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Treatment of Stage I-III Non-Small-Cell Lung Cancer in the Elderly

Treatment of Stage I-III Non-Small-Cell Lung Cancer in the Elderly

Elderly patients with stage I-III non-small-cell lung cancer (NSCLC) constitute a peculiar patient population and need specific therapeutic approaches. Limited resections are an attractive alternative for elderly patients with resectable NSCLC because of the potential reduction in postoperative complications. Curative radiation therapy is an acceptable alternative for elderly patients who are unfit for or refuse surgery. Hypofractionated stereotactic body radiation therapy is of particular interest for this population because of its favorable tolerance. Elderly patients may tolerate chemotherapy poorly because of comorbidity and organ failure. The survival benefit obtained with adjuvant platinum-based chemotherapy in the younger population may vanish or decrease in the elderly because of a potential higher toxic death rate or lower compliance to treatment. The efficacy and feasibility of adjuvant chemotherapy for elderly patients need to be investigated in specific trials. Neoadjuvant chemotherapy remains an experimental approach under investigation in the general patient population, and consequently should not be considered in clinical practice in the elderly. Retrospective analyses on chemoradiation in elderly patients should be considered globally ambiguous and at risk of selection bias. Only specifically designed prospective studies will elucidate the real role and feasibility of this combined approach in the treatment of unselected elderly patients.

More than two-thirds of the patients who die of lung cancer in the United States are over 65 years old.[1] Specific approaches to the treatment of elderly patients with non-small-cell lung cancer (NSCLC) are needed. In fact, many elderly patients tolerate all treatment modalities poorly because of comorbidity and organ failure. The prevalence of these comorbid conditions is about twice as high as in the general population.[2] The most important coexisting pathologies in lung cancer patients are cardiovascular and pulmonary diseases, which are common among heavy cigarettes smokers. Moreover, among elderly persons it is common to find a condition known as "frailty," in which most functional reserve is exhausted. Decreased hepatic, renal, and bone marrow functions have a negative impact on the degree of toxicity—in particular, on cisplatin toxicity. In order to plan the treatment of elderly NSCLC patients, a multidimensional geriatric evaluation, including not only assessment of comorbidities but also of functional, mental, and nutritional status, is needed.

Surgery

The dilemma that elderly patients with lung cancer and their physicians face is that of balancing the increased risk of surgery with conventional open thoracotomy techniques and improved long-term survival when surgery is successful. Twenty-five years ago, several authors[3] concluded that age beyond 70 years was a prohibitory factor for thoracotomy. Although small series have since suggested that carefully selected elderly patients can safely undergo thoracotomy,[4] it is still common practice to provide fewer surgical options to the elderly patient with lung cancer.

Nugent et al[5] came to this conclusion after reporting data from a series of 1,802 patients collected in the United States from 1983 to 1993. Although the incidence of stage I-II cancer was five times higher in the elderly group (6% among younger patients and 33% among older patients), the resection rate was 32% for the younger group and only 6% for the elderly. Similarly, in Europe, Damhuis and Schutte[6] found a 26% resection rate for patients who had lung cancer and were younger than 70 years, compared with a 14% rate for those who were older than 70 years. Both groups in this report had comparable operative mortality (3.2% vs 4.0%), probably indicating careful preoperative selection of elderly patients.

Some authors[7] believe that many elderly patients who have lung cancer and undergo standard anatomic pulmonary resections (lobectomy or pneumonectomy) with posterolateral thoracotomy have a higher incidence of postoperative mortality than younger individuals. The Lung Cancer Study Group (LCSG) quantified this observation in a multi-institutional study conducted in the late 1970s and early 1980s. Patients who were aged 70 years or older had a 30-day postoperative mortality of 7.1% compared with 1.3% for patients who were younger than 60 years and 4.1% for those between ages 60 and 69 years.[8]

In 14 reports from Italy, the United Kingdom, the United States, and Finland published after the LCSG data, the operative mortality after lung resection with an open thoracotomy technique has ranged from 1% to 22%, with an average of 5.9%.[8] These data compare poorly with video-assisted thoracic surgery (VATS) techniques for removal of stage I lung cancer in elderly patients. In six recent reports of 378 patients from Canada, the United States, Japan, and Hong Kong, the average operative mortality was 1.1%.[9]

Limited Resections

The operative risk of death after thoracotomy in elderly patients is due to two major anatomic changes: loss of functional lung tissue and temporary impairment of the ipsilateral muscles of respiration.[10] To serve these impaired patients with otherwise resectable lung cancer, lesser operations such as segmentectomy and wedge resection are increasingly being performed, especially among elderly patients.[11] Lung-sparing procedures such as segmentectomy better preserve lung function than lobectomy.[12] These procedures are also associated with less operative morbidity and mortality compared with lobectomy[13] but, like lumpectomy, may be associated with a higher local recurrence rate.

A multi-institutional, prospective, randomized phase III trial compared lobectomy by open thoracotomy with limited resections, also by open thoracotomy.[14] Limited resections included both segmentectomy and open wedge resection. Although there was no significant overall difference in postoperative complications and mortality, 6 of 125 patients who received lobectomy and none of the 122 patients who received limited resection developed respiratory failure. The major finding of this study was that limited resections were associated with a higher incidence of local recurrence within the chest compared with lobectomies (P = .02, one-tailed). Thus, this study has established that lobectomy remains the gold standard of surgical resection for patients who can tolerate the procedure. The difference in local recurrence, however, did not translate into a statistical difference for long-term survival (P = .088, one-tailed). Furthermore, with special regard to elderly patients, the survival curves of the two groups were nearly identical for the first 3 years after surgery.

On the basis of these data, some authors have shown an institutional bias toward wedge resection for elderly patients with early-stage lung cancer.[7,11] Limited resections are an attractive alternative for elderly patients with lung cancer because of the potential reduction in postoperative complications, the rapid recovery, and the increased prevalence of early-stage disease in this group.[15] Because long-term survival is the same after lobectomy or limited resection for the first several postoperative years, the elderly, with a lower remaining life expectancy than younger patients, may benefit the most from this strategy. Some authors[7] believe that there is an age above which lobectomy is no longer the gold standard.

Mery et al confirmed the hypothesis that at some threshold of age, lobectomy no longer provides a population survival advantage.[15] In fact, analyzing the Surveillance, Epidemiology, and End Results database, these investigators showed that for patients who are 74 years or younger, the survival curves between lobectomy and limited resection diverge after 25 months. Overall median survival after lobectomy was 66 months, compared with 50 months after limited resection (P < .0001). Kaplan-Meier curves for long-term survival after limited resection and lobectomy among patients who were 75 years or older, however, never deviated from each other.

Radiotherapy

Patients who are unfit for surgery or refuse surgery are typically treated with radiation therapy, which has shown 5-year survival rates of 5% to 30%.[16,17] Although some patients are not offered therapy because of comorbid disease or advanced age, in a review by McGarry et al,[18] cancer was the cause of death for 53% of inoperable patients who received no specific cancer therapy at time of diagnosis for stage I NSCLC. Poor performance status and comorbid conditions that preclude surgery at least partially account for the poor survival of patients with early-stage lung cancer treated with radiotherapy. Complication rates of definitive radiation therapy are low, despite poor pulmonary function and performance status.[17]

Pergolizzi et al performed a prospective study on curative radiotherapy alone in 40 elderly patients with stage IIIA disease.[19] Radiotherapy was directed toward gross tumor burden with a median of 60 Gy (conventionally fractionated). No treatment-related mortality was observed, and no clinically significant acute morbidity was scored. The median survival was 19 months and the 5-year survival rate was 12%.

Several retrospective studies have been reported on radiotherapy as curative treatment of unresectable NSCLC in elderly patients, and globally, such treatment was well tolerated by this older population. Zachariah et al reported on radiotherapy in lung cancer in patients ? 80 years old.[20] Of 36 patients, 21 were treated with conventional radiotherapy doses ranging from 59.40 to 66 Gy. Response to radiotherapy was observed in 9 patients (43%). The treatment was well tolerated by this very old population. In a study by Gava et al, for 38 patients aged at least 70 years with locally advanced disease, the 1-year survival rate approached 44%.[21]

Lonardi et al treated 48 elderly (≥ 75 years) patients with stage IIIA or IIIB, inoperable, symptomatic NSCLC using 1.8 to 2.5 Gy per fraction to a median dose of 50 Gy. These investigators observed a 2-year survival rate of 10% and a median survival of 5 months.[22] Of 47 assessable patients, 21 had a partial remission, 17 stable disease, and 9 had progressive disease. Despite the short overall median survival, dose-related survival was much better in patients given at least 50 Gy than in those treated with lower doses: 52% vs 35% at 6 months, and 28% vs 4% at 13 months. Most symptoms were successfully palliated. Toxicity was negligible, mainly consisting of World Health Organization (WHO) grade 1/2 esophagitis.

Tombolini et al used radiotherapy alone in 41 patients ≥ 70 years with medically inoperable IIIA and IIIB NSCLC. These patients received a conventionally fractionated radiotherapy dose of 50 to 60 Gy plus a 10-Gy boost to the gross tumor volume.[23] Two-year survival and disease-free survival rates were 27% and 14.6%, respectively.

Thus, although at least two studies have found advanced age to be a negative prognostic factor for stage I disease,[17,24] the toxicity of radiation therapy alone for inoperable lung cancer in elderly patients is not greater than toxicity in younger patients.[25,26] It is interesting to note that Gauden and Tripcony[26] showed a general trend for elderly patients (≥ 70 years vs < 70 years) to have better 5-year survival (34% vs 22%), median survival (26 vs 22 months), and recurrence-free survival (30% vs 18%). The cohort of patients aged 80 years or older had the smallest proportion of medical disease precluding surgery (53%) and the largest proportion with good performance status (80%). Good performance status and fewer comorbid conditions may explain the trend for a favorable outcome in the older patient subgroup.

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