Prognostic Factors and Treatment Patterns
Several studies have evaluated the role of prognostic factors for survival and response to chemotherapy for patients with NSCLC. The Southwest Oncology Group reviewed the clinical course of 2,531 patients with extensive-stage NSCLC and determined that aged 70 years and older was a favorable prognostic factor. Other favorable prognostic factors were good performance status, female sex, and receipt of cisplatin-based therapy.20 The Eastern Cooperative Oncology Group (ECOG) analyzed data from 893 patients with metastatic NSCLC with good performance status enrolled in Phase III combination chemotherapy trials. The pretreatment characteristics that distinguished patients who survived more than one year were initial performance status of 0, no bone metastases, female sex, no subcutaneous metastases, non-large cell histology, less than 5% previous weight loss, no symptoms of shoulder or arm pain, and no liver metastases. Age was not a significant prognostic factor.21 The relative importance of 77 prognostic factors, including age, were reviewed in a study of 5,000 patients with inoperable lung cancer entered in Veteran Administration Lung Group protocols. The most important prognostic factors for survival were performance status, extent of disease, and weight loss in the past six months.22 The European Lung Cancer Working Party analyzed the role of age as a prognostic factor for response to chemotherapy. Data from 1,052 patients with unresectable NSCLC treated with cisplatin- or carboplatin-based chemotherapy showed that increased age was associated with a significantly greater response to chemotherapy in both univariate and multivariate analyses.23
These studies indicate that age is not a poor prognostic factor for overall survival or response to treatment for patients with NSCLC and that treatment decisions should be based on performance status rather than age. Despite these findings, there is a pattern of undertreatment of older patients. Older patients are less likely to receive surgery for localized disease (80.2% younger than 65 years versus 54.8% aged 65 years and older).24 There is a 65% decrease in the likelihood of receiving surgery for locoregional disease with each decade of life after 65.25 Older patients are less likely to receive chemotherapy for metastatic disease (19% younger than 65 versus 5% aged 65 and older).24 Patients who are 65 years and older are more likely to receive no treatment compared with younger patients (29% younger than 65 versus 12% aged 65 and older). Below we describe the data supporting the efficacy and risk for toxicity of each of these treatment options for older patients.
Surgery remains the mainstay of treatment for patients with Stages I to III NSCLC. The five-year survival rate for patients with Stage I NSCLC is better than 60%.26 In the older patient, decisions regarding surgical treatment involve an assessment of the patient's life expectancy (Table 4). 27 Because the life expectancy from untreated NSCLC is so poor, every effort should be made to allow for curative surgery if possible.
Table TABLE 4. Life Expectancy by Age
Curative resection is feasible in older patients.28,29 In a study of octogenarians undergoing curative treatment for lung cancer, in which most were treated with standard lobectomy, the complication rates were 3.7% perioperative death, 11% major complications, and 42% nonfatal complications. The survival rates for patients with Stage I disease were 86% at one year, 62% at three years, and 43% at five years.29 Yamamoto, et al.30 analyzed the surgical results of 797 patients with Stage I NSCLC. Patients aged 70 and older (n = 132) had similar five- and 10-year survival rates compared with patients younger than 70 years (P = .35).
In a study of prognostic factors predicting outcome for patients who underwent surgical resection for Stages I and II NSCLC, older age (defined as 65 years or more), anemia, and higher stage were independent prognostic factors for survival. Patients older than 65 had a shorter event-free survival time (34 versus 55 months, P = .002) and overall survival (39 versus 58 months, P = .002) compared with younger patients.31
The difference in five-year survival rate in older and younger patients may be secondary to comorbid (coexisting) illnesses other than lung cancer. For example, van Rens, et al.32 analyzed the records of 2,361 patients who underwent pulmonary resection for Stages I, II, and IIA NSCLC. The overall five-year survival rate for patients younger than 65 was 44% compared with 38% for older patients (P < 0.001); however, the authors note that survival rates were similar for as long as four years after surgery, and thus the five-year survival rate difference may be secondary to comorbid disease.
The challenge of surgical treatment for older patients is the age-related physiologic changes in the cardiovascular and respiratory systems that may effect tolerance to surgery. Age-related cardiovascular changes include a decrease in cardiac output, decrease in maximal heart rate, prolonged recovery after exertion, and a decreased response to catecholamines during times of stress. Age-related pulmonary changes include a decreased response to hypoxemia or hypercapnia, decreased elasticity of the lung tissue, increased ventilation-perfusion mismatch, and decreased forced expiratory volume.33 In addition, other comorbid medical conditions can contribute to this risk. In a study of 3,864 patients with lung cancer, the most frequent concomitant diseases included cardiovascular disease and chronic obstructive pulmonary disease.34 Therefore a careful preoperative evaluation, guided by the patient's internist or geriatrician, can be valuable to the surgeon. In addition, close postoperative monitoring and aggressive pulmonary toilet is essential. Specific consultation by a pulmonary physician and care in a specialized treatment unit should also be considered for older patients and those at higher risk.
The risks from surgical treatment can also be minimized with the selection of the surgical procedure performed. For example, patients undergoing a lobectomy or wedge resection will be at lower risk for postoperative complications compared with patients undergoing pneumonectomy. In a study of patients 70 years and older, 78.5% of patients receiving pneumonectomy experienced a postoperative complication compared with 58% of patients undergoing lobectomy or wedge resection. All cases of postoperative death occurred in patients undergoing pneumonectomy. Prognostic factors predictive of the risk for postoperative complications in the patients receiving pneumonectomy were poor performance status (WHO 2 or more), chronic obstructive pulmonary disease, and elevated levels of blood urea nitrogen.35
The volume of procedures performed at a hospital can also influence survival rate and the risk for postoperative complications. Bach, et al.36 performed a population-based study of 2,118 patients 65 years and older who underwent surgical resection for lung cancer, to estimate the extent that the volume of procedures performed at the hospital influenced mortality and postoperative complication rates. Patients who underwent the procedure at hospitals with the highest volume had better five-year survival rates (44% versus 33%), lower postoperative complication rates (20% versus 44%), and lower 30-day mortality rates (3% versus 6%) compared with patients who underwent operations at hospitals with the lowest volume.
In summary, surgery remains the mainstay of treatment for early-stage disease for both older and younger patients. Cure is uncommon in persons with lung cancer who do not undergo surgical resection. The risk of postoperative complications in the older patient can be minimized through the selection of the surgical procedure performed, as well as consideration of the volume of procedures performed at the hospital. In addition, careful preoperative evaluation and aggressive and specialized postoperative care are needed, taking into account the physiologic changes that occur with aging. This argues for close collaboration among the patient's surgeon, internist or geriatrician, cardiologist, and pulmonologist. Additional studies reporting prognostic factors that influence the outcome of surgical procedures in the older patient are needed to develop interventions to optimize surgical outcomes and minimize risks. The increasing use of minimally invasive surgery has the potential to further diminish the morbidity and mortality from thoracic surgery in all age groups.
Radiation therapy is used for cure and palliation. The proportion of patients who receive radiation decreases with increasing age. Among patients who receive treatment, the likelihood of receiving radiation is higher than any other therapy (P < .0008).25 In a study of treatment patterns for 1,706 patients with NSCLC, patients 65 years and older were more than twice as likely than younger patients to receive radiation for local disease (14% of patients younger than 65 versus 31% of patients 65 and older).24
Radiation can be given for curative intent for patients with early-stage lung cancer who are not surgical candidates; however, the survival rates are lower than those reported after surgery. Gauden and Tripcony37 performed a retrospective review of patients with Stage I NSCLC (median age, 70 years; age range, 34–90 years) who received radiation therapy with curative intent for the treatment of T1 and T2N0M0 tumors. Surgery was withheld because of older age, poor performance status, or patient refusal. This study revealed similar overall survival and recurrence-free survival rates in older and younger patients, with a trend for older patients to fare better. For patients who were 70 years and older, the overall survival rate at five years was 34% and the median survival time was 26 months. In addition, age did not adversely influence the tolerability or delivery of the radiation.37
Additional studies have shown that treatment tolerance and efficacy of thoracic radiation is similar in younger and older patients.38 In a study of 1,208 patients who received thoracic irradiation, there was no significant difference in survival rate between patients younger than 65, aged 65 to 70, and older than 70 years (P = .82). Age had no effect on acute or late radiation toxicity, including nausea, dyspnea, esophagitis, or weakness. Older patients, however, were more likely to experience weight loss than were younger patients (P = .002).38 Weight loss has been found to be an independent predictor of death in older community-dwelling adults, and thus close attention should be paid to nutritional status in older patients who receive radiation.15
Radiation is frequently used for palliation of lung cancer-related symptoms. In particular, radiation can palliate thoracic pain and hemoptysis in 60% to 80% of cases and control other local symptoms in approximately 50% to 70% of cases. The median duration of benefit is 7 to 14 weeks. The main toxicity is esophagitis, which is self-limiting.39
Concurrent Versus Sequential Chemotherapy and Thoracic Irradiation
The role of concurrent versus sequential chemotherapy and thoracic radiation for older patients with locally advanced NSCLC was analyzed in Radiation Therapy Oncology Group 94–10, a Phase III trial comparing concurrent cisplatin-based chemotherapy and thoracic radiotherapy (given once or twice daily [hyperfractionated]) versus sequential chemotherapy and radiotherapy (Table 5). Data were analyzed by age (younger than 70, n = 488; 70 years and older, n = 104), revealing that older patients had a survival benefit for concurrent chemotherapy and radiation compared with sequential treatment. The risks for Grade ≥3 neutropenia and Grade ≥4 toxicities were increased in the older patient, but there was no difference in long-term toxicity. Grade ≥4 toxicities occurred in most older patients regardless of the treatment, but they were most common with the concurrent daily chemotherapy and radiation schedule.40
Table TABLE 5. RTOG 94-10: Concurrent Versus Sequential Chemotherapy and Radiation for Locally Advanced Non-Small Cell Lung Cancer
|Grade ≥ 4|| || || || || || |
| Toxicity (%)||57||63||38||68||75||55|
|Grade ≥ 3 Neutropenia|| || || || || || |
The Intergroup performed a Phase III trial of sequential chemotherapy (cisplatin, vinblastine) and radiation versus standard radiation or hyperfractionated radiation for the treatment of surgically unresectable Stages II, IIIA, and IIIB lung cancer. When the results were examined by age, patients younger than 60 years had superior survival rates with sequential chemotherapy and radiation (15 months sequential treatment, 12 months radiation therapy alone, and 12 months for hyperfractionated radiation). In contrast, patients older than 70 had superior survival rates with radiation therapy alone (13 months for radiation therapy alone; 11 months for sequential treatment). All deaths from toxicity of chemotherapy occurred in patients older than 70. Of note, only patients with good performance status (Karnofsky performance status [KPS] ≥70) were included in the study.41
Pooled data from six prospective Phase II or III Radiation Therapy Oncology Group studies of patients with locally advanced lung cancer were analyzed with respect to age. Data were included for 979 patients with Stages II to IIIB inoperable NSCLC who received one of six treatment regimens of either concurrent chemoradiation or radiation therapy alone. This study examined the effect of age and quality-adjusted survival scores in patients receiving combined therapy compared with radiation therapy alone. Quality-adjusted survival scores were calculated, taking into account tumor progression and weighing the length of time spent with toxicity from treatment. Patients younger than 60 had improvement in survival rate and quality-adjusted survival scores with chemotherapy and radiotherapy compared with radiation therapy alone. Patients 60 to 70 years old had a trend toward improved outcome with combined therapy. Patients older than 70 achieved the best quality-adjusted survival rate with radiation alone. For patients receiving concurrent chemoradiation, lung and upper gastrointestinal toxicities had the greatest effect on quality-adjusted survival.42
In summary, radiation therapy can be given with curative or palliative intent to older patients with lung cancer. For patients with early-stage lung cancer who are not surgical candidates in whom radiation is given with curative intent, survival rate statistics are inferior to those seen with surgery. In locally advanced lung cancer, the data suggest that although a survival rate benefit was shown with concurrent chemotherapy and thoracic radiation in the population at large, there is a significant risk for short-term toxicities in older patients who receive this treatment, which may outweigh the benefits in this subgroup. Radiation alone may represent the best choice for many older persons when both toxicity and survival rate are weighed. Therefore, these older patients would best benefit from enrollment in a clinical trial that focuses on the means for maximizing efficacy and ameliorating toxicities in older patients. For both younger and older patients with incurable disease, radiation is an effective palliative treatment for lung cancer symptoms.
There is no curative treatment for patients with Stage IV NSCLC. The goals of chemotherapy are to treat symptoms of the disease and lengthen survival time. In a meta-analysis of trials of chemotherapy, treatment with a cisplatin-based regimen lead to a reduced risk for death by 27% and improvement in one-year survival rate by 10% (95% CI, 5%-15%) compared with outcomes in similarly fit patients randomized to receive best supportive care.43 Subgroup analysis revealed no difference in benefit by age or performance status (KPS ≥60%); however, most (78%) patients included in clinical trials were younger than 65 years and patients with KPS ≤50% were not included. The hazard ratio for death for the subgroup of patients 65 and older was 0.87, although this number was based on only 120 patients.44 A similar magnitude of benefit was seen in a retrospective review of 6,232 patients older than 65 from the Survival, Epidemiology, and End Results tumor registry. In this cohort of older patients with Stage IV NSCLC, treatment with chemotherapy increased one-year survival rate by 9%.44
Single-Agent Chemotherapy Versus Best Supportive Care
Given the survival rate benefit from cisplatin-based combination chemotherapy and the risk for increased toxicity in older patients, the question of whether single-agent chemotherapy would lead to improved quality of life or a survival rate benefit in older persons was explored. The Phase III Elderly Lung Cancer Vinorelbine Italian Group Study (ELVIS) trial evaluated the efficacy of single-agent chemotherapy compared with best supportive care in older persons with Stage IIIB or IV NSCLC (Table 6). In this study, patients 70 years and older with ECOG performance status of 0 to 2 were randomized to receive best supportive care or 30 mg/m2 vinorelbine, given on days 1 and 8 of a 21-day cycle for a maximum of six cycles. The study was suspended after 154 assessable patients were enrolled because of poor accrual. Patients treated with vinorelbine had improved quality of life (the primary endpoint of the study) and lengthened one-year survival rate from 14% with best supportive care to 32%. The relative risk for death in patients treated with vinorelbine was 0.65 (95% CI, 0.45–0.93).45
Table TABLE 6. Phase III Randomized Controlled Trials in Patients With Stage IIIB or IV Non-Small Cell Lung Cancer
|ELVIS||Stage IIIB or IV Age ≥ 70 years||Vinorelbine||20||28|
| ||Best supportive care||NA||21|
| ||n = 154 patients|| || || |
|MILES||Stage IIIB or IV Age ≥ 70 years||Vinorelbine||18||36|
| ||n = 698 patients||Vinorelbine and gemcitabine||21||30|
|SICOG||Stage IIIB or IV Age ≥ 70 years||Vinorelbine||15||18|
| ||Vinorelbine and gemcitabine||22||29|
| ||n = 120 patients|| || |
The ELVIS trial was the first Phase III study that established the benefit of single-agent vinorelbine compared with best supportive care in older persons with NSCLC. Several Phase II studies have focused on the efficacy and toxicity profiles of other single agents in the treatment of older persons with NSCLC, including gemcitabine, docetaxel, or paclitaxel. Table 7 summarizes the results of selected trials.46–48
Table TABLE 7. Selected Phase II Studies of Single-Agent Chemotherapy for Older Patients With Stage IIIB/IV Non-Small Cell Lung Cancer
|Ricci, et al.46||Gemcitabine, 1,000 mg/m2 (3 weeks on, 1 week off)||44||0–2||75 (70–81)||22||6.8|
|McKay, et al.47||Docetaxel, 36 mg/m2 (6 weeks on, 2 weeks off)||36||0–2||71 (55–82)||19||5|
|Fidias, et al.48||Paclitaxel, 90 mg/m2 (6 weeks on, 2 weeks off)||35||0–3||76 (70–85)||23||10.3|
Single-Agent Versus Combination Chemotherapy
Building on the results of the ELVIS Trial, the next set of Phase III trials sought to determine whether there was a benefit of combination chemotherapy compared with single-agent chemotherapy in older patients with NSCLC (Table 6). The Multicenter Italian Lung Cancer in the Elderly (MILES) trial included patients 70 years and older with Stage IIIB or IV NSCLC randomized to receive treatment with vinorelbine (30 mg/m2), gemcitabine (1,200 mg/m2), or vinorelbine (25 mg/m2) plus gemcitabine (1,000 mg/m2) given on days one and eight of a 21-day cycle for a maximum of six cycles. Six hundred ninety-eight patients were included. The investigators found no difference in response rates or survival rate for older patients with NSCLC who received combination chemotherapy with gemcitabine-vinorelbine compared with vinorelbine alone or gemcitabine alone. Quality of life was similar for the combination versus single-agent therapy; however, toxicity was greater for patients who receive combination chemotherapy.49
The Southern Italian Cooperative Oncology Group (SICOG) trial was a Phase III trial of 120 patients 70 years and older with Stage IIIB or IV NSCLC randomized to receive treatment with gemcitabine (1,200 mg/m2) plus vinorelbine (30 mg/m2) versus vinorelbine (30 mg/m2) alone, with treatment given on days one and eight every three weeks for a maximum of six cycles (Table 6). At a median follow-up of 14 months (range, 3–22 months), patients treated with combination chemotherapy had an improved one-year survival rate (30% for gemcitabine plus vinorelbine versus 13% for vinorelbine alone). In addition, patients who received combination chemotherapy had improved symptom control, with a higher probability of being alive without symptomatic deterioration at six months (43% for gemcitabine plus vinorelbine versus 22% for vinorelbine). Patients with a higher comorbidity score or poor performance status were more likely to have an early withdrawal from treatment.50
The results of the MILES and SICOG trials yielded different conclusions regarding the benefits of combination chemotherapy. A possible reason for the discrepancy is that patients in the vinorelbine-alone arm of the SICOG trial had poorer than expected median and one-year survival rates. In fact, the results for the vinorelbine group in the SICOG trial were similar to those reported for the best supportive care group in the ELVIS trial. Differences between the two trials include that the sample size in the MILES trial was larger than that in the SICOG trial (698 versus 120 patients), making the results of the MILES trial more robust. In addition, the dosing between the two trials varied in that higher doses of gemcitabine and vinorelbine were given in the combination arm of the SICOG trial. Based on the conflicting results of these Phase III trials, the benefit of single-agent versus combination chemotherapy in the older patient is an area that needs additional study.
The role of cisplatin-based combination therapy in the treatment of older patients with NSCLC is another area of controversy. Patients participating in ECOG 5592 received one of three cisplatin-based combination regimens, consisting of cisplatin in combination with etoposide, high-dose infusional paclitaxel, or low-dose infusional paclitaxel (Table 8). Of the 574 patients enrolled on the trial, 86 (15%) were 70 years or older. Only two patients were older than 80. All patients had an ECOG performance status of 0 to1. When the results were stratified by age (younger than 70 versus 70 years and older), there was no significant difference in response rates (P = .67) or survival rate (P = .29). Toxicity between the two groups were similar except that older men were more likely to experience Grade 4 leukopenia than were their younger counterparts (42% versus 17%; P < .001) and had a higher incidence of neuropsychiatric effects. Older women were more likely to experience weight loss of 10% of their body weight than were younger women (33% older women versus 17% younger women; P = .006). When analyzing the small subgroup of patients who were older than 75 (n = 24) compared with those aged 70 to 75 years (n = 62), there were no significant differences other than a borderline increase in the risk for neutropenia (P = .06).51
Table TABLE 8. ECOG 5592: Cisplatin-Based Therapy: Response and Survival by Age
|Response Rate (%)||22||23|
|Median Survival (months)||9.1||8.5|
|One-Year Survival Rate (%)||37.7||29.1|
Other studies have suggested that a cisplatin-based combination may be too toxic for an older patient. In an analysis of the Southwest Oncology Trials 9509 (which compared paclitaxel plus carboplatin to vinorelbine plus cisplatin) and 9308 (which compared vinorelbine plus cisplatin to cisplatin alone), 46% of patients aged 70 and older who received vinorelbine plus cisplatin discontinued treatment secondary to toxicity compared with 16% of patients who received paclitaxel plus carboplatin.52 Of note, only 19% of patients in these clinical trials were 70 years or older.
The substitution of carboplatin for cisplatin may help to ameliorate toxicity. A retrospective review of a Phase III trial of carboplatin and paclitaxel revealed similar response and survival rates and toxicity patterns for patients younger than 70 years compared with those 70 years and older.53 A study from the Cancer and Leukemia Group B, presented in 2002 by Lilenbaum and colleagues54 demonstrated a survival rate benefit to combination chemotherapy with carboplatin and paclitaxel compared with paclitaxel alone for patients with Stage IIIB or IV NSCLC. A subgroup analysis of patients older than 70 also revealed a benefit to combination chemotherapy, although this was not statistically significant. A randomized study powered to answer this question specifically in older patients would be appropriate.
These studies demonstrate several important points. First, patients aged 70 to 79 years who have good performance status may benefit from a cisplatin-based regimen to the same extent as younger patients. Second, older patients will be at increased risk for certain toxicities, including an increased risk for neutropenia. This is consistent with the observation that hematopoietic reserve decreases with age and the empiric use of growth factors should be considered to ameliorate this toxicity. Third, older patients are at increased risk for significant weight loss. Therefore, a close evaluation of the nutritional status of older patients is important. Finally, too few patients older than 80 years were included in these studies to make any conclusions regarding this age group. Additional studies specifically focusing on patients aged 80 and older or those with poorer performance status are needed. A randomized study of a cisplatin versus noncisplatin combination for older patients would provide valuable information about the optimal treatment in persons in this age group.
In May 2003, the Food and Drug Administration approved the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa; ZD1839), for patients with advanced NSCLC with disease progression or intolerance to cisplatin or carboplatin and docetaxel based on two Phase II trials that showed symptom improvement and radiographic regressions. This once-daily oral tablet was developed to block the tyrosine kinase component of the epidermal growth factor receptor and thereby block signaling modulated by the pathway. Most NSCLCs tested have shown that the epidermal growth factor receptor protein is either expressed or overexpressed.
For the recommended 250-mg dosage, radiographic response rates were 18% and 12%, symptomatic benefits were seen in 40% and 43% of patients, and one-year survival rate was 35% and 27%. In both trials, there was no difference in the rates of symptomatic or radiographic response or toxicity when younger and older patients were compared.55,56
Unlike chemotherapy, there also appears to be no difference in the incidence of adverse effects when any age groups were compared. The availability of this agent offers a new approach to patients with NSCLC. This agent appears to be most effective in women, never smokers, and those with bronchoalveolar histology.