Vinorelbine

Chemotherapy for elderly patients with non-small cell lung cancer (NSCLC) has been questioned due to the perceived potential for higher toxicity in this population, possibly attributable to progressive organ failure and comorbidities. This nonsystematic review presents the authors' selection of key evidence for the use of chemotherapy for elderly patients with NSCLC. To date, single-agent chemotherapy with agents such as vinorelbine, gemcitabine, docetaxel, and paclitaxel has been a reasonable option. Data on nonplatinum-based combinations are limited, but recent investigations of gemcitabine plus vinorelbine failed to show superiority over either agent alone. Retrospective subset analyses from large randomized trials suggest that the efficacy and tolerability of platinum-based combination chemotherapy are similar in both the elderly and their younger counterparts. Further phase III trials that specifically examine platinum-based combinations in selected elderly NSCLC patients are therefore warranted. The potential impact of new targeted therapies--alone or in combination with chemotherapy--is being investigated.

Key words: chemotherapy; elderly; non-small cell lung cancer

Abbreviations: ECOG = Eastern Cooperative Oncology Group; ELVIS = Elderly Lung Cancer Vinorelbine Italian Study; MILES = Multicentre Italian Lung Cancer in the Elderly Study; MST = median survival time; NSCLC = non-small cell lung cancer; ORR = objective response rate; PS = performance status; SWOG = Southwest Oncology Group

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Lung cancer is the most common form of cancer in most developed countries and is now the leading cause of cancer death in both men and women. Approximately 1.2 million new cases are diagnosed every year worldwide, with a mortality rate of 1.1 million. (1) Approximately 80 to 85% of lung cancer subtypes are of non-small cell histology, including squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma. (2)

Like other solid tumors, lung cancer may be considered to be a disease of elderly patients. Although the median age of patients with newly diagnosed non-small cell lung cancer (NSCLC) participating in clinical trials is 60 to 62 years, > 50% of diagnoses are made in patients aged > 65 years, and 30 to 40% are made in patients > 70 years old. (3-5) The National Cancer Institute Surveillance Epidemiology End Results program (4) reported that the age-adjusted incidence rate for NSCLC was 20.2 per 100,000 inhabitants < 65 years old; however, the age-adjusted incidence rate was 306.1 for those [greater than or equal to] 65 years old.

In clinical trials, the definition of an elderly patient remains controversial. Epidemiologic literature (2,6) uses an age of 65 years for the selection of elderly patients, but 70 years is commonly used in oncology trials. However, evidence shows an increased incidence of age-related changes in patients > 70 years old with increased risk of chemotherapy-induced toxicity, and this would therefore seem to be an appropriate cut-off, (2,6) pending the availability of more reliable tools to define biological instead of chronological age.

Despite the high incidence of NSCLC and its high mortality rate in elderly patients, the likelihood of receiving treatment of any type--in particular, chemotherapy--appears to decrease with increasing age. (2) The decision to treat or not to treat is frequently based on factors other than chronological age alone. Other important factors influencing the use of chemotherapy in the elderly include the presence of comorbid diseases and performance status (PS). (2) Age-related decreases in organ function, including reductions in renal, hepatic, and bone-marrow function, have the potential to increase chemotherapy-related toxicity in the elderly; however, few guidelines are available with respect to the need for dose adjustments in this rapidly increasing patient population. (7) Physician and patient concerns about age-related toxicity may, in part, provide an explanation for the low number of elderly participants in cancer trials. In an analysis (8) of 495 phase II and III American Cooperative Group studies, it was found that patients with renal, hepatic, cardiac, or hematologic abnormalities were generally excluded, therefore potentially ruling out a large proportion of elderly patients.

Elderly patients also have approximately twice as many comorbidities compared with the general population. This may have a considerable impact on their overall health and PS, which may further complicate chemotherapy or lead to less aggressive treatment for the elderly. (2) Although comorbidity influences treatment choice in NSCLC and is a predictor of outcome (in particular, survival), clinical trials seldom report comorbid conditions or their severity, (2,7) and a standardized way of assessing comorbidity has not yet been defined. (2)

The number of elderly patients with NSCLC is likely to increase over the coming years; yet, data from chemotherapy trials designed specifically for elderly patients with NSCLC are lacking. Hutchins et al (9) analyzed data from 164 Southwest Oncology Group (SWOG) trials and found that patients aged at least 65 years only comprised 39% of all participants in lung cancer trials. (9) Furthermore, until recently, patients aged > 80 years were usually excluded from chemotherapy trials. Studies of advanced NSCLC patients not limited by age have only recently been sufficiently large and appropriately designed to assess the place of chemotherapy. These studies have shown conclusively that patients with advanced NSCLC not only achieve a survival benefit from chemotherapy, but also often experience significant relief of cancer-related symptoms during treatment. (10) A large recta-analysis (11) demonstrated modest but significant survival advantages and no age-related differences from the use of chemotherapy in patients with advanced NSCLC compared with supportive care alone. In addition, retrospective analyses of several individual clinical trials (12-16) have shown that chemotherapy is just as effective in the elderly compared with their younger counterparts. It should be remembered that the elderly patients in these clinical trials represent only a select subset of the elderly population as a whole, in that they met the strict entry criteria mandated by the studies. However, these analyses suggest that, despite early pessimism, it now appears that chemotherapy should be considered for certain elderly patients.

LITERATURE SEARCH

We conducted a PubMed literature search for all studies of chemotherapy for elderly patients with NSCLC published in the English language from 1994 to 2004. The literature search was based on the key phrases "elderly" plus "nonsmall cell lung cancer" and "elderly" plus "chemotherapy." References from key studies and review articles were checked to ensure a comprehensive search. Relevant abstracts from recent major oncology meetings were used to supplement the published studies, at the discretion of the authors. This nonsystematic review is based on the most pertinent literature (in the authors' expert opinion) published in the field.

THERAPIES

Single-Agent Chemotherapy

In an attempt to avoid toxicity while still gaining disease control, single-agent chemotherapy has been investigated as one of the first approaches in elderly patients with NSCLC. Over the past 15 years, a number of single agents have been investigated in phase II trials (Table 1).

The third-generation vinca alkaloid vinorelbine has been investigated extensively in elderly patients with advanced NSCLC. In phase II trials, objective response rates (ORRs) of 4 to 39% and median survival times (MSTs) of 5 to 10 months were achieved. (17-21) The toxicity profile was mild, with very low rates of severe hematologic and nonhematologic side effects. One study also demonstrated improved PS and symptoms in 26 to 40% of patients who were symptomatic at entry. (19) These promising findings prompted further investigation in randomized phase III trials.

In a key phase III study (the Elderly Lung Cancer Vinorelbine Italian Study [ELVIS]), (35,36) 161 chemotherapy-naive patients ([greater than or equal to] 70 years old) were randomized to receive vinorelbine (30 mg/[m.sup.2] at days 1 and 8, every 3 weeks) or best supportive care. The ORR was 20% for patients receiving vinorelbine (Table 2), and a significant survival advantage was seen compared with the control group (p = 0.03); 1-year survival rates were 32% and 14%, respectively (Fig 1). Furthermore, quality-of-life scores were better in the vinorelbine group. Vinorelbine was well tolerated, with grade 3/4 leukopenia observed in 7% of patients, grade 3/4 neutropenia in 10%, grade 2/3 thrombocytopenia in 1%, and anemia in 16%. Two phase II studies (22,23) using oral vinorelbine yielded lower ORRs (3.4% and 10.7%), but similar MSTs (7.5 months and 8.2 months) and manageable toxicity. The reason for this is not clear since oral vinorelbine has been shown to be equivalent to the IV formulation in a larger randomized trial (39) that was not limited to the elderly.

[FIGURE 1 OMITTED]

Gemcitabine has demonstrated promising activity with good tolerability in a number of retrospective analyses (40-42) in which no differences were noted between elderly and younger patients with respect to response or survival. Subsequent phase II trials specifically designed for elderly patients with advanced NSCLC have confirmed good activity and tolerability of gemcitabine. In patients aged > 70 years, gemcitabine yielded ORRs of 18 to 38% and MSTs of 6.8 to 9 months (24-28) (Table 1). In a preliminary report (43) of a study of patients aged > 65 years treated with gemeitabine, 41% achieved a partial response. These phase II data prompted further research in the form of comparative trials of gemcitabine in elderly patients with advanced NSCLC.

The taxanes have demonstrated good activity and tolerability in the treatment of NSCLC. In a phase II trial (44) of paclitaxel (210 mg/[m.sup.2]) administered every 3 weeks, results were analyzed according to age (< 70 years vs [greater than or equal to] 70 years), with no differences in ORR or survival seen between the age groups but more neutropenia in older patients (89.3% vs 73.9%). In an effort to reduce toxicity, weekly regimens of single-agent paclitaxel have been investigated in three phase II studies, (29-31) resulting in ORRs ranging from 3 to 23% and MSTs from 6.8 to 10.3 months, with good tolerability.

In a study (45) of 35 elderly patients ([greater than or equal to] 76 years), docetaxel, 60 mg/[m.sup.2] every 3 weeks, induced a 40% ORR. The main toxicities were hematologic; grade [greater than or equal to] 3 neutropenia developed in 87% of patients, and grade 3 neutropenic fever developed in 33%. However, it should be noted that only 15 of the 35 patients enrolled met the study eligibility criteria. (45) In another phase II study, (33) 30 patients aged [greater than or equal to] 70 years received docetaxel (60 mg/[m.sup.2]) on day 1 of a 28-day cycle. Of 28 evaluable patients, 5 patients (17.9%) had a partial response. Toxicities included grade 3/4 neutropenia (86.7%) and anemia (6.7%), and grade 3 nausea/vomiting (14%). One patient died due to treatment-related diarrhea and concomitant neutropenia. Based on these results and with the aim of reducing toxicity, a weekly schedule of docetaxel has also been investigated.

In a phase II trial, (32) 39 patients who were [greater than or equal to] 65 years old or poor candidates for chemotherapy received weekly docetaxel, 36 mg/[m.sup.2]. This regimen was well tolerated, with only 8% of patients experiencing grade 3 leukopenia and no grade 4 myelosuppression; grade 3/4 nonhematologic side effects were infrequent. Objective responses were achieved in 18% of patients, median survival was 5.0 months, and the 1-year survival rate was 27%. In contrast, in a phase I study (46) in an elderly Japanese population, neutropenia and diarrhea were dose limiting for weekly docetaxel at 30 mg/[m.sup.2], but no hematologic toxicity was reported for patients receiving docetaxel at 25 mg/[m.sup.2]. An ORR of 20% was reported. Docetaxel at 30 mg/[m.sup.2] administered weekly and docetaxel at 75 mg/[m.sup.2] administered every 3 weeks have been evaluated in previously untreated elderly patients ([greater than or equal to] 70 years old, n = 54) and/or poor PS patients (PS 2, n = 49.). Both schedules had acceptable toxicity profiles, although hematologic toxicity was lower for the weekly schedule. Of 65 patients evaluable for toxicity, 30% and 3% had grade 3/4 neutropenia in the 3-weekly and weekly groups, respectively. One episode of febrile neutropenia was reported in the 3-weekly group. It was noted that patients aged [greater than or equal to] 80 years (22%) tolerated weekly docetaxel better than the 3-weekly schedule. Preliminary efficacy results were similar for both groups. (34) More research may be required to determine the optimal taxane schedule for the elderly population.

Nonplatinum-Based Combination Chemotherapy

There have been several phase II trials of third-generation nonplatinum chemotherapy combinations in the elderly population (Table 3). Five phase II trials of gemcitabine plus vinorelbine have been conducted in elderly or poor PS patients with NSCLC. Response rates ranged from 18 to 65%, with MSTs of 7 to 13 months and 1-year survival rates of 31 to 37%. (26,47-50) The regimens were generally well tolerated, although one study (49) noted that patients aged [greater than or equal to] 75 years had an elevated risk of neutropenia.

Two phase III trials (37,38) have compared gemcitabine plus vinorelbine combinations with single-agent therapy. A small study (38) of gemcitabine (1,200 mg/ [m.sup.2]) plus vinorelbine (30 mg/[m.sup.2]) vs vinorelbine (30 mg/[m.sup.2]) alone (n = 120 patients) closed early when an interim analysis showed that the combination conferred a significant survival advantage over the single agent (median survival, 29 weeks vs 18 weeks, p < 0.01) and a better overall response rate (Table 2). However, the 18-week survival for single-agent vinorelbine in this study (38) is markedly lower than the 28- to 38-week survival times reported in five large randomized trials, (35-37,52-54) including one study dedicated entirely to elderly patients. (37)

The Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial of 700 patients with NSCLC is the largest phase III study of the elderly published to date. (37) Patients were randomized to receive single-agent chemotherapy with vinorelbine (30 mg/[m.sup.2]) or gemcitabine (1,200 mg/[m.sup.2]), or combination therapy with vinorelbine (25 mg/[m.sup.2]) plus gemcitabine (1,000 mg/[m.sup.2]). Combination treatment had no advantage in terms of response rate, time to progression, survival, or quality of life over single-agent therapy (Table 2; Fig 2). Moreover, although toxicity was considered acceptable in all groups, it was higher with the combination than with the single agents. The authors concluded that single-agent therapy with vinorelbine or gemcitabine is preferable to the combination for treatment of advanced NSCLC in elderly patients. Based on the results of this large randomized trial, recent American Society of Clinical Ontology (55) guidelines recommend single-agent chemotherapy for the treatment of advanced NSCLC in elderly patients.

[FIGURE 2 OMITTED]

Investigations into the role of taxane-based non-platinum combinations in elderly NSCLC patients have begun recently. In a phase II trial, (51) weekly docetaxel (30 mg/[m.sup.2]) plus gemcitabine (800 mg/ [m.sup.2]) was assessed in 64 elderly ([greater than or equal to] 70 years) and poor PS patients (Table 3). Both drugs were administered on days 1, 8, and 15, with the regimen repeated every 28 days. Of 53 evaluable patients, 28% had an objective response, and median survival was reported to be 7.0 months, with 1- and 2-year survival rates of 30% and 17%, respectively. This combination was well tolerated with respect to grade 3/4 toxicities, which included leukopenia (11%), thrombocytopenia (9%), asthenia (23%), and fatigue (23%).

Platinum-Based Chemotherapy

The role of platinum-based regimens in the elderly remains debatable. A retrospective analysis (56) of cisplatin-based chemotherapy in NSCLC patients revealed a significant increase in death within 30 days of starting chemotherapy with increasing age (0.5%, 3.3%, 3.2%, 7.1%, and 12.5% for [less than or equal to] 54, 55 to 59, 60 to 64, 65 to 69, and [greater than or equal to] 70 years, respectively; p = 0.0001). It is possible that reduction of renal excretion in elderly patients increases the potential for toxicity. Schedule and dose both require further investigation in this population; hence, special care is required when using cisplatin-based therapy in elderly patients.

Generally, when the third-generation cytotoxics are combined with cisplatin in modified schedules or attenuated doses to reduce toxicity in elderly patients, the treatment is active and tolerable (Table 4). Cisplatin plus vinorelbine was investigated in a chemotherapy-naive patient population (of whom 57% had stage III NSCLC). Attenuated doses of cisplatin (60 to 90 mg/[m.sup.2] on day 1, according to patient PS) and vinorelbine (25 mg/[m.sup.2] on clays 1 and 8) were used in a 3-week schedule. (57) A 54% ORR and an MST of 7.2 months were achieved. In a small phase II trial (59) with 15 patients, first-line treatment with weekly cisplatin (35 mg/[m.sup.2]) and gemcitabine (1,000 mg/[m.sup.2]) [days 1, 8, and 15, every 4 weeks) resulted in an ORR of 40% and an MST of 9 months. Grade 3/4 thrombocytopenia was reported in 40% of patients, with low rates of other major toxieities. Berardi et al (60) used a weekly schedule of cisplatin 35 mg/[m.sup.2] plus gemcitabine 1,000 mg/[m.sup.2], yielding a partial response rate of 31.8% and an MST of 9 months, with a favorable toxicity profile. Another phase II study (58) using a 3-week schedule of cisplatin (50 mg/[m.sup.2]) plus gemcitabine (1,000 mg/[m.sup.2]) reported a 35% partial response rate and an MST of 10.2 months.

A phase II study showed that cisplatin (25 mg/[m.sup.2]) and docetaxel (20 mg/[m.sup.2]), administered as three consecutive weekly infusions, was very active and well tolerated in 33 chemotherapy-naive elderly patients. (61) A 52% ORR, an MST of 15.8 months, and 1- and 2-year survival rates of 64% and 26%, respectively, were achieved. The treatment was well tolerated, with no grade 4 toxicities observed.

Substitution of carboplatin for cisplatin has been investigated (Table 5) as an appealing alternative due to lower rates of nausea/vomiting, neuropathy, nephrotoxicity, and neurotoxicity. However, myelotoxicity can be more severe with carboplatin, particularly when combined with other myelotoxic agents. Carboplatin plus vinorelbine failed to show any notable advantage over vinorelbine alone in two phase II studies. (62,63) In contrast, the combination of low-dose carboplatin and gemcitabine produced an ORR of 37.5% and an MST of 9.0 months, with a favorable toxicity profile. (64) Variable results have been observed with attenuated doses or modified weekly schedules of carboplatin plus paclitaxel; response rates have ranged from 16 to 40% and MSTs from 7.1 to 11.3 months. (65-68)

As yet, no elderly specific prospective phase III trials of platinum-based therapy in NSCLC have been conducted. However, retrospective subset analyses of the elderly patients enrolled in a number of phase III trials have been reported (Table 6). A retrospective analysis of Eastern Cooperative Oncology Group (ECOG) 5592 compared the effects of first-line cisplatin plus either etoposide or paclitaxel in 86 patients aged [greater than or equal to] 70 years of age with those in 488 younger patients. (14) There were no significant differences between the younger and older patients in any of the efficacy measures, with only minimal differences in toxicity between the age groups (the elderly had worse leukopenia and neuropsychiatric disorders). An additional analysis of the small subset of patients aged > 75 years revealed no differences in outcomes compared with patients aged 70 to 75 years, and there was only a borderline increase in leukopenia in the older age group (p = 0.06).

Langer et al (14,15) and Schiller et al (70) also analyzed data from ECOG 1594, in which four treatment combinations (cisplatin/paclitaxel, cisplatin/docetaxel, cisplatin/gemcitabine, and carboplatin/paclitaxel) were evaluated as first-line chemotherapy for NSCLC. No significant differences were reported for response rates (24.5% vs 22.1%) or median survival (8.3 months vs 8.2 months) for the 227 patients (20%) aged [greater than or equal to] 70 years compared with those aged < 70 years. (14) Only a marginally significant (p = 0.04) increase in grade 4 toxicities was reported in the elderly population. However, it is notable that only one of the nine patients who were > 80 years old was able to complete four cycles of chemotherapy; none achieved a response, and their MST was only 4.2 months. (15)

A similar retrospective analysis (13) was undertaken for elderly vs younger patients enrolled in the SWOG 9509 trial, which compared carboplatin plus paclitaxel with cisplatin plus vinorelbine, and the SWOG 9308 trial that compared cisplatin plus vinorelbine with cisplatin alone. In this subset analysis, (13) 117 of 608 evaluable patients were [greater than or equal to] 70 years of age (79 patients in the cisplatin-plus-vinorelbine study arm and 38 patients in the paclitaxel-plus-carboplatin arm). The results showed no statistically significant influence of age on survival (8.6 months vs 6.9 months for < 70-year-old vs [greater than or equal to] 70-year-old patients; p = 0.06), time to progression (4.2 months vs 3.9 months; p = 0.62), or toxicity. However, it should be noted that a significant number of older patients ([greater than or equal to] 70 years old) discontinued cisplatin plus vinorelbine (36 of 78 patients, 46%) with fewer older patients discontinuing paclitaxel plus carboplatin (6 of 37 patients, 16%). A third retrospective study (69) of a trial of two different schedules of carboplatin plus paclitaxel confirmed these findings.

Other elderly subset analyses have also been reported. (16,71) The Cancer and Leukemia Group B compared carboplatin plus paclitaxel with paclitaxel alone and found no differences in survival between patients aged < 70 years and those aged [greater than or equal to] 70 years. (16) First-line docetaxel plus either cisplatin or carboplatin was compared with vinorelbine plus cisplatin in the TAX 326 trial. (72) A subset analysis of 401 patients aged [greater than or equal to] 65 years was conducted (71) and showed that docetaxel plus cisplatin provided substantial increases in survival (1 year, 52% vs 41%; 2 years, 24% vs 17%) compared with vinorelbine plus cisplatin (Table 6). Both docetaxel regimens were well tolerated in the elderly subgroup, although the lowest incidence of toxicity occurred in the docetaxel-plus-carboplatin study arm.

Targeted Therapies

Our increased understanding of tumor cell biology and the identification of several molecular targets for NSCLC have led to the development of a number of new biological antitumor agents that have been evaluated in NSCLC. Gefitinib and erlotinib, two inhibitors of epidermal growth factor receptor tyrosine kinase, have demonstrated activity as single-agent therapy in heavily pretreated patients with NSCLC. (73-75)

A subset analysis of several studies that have included patients aged [greater than or equal to] 70 years suggests that gefitinib is active and generally well tolerated in this population (Table 7). The combination of gefitinib with either vinorelbine or gemcitabine was investigated in a prospective study (80) of 60 patients aged [greater than or equal to] 70 years with advanced NSCLC. Gefitinib combined with gemcitabine showed low activity, but was generally well tolerated. In contrast, toxicity was unacceptable in the vinorelbine study arm in which 18 of 25 patients (72%) had grade 3/4 neutropenia, and there were three treatment-related deaths with no objective responses reported. (80) Erlotinib, 150 mg/d, was evaluated in a study of 38 chemotherapy-naive patients aged [greater than or equal to] 70 years; 5 patients (13.2%) achieved a partial response, and 19 patients (50.0%) had stable disease. Adverse events were generally mild, although rash developed in all responding patients (severe in two cases). (81)

Ongoing Trials

Several randomized trials are ongoing in elderly advanced NSCLC patients. A European, multicenter, randomized, phase II study has been initiated with pemetrexed alone or pemetrexed followed by single-agent gemcitabine. A phase III trial of single-agent docetaxel vs docetaxel plus gemcitabine is open at the Sarah Cannon Cancer Center, in Tennessee. The role of cisplatin-based chemotherapy is being evaluated in the MILES 02 phase II randomized trial, which compares single-agent gemcitabine (1,200 mg/[m.sup.2]) to cisplatin (administered at attenuated doses of 50, 60, or 70 mg/[m.sup.2]) plus gemcitabine (1,000 mg/[m.sup.2]) or cisplatin (50, 60, or 70 mg/[m.sup.2]) plus vinorelbine (25 mg/[m.sup.2]). Based on the results of this phase II study, a phase III trial will be developed. A phase III trial comparing single-agent, weekly docetaxel to weekly cisplatin plus docetaxel is also ongoing in Japan.

Finally, with growing evidence suggesting favorable toxicity profiles of targeted therapies, many further clinical trials of new biological agents alone or combined with chemotherapy are ongoing or planned. In the United States, a randomized trial of carboplatin plus paclitaxel vs erlotinib is ongoing.

CONCLUSIONS AND FUTURE DIRECTIONS

The use of chemotherapy in the elderly NSCLC population is complicated by a number of age-related issues. The reduced organ function and higher prevalence of comorbid disorders associated with increasing age affect treatment decisions, with physicians often harboring preconceived biases against using chemotherapy in elderly patients due to concern over the potential for unacceptable side effects. This--together with the lack of a clear definition of "elderly"--contributes to disproportionately low numbers of elderly participants being included in clinical trials. Standardized measures of comorbidity, age definitions, and appropriate patient inclusion criteria may help to ensure proper representation of elderly patients in future studies and may improve our ability to define which elderly patients are most likely to tolerate and to benefit from chemotherapy.

At present, single-agent chemotherapy appears to be a reasonable choice in elderly patients with advanced NSCLC. This conclusion arises from the efficacy and tolerability observed with vinorelbine and gemcitabine as single agents in both phase II and III trials. Preliminary findings for single-agent paclitaxel and docetaxel are also encouraging and warrant further investigation.

The place of platinum-based treatment for elderly patients with NSCLC has traditionally been seen as questionable because of the perceived higher risk of toxicity. However, several retrospective subset analyses of platinum-based chemotherapy trials (13-15,69-71) have demonstrated no or minimal differences between elderly patients who met the stringent eligibility criteria of the clinical trials and younger patients treated with platinum-based therapies. The results of subset analyses, however, should be interpreted with care due to the potential risk of selection bias. Based on population data, fewer than half the expected number of elderly patients tend to be included in chemotherapy trials, which may compromise the generalization of results to other unselected elderly populations. (82) This highlights the need for prospective phase III randomized trials of platinum-based therapy, especially using modified schedules and/or attenuated doses, in selected elderly patients of good PS (PS 0-1). A new generation of clinical trials specifically designed for the elderly population is needed and should include the development and validation of new measures and tools to define "biological" vs "chronological" age.

ACKNOWLEDGMENT: We thank Samantha Richer for editorial support in the preparation of this article.

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* From the Division of Medical Oncology (Dr. Gridelli), 'S.C. Moscati' Hospital, Avellino, Italy; and University Health Network (Dr. Shepherd), Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada.

Dr. Gridelli has received honoraria for being a member of speaker bureaus for Pierre Fabre, Roche, Eli Lilly, and Aventis, and a consultant for AstraZeneca, Roche, Eli Lilly, and Aventis. Dr. Shepherd has received honoraria from and sits on advisory boards for Aventis, Eli Lilly, AstraZeneea, and OSI Pharmaceuticals.

Editorial support for the development of this article was provided by Aventis Pharmaceuticals (Bridgewater, NJ) a member of the Sanofi-Aventis Group.

Manuscript received September 24, 2004; revision accepted January 28, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Cesare Gridelli, MD, Division of Medical Oncology, 'S.G. Moscati' Hospital, Via Circumvallazione 68, 83100 Avellino, Italy; e-mail: cgridelli@libero.it

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