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					                                                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
Review Article

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: cgridelli@libero.it
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


                                                          Summary
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).


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      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).


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                                                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
                                                                      polichemotherapy
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.




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       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
                                             vs
                                 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
                                             vs
                                                                      > 70
                                          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


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                                                  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
chemotherapy

                Author                Treatment           Age           No.pts   RR (%)      MST         P
                                                                                           (months)
         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
                                   CBDCA+TAX
         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. =
not significant.




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       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



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                                                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.



                                                                 83
       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
issues. The reduced organ function and higher prevalence
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From left to right Paolo Maione, Giuseppe Colantuoni, Anna Verrengia, Filomena Del Gaizo, Cesare Gridelli, Rosa Bruno,
Carmine Ferrara, Costantina Mazza, Lucia Marra



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Rossi et al: The role of chemotherapy in the treatment of advanced non-small cell lung cancer elderly patients




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