Commentary (Langer): Treatment of Stage I-III Non-Small-Cell Lung Cancer in the Elderly

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.

Early-Stage NSCLC

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.[1] 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.[4] 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.[6] 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.[7] To date, such endeavors have not been mounted.

Surgical Considerations

A landmark trial of the Lung Cancer Study Group (LCSG)[8] 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.[9] 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.[10] 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%.[11] 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.

By the same token, cardiovascular fitness must be assessed. Pertinent studies include baseline ECG and, if necessary, cardiac echo and coronary stress profusion imaging or coronary angiography in patients with symptoms highly suggestive of active coronary artery disease. In those who are not fit, limited resection is clearly preferable; this is particularly true in the elderly, given their cardiopulmonary vulnerability and associated comorbidities.

Using SEER data, Mery analyzed nearly 1,500 patients with stage I or II NSCLC and demonstrated no overt survival benefit for patients 71 years of age or older who were treated with lobectomy vs more limited resection.[14] Landreneau and colleagues have shown that patients treated with video-assisted thoracoscopic surgery require less narcotic use and have decreased pain, improved shoulder motion, and less pulmonary dysfunction compared to those treated with open thoracotomy.[15] Such an approach might be ideal for elderly patients with borderline cardiopulmonary function.

Radiation Therapy

In patients who are not candidates for even limited resection, definitive radiation has a potential role, as long as radiation fields are tight and pulmonary reserve is adequate. Even among those with early-stage disease and multiple comorbidities, lung cancer remains the chief cause of death in more than half.[16]

However, for fit elderly patients with locally advanced NSCLC who are not candidates for surgery, emerging data, particularly from North America, suggest a conclusive role for combined-modality therapy. In earlier studies conducted by the Radiation Therapy Oncology Group (RTOG) during the 1980s and 1990s, the addition of chemotherapy appeared to confer no additional benefit compared to radiation therapy (RT) alone.[17] The median survival of patients 70 years of age or older was 11.4 months with daily RT alone, 9.3 months with twice-daily RT, 11.0 months with induction chemotherapy followed by standard RT, 14.2 months with induction chemotherapy followed by concurrent chemoradiation, and only 11.1 months for concurrent chemotherapy and twice-daily RT. No significant difference in survival based on treatment strategy emerged (P = .32). Concurrent chemotherapy and radiation resulted in significantly more grade 3 and 4 toxicity, but no overt improvement in survival. Based on these efforts, the elderly did not appear to benefit from chemotherapy and RT.

Nevertheless, in a more recent analysis of RTOG 9410, which compared sequential chemoradiation to concurrent chemoradiation given either once or twice daily, fit elderly patients with less than 5% weight loss appeared to derive a benefit.[18] Of nearly 600 patients accrued to this effort, 104 were 70 years of age or older. Across the board, regardless of regimen, grade 3/4 neutropenia was more pronounced in the elderly. In those receiving concurrent chemoradiation, grade 3/4 esophagitis was also more pronounced. Median survival in elderly patients receiving concurrent once-daily chemoradiation was 22.4 months, compared to 16.4 months for those receiving twice-daily RT and chemotherapy, and 10.8 months for those receiving sequential chemotherapy followed by RT (P = .069). There was no difference in long term toxicity.

Work by Rocha Lima and colleagues[19] in a retrospective analysis of Cancer and Leukemia Group B (CALGB) data similarly demonstrated no overt difference in long-term survival between elderly and younger patients who were fit enough to receive cisplatin and vinblastine followed by full-dose RT and platinum agents (P = .8). As in the RTOG studies, neutropenia was more pronounced (P = .04). In addition, renal toxicity was clearly worse (P = .0025).

Schild and colleagues conducted a similar analysis of the North Central Cancer Treatment Group (NCCTG) experience in patients receiving concurrent chemotherapy and either continuous or split-course radiation.[20] Of 244 enrollees, 63 (26%) were 70 years of age or older. The elderly experienced significantly more grade 4+ hematologic toxicity and more severe pneumonitis (6% vs 1%, P = .02). Once more, there was no significant difference in survival (P = .37), with 2- and 5-year survival rates of 39% and 18% for younger patients, compared to 36% and 13% in the elderly.

It should be emphasized that enrollees in these trials were generally fit, with excellent performance status and minimal or no significant weight loss. It is likely that half or more of patients with locally advanced disease do not fulfill the entry criteria of these cooperative group trials. In patients with locally advanced NSCLC and compromised performance status and/or substantial weight loss, the lessons learned in the realm of combined-modality therapy do not automatically apply.

Chemotherapy

Gridelli and colleagues have charted the standard approach for elderly individuals with advanced disease.[21,22] In the landmark Elderly Lung Cancer Vinorelbine Italian Study, or ELVIS trial, vinorelbine showed a clear-cut survival advantage compared to best supportive care, with reasonable toxicity and improved quality of life.[21] In a much larger phase III effort, combination gemcitabine (Gemzar) and vinorelbine, compared to the constituent single agents, generated more toxicity but no improvement in response rate or survival.[22] However, neither of these trials employed platinatum agents or taxanes.

More recently, a phase III effort (West Japan Thoracic Oncology Group [WJTOG] 9904) compared standard vinorelbine to docetaxel at 60 mg/m2 every 3 weeks.[23] While the docetaxel regimen yielded significantly more grade 3/4 neutropenia as well as febrile neutropenia, response rates were significantly higher (23% vs 10%, [P = .019]), with a trend toward improved median survival (14.3 vs 9.9 months) and 1-year survival rates (59.2% vs 36.5%). Under these circumstances, it is conceivable that taxanes may displace vinorelbine or gemcitabine as the standard agent. More studies are needed to ascertain if this is the case. Whether this observation applies to earlier-stage disease also remains speculative.

In fit individuals, multiple retrospective analyses of platinum-based combinations have demonstrated similar outcomes for elderly and younger cohorts with respect to response rate, quality of life, time to progression, median survival, and 1- and 2-year survival rates, although these benefits are potentially vitiated by increased toxicity in the elderly.[24-27] To date, no phase III, elderly-specific trials have demonstrated therapeutic superiority for a platinum-based combination vs a single agent.

Hence, it is difficult to extrapolate our experience with the elderly in advanced disease to the adjuvant setting. Decisions regarding treatment ultimately hinge on multiple factors, including the toxicity profiles of the agents under consideration, patient performance status, comorbidities, social support, and pharmacokinetics. Moreover, patients aged 70 to 80 and those aged 80 or older may functionally represent two entirely different groups.[28] This concern applies just as much to the adjuvant setting as it does to the advanced-disease setting.

Given these circumstances, neoadjuvant therapy is potentially more attractive. Patients are far better able to tolerate chemotherapy in the preoperative setting than after resection when they are still recuperating from the sequelae of surgery. In addition, the application of systemic treatment at the earliest time possible may ultimately yield a greater survival benefit. The vast majority of deaths from NSCLC are due to systemic relapse, not local recurrence. To date, however, there has been no retrospective analysis of elderly-specific outcomes in the largest neoadjuvant trials, including those of Depierre and Pisters.[29,30] This deficiency can be readily remedied.

-Corey J. Langer, MD, FACP

Disclosures:

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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