Taxanes represent a novel class of
antineoplastic agents with broad antitumor activity. Paclitaxel
(Taxol) was the first taxane in clinical development and the numerous
trials performed thus far have enabled researchers to precisely
define its safety profile. Myelosuppression is dose- and
schedule-dependent; musculoskeletal symptoms are dose-dependent and
cumulative but not schedule-dependent. The safety profile of
paclitaxel has been based on a careful analysis of these toxicities,
allowing the best therapeutic regimen to be developed by combining
paclitaxel with other drugs. This approach creates the most favorable
Most patients with nonsmall-cell lung cancer present with
advanced disease and, therefore, chemotherapy is indicated. Cisplatin
(Platinol)-based chemotherapy regimens have been shown to produce a
survival advantage over best supportive care. In a phase
III randomized study performed by the Eastern Cooperative Oncology
Group (ECOG), paclitaxel at 250 mg/m² over 24 hours with
cisplatin at 75 mg/m², and paclitaxel at 135 mg/m² over 24
hours with cisplatin at 75 mg/m² were compared to the standard
treatment with cisplatin at 75 mg/m²and etoposide at 100
mg/m² for 3 days. The paclitaxel combinations proved more
efficacious in terms of response and survival, with a similar
toxicity profile in comparison to etoposide/cisplatin.
In another phase III study conducted by the European Organization for
Research and Treatment of Cancer (EORTC), paclitaxel/cisplatin was
compared to cisplatin/teniposide (Vumon). The paclitaxel combination
was better tolerated with less severe myelosuppression, febrile
neutropenia, infections, treatment delays, and dose reductions. The
paclitaxel combination produced more hypersensitivity reactions,
myalgia/arthralgia, and peripheral neurotoxicity.
As a single agent, carboplatin (Paraplatin), a cisplatin analog, has
produced the best 1-year survival rate with the least toxicity in a
five-arm ECOG study of patients with nonsmall-cell lung cancer.
The Hellenic Cooperative Oncology Group (HECOG) completed a phase II
study of paclitaxel at 175 mg/m², and carboplatin at an area
under the concentration-time curve of 7 (AUC in mg/mL · min). In
55 patients, the response rate was 27.3% and the 1-year survival was
21.6%. The median survival was 8.95 months. Generally, mild toxicity
was seen in this trial. World Health Organization (WHO) grade 3
neutropenia appeared in 7% of the patients, and no neutropenic
infection occurred. Grade 3 myalgia/arthralgia was reported in 5%.
One patient developed a hypersensitivity reaction shortly after the
beginning of the administration of the second cycle.
Subsequently, our group initiated a phase III trial with two
different doses of paclitaxel (225 mg/m² vs 175 mg/m²) and
a fixed dose of carboplatin (AUC of 6). In this study, neutropenia
and neurotoxicity were significantly worse at the higher paclitaxel
dose. However, the treatments were well tolerated and no
granulocytecolony-stimulating factor was required.
The paclitaxel/cisplatin combination has been shown to have a similar
toxicity profile to standard combinations when administered via
24-hour infusion and a better toxicity profile when given in a 3-hour
infusion. Paclitaxel/carboplatin is an easier to administer and
well-tolerated combination. A phase III randomized trial of the two
platinum combinations is in progress.
The taxanes are a novel class of antineoplastic agents with broad
antitumor activity. Paclitaxel was the first taxane in clinical
development, and has since been administered to thousands of patients
throughout the world. A variety of doses and schedules have been
studied in an effort to optimize a favorable therapeutic index. A
careful analysis of paclitaxel-related side effects is important for
a safer and more effective combination of this drug with other agents.
Myelosuppression and peripheral neuropathy are the major
dose-limiting toxicities of paclitaxel. A peculiar characteristic of
paclitaxel-induced neutropenia is the schedule-dependency, which
confers a clear safety advantage to short (3-hour) infusions. This
advantage facilitates the combination of paclitaxel with other
antineoplastic agents. The lack of cumulative myelosuppression
associated with paclitaxel is also important and beneficial for
Peripheral neuropathy is not schedule-dependent but cumulative (Table
1). For this reason, combining it with other neurotoxic agents
such as cisplatin necessitates careful monitoring. Musculoskeletal
symptoms such as myalgia and arthralgia are dose-dependent and
transient, but not cumulative.
As experience with paclitaxel increased, it became evident that
hypersensitivity reactions could be prevented by proper
premedication, and that cardiac abnormalities associated with the
drug consisted mainly of asymptomatic bradycardia or hypertension.
Additional care must be taken for patients with preexisting cardiac conditions.
Emesis is very mild during paclitaxel treatment. Liver function is
rarely impaired, and renal function is usually unaffected.
Cisplatin combination chemotherapies are the cornerstone of treatment
for nonsmall-cell lung cancer. A meta-analysis has shown a
survival advantage that did not exist before the availability of cisplatin.
Many phase I and II studies have been undertaken with paclitaxel and
cisplatin in nonsmall-cell lung cancer. The most important
dose-limiting toxicity has been neurotoxicity. In one of these
studies, Le Chevalier treated 32 patients at five dose levels.
Neurotoxicity appeared to be dose-limiting, with 200 mg/m² of
paclitaxel and 100 mg/m² of cisplatin defined as the maximum
tolerated dose. Neurotoxicity was observed earlier with higher doses.
Two major phase III trials have compared paclitaxel/cisplatin with
standard chemotherapies for nonsmall-cell lung cancer. One was
conducted in Europe through EORTC, using cisplatin/teniposide as the
standard arm. The second trial was conducted in the United States
through ECOG using cisplatin/etoposide as the standard arm. In
both studies, the paclitaxel/cisplatin combination was used as the
experimental arm. Paclitaxel was infused over 3 hours in Europe, and
over 24 hours in the United States. In addition, ECOG used a third
arm with high-dose paclitaxel/cisplatin and growth factor.
Myelosuppression appeared to be the most important toxicity seen in
these studies. In the EORTC trial, myelosuppression and its
complications, neutropenic fever and infection, were significantly
worse in the cisplatin/teniposide arm. In the ECOG trial, however,
myelosuppression was more prominent in the paclitaxel/cisplatin arms.
Neutropenic infections were not more frequent among patients
receiving paclitaxel. It is evident that the use of the 24-hour
infusion increases myelosuppression. In both studies, peripheral
neuropathy and myalgia appeared more pronounced in the
Based on these studies, paclitaxel (175 to 200 mg/m² over a
3-hour infusion) combined with cisplatin (75 to 100 mg/m²) is a
safe and active combination for nonsmall-cell lung cancer.
In a five-arm randomized trial conducted by ECOG, carboplatin was
shown to offer the best 1-year survival rate with the least toxicity
in patients with nonsmall-cell lung cancer. Several phase I and
II studies have investigated the combined use of paclitaxel and
carboplatin. Langer et al used paclitaxel in a 24-hour infusion along
with carboplatin at an AUC of 7.5. The combination was well
tolerated except for myelosuppression. In this study, 71% of patients
developed grade 3 or 4 granulocytopenia.
Most of the investigators, mainly in Europe, have used paclitaxel as
a 3-hour infusion. Among them, the HECOG initiated a phase II trial
for patients with inoperable nonsmall-cell lung cancer.
Paclitaxel was given at a dose of 175 mg/m² as a 3-hour
infusion, and carboplatin at an AUC of 7. The treatment was repeated
every 3 weeks without the use of growth factors.
Among the 60 patients in the HECOG trial, 55 were evaluable. The
response rate was 27.1%, overall median survival was 8.95 months, and
1-year survival was 21%. The median relative dose intensity for
paclitaxel was 0.995. The combination was extremely well tolerated.
Hematologic toxicity was mild with grade 3 granulocytopenia occurring
in 7% of patients and grade 3 and 4 thrombocytopenia occurring in 4%.
Nonhematologic toxicity was also mild. Grade 2 neurotoxicity occurred
in 3% of patients and one patient developed a severe hypersensitivity
reaction despite the administration of premedication.
The Hellenic Cooperative Oncology Group initiated a second trial in
an effort to examine a possible dose-response relationship for
paclitaxel. In both arms of this randomized phase III study,
carboplatin was given at an AUC of 6. Paclitaxel was also given, at a
dose of 175 mg/m² in the first arm (Group A) and 225 mg/m²
in the second arm (Group B). The duration of infusion was 3 hours,
and the treatment was repeated every 3 weeks without the use of
Accrual was completed recently and the toxicity was analyzed. Again,
hematologic toxicity was mild (Table
2) Grades 3 and 4 leukopenia were observed in 12% of patients in
the high-dose paclitaxel arm. Overall leukopenia appeared
significantly worse in the high-dose paclitaxel recipients. Neither
neutropenic febrile episodes nor toxic deaths were observed, and
nonhematologic toxicity was also mild (Table
3). The most troublesome toxicity was peripheral neuropathy,
which appeared to be significantly worse in the high-dose arm.
Nausea/vomiting and myalgia/arthralgia were mild in both groups and
were well tolerated.
Based on these and other combination studies, it seems that
paclitaxel, 200 mg/m² as a 3-hour infusion, and carboplatin at
an AUC of 6, both given every 3 weeks, is a safe and active
combination for nonsmall-cell lung cancer. The results of an
ongoing phase III study comparing paclitaxel/cisplatin and
paclitaxel/carboplatin are anticipated with interest.
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