1. health and fitness
2. disease
3. cancer

Annals of Oncology 12 (Suppl. 3). S21-S25, 2001.
© 2001 Khmer Academic Publishers. Primed in the Netherlands.
Symposium article
Quality of life in lung cancer patients
C. Gridelli,1 F. Perrone,2 F. Nelli,3 S. Ramponi3 & F. De Marinis3
1
Divisionedt Oncologia Medica B, Isliluto Nazionale Tumori, Naples: 'Ufficio Sperimentazwni Cliniche Controllate, Islituto Nazionale Napoh;
5 Unita di Pneumologia. Ospedale S. Camillo-Forlanini, Rome, Italy
Summary
Factors of affecting quality of life in lung cancer
As with many other patients affected with solid tumors,
the quality of life (QoL) of lung cancer patients is
affected by several factors related to the patient, disease
and treatment characteristics. Such determinants are
correlated with the type and stage of disease affecting
treatment strategy and different treatment strategies
(e.g., surgery, radiotherapy, chemotherapy) determining
patient acceptance and side effects.
For small-cell lung cancer (SCLC), the most widely
accepted strategy is aggressive, primarily based on chemotherapy and combined with radiotherapy for a limited
disease. On the other hand, the treatment strategy for
non-small-cell lung cancer (NSCLC) is strongly dependent on the stage of the disease, surgery being the
first choice for early stages, a combination of chemoand radiotherapy for locally advanced disease, and chemotherapy alone being presently the best therapeutic
option for metastatic patients.
Surgical resection, indicated in early stage NSCLC,
implies a careful selection of patients based on the
presence of co-morbidity, general health status and
functional respiratory assessment. When feasible, the
extension of resection may significantly impair patient
QoL, e.g., in the case of pneumectomy. Combined chemoradiotherapy, employed for treatment of limited SCLC
and locally advanced NSCLC, may produce significant
toxicity, both acute (e.g., esophagitis, myelosuppression)
and late (e.g., fibrosis), particularly when concurrent
Key words: non-small-cell lung cancer, quality of life, smallcell lung cancer
schedules are used; in addition, the logistics of concurrent, combined treatments are usually more complicated
than single or sequential treatment strategies. In the
case of prophylactic brain irradiation for limited SCLC,
which was found to be effective in a meta-analysis of
randomized clinical trials (1), the impact of toxicity
(long-term neurological impairment) must be balanced,
from the patient's perspective, with the chances of prolonging survival. Chemotherapy alone, employed for
treatment of metastatic NSCLC and extensive SCLC, is
frequently characterized by relevant toxicity, particularly when cisplatin is used or when combinations of
several agents are applied. It must be acknowledged
that, from the standpoint of toxicity, chemotherapy is
usually viewed negatively by patients and relatives.
End points of lung cancer treatment
The treatment of SCLC does prolong patient survival in
comparison with no treatment, independently of stage
of disease. It produces relatively high rates of tumor
regression that have a positive impact on tumor-related
symptoms. However, no major progress has been made
during the last decade, and several schemes of chemotherapy, including the oldest ones, are similarly active
and effective. Thus, it may be argued that if no difference
in prolonging survival exists among different schemes,
their toxicity and impact on QoL should be considered
in clinical practice. Thus, QoL should also be an impor-
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The quality of life of lung cancer patients is affected by several
factors related to the patients, stage of disease and treatment
characteristics. For small-cell lung cancer (SCLC), the treatment is generally aggressive, primarily based on chemotherapy.
Treatment strategy for non-small-cell lung cancer (NSCLC) is
strongly dependent on the stage of the disease and ranges from
surgery to palliative chemotherapy. Over the last few years,
very little progress has been made in terms of survival. Therefore, the effect of treatment on quality of life has become
progressively more relevant. Among the instruments for measuring quality of life, there are some specifically developed for
lung cancer, such as the European Organization for Research
and Treatment of Cancer (EORTC) LC-13 questionnaire, the
Functional Assessment of Cancer Therapy (FACT-L) questionnaire and the Lung Cancer Symptom Scale (LCSS). Up to
now, few randomised clinical trials have correctly evaluated
quality of life. There are evident pitfalls associated with the use
of frequently non-validated tools, and poor methods of data
analysis, but quality-of-life evaluation is crucial and should be
addressed through well-planned and well-conducted prospective clinical trials.
22
Specific problems of QoL evaluation in lung cancer
QoL analysis in lung cancer is affected by some general
sources of biases that become particularly important
due to epidemiological and prognostic specificities of
the disease.
First of all, lung cancer is frequently diagnosed in
elderly patients. This implies both cultural problems,
illiteracy still being a problem in many parts of the world
for people born at the beginning of the 20th century, and
medical problems, because of co-morbidities frequently
affecting elderly patients and potentially biasing QoL
evaluation. Second, the short-term survival of advanced
lung cancer patients and the rapid deterioration of performance status produce problems in collecting QoL
questionnaires; this leads to frequent but not necessarily
random occurrences of missing data. Indeed, it has been
shown that the baseline QoL estimates are worse for
those patients who subsequently fill in a few questionnaires as compared to those who are fully compliant
with QoL assessment until the end of treatment [4].
Specific instruments for QoL evaluation in lung cancer
Among the instruments for the evaluation of QoL, there
are some specifically developed for lung cancer. The
European Organization for Research and Treatment of
Cancer (EORTC) LC-13 questionnaire, a list of symptoms usually administered together with the core C-30
questionnaire, is the most widely used in clinical trials.
The Functional Assessment of Cancer Therapy (FACT-L)
questionnaire has a similar structure of 41 items in total,
concerning both general health status and site-specific
symptoms. The Lung Cancer Symptom Scale (LCSS) is
a list of nine site-specific symptoms, evaluated by the
patient, and six symptoms evaluated by an external
observer; no items in this scale are related to the evaluation of treatment-induced toxicity [5].
QoL evaluation in NSCLC randomised clinical trials
To date there have been no published papers dealing with
QoL evaluation in the adjuvant treatment of NSCLC. In
a recently completed adjuvant Italian trial (Adjuvant
Lung Project Italy - ALPI), a QoL assessment was
planned in a satellite project, but it was not successful
because of low compliance by participating centres.
In locally advanced disease, QoL has been assessed in
only one randomized trial [6] of radiotherapy vs. radiotherapy + chemotherapy. Unfortunately, compliance
was very low, with 67 out of 446 patients evaluable for
QoL measured by the EORTC questionnaires; thus, no
conclusion can be drawn.
On the contrary, formal QoL evaluation was done in
many randomized clinical trials performed in advanced
NSCLC, although it was indicated as the primary end
point of the study in only two cases [4,7].
Several studies have dealt with a comparison of
chemotherapy to best supportive care [4, 6, 8-13]. The
number of patients enrolled in these studies ranged from
48 to 351, although compliance with QoL analysis was
never complete. In addition, some of these studies were
flawed by inappropriate methods of analysis and some
of them have not yet been published as extended papers.
The ELVIS (Elderly Lung cancer Vinorelbine Italian
Study) group, coordinated by our institution, organised
thefirstrandomised trial dedicated to advanced NSCLC
patients over 70 years old, comparing vinorelbine to
best supportive care. In that study, QoL evaluated by
EORTC C-30 and LC-13 was the primary objective
because the investigators thought that a significant impact of single agent vinorelbine on survival was not
probable. To their surprise, the treatment significantly
prolonged survival (28 vs. 21 weeks of median survival)
to the same extent observed with cisplatin-based chemotherapy in adult patients, as reported by the metaanalysis [2]. Patient compliance with QoL assessment
was high on the baseline questionnaire (91.6%) and
progressively decreased (39.0% on the 6th questionnaire). The longer survival in the vinorelbine arm meant
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tant end point in clinical trials evaluating treatments
that a priori have no more chance of prolonging survival
than standard ones.
For early stage NSCLC patients, cure is a possible
end point of treatment; unfortunately, only about the
half of such patients are actually saved by surgery alone.
Thus, adjuvant and neoadjuvant chemotherapy are actually being studied, with the aim of measuring their
possible impact on patient survival. From this standpoint,
short-term QoL seems to be a secondary end point. For
locally advanced NSCLC, the standard strategy is based
on a combination of chemo- and radiotherapy. However, the manner of the combination (concurrent or
sequential), the type of drugs, the radiotherapy dose
and schedule are all investigational both in terms of
patient survival and of QoL. In metastatic NSCLC,
chemotherapy has only palliative effects; its impact on
survival is modest [2] and cisplatin induces toxicity and
patient discomfort. Thus, in this stage of disease, QoL
should more frequently be considered as a primary end
point of treatment both in clinical practice and, more
importantly, in clinical trials. Indeed, when patient preferences have been assessed, it has been shown [3] that
the degree of expected toxicity does significantly affect
the minimum survival gain as patients regard the effects
of toxicity to be a reason for not accepting chemotherapy. In the same study, when patients were informed
of a possible three-month survival prolongation, only
one-fifth of patients accepted chemotherapy. On the
other hand, two-thirds of the patients opted for chemotherapy in the scenario in which this form of therapy
demonstrated no effect on survival but provided significant reduction of pain and other tumour-related symptoms.
23
worsening
improving
physical functioning
role functioning
emotional functioning
cognitive functioning
social functioning
global health status
-25
-20
-15
-10
-5
0
5
10
15
20
25
Estimated score differences (mean and 95% Cl)
Figure I. Improvement of functional QoL scale data under vinorelbine
worsening
improving
fatigue
nausea/vomiting
pain
insomnia
appetite loss
constipation
diarrhoea
financial impact
dyspnoea
cough
hemoptysis
sore mouth
trouble swallowing
periph. neuropathy
hair loss
pain in chest
pain in shoulder
pain elsewhere
QoL evaluation in SCLC randomised clinical trials
Many trials have been conducted on SCLC in the last
few years, addressing questions like duration of chemotherapy, feasibility of oral treatment, efficacy of intensified chemotherapy, the role of 'new generation' drugs in
second-line treatment and supportive care benefit concomitant with chemotherapy. Some of these trials have
also had quality of life as a primary objective.
The effect of the duration of chemotherapy on QoL
was investigated in a randomised trial [20] of 458
patients with extensive disease SCLC. The trial compared six cycles of the ECMV regimen (etoposide, cyclophosphamide, methotrexate, vincristine) to three cycles
of the same regimen and to six cycles of IE (ifosfamide,
analgesics
0
-5
1
-10
I
-15
T
-20
I
-25
Estimated score differences (mean and 95% Cl)
Figure 2. Changes for lung cancer-specific items under vinorelbine.
etoposide). There was no difference in terms of toxicity,
response rate, survival, symptom palliation and QoL
among the three arms. Symptom control (cough, haemoptysis, chest pain, anorexia and dysphagia) was
achieved by 63% of the patients overall. These results
confirmed the ineffectiveness of a long-lasting treatment
for extensive disease SCLC.
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that patients in this group completed more questionnaires than those in the control arm. A pattern of
missing data was dependent on baseline values and time
of the QoL assessment. It was shown that patients with a
lower baseline global health status score tended to drop
out of the study earlier than those with a higher score,
and the probability of their dropping out was related to
previously observed scores. Furthermore, the global
health status of subjects who no longer provided QoL
assessments had worsened by the time of the previous
available observation. Vinorelbine induced an overall
improvement on the functional scales (Figure 1), which
was statistically significant for cognitive function and
borderline for global health status. Furthermore, patients treated with vinorelbine had higher scores than
control patients for some lung cancer-specific items
(pain, dyspnoea) but they scored lower for treatmentrelated toxicity items (constipation, nausea and vomiting, hair loss, and peripheral neuropathy), as shown in
Figure 2.
Many studies comparing different chemotherapy regimens have dealt with QoL analysis [7, 14-19]. Two large
randomised trials showed a difference in QoL (measured
by EORTC scales) favouring cisplatin + paclitaxel over
cisplatin + VM26 [16] and over cisplatin alone [15]. In
both studies the survival rate was the same; thus, the
advantage of QoL could be crucial to the interpretation
of study results. An ECOG trial comparing cisplatin +
paclitaxel (2 different doses) to cisplatin + etoposide
found a statistically significant survival advantage for
paclitaxel-containing regimens, with no difference in
QoL, measured by the FACT-L scale [17]. Other studies
failed to demonstrate any difference in QoL and survival
between the compared arms. As a criticism of these
trials, one can consider that the treatments under study
were not very different from one another in terms of
potential toxicity; indeed, in most of these studies cisplatin was present in both arms [18, 19]. A challenge for
the future is to determine whether non-cisplatin-based
chemotherapy provide better QoL outcomes with similar survival and less toxicity than standard cisplatinbased treatment.
24
strol. QoL data, measured by a visual analogue developed by the authors, showed that megestrol acetate did
not produce any significant improvement of the investigated items. Thus, the authors did not recommend the
routine use of megestrol acetate with chemotherapy in
SCLC. Unfortunately, the use of a non-validated tool for
QoL analysis does not allow a definitive conclusion.
Conclusions
Over the past few years, very little progress has been
made in the treatment of lung cancer patients in terms of
increased survival. As a consequence, the effect of treatment on QoL has become progressively more important
when discussing treatment options with patients. Sadly,
few randomised clinical trials have correctly evaluated
QoL. Improving the quality of our knowledge of the
impact of available treatments on patient QoL is mandatory and can be addressed only through well-planned
and conducted prospective clinical trials.
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Correspondence to:
C. Gridelli. MD
Divisione di Oncologia Medica B
Istituto NazionaleTumori
Via M. Semmola
80131, Naples
Italy
E-mail1 [email protected]
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