Treatment of Non–Small-Cell Lung Cancer in Older Persons

January 1, 2003
Michele Basche, MD

,
Karen Kelly, MD

Oncology, ONCOLOGY Vol 17 No 1, Volume 17, Issue 1

The majority of individuals diagnosed with lung cancer in theUnited States are 70 years of age and older. Defining appropriatetherapy for older patients with non–small-cell lung cancer (NSCLC) isbecoming a major focus of clinical research. In this article, we reviewthe available data on clinical predictors of risk and benefit for elderlyNSCLC patients receiving treatment via a variety of modalities, includingsurgery, radiotherapy, combined radiotherapy and chemotherapy,and chemotherapy alone. The data demonstrate that subgroups ofelderly patients benefit from appropriately selected treatment. Participationof older patients in clinical trials designed to assess efficacy,toxicity, and quality-of-life outcomes for recently developed treatmentmodalities in this population is critical.

ABSTRACT: The majority of individuals diagnosed with lung cancer in the United States are 70 years of age and older. Defining appropriate therapy for older patients with non–small-cell lung cancer (NSCLC) is becoming a major focus of clinical research. In this article, we review the available data on clinical predictors of risk and benefit for elderly NSCLC patients receiving treatment via a variety of modalities, including surgery, radiotherapy, combined radiotherapy and chemotherapy, and chemotherapy alone. The data demonstrate that subgroups of elderly patients benefit from appropriately selected treatment. Participation of older patients in clinical trials designed to assess efficacy, toxicity, and quality-of-life outcomes for recently developed treatment modalities in this population is critical.

FIGURE 1


Age-Adjusted Incidence Rates for Lung Cancer FIGURE 2


Age Distribution of Lung Cancer Cases

Lung cancer is the leading cause of cancer death in the United States among both women and men. In 2002, an estimated 169,400 people were diagnosed with lung cancer, and 154,900 died of the disease.[ 1] Advancing age is associated with an increased incidence of lung cancer (Figure 1).[2] Approximately 51% of patients diagnosed with lung cancer are 70 years of age and older, and 16% are ≥ 80 years old (Figure 2).[3]

The treatment of older persons (age ≥ 70) with lung cancer deserves careful attention because this subgroup represents a substantial and growing segment of the population, and most importantly, because clinical decision- making is fairly complex in these patients. Aging involves physiologic changes that may affect drug pharmacology and treatment tolerance, including decreased renal function, bone marrow reserve, and lean body mass.[4] In addition, the older population comprises those with a wide range of physiologic reserve, including the most fit (who typically participate in clinical trials), patients with significant comorbid disease or poor performance status, and the very old. A key question for oncologists is how to assess the characteristics of an older patient in order to predict the therapeutic ratio for that patient and make appropriate recommendations.

Fortunately, the evaluation of appropriate therapies for older patients with lung cancer has indeed become a major focus of research.[5] The results of several clinical trials specifically designed to evaluate treatment modalities in older patients have recently been published. This article will review the available data pertaining to clinical predictors of risk and benefit for specific treatments in older patients with non-small-cell lung cancer (NSCLC).

Surgery

Surgical resection is the treatment of choice for stage I/II NSCLC because it offers the best chance for long-term cure. Overall 5-year survival rates range from 60% to 80% for patients with stage I disease and 25% to 50% for patients with stage II disease.[6] Age alone should not exclude a patient from consideration for surgical therapy, as many older patients live long enough to enjoy the survival benefit conferred by surgical resection. The average life expectancy for US men and women 80 years of age is 6.7 and 8.8 years, respectively, and for men and women 85 years of age, 5.3 and 6.7 years.[7] The critical questions to be addressed are whether the overall survival of older patients undergoing surgical resection for NSCLC is similar to that of younger patients, and whether surgical risks for older patients are too high to achieve a survival benefit.  

Long-Term Outcomes

Older vs Younger Patients-The results of two large retrospective analyses suggest that long-term outcomes for appropriately selected older patients undergoing surgical resection are comparable to those of younger patients. Van Rens et al conducted a retrospective study analyzing survival among 2,361 patients who underwent surgical resection for stage I, II, or IIIA primary NSCLC.[8] A total of 1,115 patients (47%) were over age 65 at the time of surgery, with the age range extending to 85. In comparing the overall survival of patients over 65 to that of patients younger than 65, no difference was observed at up to 4 years of followup.At 5 years, the overall survival of older patients was slightly inferior to that of younger patients (38% vs 44%, P < .0001).

TABLE 1


Outcomes for Patients 65 ≥ Years Old Treated With Surgery

Ishida et al conducted a retrospective analysis of patients with NSCLC who underwent treatment with surgical resection at a university hospital in Japan between 1974 and 1989.[9] Of 662 cases analyzed, 185 (28%) were age 70 and older (Table 1). Outcomes were compared for elderly patients (≥ 70) and younger patients (< 70). No significant differences in overall 5-year survival were found, and the 5-year overall survival of the older group compared favorably to that of the younger group (67% vs 68% for stage I disease and 40% vs 17% for stage II disease). The inferior survival of younger patients with stage II disease was not explained by the authors.[9]

Case Series-Kamiyoshihara et al published a series on 37 patients aged ≥ 70 years with resectable stage I-IIIA lung cancer. These investigators observed a 35% 5-year survival rate.[10]

With five small case series, researchers reported on the outcomes of patients ≥ 80 years old who underwent lung resection for NSCLC (Table 1). Three series involving 103 patients with stage I, II, or IIIA disease showed acceptable 5-year survival rates ranging from 30% to 55%.[11-13] Two studies focused on patients with stage I NSCLC. The largest series included 54 patients aged ≥ 80 years and demonstrated a 57% 5-year survival rate.[14] The smaller study involved 18 patients and showed a 43% 5-year survival rate.[15] Shirakusa and colleagues also performed a subset analysis on data from patients with stage I disease and reported an impressive 5-year survival rate of 79% in 18 patients.[11]

Morbidity and Mortality

Although appropriately selected older patients can enjoy long-term benefits from surgical resection of stage I and II NSCLC, evidence suggests that this population also faces increased short-term morbidity and mortality associated with surgical therapy. Ginsberg et al analyzed 30- day surgical mortality rates for resections performed between 1979 and 1981 at centers participating in the Lung Cancer Study Group. Among enrolled patients, 416 were age 70 to 79, and 37 were age 80 or older.

By univariate analysis, the postoperative mortality rate increased from 1.3% among patients aged < 60 years to 4.1% among patients aged 60 to 69, 7% among those aged 70 to 79, and 8.1% among those aged 80 and older (P < .01). Compared to patients aged 50 to 59 years, complication rates were 2.5 times greater for patients aged 70 to 79 and 2 times greater for those aged 80 and older. Common causes of surgical mortality included pneumonia, respiratory failure, bronchopleural fistula, empyema, and myocardial infarction.[16]

Although Ginsberg's results are frequently used to demonstrate an association between age and increased postoperative morbidity and mortality, their applicability to contemporary clinical decision-making is limited. These results describe outcomes for cases performed 20 years ago and do not reflect advances in surgical technique or postoperative care, which may influence outcomes. Additionally, because only univariate analysis was performed, Ginsberg's results do not help us determine whether the more powerful predictor of surgical risk is advancing age or the comborbid diseases commonly associated with aging.

Romano and Mark analyzed inhospital mortality for 12,437 lung cancer resections performed in California hospitals between 1983 and 1986.[17] Compared to patients less than age 60, the adjusted odds ratio (OR) for postoperative death was 2.3 for patients aged 60 to 69, 3.6 for those aged 70 to 79, and 5.4 for those > 79. Other significant predictors of postoperative death included chronic heart disease (adjusted OR = 1.8), extended resection (OR = 1.8), diabetes (OR = 1.5), male gender (OR = 1.5), chronic obstructive pulmonary disease (OR = 1.4), and volume of lung resections performed at the hospital (OR = 0.6).[17] This study may have underestimated the contribution of comorbid disease to in-hospital mortality because only comorbid diseases recorded as secondary diagnoses at hospital discharge were noted. 

Other Variables-In a more recent study, several variables were found to be more powerful independent predictors of postoperative morbidity and mortality than age. The National Veterans Affairs Surgical Quality Improvement Program conducted a prospective multicenter study involving 194,319 major pulmonary resections performed between 1991 and 1995. In multivariate models, age was a significant predictor of postoperative morbidity and mortality. Compared to 50-year-old patients, the postoperative mortality risk was 1.33 for 60-year-old patients, 1.66 for 70-year-old patients, and 1.99 for 80-year-old patients. Other independent prognostic variables included do-not-resucitate status (OR = 4.3), pneumonectomy (OR = 3.0), impaired sensorium (OR = 2.7), hypoalbuminemia (OR = 1.7), and dyspnea (OR = 1.4).[18]

In another recent prospective single- institution study in 500 patients, Bernard et al found that age was associated with increased risk of postoperative mortality only in the univariate analysis.[19] In a logistic model accounting for indication for surgery, type of procedure performed, pulmonary function, comorbidity indices, and preoperative chemotherapy, age was not an independent predictor of postoperative mortality.[ 19] Both these results and those of the Veterans Affairs Surgical Quality Improvement Program suggest that adequate physiologic reserve (as measured by pulmonary function, comorbidity indices, and nutrition) is a more useful criterion for appropriate selection of patients than age alone.

To our knowledge, no validated models have been developed to predict the risk of surgical morbidity and mortality among older patients undergoing lung resection. In two of the series cited in Table 1, the authors specified that they used standard criteria to assess cardiopulmonary function when selecting patients for surgery or chose the type of resection based on prediction of postoperative pulmonary function.[14,9] In other series, the method of patient selection was not specified, but the prevalence of ischemic heart disease was low.

In Kamiyoshihara's series, 5% of patients aged 70 years and older had a history of ischemic heart disease.[ 10] In the series published by Osaki et al, 12% of patients had ischemic heart disease (angina or history of myocardial infarction), and in Hanagiri's series, 17% of patients had a history of angina and 6%, a history of myocardial infarction.[13,15] The prevalence of arrhythmias in these three series was also fairly low (19%, 30%, and 22%).[10,13,15]

Choice of Procedure-In addition to the factors discussed above, surgical morbidity and mortality are dependent on the procedure performed. In all of the case series cited, the use of pneumonectomy was avoided or limited, because the procedure is associated with a high rate of postoperative complications and mortality. Additionally, Dyszkiewicz et al compared pneumonectomy to lobectomy among 90 patients older than age 70.[20] Postoperative complications developed in 79% of patients undergoing pneumonectomy vs 58% of patients undergoing lobectomy.[ 20] De Perrot compared postoperative mortality rates for pneumonectomy in 208 patients aged ≥ 70 years to those in 416 patients aged < 60. The mortality rate among the older patients was 13.7%, compared with 6.5% among the younger patients.[21]

Landreneau et al evaluated wedge resection vs lobectomy in 219 patients with T1, N0, M0 NSCLC and found that the mean hospital stay decreased by 3 to 4 days in the wedge resection population, even though this group of patients was older and had poorer lung function.[22] Additionally, wedge resection via video-assisted thoracic surgery was associated with decreased postoperative pain and better postoperative pulmonary function. This may be especially beneficial to older patients, for whom postoperative pulmonary rehabilitation may be slower and the risk of postoperative delirium, higher.

Five-year survival was inferior for patients undergoing wedge resection (58% for open wedge, 65% for video-assisted wedge, and 70% for lobectomy, P = .02), but these differences in survival were due to an increased death rate from other causes. At 5 years, the non-cancerrelated death rate was 38% for patients who had undergone wedge resection vs 18% for patients who had a lobectomy.[22]

Conclusions Regarding Surgery

Overall, the evidence suggests that 5-year survival for patients ≥ 70 years old who undergo surgical resection is similar to that of patients < 70 years old. In addition, 5-year survival for appropriately selected octogenarians is quite favorable. Older patients should not, therefore, be excluded from consideration for surgical therapy on the basis of age alone. Rather, older individuals should be risk-stratified so that appropriate recommendations for therapy are made.

Unfortunately, no validated method has been developed to enable physicians to take into account the multiple factors that influence postoperative risk and accurately predict that risk for older patients undergoing lung resection. In most studies, age was an independent risk factor for postoperative morbidity and mortality. The presence of comorbid disease, including cardiopulmonary disease, diabetes, poor nutrition, and impaired sensorium, further increased surgical risk. Postoperative risk was also influenced by the extent of the surgical procedure and the volume of lung resections performed at a given institution.

Recommendations

Surgical therapy should be offered to older patients with stage I or II NSCLC who have minimal significant comorbid disease. Surgery should be performed by experienced thoracic surgeons at high-volume institutions with care to avoid pneumonectomy. Further research is needed to define methods of optimizing postoperative care and rehabilitation for older patients who undergo curative lung resection.

Radiation Therapy

Older patients ineligible for surgery are frequently referred for radiotherapy. Gauden and Tripcony conducted a single-institution retrospective analysis of 347 clinically staged patients with T1/2, N0, M0 NSCLC who did not undergo surgical therapy because of comorbid disease, poor performance status, age, or patient refusal.[23] Patients had been treated between 1985 and 1992 with standard-fractionation externalbeam radiotherapy to a total dose of 50 Gy. For patients aged 70 and older (n = 173), 5-year overall survival was 34%, and 5-year disease-free survival was 30%. Compared to results in patients younger than 70, no significant differences in survival or toxicity were found. There were no treatment-related complications requiring hospitalization in the older group.

Gauden and Tripcony's experience was more favorable than other reports in the literature, in which 5- year overall survival for patients with stage I NSCLC treated with radiotherapy ranged from 6% to 22%.[23] Although standard-fractionation radiotherapy is well tolerated by older persons, results with this therapy are clearly inferior to those achieved with surgical resection. 

Recent advances in radiotherapy such as three-dimensional (3D) conformal radiation and sterotactic radiosurgery may improve survival and decrease toxicity. Both techniques are designed to more precisely deliver radiation to the tumor while sparing normal lung tissue. A pilot study of 3D radiation therapy for stage I/IIA NSCLC was recently reported. Thirty- two medically inoperable patients with an average age of 76 years received a median dose of 70.2 Gy. The 5-year local control rate was 43%, with a 5-year overall survival rate of 33%. Toxicity was mild with no reports of grade 3 esophagitis, grade 3 pneumonitis in 6%, and late toxicity in one patient.[24] Early results with stereotactic radiosurgery have also been promising.[25] The use of these treatment modalities in older patients should be explored further.

Radiation and Cisplatin-Based Chemotherapy

Patients with locally advanced disease benefit from combined-modality treatment. Two large randomized trials have confirmed the benefit of concurrent therapy for patients with inoperable stage III NSCLC and good performance status.

WJLCG Trial-The West Japan Lung Cancer Group (WJLCG) showed that concomitant chemotherapy (cisplatin/vindesine/mitomycin [Mutamycin]) and radiation therapy (56 Gy) resulted in a 16.5-month median survival,[26] compared with 13.3 months for sequential chemotherapy and the same radiation therapy.

RTOG Trial-The US confirmatory trial conducted by the Radiation Therapy Oncology Group (RTOG- 9410) compared cisplatin and vinblastine followed by thoracic radiotherapy (60 Gy) to concurrent cisplatin/vinblastine with radiotherapy (60 Gy) or an experimental regimen of cisplatin/oral etopside and hyperfractionated radiation (69.6 Gy in 1.2 Gy per fraction twice daily) in patients with inoperable or unresectable stage II/III NSCLC. The median survival was 17 months for concurrent therapy vs 14.6 months for sequential therapy (P = .038) and 16 months for the experimental arm (not statistically significant).[27]

TABLE 2


Toxicity and Survival by Age for Patients Enrolled in RTOG 94-10

The WJLCG trial excluded patients aged ≥ 75, whereas there was no age limit in the RTOG trial. Langer et al reexamined the data with respect to the elderly participating in the RTOG trial (Table 2).[28] Of the 610 patients enrolled between 1994 and 1998, 104 (17%) were age 70 or greater. Sequential therapy was administered to 40 patients, concurrent therapy to 24, and hyperfractionated therapy to 40.

Overall, the elderly experienced more toxicity regardless of treatment. Grade 4 or greater toxicity occurred in 68%, 75%, and 55% of older patients, compared with 57%, 63%, and 38% of younger patients in the sequential, concurrent, and hyperfractionated arms, respectively. The frequency of grade ≥ 3 neutropenia was 10% to 20% higher in older patients across treatment arms. Grade ≥ 3 esophagitis was uncommon (< 5%) among both younger and older patients receiving sequential therapy but occurred more commonly among older patients receiving concomitant therapy (33% vs 23%) and hyperfractionated therapy (60% vs 42%). There were no clinically significant differences in late grade %ge; 3 toxicity between older and younger patients in the three treatment arms.

Median survival of the older patients was more favorable in the concurrent- therapy arm (22.4 months) than in the sequential (10.8 months) and hyperfractionated (16.4 months) arms (P = .069). The duration of survival in older patients was also superior to that in younger patients regardless of treatment arm.[28]

Intergroup Trial-These results contrast with those of an earlier Intergroup trial. Between 1989 and 1992, 490 patients with stage II, IIIA, and IIIB NSCLC were accrued to a randomized controlled trial comparing standard radiotherapy to cisplatin and vinblastine followed by standard fractionation or hyperfractionated radiotherapy. Of the 490 patients in the trial, 66 were over age 70.

For patients under age 60, median survival was 15.4 months in the standard- radiation-with-chemotherapy arm, compared with 11.7 months in the radiotherapy-alone arm and 11.5 months in the hyperfractionated- therapy arm. However, for patients over age 70, median survival was most favorable in the standard-radiotherapy- alone arm (13.1 months), and median survival in the chemotherapy- with-standard-radiotherapy arm was only 10.9 months.

Patients older than age 60 accounted for 62% of all those enrolled in the trial but for 100% of toxic deaths. All eight toxic deaths occurred in patients who received chemotherapy with standard fractionation or hyperfractionated radiotherapy. Two toxic deaths were secondary to acute radiation toxicity, three were secondary to acute complications of chemotherapy, and three were secondary to late radiation toxicity.[29]

Both the RTOG and Intergroup trials suggested that cisplatin-based chemotherapy combined with radiotherapy was associated with significant toxicity among older patients. It is plausible that the more recent RTOG study demonstrated a survival benefit with concomitant chemotherapy and radiotherapy because supportive care as well as radiotherapy techniques have improved over the past decade. Despite recent advances, better tolerated chemotherapy regimens have been developed and are being evaluated in all patients and specific subsets.

Radiation and Carboplatin-Based Chemotherapy

The Southwest Oncology Group (SWOG) conducted a phase II trial of concurrent carboplatin (Paraplatin), etoposide, and radiation in poor-risk stage III NSCLC patients. Poor-risk patients were defined as those deemed ineligible for cisplatinbased chemoradiotherapy due to poor respiratory function (FEV1 < 2.0 L but > 1.0 L), creatinine clearance ranging from 20 to 50 mL/min, hearing loss or peripheral neuropathy, congestive heart failure, or a performance status of 2.

Among the 60 patients enrolled in the trial, 50% were aged 66 to 79 years and 82% had a performance status of 0 or 1. The majority of enrolled patients were considered poor risk because of compromised pulmonary nary function. Median overall survival was 13 months. Importantly, therapy was well tolerated, and there were no treatment-related deaths. Grade ≥ 3 leukopenia occurred in 50% of patients, grade ≥ 3 nausea in 5%, and grade ≥ 3 esophagitis in 17%.[30]

Palliative Radiation

In noncurative settings, radiation should be considered for palliation of symptoms. Palliation of symptoms can be achieved for thoracic pain and hemoptysis in 60% to 80% of cases and for cough or hoarseness in 50% to 70% of cases.[31]

Recommendations

Older patients with early-stage NSCLC who are deemed inoperable should be offered radiotherapy for local control and possibly cure. Radiotherapy alone should be discussed with all patients who have stage III disease because this modality produces reasonable survival times and palliates symptoms. Good performance status patients with regionally inoperable NSCLC should also consider combined chemoradiotherapy to prolong survival, but toxicity may be increased. Older patients should be encouraged to enroll in clinical trials designed to address important issues related to radiotherapy and chemotherapy.

Chemotherapy

The median survival of patients with stage IV NSCLC receiving best supportive care is 16 to 17 weeks.[32] Recent data suggest that chemotherapy modestly improves survival. Randomized trials and meta-analyses comparing cisplatin-based chemotherapy to best supportive care in patients with advanced NSCLC have demonstrated a 10-week improvement in median survival.[32] Although cisplatin-based regimens have become the standard of care in the United States for advanced NSCLC patients with good performance status, concern has been raised about the tolerability and efficacy of cisplatin- based regimens for older persons with the disease.

Combination Regimens

ECOG Trial-Langer et al compared the outcome of patients ≥ 70 years to that of patients < 70 years participating in Eastern Cooperative Oncology Group (ECOG) trial E5592-a phase III study comparing cisplatin/etoposide to cisplatin/paclitaxel with or without granulocyte colony- stimulating factor (G-CSF [Neupogen]) support in patients with stage IIIB or IV disease and an ECOG performance status ≤ 1.[33] Of 574 patients enrolled in the trial, 86 (15%) were ≥ 70 years old. In a comparison of outcomes in older patients vs younger patients, no significant differences were found in response rate (23.3% vs 21.5%), time to progression (4.3 vs 4.37 months), and median survival (8.53 vs 9.05 months). Leukopenia and neuropsychiatric toxicities occurred more commonly among older patients (P < .01).

SWOG Trials-Kelly et al pooled data from two large Southwest Oncology Group (SWOG) trials in order to determine the effect of age on survival and toxicity in patients aged 70 and older who received combination chemotherapy for advanced NSCLC.[34] In SWOG-9509, investigators randomized patients with good performance status to carboplatin/paclitaxel or vinorelbine (Navelbine)/cisplatin, and in the previous trial, SWOG-9308, patients were randomized to vinorelbine/cisplatin or cisplatin alone. The combination of paclitaxel and carboplatin was administered to 202 patients and vinorelbine plus cisplatin to 406 patients. Patients who received singleagent cisplatin were not included in the analysis. Of the 608 patients enrolled in these trials, 117 (19%) were 70 years of age and older and 491 were younger than age 70.

A trend toward decreased median survival was observed among the older patients, with a median survival of 6.9 months compared to 8.6 months for younger patients (P = .06). However, in a multivariate analysis accounting for treatment arm, stage, performance status, and weight loss, age was not found to be significantly associated with survival (P = .10).

When toxicity was analyzed by age, 94% of elderly patients vs 88% of younger patients (P = .06) experienced a grade 3 to 5 toxicity. Hematologic toxicity accounted for the increased incidence of grade 3 to 5 toxicity, which developed in 83% of elderly patients and 76% of younger patients. Significant nonhematologic toxicities were similar in each group (56% and 54%, respectively). Importantly, 46% of older patients in the vinorelbine/cisplatin arm (vs 29% of younger patients [P = .003]) were taken off study due to significant toxicity, whereas 16% of older patients and 11% of younger patients in the paclitaxel/carboplatin arm discontinued therapy due to toxicity (P = .003).

Hensing Trial-Hensing and colleagues conducted a retrospective analysis of outcomes by age for patients with stage IIIB/IV NSCLC and Karnofsky performance status ≥ 70% who received treatment in a phase III clinical trial evaluating four cycles of CP (carboplatin/paclitaxel) to CP until disease progression.[35] Of the 230 patients randomized in this trial, 67 (29%) were ≥ 70 years. The 1-year survival was 33% for the older patients and 32% for the younger patients (P = .62). There were no significant differences in toxicity between groups.

Comparing older patients to younger patients, grade ≥ 2 neutropenia occurred in 36% and 37% of patients, grade ≥ 2 neuropathy in 15% and 14%, and grade > 2 myalgias/ arthralgias in 8% and 16%, respectively. Both younger and older patients received a median of 3.1 treatment cycles. These retrospective analyses suggest that older persons with good performance status benefit from combination chemotherapy but  that carboplatin-based regimens are more tolerable.

Single-Agent Regimens

TABLE 3


Results of Phase III Randomized Controlled Trials Involving Patients ≥ 70 Years Old With Advanced Non–Small-Cell Lung Cancer

Recognizing the importance of developing less toxic regimens for elderly patients with advanced NSCLC, Italian investigators have conducted several randomized controlled trials in this population (Table 3).[36-38]

ELVIS Trial-The Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) was a multicenter randomized controlled trial that compared vinorelbine at 30 mg/m2 (days 1 and 8 every 21 days) to best supportive care in patients aged 70 and older with stage IIIB or IV NSCLC and a performance status of 0 to 2.[36] Data from 161 patients were analyzed.

Treatment with vinorelbine was associated with significant improvement in pain (P = .02), dyspnea (P = .05), and cognitive functioning (P = .02), and a trend toward improved global health (P = .06). Additionally, treatment with vinorelbine resulted in a 19.7% objective response rate (95% confidence interval [CI] = 11.5%-30.5%) and a significant survival advantage. The median survival was 28 weeks, compared to 21 weeks in the supportive care arm (P = .03). Among 71 patients assessable for toxicity, treatment was discontinued in 5 due to toxicity (grade 3 or 4 constipation in 3 patients and grade 2 cardiac toxicity in 1 patient).

Subsequently, two large Italian cooperative groups conducted independent trials to assess whether combination therapy is superior to single-agent therapy in this setting.

MILES Trial-The Multicenter Italian Lung Cancer in the Elderly Study (MILES) compared gemcitabine (Gemzar)/vinorelbine to vinorelbine alone and gemcitabine alone in patients aged 70 and older with stage IIIB/IV NSCLC and a performance status ≤ 2.[37] Among the 698 evaluable patients, no significant difference in survival or quality of life was demonstrated for combination chemotherapy, and all three treatment regimens were well tolerated.

Grade 3/4 neutropenia was the most serious adverse effect, occurring in 25% of patients in the vinorelbine group, 8% in the gemcitabine group, and 18% in the combined group. Increased incidences of peripheral neuropathy and alopecia were observed in the gemcitabine/navelbine arm after three cycles. Thus, this trial failed to demonstrate a benefit for combination therapy.

SICOG Trial-The Southern Italian Cooperative Oncology Group (SICOG) conducted a small, randomized phase III trial of gemcitabine plus vinorelbine vs vinorelbine alone in patients aged 70 and older with advanced NSCLC and an ECOG performance status ≤ 2.[38] The median survival for the combination arm was 29 weeks vs 18 weeks for vinorelbine alone (P = .01). Moreover, time to symptom deterioration was greater in the combined chemotherapy arm (21 vs 13 weeks, P = .002).

Grade ≥ 3 neutropenia developed in 38% of patients in the combined treatment arm vs 28% in the vinorelbine- alone arm. Two toxic deaths occurred in the vinorelbine/gemcitabine arm and one in the vinorelbine- alone arm. Importantly, the median survival of patients in the vinorelbine arm was substantially shorter in this trial than in the ELVIS and MILES trials. The inclusion of patients with brain metastases in the SICOG study may partly explain the difference in survival between the vinorelbine-alone arms across studies.

Conclusions Regarding Chemotherapy

Overall, randomized controlled trials have demonstrated a benefit for single-agent therapy in older patients with advanced disease. Although retrospective analyses of large trials suggested a benefit for older patients with combination therapies, the number of patients enrolled in these trials was small. Further studies are required to define the role of combination chemotherapy in the older population.

One clinical trial design could involve giving the agents sequentially, as proposed by the SWOG. In their recently activated phase II trial in poor-risk patients (S0027), vinorelbine, 25 mg/m2 on days 1 and 8 every 3 weeks for three cycles, is followed by three cycles of docetaxel (Taxotere), 35 mg/m2/wk for 3 of 4 weeks. Meanwhile, evaluation of other welltolerated single agents should be pursued. For example, paclitaxel was recently evaluated in a phase II trial involving patients aged 70 and older with advanced NSCLC.[39] The 35 patients received paclitaxel at 90 mg/m2/wk for 6 of 8 weeks. Median survival was 10.3 months, and 1- and 2-year survival rates were 45% and 22%, respectively. Grade ≥ 3 toxicities occurred in less than 10% of patients.

Recommendations

Elderly patients with advanced NSCLC should be offered singleagent chemotherapy with vinorelbine or gemcitabine to palliate symptoms and prolong survival with minimal toxicity. Older patients with good performance status may be candidates for combination therapy with carboplatin- containing regimens. Furthermore, patients should enroll in available clinical trials of promising therapies to guide us in identifying optimal treatments for the elderly.

Future Directions

Lung cancer is common in older persons, and the incidence of the disease is expected to increase in this group. Treatments designed to address the special needs of this population are critical. This is particularly challenging because older patients represent a diverse group with variable comorbid diseases and physiologic ages. The data suggest that subgroups of elderly patients can benefit from treatment-even aggressive treatment-with acceptable toxicity. However, the evaluation of promising therapies should continue, with comprehensive analyses of patient selection, efficacy, toxicity, and quality of life.

Older patients are ideal candidates for the evaluation of modern treatment modalities including minimally invasive surgery, 3D conformal radiotherapy, and biologically targeted therapies-all of which are designed to be effective with minimal toxicity. Thus, more clinical trials are likely to be available for older patients. We strongly urge patients and physicians to support this important effort.

This article is part of an ongoing series on Cancer in the Older Patient, which is guest edited by B.J. Kennedy, MD, MACP, Regents’ Professor of Medicine, Emeritus, at the University of Minnesota Medical School, Minneapolis.

Financial Disclosure:The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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