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The Emerging Role of Paclitaxel Plus Carboplatin in Non–Small-Cell Lung Cancer

The Emerging Role of Paclitaxel Plus Carboplatin in Non–Small-Cell Lung Cancer

ABSTRACT: The activity and toxicity profiles of carboplatin (Paraplatin) and paclitaxel (Taxol) used as single agents in non–small-cell lung cancer made them logical agents for study in combination therapy. Once preliminary trials demonstrated that both agents could be combined safely in full doses, phase II and III trials of the combination were started. The authors review the results of these trials of paclitaxel plus carboplatin in advanced non–small-cell lung cancer, in combination with chest radiotherapy in stage III disease, and as neoadjuvant therapy in stage I and II non–small-cell lung cancer.[ONCOLOGY 13(Suppl 4):35-41, 1999]

Introduction

Lung cancer is the leading causeof cancer death in both men and women
in the United States.[1] The 160,100 deaths predicted for 1998
represent 28% of all cancer deaths.[1] The cure rate is extremely low
(14%) because most patients have metastatic disease at the time of
presentation, and because systemic therapies are unable to cure
advanced metastatic disease. Attitudes toward lung cancer therapy
began to change when cisplatin-based therapies were shown to prolong
survival,[2,3] relieve symptoms,[4] and improve quality of life[5] at
acceptable medical costs in advanced non–small-cell lung cancer.[6]

Although cisplatin-based therapy accomplished the results described
above, there was debate regarding its general utility because of its
toxicity profile, inconvenience, and marginal therapeutic gains.
Carboplatin (Paraplatin) has gained increasing usage in place of
cisplatin in non–small-cell lung cancer because of its
convenient administration, low toxicity profile, and equivalent or
superior efficacy compared to cisplatin.[7]

Paclitaxel (Taxol) as a single agent was shown to have efficacy
equivalent or superior to that of cisplatin and carboplatin.[8] When
given as a short infusion, paclitaxel can be given on an outpatient
basis with relatively mild toxicity. The activity and toxicity
profiles of carboplatin and paclitaxel in non–small-cell lung
cancer made them logical agents for combination therapy. Preliminary
trials showed that both agents could be combined safely in full
doses.[9-14] This led to phase II and III trials of the combination
in advanced non–small-cell lung cancer, to combination with
chest radiotherapy in stage III disease, and to neoadjuvant therapy
in stage I and II non–small-cell lung cancer.

Carboplatin in Advanced Non–Small-Cell
Lung Cancer

Carboplatin was introduced into clinical trials in advanced
non–small-cell lung cancer because it could be administered
easily as a short, outpatient infusion; because it lacked the
toxicity and nephrotoxicity of cisplatin; and because it produced far
less nausea and vomiting compared to cisplatin.[7] Since its
introduction, several randomized trials have compared carboplatin,
alone or in combination, to cisplatin-based combinations. The results
of such trials are summarized in Table
1
. The Eastern Cooperative Oncology Group compared single-agent
carboplatin to several cisplatin-based combinations.[15] Patients not
responding to carboplatin could receive a cisplatin combination after
two cycles. As shown in Table 1,
the 9% response rate to carboplatin was lower than the 13% to 20%
response rates for cisplatin combinations. However, the toxicity rate
was significantly lower and the survival was significantly longer in
patients receiving carboplatin. The European Organization for
Research and Treatment of Cancer compared a combination of etoposide
and cisplatin to a combination of etoposide and carboplatin.[16] The
dose of carboplatin in this trial (325 mg/m²) was low and was
not based on renal function. Nonetheless, the efficacy of the two
regimens was similar, whereas the toxicity was considerably less in
the carboplatin arm.

More recently, a comparative randomized trial using a higher dose of
carboplatin (500 mg/m²) was completed.[17] In this trial,
mitomycin-C and vindesine were combined with either cisplatin (120
mg/m²) or carboplatin (500 mg/m²). The efficacy of the
carboplatin arm was superior to that of the cisplatin arm both in
response rate and survival. Myelosuppression in the two arms was
similar although the rate of nausea, vomiting, ototoxicity, and
nephrotoxicity remained lower in the carboplatin arm. These trials
provide a strong rationale for the use of carboplatin in combination
therapy trials in advanced non–small-cell lung cancer.

Single-Agent Paclitaxel

Paclitaxel was introduced into lung cancer therapy in the early 1990s
and rapidly became established as one of the most effective agents
for the disease. The earliest trials used a 24-hour infusion of
high-dose paclitaxel (200 to 250 mg/m²).[18,19] This dose was
given on an inpatient basis and required both granulocyte-colony
stimulating factor (G-CSF) and combination premedication with
diphenhydramine, cimetidine, and prednisone. The response rates to
these 24-hour infusions are summarized in
Table 2
,[18-20] along with a summary of the results of
single-agent paclitaxel given as a 3-hour infusion and as a 1-hour
infusion at 3-week intervals.[21-25] This table also shows the
results of a single trial in which the paclitaxel was given
weekly.[26] The response rates appear to be quite similar with each
schedule. In each of these trials, the survival results were also
similar with 1-year survival rates of approximately 40% in each
trial. The results of the weekly schedule gave the highest response
rate and the longest survival. It also gave the greatest dose
intensity. However, this was a single-institution trial and
additional studies with this regimen are necessary. There were no
phase II studies with a 96-hour infusion in untreated patients, but a
single study in previously treated patients showed no responses.[27]

Combination Studies with Paclitaxel Plus Carboplatin

Long-Infusion (24-h) Paclitaxel

Studies with long-infusion paclitaxel (24 hours) plus carboplatin are
summarized in Table 3. The
study of Langer et al[9] escalated doses in each patient, starting
from 135 mg/m² and escalating to 215 mg/m². The study of
Johnson et al[11] gave doses of 135 mg/m² or 175 mg/m² to
different groups of patients. The study of Belani et al[10] escalated
doses of both paclitaxel and carboplatin. The overall response rate
in these studies was 46% with the highest response rate (61%) seen in
the escalating dose study of Langer et al.[9] This study required
inpatient administration of the drugs and routine G-CSF
administration due to the high rates of grade 4 neutropenia. The
average median survival was 46 weeks in these studies and the average
1-year survival rate was 43%.

Short-Infusion 1- or 3-h Paclitaxel

A summary of United States studies combining 1-hour or 3-hour
infusions of paclitaxel with carboplatin is provided in Table
4.[12-14,28-34] The studies of Bunn,[12] Natale,[13] and Rowinsky[14]
were phase I dose-escalation studies. In these studies, paclitaxel
doses below 175 mg/m² were associated with lower response rates
and shorter survival.[12-14] Each of these three studies recommended
paclitaxel at a dose of 225 mg/m² and carboplatin (area under
the concentration-time curve of 6 [AUC in mg/mL · min]) for
phase II and III studies. Surprisingly, these studies found a much
lower rate of thrombocytopenia than expected. This was not due to a
pharmacokinetic interaction but rather appeared to be due to a
platelet-sparing effect of paclitaxel. Grade 4 neutropenia occurred
in only a minority of patients given these doses and febrile
neutropenia was rare. G-CSF was not administered, and all therapy was
given on an outpatient basis.

Some of the paclitaxel plus carboplatin combination studies with
short paclitaxel infusion times gave lower doses of paclitaxel (175
mg/m²). These studies had slightly lower response rates and
shorter survival compared to those with higher paclitaxel doses (200
mg/m²). There is an ongoing randomized trial in Greece to
determine if 225 mg/m² of paclitaxel infused over 3 hours is
preferred over 175 mg/m² over 3 hours.[35] Preliminary results
show superiority for the higher dose. One study gave higher doses of
carboplatin (AUC of 9 or 11).[33] This study reported greater
toxicity without an apparent advantage in response or survival rates.
Finally, one study gave the two drugs every other week.[34] This
study reported a low response rate with considerable toxicity so it
cannot be recommended.

The overall response rate in Table 4
(35%) and the 1-year survival rates 42% to 50% (average 45%) compare
favorably to studies with paclitaxel combined with cisplatin, and
with studies employing longer paclitaxel infusions with carboplatin (Table
3
).

Due to the low rates of toxicity, the convenience, and the
effectiveness of this combination, it was widely adopted into
community practice. Cooperative groups selected this combination to
compare to their previous standard. The ongoing cooperative group
trials in advanced non–small-cell lung cancer are summarized in Table
5
. This combination was also incorporated into combined-modality
studies in stage III non–small-cell lung cancer with
radiotherapy and stages I and II non–small-cell lung cancer with surgery.

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