Treatment of Advanced Non–Small-Cell Lung Cancer in the Elderly: Results of an International Expert Panel
Publication: Journal of Clinical Oncology
Abstract
The best treatment for elderly patients with advanced non–small-cell lung cancer (NSCLC) is still debated. To guide clinical management of these patients and suggest the priorities for clinical research in this field, an International Expert Panel met in Naples, Italy, on April 19 to 20, 2004. Results and conclusions based on a review of evidence available in the literature to date are presented in this article. A comprehensive geriatric assessment is recommended to better define prognosis and to predict tolerance to treatment. In the first randomized study dedicated to elderly NSCLC patients, single-agent vinorelbine showed superiority over supportive care alone, both in terms of survival and quality of life. In a large randomized trial, gemcitabine plus vinorelbine failed to show any advantage over either agent alone. Subset analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with an acceptable increase in toxicity for elderly patients. These data should be interpreted cautiously because retrospective subgroup analyses are encumbered by selection bias; hence, randomized trials dedicated to platinum-based chemotherapy for nonselected elderly patients are warranted. Several promising biologic therapies are under investigation; however, with present data, target-based agents as first-line treatment for elderly NSCLC patients are not yet recommended. Clinical research, with trials specifically designed for elderly patients, is mandatory. With the current evidence, single-agent chemotherapy with a third-generation drug (vinorelbine, gemcitabine, a taxane) should be the recommended option for nonselected elderly patients with advanced NSCLC. Platinum-based chemotherapy is a viable option for fit patients with adequate organ function. Best supportive care remains important, in addition to chemotherapy or as the exclusive option for patients who are unsuitable for more aggressive treatment.
Introduction
Lung cancer is the most common cancer in the world and the leading cause of cancer-related deaths in Western countries1. Non–small-cell lung cancer (NSCLC), including squamous carcinoma, adenocarcinoma, and large-cell carcinoma, represents approximately 80% to 85% of all lung cancers. Unfortunately, at the time of diagnosis, the majority of patients already have metastatic disease and a systemic, palliative treatment is the only therapeutic option.
More than 50% of cases of advanced NSCLC are diagnosed in patients older than age 65 years, and approximately 30% to 40% of cases are diagnosed in patients older than age 70 years.2,3 Surveillance, Epidemiology, and End Results data in the United States suggest that 69 years is the median age at diagnosis.4 With the aging of the population one may expect that the prevalence of lung cancer among the elderly will increase. Of special interest, during the last decade the incidence and the mortality from lung cancer has decreased among individuals age 50 and younger, but has increased among those age 70 and older.5 Clearly, NSCLC in the older person is an increasingly common problem faced by the practitioner of oncology.
Elderly patients often present with medical and physiologic characteristics6,7 that make the selection of their optimal treatment more challenging. Unfortunately, because of this, these patients are at risk of being undertreated.8 Aging objectively determines physiologic changes in functional status, organ function, and drug pharmacokinetics. Furthermore, concomitant diseases, which may significantly affect functional status, general health, and tumor symptoms, are frequently present in this patient population.9 These comorbidities may also result in higher prevalence of polypharmacy and related risks.10 Last but not least, the biology of lung cancer may also change with age and become more indolent.11
Oncologists must choose among several treatment options for elderly patients with advanced NSCLC: best supportive care without chemotherapy, single-agent chemotherapy with a third-generation drug, non–platinum-based combination chemotherapy, platinum-based combination chemotherapy, or new biologic agents.
With the aims of reviewing the evidence supporting each of these therapeutic options for treatment of elderly patients affected by advanced NSCLC in clinical practice, and suggesting the priorities for clinical research in this field, an international expert panel met in Naples, Italy. Results and conclusions of that meeting are presented in this article.
Search Strategy and Selection Criteria
The International Expert Panel on the Treatment of Advanced NSCLC in the Elderly was held in Naples, Italy, on April 19 to 20, 2004. Twelve oncologists from five European countries (France, Germany, Italy, Spain, and Switzerland), Canada, and the United States, with clinical and research experience in NSCLC, formed the scientific panel of the meeting.
Published data useful for this panel and review were identified by a search in PubMed. The search was performed with combinations of the following search terms: chemotherapy, treatment, elderly, and non–small-cell lung cancer. Only articles published in English between 1990 and 2004 were considered.
Abstracts presented at the meetings of the American Society of Clinical Oncology between 1995 and 2004 (available online at http://www.asco.org/ac/1,1003,_12-002629-00_18-0012014,00.asp) were also searched for the same terms. In addition, abstracts presented in the same years at the meetings of the International Association for Study of Lung Cancer, European Society of Medical Oncology, and European Conference of Clinical Oncology were searched. Important references from relevant articles were also included, and other articles were selected from the personal collections of the authors.
Available Evidence and Methodologic Considerations
Despite universal recognition of the importance of clinical research to inform clinical practice and to guide therapeutic decisions, it has been reported repeatedly that elderly patients are largely under-represented in cancer treatment trials.12-15 Lung cancer is no exception to this observation; on the contrary, data show that it can be considered the paradigm of elderly under-representation in clinical research. A major survey analyzed clinical trials conducted by the Southwest Oncology Group between 1993 and 1996, comparing the proportion of elderly patients enrolled onto that group’s trials with the proportion of elderly people diagnosed with cancer in the general population.13 Only 39% of the patients enrolled onto lung cancer trials were older than age 65, compared with 66% of the overall cancer patient population. A similar analysis of cancer treatment trials sponsored by the National Cancer Institute demonstrated that this problem had not decreased in the following years (42% of patients enrolled onto clinical trials for advanced NSCLC in the period from 1997 to 2000 were elderly v 70% in the general population).14 To confirm these data, a survey analyzing trials for cancer drug registration conducted during 7 years (from 1995 to 2002) showed a great disparity between percentages of elderly patients in the general population and those enrolled onto clinical trials for lung cancer: 67% v 35%, respectively.15 Under-representation was particularly notable for patients older than 75 years.
This phenomenon can significantly affect the generalizability of trial results that depend largely on whether participants enrolled onto clinical trials are fully representative of the entire spectrum of patients suffering from that disease.
There is no doubt that one of the factors determining the limited enrollment of elderly patients onto clinical trials is the presence of restrictions in the inclusion and exclusion criteria.14 In addition to chronologic age, the presence of comorbidities and age-related changes in organ function (eg, creatinine clearance) excludes a significant proportion of elderly patients at the time of their evaluation for enrollment onto many trials. It has been demonstrated that relaxed exclusion criteria (ie, not excluding patients with cardiac or pulmonary dysfunction, hypertension, low hematologic values, or impaired performance status [PS]) might result in the proportion of elderly patients in clinical trials approaching that of the general population.14 However, such relaxed exclusion criteria could be considered only when testing experimental treatments expected to produce little toxicity, which is unlikely to be the usual case for trials of chemotherapy.
The evidence regarding the tolerability and efficacy of anticancer treatments for elderly patients affected by NSCLC comes from two different types of publications: prospective clinical trials specifically designed for the elderly and retrospective analyses conducted on the subgroup of elderly patients enrolled onto clinical trials that did not have an upper age limit. For the latter type of studies, it is easy to argue that when a clinical trial is designed to test the efficacy of a treatment intended for younger patients, only a selected proportion of elderly patients will be considered for enrollment, and so the results may not necessarily extend to the general nonselected elderly population.16
Advanced Age Should Not Constitute A Contraindication to Treatment
Several studies (or retrospective reviews) have demonstrated that age is not a poor prognostic factor for overall survival in advanced NSCLC.17-19 The largest study analyzed the prognostic role of 77 variables, including age, of 5,000 patients with inoperable lung cancer.19 Age showed no impact on survival, whereas the most important prognostic factors for survival were PS, extent of disease, and weight loss in the last 6 months. Despite these observations, chronologic age has often been considered in NSCLC (as in other tumors) as an absolute or relative contraindication to treatment. Several surveys conducted in the 1980s and 1990s described the influence of age on treatment choices for advanced NSCLC and showed that elderly patients were less likely to receive active treatments.20-23 Earle et al24 studied 6,308 patients older than 65 years who were diagnosed with stage IV NSCLC and found that only 21.5% of patients received chemotherapy at any time, and that increasing age was significantly associated with a lower likelihood of receiving chemotherapy.
In the United States, these trends are reflected at least partially in mortality figures. Although lung cancer mortality declined between 1980 and 1996 in patients younger than 65 years, it continued to increase in elderly patients—more than 10% in those between age 75 and 85, and nearly 50% in those older than age 85 years.5
In more recent years, since the demonstration of chemotherapy efficacy in elderly patients25,26 and the introduction of better tolerated drugs, this nihilistic approach to treatment of elderly patients has waned in many parts of the world. During the conduct of the Elderly Lung Cancer Vinorelbine Italian Study (1996 to 1997), which randomly assigned patients to chemotherapy or to best supportive care, accrual progressively decreased.27 As investigators became convinced of the efficacy and tolerability of chemotherapy in the elderly, they became reluctant to subject their patients to the risk of being assigned to the no-chemotherapy arm.
Elderly patients have positive attitudes toward chemotherapy, although this may be motivated by higher than realistic expectations of benefits.28 However, bearing in mind the limited results realistically obtainable with currently available treatments, the patient’s point of view is important, and a careful patient-physician communication should precede the choice of treatment strategy.
Patients may select active treatment especially if symptomatic improvement can be obtained. When patients with advanced NSCLC who had already experienced a cisplatin-based chemotherapy were asked about the benefit thresholds to accept chemotherapy, only 22% would have chosen chemotherapy over best supportive care when a 3-month improvement in survival was hypothesized and there was no expectation of symptom benefit. In contrast, a much larger proportion (68%) would have chosen chemotherapy if it significantly reduced symptoms, even if it did not prolong survival.29
The Role of Clinical Evaluation of Elderly Patients
Elderly patients with advanced NSCLC represent a heterogeneous population. A corollary of the notion that chronologic age itself should not preclude appropriate treatment is that each patient should undergo a comprehensive, multidimensional assessment, with the aim of better defining prognosis, predicting tolerability to treatment, and selecting the most appropriate management.
For advanced NSCLC, the basic question is whether the therapeutic index of chemotherapy (ie, the ratio between benefits and risks) is favorable. Age is associated with a progressive decline in the functional reserve of multiple organ systems that may alter drug pharmacokinetics and enhance the vulnerability of normal tissues to the toxicity of chemotherapy.6,30,31 The most common pharmacokinetic changes include reduced renal excretion of drugs and their toxic metabolites, reduced volume of distribution of hydrosoluble agents, and possibly reduced intestinal absorption. The organs more susceptible to toxicity include the hematopoietic system, the heart, the central and peripheral nervous systems, and the mucous membranes.
Some guidelines intended to minimize the toxicity of chemotherapy in elderly patients were issued by the National Comprehensive Cancer Network and include geriatric assessment for individuals age ≥ 70; dose adjustment of chemotherapy to the renal function for individuals age ≥ 65; prophylactic use of filgrastim or pegfilgrastim in patients age ≥ 65 receiving chemotherapy of dose-intensity comparable to that of cyclophosphamide, doxorubicin, vincristine, and prednisone; maintenance of hemoglobin levels more than 12 g/dL; and preferential use of chemotherapy agents of low toxicity.32 Patient selection is essential because the presence of serious comorbid conditions or serious risk factors for chemotherapy may render the management of metastatic NSCLC futile or too risky.
A comprehensive geriatric assessment (CGA) with proper and validated instruments should evaluate functional status, comorbidities, socioeconomic issues, nutritional status, polypharmacy, and the presence of geriatric syndromes (Table 1). The aims of a CGA are to recognize potentially treatable conditions (such as depression or malnutrition) that may otherwise decrease the tolerability to cancer treatment, to assess individual functional reserve, and to estimate individual life expectancy. The adoption of a common language to classify older cancer patients in clinical practice is strongly recommended but has not yet entered standard oncologic practice.31 CGA has been demonstrated to add substantial information with respect to the functional assessment of elderly cancer patients,33 allowing important prognostic discrimination even among patients characterized by a good PS.
The CGA may be too lengthy for a busy clinical practice. Therefore, a number of screening instruments have been developed to select those older patients who may benefit from a full CGA. Of these, the evaluation proposed by the Cardiovascular Health Study, which allows the classification of elderly patients into three groups (fit, prefrail, frail) according to five items (unintentional weight loss, self-reported exhaustion, weakness, walking speed, and level of physical activity),34 has gained particular prominence because it is well correlated with mortality and risk of functional dependence. This classification has been proposed as a standard language for the classification of older individuals. Another simple screening instrument is the Vulnerable Elderly Survey 13, which includes 13 simple questions. The answers are scored and patients whose total score is four or higher may benefit from a full CGA.35
Instruments of this type34-36 represent useful tools to guide clinical management of elderly patients, and the International Society for Geriatric Oncology has instituted a task force to evaluate such instruments and validate their use in oncology, not only for risk definition but also for possible prediction of adequate drug dosage.
In addition, patients’ self-reported quality of life (QoL) evaluation can add significant prognostic information. When the prognostic role of the baseline QoL (as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [QLQ] C30 global QoL score) was evaluated in elderly patients diagnosed with NSCLC, QoL score was a strong and independent prognostic factor for survival in patients undergoing first-line treatment for their NSCLC.37 These results also confirm in elderly patients the strong prognostic role of self-assessed QoL in patients with advanced lung cancer,38 and show that a simple, self-reported questionnaire may add useful information to the baseline evaluation of the patient.
The discussion of geriatric assessment begs the question: who are the elderly? That is, who are those individuals who may benefit most from this special evaluation? Although we prefer to think of age in functional rather than chronologic terms, it is reasonable to consider age 70 as the threshold of senescence30 because this age generally heralds an increased incidence of age-related changes, including functional decline, comorbidities, geriatric syndromes, and limited socioeconomic resources.
Evidence On Treatment
Role of Single-Agent Chemotherapy in Elderly Patients
Single-agent chemotherapy was one of the first approaches to be evaluated in elderly patients with NSCLC (Table 2).
Among the third-generation chemotherapy drugs, the vinca alkaloid vinorelbine has been investigated extensively in elderly NSCLC patients. In phase II trials in elderly patients with advanced NSCLC, objective responses of 5% to 39% and median survival times of 5 to 10 months were achieved.39-43 The toxicity profile was considered to be mild, with low rates of severe hematologic and nonhematologic adverse effects. These promising phase II data prompted additional investigation in randomized phase III trials. The Elderly Lung Cancer Vinorelbine Italian study, a randomized phase III trial, demonstrated the first evidence of the utility of chemotherapy in elderly patients with advanced NSCLC27 (Table 3). Patients older than 70 years were randomly assigned to receive best supportive care alone or best supportive care plus chemotherapy (single-agent vinorelbine 30 mg/m2 on days 1 and 8 every 3 weeks for a maximum of six cycles). The main end point of the study was QoL, and for its assessment the European Organization for Research and Treatment of Cancer core questionnaire QLQ-C30 and lung-cancer–specific module (QLQ-LC13) were used. With 161 patients analyzed, those assigned to the chemotherapy arm had significantly longer survival (28 v 21 weeks; log-rank test P = .03) and a greater chance of survival at 6 months (55% v 41%) and at 1 year (32% v 14%) than those who did not receive chemotherapy. When adjusted by tumor stage and PS, the relative risk of death in the group treated with chemotherapy was 0.65 (95% CI, 0.45 to 0.93; P = .02). QoL analysis showed several significant differences between the two arms related to the adverse effects of chemotherapy and to its benefits in terms of tumor symptoms and functioning scales. As expected, patients receiving chemotherapy reported worse scores for nausea and vomiting, constipation, peripheral neuropathy, and hair loss. However, patients treated in the vinorelbine arm scored better than controls on many subscales including global health status/QoL, several functioning scales (role, cognitive, social, and physical functioning), fatigue, pain, dyspnea, and cough. Recently, an oral formulation of vinorelbine was tested in elderly patients, with acceptable toxicity and comparable overall survival.44,45
Gemcitabine is one of the most widely used drugs for the treatment of NSCLC. Before the conduct of phase II trials specifically dedicated to elderly patients, gemcitabine demonstrated promising activity with good tolerability in several retrospective analyses that showed no significant differences between therapy outcomes in elderly and younger patients subgroups.57-59 More recently, several phase II trials specifically designed for elderly patients with advanced NSCLC have confirmed the role of gemcitabine in this setting. In patients older than age 70 years, gemcitabine yielded overall response rates of 18% to 38% and median survival times of 6.8 to 9 months.46-50 Gemcitabine was generally well tolerated, with only two of these studies showing any grade 3 to 4 hematologic toxicities.
The taxanes (paclitaxel and docetaxel) have demonstrated both activity and tolerability in the treatment of advanced NSCLC.
A recent review of two phase II trials of paclitaxel 210 mg/m2 every 3 weeks compared outcome according to age (< 70 v ≥ 70 years). This study showed no differences in response rate or survival between the age groups but the most frequent toxicity, neutropenia, tended to occur more frequently in the older patient group (89.3% v 73.9% in younger patients).60 In an effort to reduce toxicity, weekly regimens of single-agent paclitaxel have been investigated in three phase II studies resulting in overall response rate and median survival ranging from 3% to 23% and from 6.8 to 10.3 months, respectively, with good tolerability.51-53
Regarding docetaxel, a recent phase I study showed that weekly doses of docetaxel 30 mg/m2 resulted in high rates of myelosuppression in elderly patients with advanced NSCLC, whereas no hematologic toxicity was reported for patients receiving a starting dose of 25 mg/m2.61 A partial response rate of 20% was reported. In contrast, in another phase II trial, weekly doses of docetaxel 36 mg/m2 were well tolerated,54 with only 8% of patients experiencing grade 3 leucopenia and no occurrences of grade 4 myelosuppression; grade 3 to 4 nonhematologic adverse effects were infrequent. Objective responses were achieved in 18%, median survival was 5.0 months, and the 1-year survival rate was 27%. A phase II randomized trial of the two different schedules of administration of docetaxel (weekly or every 3 weeks) in elderly patients or patients with PS 2 and advanced NSCLC confirmed comparable activity and lower hematologic toxicity for the weekly schedule (30 mg/m2).55
Sequential chemotherapy with single agents offers the opportunity to administer several drugs without the negative effects of increased toxicity caused by combination chemotherapy. This approach employing the sequential administration of vinorelbine and docetaxel has been evaluated in both elderly patients and patients with PS 2.62 In the 75 elderly patients with PS 0 or 1, this sequential approach produced encouraging results, with good tolerability, a response rate of 21%, and a median survival of 9 months.
Role of Non–Platinum-Based Third-Generation Combination Chemotherapy in Elderly Patients
Given the good results in terms of activity and tolerability described above with single-agent chemotherapy, non–platinum-based third-generation combinations for elderly patients with advanced NSCLC have been evaluated.
The most studied non–cisplatin-based regimen is that of gemcitabine plus vinorelbine. Phase II trials in elderly patients or patients with poor PS yielded response rates of 18% to 65%, median survival times of 7 to 10 months, and 1-year survival rates of 31% to 37%.49,63-66
Two phase III trials testing the efficacy of this combination in elderly NSCLC patients have been published; both were conducted in Italy (Table 3). The first study by Frasci et al56 compared the combination of vinorelbine and gemcitabine with vinorelbine alone. Patients received vinorelbine 30 mg/m2 days 1 and 8 every 3 weeks, either alone or in combination with gemcitabine 1,200 mg/m2 days 1 and 8. Although the study was designed to enroll 120 patients per arm, an interim analysis conducted on the first 120 patients indicated a significant advantage for the combination regimen. Median survival was 7 months for the combination arm and only 4.5 months for single-agent vinorelbine; 1-year survival rates were 30% and 13%, respectively. Moreover, the combination regimen, although it produced significantly more toxicity, resulted in a clear delay in symptom and QoL deterioration. In view of these results, the study was interrupted after the interim analysis. However, in this study the negative outcome associated with single-agent vinorelbine was not consistent with other trials testing this drug both in unselected adults and in elderly patients,27,67 and was more similar to the outcome frequently described with supportive care alone.27,68
Another much larger Italian trial compared the combination of vinorelbine 25 mg/m2 and gemcitabine 1,000 mg/m2 with either single-agent drug: vinorelbine 30 mg/m2 or gemcitabine 1,200 mg/m2.9 All drugs were administered on days 1 and 8 every 3 weeks, for a maximum of six cycles. At the end of enrollment, 698 patients were analyzed. Their median age was 74 years, and 275 patients (39%) were age ≥ 75 years. Combination chemotherapy proved slightly more toxic, resulting in more thrombocytopenia and hepatic toxicity than single-agent vinorelbine, and more neutropenia, vomiting, fatigue, extravasation sequelae, cardiac toxicity, and constipation than single-agent gemcitabine. Unfortunately, overall survival was not significantly different in the three arms: median survival was 36, 28, and 30 weeks, and the probability of survival at 1-year was 38%, 28%, and 30% for vinorelbine, gemcitabine, and the combination, respectively. Regarding QoL, there were no significant differences in functional or symptoms scales between patients assigned to the combination and those assigned to single-drug treatments.
A recently published phase III study that included elderly patients but also a proportion of younger, unfit patients, has compared a combination of gemcitabine with either paclitaxel or vinorelbine to single-agent chemotherapy with gemcitabine or paclitaxel.69 In this trial, treatment with doublets was significantly associated with a longer survival and acceptable toxicity. The median overall survivals were 5.1, 6.4, 9.2, and 9.7 months for gemcitabine, paclitaxel, gemcitabine/paclitaxel, and gemcitabine/vinorelbine, respectively.
Among other nonplatinum combinations tested in elderly patients, the combination of weekly docetaxel and gemcitabine should be mentioned. This combination was tested in 64 patients considered unsuitable for standard chemotherapy (elderly or poor PS), demonstrating a response rate of 28%, a median survival of 7 months, and a 1-year survival rate of 30%.70 Treatment was well tolerated by most patients, with only 11% grade 3 to 4 leucopenia; no patient required hospitalization for neutropenia/fever.
Role of Platinum Added to Third-Generation Single Agents in Elderly Patients
In a meta-analysis evaluating the efficacy of chemotherapy in patients with NSCLC,25 cisplatin-based chemotherapy resulted in a slight but statistically significant survival advantage over supportive care. Given that platinum-based chemotherapy can also improve QoL and control symptoms, it is currently recommended as the standard approach for patients with advanced NSCLC.71-73
However, to date no prospective phase III study has explored the reproducibility of this benefit in elderly patients. Cisplatin administration is associated with significant hematologic and nonhematologic toxicity (nephrotoxicity, ototoxicity, neurotoxicity) and the evaluation of the risk-versus-benefit ratio should be particularly rigorous in elderly patients. In this patient population, reduction of creatinine clearance and cisplatin renal excretion is expected to increase the potential for toxicity, and the presence of comorbidities and compromised PS may preclude cisplatin administration in a significant proportion of elderly patients.74A retrospective analysis of cisplatin-based chemotherapy in NSCLC patients revealed a significant increase in death rates within 30 days of starting chemotherapy with increasing age (0.5%, 3.3%, 3.2%, 7.1%, and 12.5% for patients ≤ 54, 55 to 59, 60 to 64, 65 to 69, and ≥ 70 years, respectively; P = .0001).75 However, the frequency of renal toxicity after cisplatin administration to elderly patients has been studied by several authors, and with the exception of one study,76 the studies demonstrated an acceptable rate of renal function deterioration without a significant increase in age-related incidence.77-79
These data support the feasibility of administering cisplatin to elderly patients, but the benefit of platinum-based combination chemotherapy (eventually modified in dose and/or schedule) should be proven by clinical trials specifically designed for elderly patients. These studies are still lacking, and evidence to support the use of platinum agents in elderly patients with advanced NSCLC comes only from several retrospective analyses of the subgroup of elderly patients enrolled onto randomized trials without an upper age limit in the inclusion criteria80-87 (Table 4). These analyses show a similar outcome of platinum-based therapy for elderly patients compared with their younger counterparts, in terms of response rate and overall survival, with similar toxicity and no significant adverse effect on QoL (as shown by Eastern Cooperative Oncology Group trial 559282). It is important to note, however, that the percentage of elderly patients enrolled onto these studies with cisplatin did not exceed 20% of the actual study population. In general, little data exist regarding the outcome of chemotherapy in NSCLC patients age ≥ 80 years, a rapidly expanding, potentially vulnerable population cohort. In an age-specific subanalysis of Eastern Cooperative Oncology Group trial 1594, investigators observed only nine patients older than 80 years of age (< 1% of all enrollees). Efficacy in this group was poor: 0% response rate, median progression-free survival of 2.2 months, and median survival of only 4.2 months. These results are comparable to those observed in patients with PS 2.85
Interest in reproducing cisplatin efficacy in elderly patients led to several trials testing the combination of third-generation cytotoxic agents with cisplatin in modified schedules or attenuated doses to obtain an active and well-tolerated treatment. Interesting results were obtained with the combination of cisplatin and gemcitabine,88-90 vinorelbine,91 and docetaxel.92
Compared with cisplatin, carboplatin causes lower rates of emesis, nephrotoxicity, and neurotoxicity, and it represents an appealing alternative for platinum-based chemotherapy, although safety remains a problem, especially in terms of hematologic toxicity, particularly if it is administered in combination with other myelotoxic agents. Analyses of Southwest Oncology Group trials 9509 and 930881 seem to support the higher tolerability of carboplatin versus cisplatin, at least at a dose of 100 mg/m2: 46% of elderly patients who received cisplatin and vinorelbine discontinued chemotherapy because of unacceptable toxicity, and this proportion was significantly higher than the discontinuation rate for toxicity in younger patients. In contrast, only 16% of elderly patients treated with carboplatin and paclitaxel stopped treatment for toxicity reasons, without a significant age-related trend.
A study from the Cancer and Leukemia Group B presented in 200283 demonstrated a potential advantage of combination chemotherapy with carboplatin and paclitaxel over paclitaxel alone for patients with advanced NSCLC. A secondary analysis of the study showed that the survival advantage for the platinum-based doublet was also seen in the subgroup of elderly patients (8 v 5.8 months), although this difference was not statistically significant because of the limited number of elderly patients enrolled.
Additional evidence regarding the outcome of carboplatin-containing chemotherapy in elderly patients can be derived from several subgroup analyses of phase III randomized trials without an upper age limit (Table 4). In addition, several recently published phase II studies of combination chemotherapy based on modified schedules of carboplatin (low-dose or weekly administration) have shown a reasonable level of activity and tolerability.93-96
Randomized phase III trials with adequate power to address the unanswered questions regarding the efficacy and tolerability of platinum-based chemotherapy are needed.
Role of New Targeted Agents
In recent years, the rapidly expanding knowledge of the molecular basis of cancer has provided new targets for drug discovery, and a great number of new anticancer drugs have been developed. Many of these biologic agents are currently in different stages of clinical development for the treatment of advanced NSCLC.
Several features of target-based molecules make these drugs potentially ideal treatment for elderly patients. First, biologic therapies hold the promise of being more selective against tumor and less toxic to normal tissues, both in terms of hematologic and nonhematologic adverse effects. Second, given a cytostatic rather than cytotoxic mechanism of action, these agents are more likely to be effective when they are administered continuously rather than in pulse doses; the oral formulations of many of these compounds are convenient and preferred for continuous-dosing schedules. Gefitinib and erlotinib are orally available selective and reversible inhibitors of tyrosine-kinase activity of the epidermal growth factor receptor. Gefitinib has been recently licensed for third-line treatment of platinum- and docetaxel-refractory advanced NSCLC in several countries, including Japan, Australia, and the United States.97 Clinical activity and low toxicity have been reported for gefitinib in elderly patients with advanced NSCLC pretreated with chemotherapy by several subset analyses of the patients included in the extended-access protocol,98-102 and additional research with this agent is warranted. The activity and tolerability of gefitinib combined with either gemcitabine or vinorelbine has been investigated in an Italian phase II study.103 Although the gemcitabine and gefitinib combination was safe, the vinorelbine arm was closed after 25 patients, before completion of planned accrual, because of safety concerns: 72% grade 3 to 4 neutropenia, 12% grade 3 to 4 diarrhea, and three toxic deaths.101 Regarding activity, similar to the disappointing results obtained in younger patients with the concomitant administration of gefitinib and standard chemotherapy,104,105 the addition of gefitinib to either single-agent drug did not appear to provide additional benefit to chemotherapy alone in elderly patients. Recently, erlotinib as a single agent has demonstrated efficacy in terms of survival compared with best supportive care in a phase III trial for patients with advanced NSCLC after first- and second-line treatment failure.106 Erlotinib 150 mg/d was evaluated in 45 chemotherapy-naive elderly patients ≥ 70 years of age; six patients (13.3%) achieved a partial response and 22 patients (48.8%) had stable disease. Adverse events were generally mild, although all six responding patients developed a rash.107
Several other target-based agents are promising for advanced NSCLC (among them, other anti–epidermal growth factor receptor therapies, angiogenesis inhibitors, proteosome inhibitors, cyclooxygenase inhibitors) but, although a number of clinical trials are underway or planned in the near future, to date no prospective data have been published on targeted therapies in elderly patients with NSCLC.108 The first generation of clinical trials currently underway is evaluating targeted therapies in the elderly include single-agent treatment or combination regimens with cytotoxic chemotherapy. However, combinations of targeted therapies with the aim of targeting two or more growth-controlling pathways are particularly appealing, and clinical trials of multiple-targeted therapy may represent the next generation of studies in this field.
Evidence for Clinical Practice
The attempt to develop treatment indications for elderly patients with advanced NSCLC should be based on the awareness of the heterogeneity of the elderly and of the importance of an individualized comprehensive assessment for these patients.
With the evidence currently available, single-agent chemotherapy with a third-generation agent (vinorelbine, gemcitabine, docetaxel, or paclitaxel), can be considered a recommended option for elderly advanced NSCLC patients (Table 5). This is consistent with the latest update of the American Society of Clinical Oncology guidelines for treatment of elderly patients with advanced NSCLC.72 Several factors should be considered by the clinician when the drug to be administered is chosen: this choice should take into account the expected toxicity profile of the agent, pharmacokinetics, organ function, and comorbidities. After an appropriate communication process, patients’ preferences may also facilitate decision making.
Platinum-based chemotherapy may represent a valid option for fit elderly patients with adequate organ function. Obviously, a proper selection of these patients is mandatory, and additional experimental evidence on this topic seems essential.
Best supportive care, including growth factors where appropriate,109 should be offered to all patients, especially those suffering from comorbidities and disease symptoms. Best supportive care should be offered in addition to chemotherapy, but may also represent the only therapeutic option for patients who are unsuitable for active treatments. The choice of the best active treatment should not make less important a careful evaluation and management of disease symptoms, such as pain, that unfortunately are often undertreated.110
Future Directions for Clinical Research
The analysis of available literature performed for this review shows the absolute need of clinical trials specifically dedicated to elderly patients with advanced NSCLC. They represent a significant proportion of the patients every oncologist has to manage in daily practice, and clinical decision making could be more strongly founded based on the results of prospective studies. Similar to clinical research focused on patients with PS 2,111 to avoid selection bias, final evidence should be based on clinical trials dedicated to these patients.
However, out of 30 ongoing phase II/III clinical trials for first-line treatment of advanced NSCLC registered in National Cancer Institute Clinical Trials database on June 28, 2004,112 26 trials did not specify an upper limit of age in inclusion criteria, one trial was limited to patients younger than 75 years, one trial was dedicated to unfit patients (elderly or poor PS), and only two trials were dedicated to elderly patients. Both of these trials were phase II studies, and no randomized phase III trial dedicated to elderly patients could be found.
In recent years, elderly patients are often enrolled onto clinical trials together with unfit patients and patients affected by major comorbidities under the common label of special patient population or patients unsuitable for platinum-based chemotherapy. We strongly disagree with this approach because it mixes together different categories with strikingly different prognoses (ie, median survival of 7 to 9 months in fit elderly advanced NSCLC patients v 4 to 5 months in younger patients with PS 2 and advanced NSCLC), leading to heterogeneous study populations and inconsistent or uninterpretable therapeutic results. Elderly patients have peculiar characteristics related to physiologic aging. In our opinion, differentiation of unfit patients of any age from fit elderly patients is mandatory for a clear interpretation and general application of trial results.
To better define elderly patients enrolled onto clinical trials, every patient should receive a complete functional assessment at baseline (eg, CGA or an acceptable alternative as discussed in the section The Role of Clinical Evaluation of Elderly Patients, QoL questionnaires, comorbidities evaluation). This will facilitate a common language to describe study populations, allowing a clearer interpretation of trial results.
From an evidence-based point of view, single-agent chemotherapy with a third-generation agent (eg, gemcitabine, vinorelbine, or taxanes) should be the standard arm against which experimental treatments should be tested in randomized clinical trials dedicated to elderly patients. As described in the section Advanced Age Should Not Constitute a Contraindication to Treatment, there is an acceptable amount of data both in terms of survival and QoL that justifies the exclusion of best supportive care alone in future clinical studies in elderly patients. Furthermore, there is an undeniable demand for specific treatment by patients and their relatives: patients are often much more willing to receive intensive treatments, even when clinicians forecast little benefit, if any.113 In a descriptive study based on interviews asking for the preferences for chemotherapy in patients with advanced NSCLC, only 17% of the patients would have accepted random assignment between supportive care and chemotherapy.29
Table 6 lists the most important research priorities for elderly patients with advanced NSCLC. High priority should be dedicated to prospective clinical trials evaluating tolerability and efficacy of platinum-based combinations (carboplatin-based or low-dose cisplatin-based doublets), as well as to trials testing the new biologic target-oriented agents. Another interesting experimental field for these patients takes into account the frequency of tumor-related symptoms, concomitant diseases, and treatment adverse effects. Studies are needed to improve supportive care during cytotoxic chemotherapy, with the aim to better define the role of optimizing the administration of a wide spectrum of drugs (eg, antidepressants, analgesics, hematological growth factors, and so on).
Clinical trials should include geriatric screening and CGA, and should collect tumor biopsy specimens so that genomic investigations can be performed in the elderly cancer patients.
Since the early 1990s, we have entered a new therapeutic era, and now we recognize clearly that elderly individuals with advanced NSCLC should not be excluded from therapy or clinical trials that can result in significant palliation and life prolongation. To exclude arbitrarily the elderly patient represents untenable bias.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: Cesare Gridelli, Astra Zeneca, Eli Lilly, Aventis, Roche; Matti Aapro, Pierre Fabre, Eli Lilly, Aventis; Andrea Ardizzoni, Eli Lilly, Aventis, Bristol Myers Squibb; Lodovico Balducci, Amgen; Filippo De Marinis, Astra Zeneca; Christian Manegold, Eli Lilly; Francesco Perrone, Astra Zeneca; Frances Shepherd, Eli Lilly, Aventis, OSI; Corey Langer, Eli Lilly. Stock Ownership: Frances Shepherd, Eli Lilly. Honoraria: Cesare Gridelli, Eli Lilly, Aventis; Matti Aapro, Pierre Fabre, Eli Lilly, Aventis; Andrea Ardizzoni, Eli Lilly, Aventis, Bristol Myers Squibb; Lodovico Balducci, Amgen, Novartis, GOC; Christian Manegold, Eli Lilly; Frances Shepherd, Eli Lilly, Aventis, OSI. Research Funding: Matti Aapro, Pierre Fabre; Lodovico Balducci, Eli Lilly, Novartis; Christian Manegold, Eli Lilly. Expert Testimony: Frances Shepherd, Eli Lilly. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
| Parameter | Elements of the Assessment |
|---|---|
| Functional status | Performance status |
| ADL | |
| IADL | |
| Comorbidity | Number of comorbidities |
| Severity of comorbidities | |
| Comorbidity index or scale (eg, Charlson Comorbidity Index, Cumulative Illness Rating Scale–Geriatrics) | |
| Socioeconomic status | Living conditions |
| Presence and adequacy of a caregiver | |
| Income | |
| Access to transportation | |
| Cognitive status | Folstein's Mini-Mental Status |
| Other tests | |
| Emotional status | Geriatric Depression Scale |
| Polypharmacotherapy | Number of drugs assumed |
| Appropriateness of medications | |
| Risk of drug interactions | |
| Nutritional status | Mini-Nutritional Assessment |
| Presence of geriatric syndromes | Dementia, delirium, depression, falls, neglect and abuse, spontaneous bone fractures, failure to thrive |
Abbreviations: ADL, activities of daily living; IADL, instrumental activities of daily living.
| Author and Reference | Drug | Schedule | Age (years) | No. of Patients | Response Rate (%) | Median Overall Survival (months) |
|---|---|---|---|---|---|---|
| Colleoni et al39 | Vin | 25 mg/m2 w | > 65 | 25 | 16 | 5.0 |
| Veronesi et al40 | Vin | 25-30 mg/m2 w | > 70 | 23 | 39 | NR |
| Tononi et al41 | Vin | 25 mg/m2 w | > 65 | 25 | 12 | 10.0 |
| Gridelli et al42 | Vin | 30 mg/m2 w | > 70 | 43 | 23 | 8.3 |
| Buccheri et al43 | Vin | 25 mg/m2 w | > 70 | 46 | 5 | 7.9 |
| Gridelli et al44 | Oral vin | 60-80 mg/m2 w | > 70 | 50 | 10.7 | 8.2 |
| Kanard et al45 | Oral vin | 60 mg/m2 w | > 70 | 58 | 3.4 | 7.5 |
| Ricci et al46 | Gem | 1,000 mg/m2 days 1, 8, 15 every 28 days | > 70 | 44 | 22 | 6.8 |
| Altavilla et al47 | Gem | 1,250 mg/m2 days 1, 8 every 21 days | > 70 | 21 | 33 | 7.4 |
| Martoni et al48 | Gem | 1,000 mg/m2 days 1, 8, 15 every 28 days | > 70 | 46 | 22 | 9.0 |
| Gridelli et al49 | Gem | 1,200 mg/m2 days 1, 8 every 21 days | > 70 | 49 | 18 | NR |
| Bianco et al50 | Gem | 1,000 mg/m2 days 1, 8, 15 every 28 days | > 70 | 52 | 38 | 7.9 |
| Fidias et al51 | Pac | 90 mg/m2 w for 6 weeks every 8 weeks | > 70 | 35 | 23 | 10.3 |
| Garbo et al52 | Pac | 80 mg/m2 days 1, 8, 15 every 28 days | > 70* | 60 | 3.3 | 8.2 |
| West et al53 | Pac | 60-80 mg/m2 days 1, 8, 15 every 28 days | > 65 | 21 | 19 | 6.8 |
| Hainsworth et al54 | Doc | 36 mg/m2 w for 6 weeks every 8 weeks | > 65* | 39 | 18 | 5.0 |
| Lilenbaum et al55 | Doc | 75 mg/m2 every 3 weeks | > 70* | 96 | 15 | NR |
| Lilenbaum et al55 | Doc | 30 mg/m2 days 1, 8, 15 every 28 days | > 70* | 15 | NR |
Abbreviations: NSCLC, non–small-cell lung cancer; Vin, vinorelbine; Gem, gemcitabine; Pac, paclitaxel; Doc, docetaxel; w, weekly; NR, not reported.
*
Elderly and/or unfit patients.
| Trial | Study Arm | No. of Patients | Response Rate (%) | Median Overall Survival (weeks) | 1-Year Overall Survival (%) | Quality-of-Life Comparison |
|---|---|---|---|---|---|---|
| ELVIS27 | BSC | 78 | NA | 21 | 14 | Functional scales and several cancer-related symptoms better for vinorelbine |
| Vinorelbine | 76 | 20 | 28 | 32 | ||
| SICOG56 | Vinorelbine | 60 | 15 | 18 | 13 | Combination therapy associated with a clear delay in deterioration of symptom and quality of life |
| Gemcitabine + vinorelbine | 60 | 22 | 29 | 30 | ||
| MILES9 | Vinorelbine | 23 | 18 | 36 | 38 | Quality of life similar among the three treatment arms |
| Gemcitabine | 233 | 16 | 28 | 28 | ||
| Vinorelbine + gemcitabine | 232 | 21 | 30 | 30 |
Abbreviations: NSCLC, non–small-cell lung cancer; BSC, best supportive care; ELVIS, Elderly Lung Cancer Vinorelbine Italian Group Study; SICOG, Southern Italian Cooperative Oncology Group; MILES, Multicenter Italian Lung Cancer in the Elderly; NA, not applicable.
| Author and Trial | Treatment | Platinum Dose | Age (years) | No. of Patients | % | RR (%) | OAS (months) | 1-Year OAS (%) | P | Toxicity of Elderly Patients Compared With Younger Cohort |
|---|---|---|---|---|---|---|---|---|---|---|
| Nguyen et al, Hoosier Oncology Group80 | CDDP/gemcitabine | 100 mg/m2 | ≥ 70 | 53 | 20 | 15 | 7.7 | NR | NS | No significant difference in toxicity |
| < 70 | 207 | 80 | 29 | 9.4 | NR | |||||
| Kelly et al, SWOG 9509 and 930881 | CBDCA/paclitaxel | CDDP 100 mg/m2 | ≥ 70 | 117 | 19 | NR | 6.9 | 30 | .06 | Grade 3-5 toxicities similar between the two age groups; a significantly higher number of older patients discontinued CDDP/vinorelbine due to toxicity; no difference for CBDCA/paclitaxel |
| CDDP/vinorelbine | CBDCA AUC 6 | < 70 | 491 | 81 | NR | 8.6 | 40 | |||
| Langer et al, ECOG 559282 | CDDP/etoposide | 75 mg/m2 | ≥ 70 | 86 | 15 | 23.3 | 8.5 | 29 | NS | Older men, more grade 4 leukopenia and higher incidence of neuropsychiatric effects; Older women, more weight loss |
| CDDP/paclitaxel | < 70 | 488 | 85 | 21.5 | 9.1 | 38 | ||||
| Lilenbaum et al, CALGB 973083 | CBDCA/paclitaxel | AUC 6 | ≥ 70 | 77 | 27 | 36 | 8.0 | 35 | NS | Differences by age not described |
| < 70 | 207 | 73 | 30 | 8.5 | 36 | |||||
| Rocha Lima et al, CALGB 893184 | CDDP/vinblastine | 100 mg/m2 | ≥ 70 | 31 | 12 | 16 | 5.7 | 30 | NS | No negative impact of age on treatment tolerance; increase in leukopenia for older patients |
| < 70 | 222 | 88 | 31 | 8* | 27 | |||||
| Langer et al, ECOG 159485 | CDDP/paclitaxel | CDDP 75 or 100 mg/m2 | ≥ 70 | 227 | 20 | 25 | 8.3 | 33 | NS | No significant difference in toxicity |
| CDDP/docetaxel | ||||||||||
| CDDP/gemcitabine | ||||||||||
| CBDCA/paclitaxel | CBDCA AUC 6 | < 70 | 912 | 80 | 22 | 8.2 | 35 | |||
| Fossella et al, TAX 32686 | CDDP/docetaxel | CDDP 75 mg/m2 | ≥ 65 | 149 | 36 | NR | 12.6 | 52 | NS | Moderately higher incidence of grade 3-4 asthenia, infection and pulmonary toxicities across all three treatment arms, and diarrhea and sensory neurotoxicity for CDDP-containing arms, in elderly patients compared with patients < 65 years |
| All ages | 408 | 32 | 11.3 | 46 | ||||||
| CDDP/vinorelbine | CDDP 100 mg/m2 | ≥ 65 | 134 | 33 | NR | 9.9 | 41 | NS | ||
| All ages | 404 | 25 | 10.1 | 41 | ||||||
| CBDCA/docetaxel | CBDCA AUC 6 | ≥ 65 | 118 | 29 | NR | 9.0 | 38 | NS | ||
| All ages | 406 | 24 | 9.4 | 38 | ||||||
| Hensing et al, LCCC 971987 | CBDCA/paclitaxel | AUC 6 | ≥ 70 | 67 | 29 | 27 | 7.1 | 33 | NS | Similar; greater proportion of elderly patients experienced malaise and fatigue |
| < 70 | 163 | 71 | 20 | 7.8 | 30 |
Abbreviations: NS, not significant; RR, response rate; OAS, overall survival; CDDP, cisplatin; SWOG, Southwest Oncology Group; CBDCA, carboplatin; NR, not reported; AUC, area under the time-concentration curve; ECOG, Eastern Cooperative Oncology Group; CALGB, Cancer and Leukemia Group B; LCCC, Lineberger Comprehensive Cancer Center.
| Single-agent chemotherapy with a third-generation drug (eg, vinorelbine, gemcitabine, taxanes) in PS 0-2 patients |
| Platinum-based (cisplatin or carboplatin) doublets in fit patients (PS 0-1) selected for adequate organ function |
| Best supportive care (in addition to chemotherapy or as exclusive therapeutic option for those patients unsuitable for active treatment) |
Abbreviations: NSCLC, non–small-cell lung cancer; PS, performance status.
| Experimental Question | Priority |
|---|---|
| Platinum-based combination | High |
| Biologic target-based agent without chemotherapy | High |
| Biologic target-based agents combination (chemobiotherapy or polibiotherapy) | High |
| Investigational cytotoxic agents (eg, pemetrexed, oral formulations) | Medium |
| Alternative dose and/or scheduling of single agents | Medium/high |
| Supportive treatment added to chemotherapy (eg, hematologic growth factors, antidepressants, analgesics) | Medium |
| Prognostic implication of geriatric screening and CGA | High |
| Influence of age on the biology of lung cancer | High |
Abbreviations: NSCLC, non–small-cell lung cancer; CGA, comprehensive geriatric assessment.
Acknowledgments
We thank Eli Lilly for its support of the International Expert Panel.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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© 2005 by American Society of Clinical Oncology.
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Published in print: May 01, 2005
Published online: September 21, 2016
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Treatment of Advanced Non–Small-Cell Lung Cancer in the Elderly: Results of an International Expert Panel. JCO 23, 3125-3137(2005).
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Journal of Clinical Oncology 2005 23:13, 3125-3137
Journal of Clinical Oncology 2005 23:13, 3125-3137
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