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Paclitaxel Plus Carboplatin in Advanced Non–Small-Cell Lung Cancer

Paclitaxel Plus Carboplatin in Advanced Non–Small-Cell Lung Cancer

ABSTRACT: Despite a response rate of only 9%, single-agent carboplatin (Paraplatin) produced the best 1-year survival rate with the lowest toxicity in a five-arm Eastern Cooperative Oncology Group study of cisplatin (Platinol) combinations and analogs. Single-agent paclitaxel (Taxol) has also proven to be active in non–small-cell lung cancer, with objective responses of over 20% when administered as a 24-hour infusion and a similar response rate when administered by short 3-hour infusion. For instance, in a Spanish Lung Cancer Group study, 17 out of 58 patients (29%) achieved an objective response when treated with paclitaxel at 210 mg/m² by 3-hour infusion in 21-day cycles. Several European studies have focused on the paclitaxel/carboplatin combination administered by short (3-hour) infusion. These studies have confirmed that myelosuppression is generally mild and thrombocytopenia is rare with this regimen. In total, eight European studies, including 260 evaluable patients with an overall 28% objective response rate, have been reported so far. Among these studies, the two Greek studies confirmed the tolerability of the paclitaxel/carboplatin regimen and reported higher response rates for higher paclitaxel doses, 175 mg/m² vs 225 mg/m². The Dutch and Italian studies, on the other hand, observed a possible dose-response relationship. It can be inferred from these studies that a paclitaxel dose of at least 200 mg/m² by 3-hour infusion is needed to induce objective response in advanced non–small-cell lung cancer. Moreover, the paclitaxel/carboplatin regimen in a 21-day cycle does not require special ancillary measures (ie, blood transfusions, antiemetic therapy, or hospitalization). And finally, neither the paclitaxel/carboplatin nor the carboplatin/paclitaxel combination produces a sequence-dependent cytotoxic effect. The paclitaxel/carboplatin regimen has recently been examined in a large-scale Pan-European clinical trial in which patients were randomized to receive either 200 mg/m²of paclitaxel (3 h) plus carboplatin at an area under the concentration-time curve of 6 (AUC in mg/mL · min) or 200 mg/m² of paclitaxel (3 h) plus 80 mg/m² of cisplatin (1 h) in a 21-day cycle. A total of 618 patients have been included and interim results of the first 289 patients were reported at the 1998 meeting of the American Society of Clinical Oncology. [ONCOLOGY 13(Suppl 4):30-34,1999]

Introduction

Although lung cancer is not the most common
cancer, it is still the leading cause of cancer death in men
throughout the world, accounting for 29% of all cancer deaths in men
in the European Community countries. The corresponding figure for
women is 9%.[1,2] Closer to our home in Spain, data from the
Tarragona Cancer Registry and the Catalonia Mortality Registry
indicate that one in 14 men will develop lung cancer and nearly all
of them will die of the disease.[3] However, survival time can be
improved. A meta-analysis of cisplatin (Platinol)-based chemotherapy
showed an increase of 1.5 months in median survival, with a 10%
absolute increase of survival at 1 year.[4]

A recent randomized trial indicates that the addition of paclitaxel
(Taxol) to cisplatin may lead to an additional 2-month improvement in
survival.[5] Interestingly, single-agent paclitaxel has attained a
promising median survival time of 40 weeks in patients with advanced
non–small-cell lung cancer.[6] Prompted by the promising
activity of paclitaxel, several groups are currently testing
paclitaxel combinations to find the best chemotherapy regimen.

Logically, the first step is to combine paclitaxel with a platinum
compound—either cisplatin or carboplatin (Paraplatin). The
rationale for combining paclitaxel with carboplatin stems from the
five-arm Eastern Cooperative Oncology Group (ECOG) study in which 400
mg/m² of single-agent carboplatin, followed by mitomycin
(Mutamycin), vinblastine (Velban), and cisplatin at the time of
progression produced the best median survival (31.7 weeks) despite a
9% objective response rate. In addition, single-agent carboplatin
turned out to be much less nephrotoxic and neurotoxic than the
cisplatin combinations.[7] The European Lung Cancer Working Party
study also showed that toxicity with a carboplatin/etoposide
combination was significantly less than with a cisplatin/etoposide
combination, although there were no differences in response rate or
survival between the two arms.[8]

It can also be speculated that certain paclitaxel multiagent
combinations may potentially overcome drug resistance, and that
paclitaxel cytotoxicity may increase with prolonged exposure
duration.[9] For instance, recently, a unique resistance mechanism
linked to molecular alterations in microtubules has been described in
paclitaxel-resistant human ovarian cancer cells.[10] Likewise,
automatic DNA sequencing has been used to detect b-tubulin
point mutations in five of 49 (10%) tumors of non–small-cell
lung cancer patients who were treated with single-agent
paclitaxel.[11] None of those five patients whose tumors contained b-tubulin
mutations obtained an objective response, whereas 12 of the
remaining 44 patients without tubulin mutation (27%) had a partial or
complete response. Moreover, median survival for patients without
tubulin mutations was 8 months, with 1-year, 3-year, and 5-year
survival rates of 22%, 10%, and 5%, respectively. In contrast, the
median survival was only 2 months for the subset of patients with
tubulin mutations (P = .029).

Recently, the paclitaxel/carboplatin combination for advanced
non–small-cell lung cancer has been the focus of several phase
II trials in Europe. Extensive experience has been reported by
Greek,[12,13], Dutch,[14] and Italian[15] investigators. These and
other investigated studies[16-19] are reviewed here (Table
1
). Although only four of these studies have been fully
reported, results are encouraging.

Paclitaxel/Carboplatin Combination Studies

The Two Greek Phase II Studies

The first Greek study was a paclitaxel/carboplatin trial in
previously untreated patients with locally advanced or metastatic
(inoperable stage IIIA, IIIB, or IV) non–small-cell lung cancer.
The primary objective was to assess response rate. The secondary
objectives were to examine survival, time to progression, and
toxicity. Patients received 175 mg/m² of paclitaxel by 3-hour
infusion and carboplatin at an area under the concentration-time
curve of 7 (AUC in mg/mL · min) in each 21-day cycle. Grade 3
neutropenia occurred in 7% of the patients, and grades 3 and 4
thrombocytopenia were observed in only 2%. Results have been
published elsewhere.[12]

Inclusion criteria limited entry into the trial to chemotherapy-naive
patients with histologically confirmed inoperable stage IIIA, IIIB,
or IV non–small-cell lung cancer. All participants were required
to have an ECOG performance status equal to or lower than 2, adequate
hematological function (white blood cell count > 4.0 × 109/L
and platelet count > 100 × 109/L), and an
estimated life expectancy of more than 12 weeks. All patients gave
their informed consent. Sixty patients were entered: 56 were male and
four female; median age was 57; six patients were stage IIIA (10%),
20 patients were stage IIIB (33.3%), and 34 patients were stage IV
(56.7%). This study found a 27.3% overall tumor response rate,
progression-free survival of 6.85 months, and a median survival of
8.95 months with a 21.6% 1-year survival probability.

Based on the safety profile of paclitaxel/carboplatin, Kosmidis et
al[13] carried out a randomized study of two dose levels of
paclitaxel plus a fixed dose of carboplatin in previously untreated
patients with locally advanced or metastatic non–small-cell lung
cancer. The primary objective of this study was to compare the
objective response rate of patients treated with one of two doses of
paclitaxel. The secondary aims were to compare time to disease
progression, survival, toxicity, and quality of life. Patients were
randomized to receive either 175 mg/m² or 225 mg/m² of
paclitaxel (3-hour infusion) plus a fixed dose of carboplatin at an
AUC of 6 in each 21-day cycle.

Ninety-nine patients were randomized to paclitaxel at 175 mg/m²
(Group A) and 99 to paclitaxel at 225 mg/m² (Group B). The
response rate among 90 evaluable patients in Group A was 25.6% (6 CR,
17 PR), whereas in Group B, the response rate among 88 evaluable
patients was 31.8% (3 CR, 25 PR) (P = .733). Median time to
progression favored the high-dose paclitaxel arm (4.3 months vs 6.4
months, P = .044). The median survival was 9.5 months for Group A vs
11.4 months for Group B (P = .16). The 1-year survival was 37% for
Group A and 44% for Group B (P = .35). With a relative dose intensity
of P = .94 in both groups, neurotoxicity (P = .025) and leukopenia (P
= .038) were more pronounced in the high-dose paclitaxel arm. No
toxic death was noticed. The authors concluded that higher dose
paclitaxel prolongs the median time to progression but causes more
neurotoxicity and leukopenia.[20]

The Dutch Dose-Evaluation and Dose-Sequencing Phase I Study

The background of this study derives from preclinical studies that
had demonstrated a sequence-dependent cytotoxic effect for the
cisplatin/paclitaxel combination in vitro. The paclitaxel/cisplatin
sequence was shown to be more cytotoxic than the reverse sequence.
Other sequence-dependent interactions had been reported for
paclitaxel combined with doxorubicin (Adriamycin), cyclophosphamide,
or etoposide.[21] Hence, the primary objective of this phase I trial
was to evaluate a potential sequence-dependent interaction between
paclitaxel and carboplatin. Secondary objectives were to examine
survival, response rate, and toxicity. Six patients were allocated to
each dose level and randomized to receive either paclitaxel followed
by carboplatin or carboplatin followed by paclitaxel. The original
dose levels were 100 mg/m² of paclitaxel and 300 mg/m² of
carboplatin every 28 days.

Inclusion criteria limited entry in the trial to chemotherapy-naive
patients with histologically confirmed stage IIIB or IV
non–small-cell lung cancer. All participants were required to
have an ECOG performance status less than or equal to 2 and adequate
hematological function (absolute granulocyte count > 2.5 ×109/L,
platelet count > 100 × 109/L). All patients gave
their informed consent. Nine dose levels were tested; at the ninth
dose level, paclitaxel was administered at 250 mg/m² and
carboplatin at 350 mg/m² in three patients. This study found an
overall response rate of 11% (three complete responses and two
partial responses) with a 6-month median survival time and a 20%
1-year survival probability. When the response rate was broken down
by paclitaxel dose with a cutoff level of 175 mg/m², a higher
objective response rate was observed with paclitaxel doses above this level.

From this Dutch study,[14] we can draw five conclusions. First, a
28-day paclitaxel/carboplatin cycle induces a higher response rate
and survival as a function of the paclitaxel dose. Second, a minimum
paclitaxel dose (175 mg/m²) in a 3-hour infusion is required for
activity in advanced non–small-cell lung cancer. Third, no
sequence-dependent toxicities or sequence-dependent pharmacokinetic
interactions occur with a paclitaxel/carboplatin combination. Fourth,
the paclitaxel/carboplatin regimen is well tolerated (grade 4
neutropenia occurred in only 15% of the patients). Finally, less
thrombocytopenia was observed with paclitaxel/carboplatin than with
single-agent carboplatin.

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