institute, Aventis, Amgen, Cell Therapeutics Inc, OrthoBiotech, Celgene, Vertex, Genentech, AstraZeneca, and Pfizer; is a scientific advisor for ImClone, Bristol-Myers Squibb, Aventis, Pharmacia, Intrabiotics, GlaxoSmithKline, TAP Pharmaceutical Products Inc, Amgen, and AstraZeneca; and is a member of the speakers bureau for Bristol-Myers Squibb, Aventis, Pharmacia, Lilly, and OrthoBiotech.
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