Cancer Therapy Vol 5, page 77
Cancer Therapy Vol 5, 77-88, 2007
The role of chemotherapy in the treatment of
advanced non-small cell lung cancer elderly patients
Antonio Rossi, Paolo Maione, Giuseppe Colantuoni, Carmine Ferrara, Alba De
Vita, Ciro Guerriero, Dario Nicolella, Filomena del Gaizo, Cesare Gridelli*
Division of Medical Oncology, “S.G. Moscati” Hospital, Avellino – Italy
*Correspondence: Cesare Gridelli, M.D., Division of Medical Oncology, “S.G. Moscati” Hospital, Città Ospedaliera, Contrada
Amoretta, 83100 Avellino, Italy; Tel: + 39 0825 203573; Fax: + 39 0825 203556; e-mail: firstname.lastname@example.org
Key words: NSCLC, elderly patients, chemotherapy
Abbreviations: Eastern Cooperative Oncology Group, (ECOG); Elderly Lung cancer Vinorelbine Italian Study, (ELVIS);
comprehensive geriatric assessment, (CGA); median survival time, (MST); Multicenter Italian Lung cancer in the Elderly Study,
(MILES); non-small-cell lung cancer, (NSCLC); overall response rates, (ORR); performance status, (PS); progression-free survival,
(PFS); quality of life, (QoL); small-cell lung cancer, (SCLC); Southwest Oncology Group, (SWOG); time to progression, (TTP)
Received: 27 December 2006; Revised: 19 January 2007
Accepted: 30 January 2007; electronically published: March 2007
More than 50% of non-small-cell lung cancer (NSCLC) patients are diagnosed over the age of 65 and
approximately one-third of all patients are over the age of 70. Elderly patients tolerate chemotherapy poorly
compared to their younger counterpart because of the progressive reduction of organ function and comorbidities
related to age. This is why these patients are often not considered eligible for aggressive platinum-based
chemotherapy, the standard of care for advanced NSCLC. With the current evidence, in clinical practice, single-
agent chemotherapy with a third-generation drug should be the recommended option for non-selected elderly
patients with advanced NSCLC. 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. However, feasibility of platinum-based chemotherapy remains an open issue and has to be proven in
prospective randomised trials. High priority should be also given to the evaluation of the role of new targeted
therapies. Moreover, a comprehensive geriatric assessment for individualized treatment choice in NSCLC elderly
patients is mandatory. The Authors review the currently-available evidences for the treatment of elderly patients
affected by advanced NSCLC reporting their own experiences in the field.
I. Introduction (Fentiman et al, 1990). Moreover, many of these patients
More than 50% of lung cancers, the leading causes of have pre-existing co-morbid conditions, which,
cancer-related deaths in Europe and in other Western independent of cancer-related symptoms, may adversely
countries, are diagnosed in patients aged over 65 and affect organ function and impact on functional status
about 30% in patients aged over 70 (Jemal et al, 2006). In (Yancik et al, 2001). Further, co-morbidities often require
the United States (US), approximately 13% of the patients treatment with multiple drugs, which may interfere with
have small-cell lung cancer (SCLC) and, consequently, chemotherapy or its toxicity profile. Moreover, the
more than 85% have non-small cell lung cancer (NSCLC) disparity between apparent decreased cancer
(Govindan et al, 2006). Clearly, lung cancer in elderly aggressiveness in an individual patient and the high rate of
patients is an increasingly common problem which the cancer mortality in older age groups may be because the
practitioner of oncology must face. survival data are confounded by special problems common
Since most patients with NSCLC have advanced to geriatric populations (comorbidity, ‘poly-pharmacy’,
disease at diagnosis, chemotherapy is the mainstay of physician or family bias regarding diagnosis and treatment
management. Elderly patients often present with medical of elderly, age-associated life stresses). These factors may
and physiological characteristics that make the selection of increase death rates and counteract any primary influence
their optimal treatment more challenging. Unfortunately, that aging might have to reduce tumour aggressiveness
as a result, these patients are at risk of being under-treated (Ershler and Long, 1997).
Rossi et al: The role of chemotherapy in the treatment of advanced non-small cell lung cancer elderly patients
In current practice, the elderly, often excluded from In order to further individualize treatment choice in
participation in clinical trials, receive untested or elderly patients, it is important to practice not only the
inadequate treatment, based on a long-held but completely patient’s basic medical history and the standard cancer
undocumented notion that cancers in older people are less staging, but also a comprehensive geriatric assessment
aggressive (Rossi and Gridelli 2006). Lung cancer is no (CGA). The CGA includes assessment of comorbidity,
exception to this observation; on the contrary, data show socio-economic issues, nutritional status, poly-pharmacy,
that it can be considered the paradigm of elderly under- functional dependence, emotional and cognitive
representation in clinical research (Hutchins et al, 1999; conditions, an estimate of life expectancy and recognition
Lewis et al, 2003; Yee et al, 2003). To confirm these data, of frailty. All these various facets of the patient’s health
a recent survey analyzing trials for cancer drug registration and environment may interfere with therapy. CGA has
conducted over seven years (from 1995 to 2002), showed been demonstrated to add substantial information with
a great disparity between percentages of elderly patients in respect to the functional assessment of elderly cancer
the general population and in those on clinical trials for patients (Repetto et al, 2002) allowing important
lung cancer: 67% versus 35% (Talarico et al, 2004). prognostic discrimination even among patients
Under-representation was particularly notable for patients characterized by a good performance status (PS). The
older than 75 years. This phenomenon can significantly CGA may be too lengthy for a busy clinical practice.
affect the generalizability of trial results that depend Therefore, a number of screening instruments have been
largely upon whether subjects enrolled in clinical trials are developed to select those older patients who may benefit
fully representative of the entire spectrum of patients from a full CGA. Of these, the evaluation proposed by the
suffering from that disease. Cardiovascular Health Study, that allows the classification
We must consider that it is very difficult to establish of elderly patients into three groups (fit, pre-frail, frail)
a maximum age for chemotherapy in the elderly. Within according to five items (unintentional weight loss, self-
epidemiological literature the age of 65 is usually reported exhaustion, weakness, walking speed and level of
considered as a cut-point to select elderly population. On physical activity) (Fried et al, 2001) has gained particular
the contrary, in clinical trials, the age of 70 is frequently prominence, because it is well correlated with mortality
used as lower limit for patient selection while a cut-off age and risk of functional dependence. This classification has
of 75 years is less common. Obviously, indirect been proposed as a standard language for the classification
comparison of trials including or not patients aged 65 to of older individuals. Another simple screening instrument
70 may be biased. In clinical practice biological instead of is the Vulnerable Elderly Survey 13 (VES-13), which
chronological age should be considered. Unfortunately, to includes 13 simple questions, the answers of which are
date, laboratory tests and geriatric evaluation are scored; patients whose total score is four or higher may
inadequate to define ageing; therefore, at present, benefit from a full CGA (Saliba et al, 2001). Also patients’
chronological age should be used as a frame of reference self-reported quality of life (QoL) evaluation can add
for clinical trials. A cut-off of 70 years of age seems to be significant prognostic information. When the prognostic
the most appropriate. In fact, 70 years of age may be role of the baseline QoL, as measured by the EORTC C30
considered as the lower boundary of senescence, because global QoL score, was evaluated in elderly patients
the incidence of age-related changes starts to increase after diagnosed with NSCLC, QoL score was a strong and
the age of 70 years (Balducci, 2000). independent prognostic factor for survival in patients
The evidence regarding the tolerability and efficacy undergoing first-line treatment for their NSCLC (Maione
of anticancer treatments for elderly patients affected by et al, 2005). These results confirm also in elderly patients
NSCLC comes from two different types of publications: the strong prognostic role of self-assessed QoL in patients
prospective clinical trials specifically designed for the with advanced lung cancer (Ganz et al, 1991) and show
elderly and, retrospective analyses conducted on the that a simple, self-reported questionnaire may add useful
subgroup of elderly patients enrolled onto clinical trials information to baseline evaluation of the patient.
that did not have an upper age limit. For the latter type of This report is focused on the currently-available
studies, it is easy to argue that when a clinical trial is evidences for the treatment of elderly patients affected by
designed to test the efficacy of a treatment intended for advanced NSCLC and the Authors report their own
younger patients, only a selected proportion of elderly experiences in this setting.
patients will be considered for enrolment, and so the
results may not necessarily extend to the general non- II. Single-agent chemotherapy
selected elderly population (Perrone et al, 2002). In fact, a The introduction into clinical practice of new, active
recent report demonstrated that elderly specific trials are and well-tolerated drugs has stimulated clinical research.
needed to define optimal cancer therapy in this subset of The first randomized phase III trial in advanced NSCLC
patients. This was a pooled analysis of elderly patients elderly patients was the Elderly Lung cancer Vinorelbine
who participated in elderly-specific trials (age > 65 years) Italian Study (ELVIS). In this trial, 161 chemotherapy-
or in age-unspecified studies (age > 18 years). The median naïve patients (! 70) were randomized to receive
age of elderly patients was greater in elderly-specific trials vinorelbine (30 mg/m2 on days 1 and 8, every 3 weeks) or
and the toxicity reported in elderly patients was lower in best supportive care (ELVIS Group 1999). A significant
elderly-specific trials than that reported in age-unspecified survival advantage with a better QoL was observed for
studies (Jatoi et al, 2005). It means that elderly-specific vinorelbine compared with the control group (median
trials are providing quality care in the elderly. survival time [MST]: 27 versus 21 weeks, P = 0.04).
Cancer Therapy Vol 5, page 79
Patients treated in the vinorelbine arm scored better than III. Non-platinum-based
controls on many QoL subscales. The ELVIS trial
represents a landmark regarding the feasibility and the
palliative role of chemotherapy in elderly advanced In order to improve the results obtained with single-
NSCLC patients. agent chemotherapy, some non-platinum-based
Gemcitabine is one of the most widely used drugs for combinations have been developed. The most studied non-
the treatment of NSCLC. Several phase II trials platinum-based regimen is gemcitabine plus vinorelbine.
specifically designed for elderly patients with advanced Two phase III trials have compared gemcitabine plus
NSCLC have confirmed the role of gemcitabine in this vinorelbine combination with a single-agent therapy
setting. In patients older than 70 years, gemcitabine (Frasci et al, 2000; Gridelli et al, 2003). A small study of
yielded overall response rates (ORR) of 18% to 38% and gemcitabine 1200 mg/m2 plus vinorelbine 30 mg/m2
MST of 6.8 to 9 months (Ricci et al, 2000; Altavilla et al, versus vinorelbine 30 mg/m2 alone (n = 120 patients)
2000; Martoni et al, 2001; Gridelli et al, 2001). closed early when an interim analysis showed that the
Gemcitabine was generally well tolerated, with only two of combination conferred a significant survival advantage
these studies showing any grade 3 to 4 hematologic over the single agent (MST: 29 versus 18 weeks, p < 0.01)
toxicities. and a better ORR (Frasci et al, 2000). However, the 18-
The taxanes (paclitaxel and docetaxel) have week survival for single-agent vinorelbine in this study is
demonstrated both activity and tolerability in the treatment markedly lower than the 28- to 38-week survival times
of advanced NSCLC. A recent review of two phase II trials reported in six large randomised trials, including three
of paclitaxel 210 mg/m2 every 3 weeks compared outcome studies dedicated entirely to elderly patients (Rossi et al,
according to age (< 70 versus ! 70 years). This analysis 2005; Kudoh et al, 2006). The Multicenter Italian Lung
cancer in the Elderly Study (MILES) trial, enrolling 700
showed no differences in ORR or MST between the age
patients with NSCLC, is the largest phase III study of the
groups but the most frequent toxicity, neutropenia, tended
elderly published to date (Gridelli et al, 2003). Patients
to occur more frequently in the older patient group (89.3%
were randomised to receive single-agent chemotherapy
versus 73.9% in younger patients) (Nakamura et al, 2000).
with vinorelbine 30 mg/m2 or gemcitabine 1200 mg/m2 or
In an effort to reduce toxicity, weekly regimens of single-
combination therapy with vinorelbine 25 mg/m2 plus
agent paclitaxel have been investigated in three phase II
gemcitabine 1000 mg/m2, all treatments recycled every 3
studies resulting in ORR and MST ranging from 3% to
weeks. Combination treatment had no advantage in terms
23% and from 6.8 to 10.3 months, respectively, with
of ORR, time to progression (TTP), MST or QoL over
reasonable toxicity profiles (Fidias et al, 2001; Garbo et al,
single-agent therapy. Moreover, although toxicity was
2001; West et al, 2001). Regarding docetaxel, in a phase II
considered acceptable in all groups, it was higher with the
trial, weekly doses of docetaxel were well tolerated
combination than with the single agents. The authors
(Hainsworth et al, 2000). A phase II randomized trial of
concluded that single-agent therapy with vinorelbine or
the two different schedules of administration of docetaxel
gemcitabine is preferable to the combination for treatment
(weekly or every 3 weeks) in advanced NSCLC elderly
of advanced NSCLC in elderly patients.
patients or patients with PS 2 confirmed comparable
Table 1 summarises the randomized phase III trials
activity and lower hematologic toxicity for the weekly
performed in advanced NSCLC elderly patients.
schedule (Lilenbaum et al, 2004).
Recently, a randomized phase III trial reported that
docetaxel (60 mg/m" day 1 every 3 weeks) provided IV. Platinum-based chemotherapy
significantly longer progression-free survival (PFS) (5.5 Cisplatin administration is associated with significant
months versus 3.1 months; p < 0.001), a significantly haematological and non-haematological toxicity
higher ORR (22.7% versus 9.9%; p = 0.019) a more (nephrotoxicity, ototoxicity, neurotoxicity) and the
favourable 1-year survival rate (58.6% versus 36.7%) and evaluation of the risk versus benefit ratio should be
significantly better disease-related symptom improvement particularly rigorous in elderly patients. In this patient
than vinorelbine (25 mg/m" days 1 and 8, every 3 weeks) population, reduction of creatinine clearance and cisplatin
in elderly patients with advanced NSCLC (Kudoh et al, renal excretion is expected to increase the potential for
2006). These trial, enrolling 182 patients, fails to detect a toxicity, and the presence of comorbidities and
significant difference in MST, the primary objective of the compromised PS may preclude cisplatin administration in
study, despite a longer median survival in favour of a significant proportion of elderly patients (Oshita et al,
docetaxel-treated patients than vinorelbine-treated patients 1995).
(14.3 versus 9.9 months, respectively; p = 0.065). Major Compared to cisplatin, carboplatin causes lower rates
toxicity was grade 3-4 neutropenia in both arms, 82.9% in of emesis, nephrotoxicity and neurotoxicity, and it
docetaxel and 69.3% in vinorelbine group (p = 0.031). represents an appealing alternative for platinum-based
This is the first prospective, randomized phase III trial in chemotherapy, although safety remains a problem
which a single-agent treatment results superior, in several especially in terms of hematological toxicity, particularly
outcomes but the primary end-point, to another one in the if it is administered in combination with other myelotoxic
treatment of advanced NSCLC elderly patients. Therefore, agents. Platinum-based chemotherapy for elderly patients
further larger phase III trials needed to confirm these with advanced NSCLC has been evaluated both in
results. retrospective and prospective trials.
Rossi et al: The role of chemotherapy in the treatment of advanced non-small cell lung cancer elderly patients
Table 1. Results from phase III trials of advanced non-small-cell lung cancer in elderly patients.
Author Regimen Age (years) No.pts RR (%) MST (months)
ELVIS trial, 1999 Vinorelbine 76 20 6.5
vs ! 70
Best Supportive Care 78 NA 4.8
Frasci, 2000 Vinorelbine 60 15 4.2
Vinorelbine + Gemcitabine ! 70 60 22 6.7
Gridelli, 2003 Vinorelbine or 233 18 8.3
Gemcitabine 233 16 6.5
vs ! 70
Vinorelbine + Gemcitabine 232 21 6.9
Kudoh, 2006 Vinorelbine 91 9.9 9.9
Docetaxel 88 22.7 14.3
ELVIS = Elderly Lung cancer Vinorelbine Italian Study; RR = response rate; MST = median survival time; NA = not applicable.
A. Retrospective analyses of platinum- vinorelbine, and the SWOG 9308 trial that compared
based chemotherapy cisplatin plus vinorelbine with cisplatin alone (Nguyen et
The issue of cisplatin- and carboplatin-based therapy al, 1999). The results showed no statistically significant
for elderly patients with advanced NSCLC has been influence of age on MST (8.6 versus 6.9 months for < 70
addressed in some retrospective analyses of large versus ! 70 year old patients; p = 0.06), TTP (4.2 versus
randomised trials without an upper age limit in the 3.9 months; p = 0.62) or toxicity. Moreover, these trials
inclusion criteria (Nguyen et al, 1999; Kelly et al, 2001; seem to support the higher tolerability of carboplatin
Langer et al, 2002, 2003; Rocha Lima et al, 2002; Hensing versus cisplatin, at least at a dose of 100 mg/m2: 46% of
et al, 2003; Belani and Fossella 2005; Belani et al, 2005; elderly patients who received cisplatin and vinorelbine
Lilenbaum et al, 2005). discontinued chemotherapy due to unacceptable toxicity,
A retrospective analysis of Eastern Cooperative and this proportion was significantly higher than the
Oncology Group (ECOG) 5592 compared the effects of discontinuation rate for toxicity in younger patients. In
first-line cisplatin plus either etoposide or paclitaxel in 86 contrast, only 16% of elderly patients treated with
patients aged ! 70 years with those in 488 younger carboplatin and paclitaxel stopped treatment for toxicity
patients (Langer et al, 2002). There were no significant reasons, without a significant age-related trend (Nguyen et
differences between the younger and older patients in any al, 1999). A third retrospective study of a trial of two
of the efficacy measures, with only minimal differences in different schedules of carboplatin plus paclitaxel
toxicity between the age groups (the elderly had worse confirmed these findings (Hensing et al, 2003).
leukopenia and neuropsychiatric disorders). An additional Other elderly subset analyses have also been reported
analysis of the small subset of patients aged > 75 revealed recently (Lilenbaum et al, 2005; Belani and Fossella
no differences in outcomes compared with patients aged 2005). The Cancer and Leukemia Group B (CALGB)
70–75, and there was only a borderline increase in compared carboplatin plus paclitaxel with paclitaxel alone
leukopenia in the older age group (p = 0.06). and found no differences in MST between patients aged <
Langer et al, also analysed data from ECOG 1594 in 70 and those aged > 70. A secondary analysis of the study
which four treatment combinations (cisplatin/paclitaxel, showed that the survival advantage for the platinum-based
cisplatin/docetaxel, cisplatin/gemcitabine and doublet was also seen in the subgroup of elderly patients
carboplatin/paclitaxel) were evaluated as first-line (8 versus 5.8 months), although this difference was not
chemotherapy for NSCLC (Langer et al, 2003). No statistically significant, due to the limited number of
significant differences were reported for RR (24.5% elderly enrolled (Lilenbaum et al, 2005). First-line
versus 22.1%) or MST (8.3 versus 8.2 months) for the 227 docetaxel plus either cisplatin or carboplatin was
patients (20%) aged ! 70 compared with those aged < 70. compared with vinorelbine plus cisplatin in the TAX 326
Only a marginally significant (p = 0.04) increase in grade trial. A subset analysis of 401 patients aged ! 65 was
4 toxicities was reported in the elderly population. A conducted (Belani and Fossella 2005) and showed that
similar retrospective analysis was undertaken for the docetaxel plus cisplatin provided substantial increases in
Southwest Oncology Group (SWOG) 9509 trial, which survival (1 year: 52% versus 41%; 2 year: 24% versus
compared carboplatin plus paclitaxel with cisplatin plus 17%) compared with vinorelbine plus cisplatin. Both
docetaxel regimens were well tolerated in the elderly
Cancer Therapy Vol 5, page 81
subgroup, although the lowest incidence of toxicity Table 2 summarizes retrospective data analyses of
occurred in the docetaxel plus carboplatin arm. elderly patients enrolled in phase III trials with platinum-
Belani et al, reported retrospective analyses related to based chemotherapy.
elderly patients randomized to receive carboplatin plus
weekly paclitaxel versus carboplatin plus standard B. Prospective trials with platinum-based
paclitaxel. For the elderly subgroup, the efficacy of the chemotherapy
weekly regimen appeared to be higher in terms of RR, Prospective clinical trials of platinum-based
TTP and MST with reduction in neuropathy as compared chemotherapy with inclusion criteria limited to the elderly
to the standard regimen of paclitaxel and carboplatin population are needed. Interest in reproducing cisplatin
(Belani et al, 2005). efficacy in elderly patients led to several prospective phase
Overall, these analyses show a similar outcome of II trials testing the combination of third-generation
platinum-based therapy for elderly patients compared to cytotoxic agents with cisplatin in modified schedules or
their younger counterparts, in terms of RR and MST, with attenuated doses to obtain an active and well-tolerated
a small but significant increase in toxicity in the elderly treatment. These employed schemas are not the
and no significant adverse effect on QoL. conventional ones (75-100 mg/m" on day 1, every 3
However, it must be noted that the aforementioned weeks) in fact, weekly regimens (Lippe et al, 2000;
analyses suffer from selection bias. In fact, the percentage Mattioli et al, 2002; Berardi et al, 2003; Ohe et al, 2004),
of elderly patients enrolled in these studies did not exceed fractionated doses (Buffoni et al, 2006), low doses (Feliu
20% of the actual study population. So, elderly patients et al, 2003) and 4 weeks recycled schedules (Perreira et al,
enrolled in these sort of trials are not representative of the 2004), were used in order to improve chemotherapy
whole elderly population but rather of a small subgroup tolerability. Four main phase II trials tested the
thought by investigators to be eligible for aggressive combination of cisplatin and gemcitabine reporting a ORR
treatments (Perrone et al, 2002). ranging between 32-44% with a MST of 9-10 months.
Table 2. Retrospective data analyses of elderly patients enrolled in phase III trials with cisplatin- or carboplatin-based
Author Treatment Age No.pts RR (%) MST P
Nguyen, 1999 CDDP+GEM > 70 53 15 7.7 n.s.
< 70 207 29 9.4
Kelly, 2001 CBDCA+TAX > 70 117 n.r. 6.9 0.06
CDDP+VNR < 70 491 n.r. 8.6
Langer, 2002 CDDP+VP-16 > 70 86 23.3 8.5 n.s.
CDDP+TAX < 70 488 21.5 9.1
Rocha Lima, 2002 CDDP+VBL > 70 31 16 5.7 n.s.
< 70 222 31 8.0
Langer, 2003 CDDP+TAX
CDDP+TXT > 70 227 25 8.3 n.s.
CDDP+GEM < 70 912 22 8.2
Hensing, 2003 CBDCA+TAX > 70 67 27 7.1 n.s.
< 70 163 20 7.8
CDDP+TXT > 65 149 n.r. 12.6 n.s.
all ages 408 32 11.3
Belani, 2005 CDDP+VNR > 65 134 n.r. 9.9 n.s.
all ages 404 25 10.1
CBDCA+TXT > 65 118 n.r. 9.0 n.s.
all ages 406 24 9.4
CBDCA+TAXw > 70 70 25.7 9.2 n.r.
Belani, 2005 < 70 147 28.6 9.6
CBDCA+TAX > 70 63 19 7.7 n.r.
< 70 151 19.2 11.4
Lilenbaum, 2005 CBDCA+TAX > 70 77 36 8.0 n.s.
< 70 207 30 8.5
CDDP = cisplatin; CBDCA = carboplatin; TAX = paclitaxel; TXT = docetaxel; VNR = vinorelbine, GEM = gemcitabine; VBL =
vinblastine; VP-16 = etoposide; RR = response rate; MST = median survival time; S = survival; w = weekly; n.r. = not reported; n.s. =
Rossi et al: The role of chemotherapy in the treatment of advanced non-small cell lung cancer elderly patients
The treatment was well tolerated (Lippe et al, 2002; or more achieved similar benefit from this combination in
Berardi et al, 2003; Feliu et al, 2003; Moscetti et al, 2005). terms of RR and MST with equally good tolerability of
The cisplatin plus vinorelbine schedule has been tested in younger ones (Masters et al, 2005).
three phase II trials reporting a ORR of 33-50% with a Variable results have been observed with attenuated
MST of 7.4-11 months. This combination was safe, too doses or modified weekly schedules of carboplatin plus
(Mattioli et al, 2002; Pereira et al, 2004; Buffoni et al, paclitaxel; RRs have ranged from 14% to 60.9% and
2006). Ohe et al, treated 33 patients aged > 75 years with MSTs from 7.1 to 13.6 months (Jatoi et al, 2003; Choi et
weekly cisplatin plus docetaxel reporting a ORR of 52% al, 2003; Okamoto et al, 2003; Marsland et al, 2005; Inoue
and a MST of 15.8 months with a modest toxicity (Ohe et et al, 2006; Pujol et al, 2006).
al, 2004). Table 4 summarises the results of phase II trials with
The results of phase II trials employing third third-generation carboplatin-based chemotherapy in
generation cisplatin-based chemotherapy are reported in advanced NSCLC elderly patients employing attenuated
Table 3. doses or weekly administration of carboplatin.
Among the new generation carboplatin-based
regimens, two phase II studies were performed adding V. Targeted therapies
carboplatin to vinorelbine, but reported activity (14% and Gefitinib (ZD1839, Iressa) and erlotinib (OSI774,
27% RR) does not suggest any clinical improvement Tarceva), two orally available selective and reversible
compared to single agent chemotherapy also in inhibitors of epidermal growth factor receptor (EGFR)
consideration of a significant rate and degree of tyrosine kinase, have demonstrated activity as single-agent
mielotoxicity (Colleoni et al, 1996; Santomaggio et al, therapy in heavily pretreated patients with NSCLC
1996). In contrast, the combination of low-dose (Gridelli et al, 2004).
carboplatin (AUC 4) and gemcitabine produced a RR of Subset analysis of several studies that have included
37.5% and a MST of 9.0 months, with a favourable patients aged ! 70 years suggests that gefitinib is active
toxicity profile (Maestu et al, 2003). Recently, the results and generally well tolerated in this population (Gridelli et
of a subset analysis of carboplatin plus gemcitabine from a al, 2004). The combination of gefitinib with either
randomized phase II study were reported. Patients aged 70
Table 3. Phase II trials of cisplatin-based chemotherapy with third-generation agents and modified schedules or attenuated
doses of cisplatin
Author Regimen CDDP dose Age (years) No. Pts RR (%) MST (months)
Mattioli, 2002* CDDP + VNR 25 mg/m2, weekly > 65 36 36 11
Pereira, 2004 CDDP + VNR 60-90 mg/m" > 70 44 50 7.5
Buffoni, 2006 CDDP + VNR 30 mg/m", day 1 and 8 > 70 30 33 7.4
Lippe, 2002 CDDP + GEM 35 mg/m2, weekly ! 65 29 48 10
Berardi, 2003 CDDP + GEM 35 mg/m2, weekly ! 70 48 31.8 9
Feliu, 2003 CDDP + GEM 50 mg/m2 ! 70 46 35 10.2
Moscetti, 2005 CDDP + GEM 75 mg/m", day 2 > 65 46 45.6 15
Ohe, 2004 CDDP + TXT 25 mg/m2, weekly ! 75 33 52 15.8
*including 3 unfit patients; CDDP = cisplatin; VNR = vinorelbine; GEM = gemcitabine; TXT = docetaxel; RR = response rate; MST =
median survival time; S = survival
Table 4. Phase II trials of modified administration of carboplatin-based chemotherapy with third-generation agents
Author Regimen Age (years) No. RR (%) MST (months)
Colleoni, 1996 Carboplatin + vinorelbine ! 70 22 14 n.r.
Santomaggio, 1996 Carboplatin + vinorelbine ! 60 44 27 6.5
Maestu, 2003 Carboplatin + gemcitabine ! 65 88 37.5 9.0
Masters, 2005° Carboplatin + gemcitabine > 70 32 43.3 10.2
Jatoi, 2003 Carboplatin + paclitaxel > 65 49 14 1-year S 31%
Choi, 2003* Carboplatin + paclitaxel ! 65 35 40 8.6
Okamoto, 2005 Carboplatin + paclitaxel ! 70 25 28 12.3
Carboplatin ! paclitaxel 61 22.4 8.2
Marsland, 2005* ! 70
Carboplatin + paclitaxel 60 60.9 9.2
Inoue, 2006 Carboplatin + paclitaxel ! 70 42 45 14
Pujol, 2006 Carboplatin + paclitaxel > 70 51 43 13.6
°Retrospective analysis from a phase II study; *Including unfit patients; RR = response rate; MST = median survival time; n.r. = not
reported; S = survival
Cancer Therapy Vol 5, page 83
vinorelbine or gemcitabine was investigated in a VI. Octogenarians
prospective study of 60 patients aged ! 70 years with In general, little data exist regarding the outcome of
advanced NSCLC. Gefitinib combined with gemcitabine chemotherapy in NSCLC patients aged 80 or more, a
showed low activity, but was generally well tolerated. In rapidly expanding, potentially vulnerable population
contrast, toxicity was unacceptable in the vinorelbine arm cohort. In an age-specific subanalysis of trial ECOG 1594,
in which 18 of 25 patients (72%) had grade 3/4 investigators observed only 9 patients more than 80 years
neutropenia, and there were 3 treatment-related deaths of age (less than 1% of all enrolees). It is notable that only
with no ORR reported (Scagliotti et al, 2004). Very 1 of these 9 patients was able to complete four cycles of
recently, erlotinib has been tested prospectively in a phase chemotherapy. Efficacy in this group was very poor: 0%
II study in patients aged more than 70 years with ORR; PFS of 2.2 months, and MST of only 4.2 months.
previously untreated advanced NSCLC. Preliminary These patients fared worse than patients aged 70-79 when
results on 80 patients, suggest that erlotinib is well treated with platinum-based combinations with time to
tolerated with encouraging activity (ORR of 10.9%) as progression and survival roughly half that observed in the
first-line treatment of advanced NSCLC of elderly much larger cohort of patients 70-79 years of age (Langer
patients. Adverse events were generally mild, although all et al, 2003).
responding patients developed a rash (which in 2 cases A combined analysis of two separate trials performed
was severe) (Jackman et al, 2005). in elderly patients provides additional information
Recently, we concluded the accrual in a randomized (Hesketh et al, 2005). One study compared weekly
phase II study, named CALC-1 (Cetuximab in Advanced docetaxel to every 3-week docetaxel, and enrolled 26
Lung Cancer), in which cetuximab (IMC-C225), a human- patients aged 80 or older. The second trial, tested
mouse chimeric anti-EGFR monoclonal antibody, is sequential vinorelbine-docetaxel and included 23 patients
administered in combination with gemcitabine or over age 80. Tolerance to treatment was similar between
gemcitabine followed by cetuximab in advanced NSCLC patients aged 70-79 and those over 80 years. For patients
patients unsuitable for combination chemotherapy. with performance status 0-1, median survival was actually
The humanized monoclonal antibody bevacizumab, shorter in the octogenarian group compared to patients
directed against vascular endothelial growth factor aged 70-79 (7 versus 11 months). For PS 2 patients,
(VEGF), is the first and, currently, the only pure anti- survival was equally poor in both groups (4 versus 5
angiogenic agent licensed for use in combination with months). Clearly, more studies in this age group need to be
fluorouracil-based chemotherapy for first-line treatment of conducted.
patients with metastatic colorectal cancer in the US and
Europe (Gridelli et al, 2006). The clinical development of
bevacizumab combined with chemotherapy in the
VII. Second-line chemotherapy
treatment of advanced NSCLC has produced exciting Very recently, evidences regarding the feasibility of a
results (Johnson et al, 2004; Sandler et al, 2006). These second-line chemotherapy in advanced NSCLC elderly
studies represent the first evidence of superior efficacy of patients are emerging. A retrospective analysis of a
targeted therapy combined with chemotherapy over randomized phase III trial of pemetrexed versus docetaxel
chemotherapy alone in the treatment of NSCLC. Despite in the second-line treatment of advanced NSCLC showed
squamous histology was excluded, because of risk of that elderly benefit of treatment as their younger
grade 5 hemoptysis reported in the phase II randomized counterparts.
study (Johnson et al, 2004), in the following phase III trial, The reported results for elderly patients are as
there were 15 treatment-related deaths in bevacizumab follows: 47 patients enrolled in the pemetrexed arm and 39
group, including 5 from pulmonary haemorrhage (Sandler in the docetaxel group; TTP was 4.6 and 2.9 months, MST
et al, 2006). No data about bevacizumab and elderly was 9.5 and 7.7 months, 12-months survival was 20.4%
patients have been reported, but the toxicity profile of and 23.1%, 24-months survival was 6.1% and 10.6%,
bevacizumab, does not appear particularly suitable to the respectively. A smaller number of patients, 40 in the
elderly population, often characterised by cardiovascular pemetrexed group and 36 in the docetaxel arm, were
comorbidities. In fact, a recent analysis from 1,745 evaluable for ORR which was 5% and 5.6% with a stable
patients included in 5 different clinical trials, with disease of 60% and 41.7%, respectively. Overall, 40
different tumours, showed that 7.1% of patients older than patients in the pemetrexed group and 37 in the docetaxel
65 years and treated with bevacizumab suffered arm were evaluable for grade 3-4 toxicity reported
thromboembolic complications, and that it went up to neutropenia in 12.5% and 29.7%, neutropenia febrile in
17.9% in those with a previous history of atherosclerosis 2.5% and 18.9%, anemia in 0% and 2.7%, muscle
(Skillings et al, 2005). Moreover, bevacizumab is to be weakness in 5% and 0%, respectively (Weiss et al, 2006).
administered intravenously and in combination with The authors concluded that for elderly patients with
chemotherapy, thus not being associated with the advanced NSCLC and good PS, second-line cytotoxic
advantages of oral single agent targeted therapies. In fact therapy is appropriate, with pemetrexed producing a more
oral adiministration and the possibility of some targeted favorable toxicity profile compared to docetaxel. These
agents to be administered without chemotherapy are results may appear very attractive, but we strongly suggest
factors encouraging their use in elderly patients. to be careful in overemphasizing them, as they derived
from a retrospective analysis which could be influenced by
selection bias like that reported in the first-line setting.
Rossi et al: The role of chemotherapy in the treatment of advanced non-small cell lung cancer elderly patients
In addition, a phase II trial reported good activity and of age. This group is a particularly attractive target for
toxicity profile for a modified schedule of docetaxel (37.5 studies using molecular targeted and other potentially less
mg/m2 on days 1 and 8 every 3 weeks) (Tibaldi et al, toxic oral single agents.
2006). While we are still working hard to define the best
first-line treatment to be generalized for this growing
VIII. Conclusions population, we are going into another minefield, such as
NSCLC remains a major problem in the US, western second-line therapy. It may be very dangerous without a
civilization, and developing countries. Unfortunately, correct and pragmatic strategy. In our opinion, only
approximately 90% of all NSCLC patients will eventually second-line prospective studies, specifically addressed to
die from their disease. SEER data in the U.S. suggest that elderly patients with advanced NSCLC, are welcome.
69 is the median age at diagnosis (Havlik et al, 1994). Moreover, in order to better define elderly patients
With the aging of the population one may expect that the enrolled in clinical trials, every patient should receive a
prevalence of lung cancer among the elderly will increase. complete functional assessment at baseline allowing a
The use of chemotherapy in the elderly NSCLC clearer interpretation of trial results.
population is complicated by a number of age-related
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From left to right Paolo Maione, Giuseppe Colantuoni, Anna Verrengia, Filomena Del Gaizo, Cesare Gridelli, Rosa Bruno,
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