Nonsmall-cell lung cancer, including
squamous cell, adeno and large-cell carcinomas, accounts for
approximately 80% of lung cancers; its 5-year survival rate is about
12% across all stages. The median survival duration in metastatic
nonsmall-cell lung cancer, however, which constitutes
approximately 60% of all nonsmall-cell lung cancer cases, is
around 6 months, and the 1-year survival rate ranges between 10% and 20%.
Chemotherapy is by far the most widely used treatment for advanced
nonsmall-cell lung cancer, but survival has been only
marginally improved, even with the use of modern cisplatin
(Platinol)-based regimens. Meta-analyses of randomized clinical
studies in patients with metastatic nonsmall-cell lung cancer
comparing chemotherapy to best supportive care have recently shown
marginal benefits of cisplatin-based regimens on survival and on
One of the meta-analyses suggests that cisplatin-based chemotherapy
may provide a 27% reduction in the risk of death and an absolute
benefit of about 10% at 1 year in metastatic disease. Because of
this really modest benefit, it has become mandatory to evaluate the
toxicity of chemotherapy regimens and their impact on patients
quality of life.
Quality of life may be improved with chemotherapy for patients with
unresectable stage III and stage IV disease, but data to support this
supposition are sparse.[4-6] Evidence documenting symptomatic
improvement that supports a palliative role for chemotherapy in
nonsmall-cell lung cancer is principally derived from
retrospective reviews of patients and physicians
perception or, when prospectively derived, is not obtained from
randomized trials in which some patients received no therapy.[4,7]
Furthermore, balancing symptomatic improvement related to treatment
with the toxicities caused by chemotherapy can be difficult.
A number of new chemotherapeutic agents with innovative mechanisms of
action have recently become available in clinical practice. These
novel compounds, such as paclitaxel (Taxol), docetaxel (Taxotere),
vinorelbine (Navelbine), gemcitabine (Gemzar), and irinotecan
(CPT-11; Camptosar) have shown activity as single agents. They have
also been tested in combination with platinum compounds in phase II
trials in nonsmall-cell lung cancer showing promising efficacy
with a relatively low toxicity profile.
Paclitaxel has been shown to be one of the most active agents in
nonsmall-cell lung cancer. In phase II trials conducted by the
Eastern Cooperative Oncology Group (ECOG) and at M. D. Anderson
Cancer Center, paclitaxel as a single agent yielded response rates of
21% and 24%, with 1-year survival rates of 30% and 40%,
respectively.[9,10] The combination of paclitaxel with cisplatin
improved the response rate (range, 35% to 38%) in some phase II
studies including a small number of patients.[11,12]
More importantly, quality-of-life improvement could be a possibility
when using these combinations because of their safety profile. Of
course, before any generalized conclusion can be made, such an
improvement should be demonstrated in phase III randomized trials in
which quality of life represents an important end point, and the
evaluation is formally requested through a validated instrument.
Two phase III trials of platinum/paclitaxel combinations reporting
quality-of-life evaluation trials have recently been published.[13,14]
In the ECOG trial, the standard therapy for
nonsmall-cell lung cancer (cisplatin [75 mg/m²]/etoposide
[VP-16] [100 mg/m², days 1 through 3]) was compared with the
experimental arms containing two dose levels of paclitaxel (135
mg/m² and 250 mg/m² in 24 h) combined with cisplatin (75
mg/m²). In 560 eligible patients with stage IIIB and IV disease,
the response rate, median survival time in months, and 1-year
survival were 12%, 7.69 months, and 31.6% for the standard regimen;
26.5%, 9.56 months, and 36.9% for the low-dose paclitaxel regimen;
and 32.1%, 9.99 months, and 39.1% for the high-dose paclitaxel
regimen, respectively. These results show a significantly higher
response rate for the paclitaxel-containing regimens, together with a
trend for longer survival.
In the Eastern Cooperative Oncology Group trial, quality of life was
evaluated using the Functional Assessment of Cancer TherapyLung
(FACT-L) assessment scale at baseline, 6 weeks, 12 weeks, and 6
months. Subscale scores for physical, functional, emotional, and
social well-being, plus a score of lung cancer symptoms, were also
recorded. Despite some improvement of quality of life in the
paclitaxel-containing arms, the conclusion was that, on all scores,
there were no treatment arm differences, despite increased myalgias
and neurotoxicities on the paclitaxel-containing arms.
The European Organization for Research and Treatment of Cancer
(EORTC) study compared the combination of cisplatin (80 mg/m²)
and teniposide (VM-26; Vumon) (100 mg/m² x 3) (Arm A) which was,
at that time, the standard of the group, with the
cisplatin/paclitaxel (175 mg/m², 3-hour infusion) (Arm B)
regimen in 132 patients with stage IIIB or IV disease. Response rates
were 44% in the paclitaxel arm and 30% in the teniposide arm, whereas
survival was almost the same (9.4 and 9.7 months, respectively).
Selected centers participated in quality-of-life assessment, which
was performed by the EORTC Quality of Life Questionnaire (QLQ)-C30,
and the lung module, administered at baseline and every 6 weeks
thereafter. Arm A achieved a better score at week 6 for emotional,
cognitive, and social functioning; global health status; fatigue;
appetite loss; and hair loss (which was still partially maintained at
12 weeks). Arm B attained a better score for cough, and tingling in
the hands and feet. The authors conclusions were that the
paclitaxel-containing regimen appeared to be superior in response
rate, side effects, and quality of life, although median survival did
not seem to be improved.
Ongoing Trials Evaluating Quality of Life
Other trials comparing paclitaxel-containing regimens and evaluating
quality of life are still ongoing. In some of these trials, cisplatin
has been replaced by carboplatin (Paraplatin) because of the frequent
findings of myalgia and peripheral neurotoxicity in the
cisplatin/paclitaxel combination, due to the overlapping
neurotoxicity of the two drugs. The combination of carboplatin and
paclitaxel was tested in many phase II trials with different infusion
times for paclitaxel (24 hours, 3 hours, 1 hour).[17-19]
Dose-limiting toxicity was myelosuppression with 24-h infusion and
neuropathy with shorter infusions.
Response rates ranged from 12% to 62%, and 1-year survival was 54%
for patients treated at the Fox Chase Cancer Center. On the basis
of these data, the carboplatin/paclitaxel regimen was included in
some large cooperative trials ongoing in the United States (Southwest
Oncology Group [SWOG]) and in Europe (EORTC, Italian Lung Cancer
Project), and in evaluating quality of life. The SWOG study is
comparing the combination of cisplatin/vinorelbine vs the
carboplatin/paclitaxel regimen in 400 patients. The Italian Study is
a three-arm study evaluating the standard cisplatin/vinorelbine vs
the new combinations cisplatin/gemcitabine and
carboplatin/paclitaxel. The planned accrual is 600 patients at more
than 40 participating centers. Quality of life is being evaluated
with the EORTC Quality of Life Questionnaire-C30. Another of these
trials, the PAN-European Trial (BMS-271), comparing paclitaxel (200
mg/m², 3-hour infusion) plus carboplatin (area under the
concentration-time curve of 6 [AUC in mg/mL · min]) vs
paclitaxel plus cisplatin (80 mg/m²), completed the accrual of
618 patients in July 1997 and its results are eagerly awaited.
Despite the discovery of new active drugs and the improved response
rates, overall survival is only slightly better than in the recent
past, and, as a consequence, it is of fundamental importance to
evaluate the toxicity of a given therapy and its impact on the
quality of life of treated patients. Standard end points do not
measure the effects of cancer or its treatment on the emotional,
spiritual, and social dimensions of patients lives. The use of
a quality-of-life instrument may help in determining a patients
preference for treatment.
In the past, there were few formal studies of quality of life in
patients with nonsmall-cell lung cancer. In a randomized
comparative trial of chemotherapy and radiotherapy, using a
patient-rated psychological scale, results indicated that patients
are willing to trade toxicity for the chance of responding to
treatment. No differences in quality of life were detected in the
follow-up period in patients treated with radiotherapy or with
Unfortunately, gathering data from properly validated questionnaires
on quality of life is very time-consuming, and there are considerable
difficulties in the methodology for analyzing the data. Nevertheless,
there are now several instruments to measure quality of life such as
the FLIC, the FACT-L, and the newer EORTC QLQ-C30 and lung
cancer module questionnaire described previously.
Though they are far from being ideal questionnaires, the ECOG and
EORTC trials used two of the better validated instruments. The ECOG
study could not demonstrate a significant difference in quality of
life among the three arms, though a short-lived improvement in
quality of life was more frequent in the paclitaxel arms.
An interesting finding of the ECOG study was that the use of FACT
Physical Well-being, and FACT Trial Outcome Index (which combines the
physical, functional, and lung cancer scores) can predict response
and survival. This confirms the earlier propositions that quality of
life can be considered an independent prognostic variable for
survival in lung cancer.[23,24]
The EORTC study presents some limitations regarding the validity of
the quality-of-life assessment. In fact, quality of life was
evaluated in a limited number of patients (104/317) because only a
few centers decided to participate. Besides, the reference regimen
(cisplatin-teniposide) cannot be considered the best standard outside
the specific experience of the group. Finally, there was a consistent
dropout in serial assessment of quality of life (104 down to 32
patients from baseline to 24 weeks).
This consistent dropout is a difficulty that researchers are facing
in almost every study. Reasons for this can be the worsening of
the patients symptoms, the lack of motivation by the
investigators, and also the lack of a dedicated staff member or team
for quality-of-life evaluation. This could result in difficulties in
explaining the procedures and in collecting quality-of-life data in
order to optimize completeness and reduce variability and noncompliance.
Despite these problems, some large ongoing trials contain a formal
quality-of-life-evaluation, and some include a pharmacoeconomic
analysis. It is to be hoped that through the interweaving of the
results of such trials (or the confirmation of activity in different
settings and situations, similar trends in toxicity, and quality of
life), a standard therapy can be identified. Also, when determining
the balance between quality and quantity of life, the patients
views should always be considered. Patients generally believe that
small improvements in survival are worthwhile, despite the
perceptions among medical and nursing staff of toxic chemotherapy.
The support of appropriate clinical studies represents the only valid
way of improving the outlook of patients in order to develop and
confirm the benefits of new treatments for advanced
nonsmall-cell lung cancer.
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