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Docetaxel for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Docetaxel for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

ABSTRACT: Docetaxel (Taxotere) has shown activity both as a single-agent and in combination with multiple other cytotoxic agents in the front-line therapy of advanced, metastatic non-small-cell lung cancer (NSCLC). A randomized, phase III trial demonstrated a survival advantage for docetaxel over best supportive care in the front-line setting, with docetaxel achieving a 2-year survival of 12% vs 0% for best supportive care. Combinations of docetaxel with the platinum agents have been the most extensively studied in the front-line setting and have produced notably high response rates and encouraging median survivals. When compared to the paclitaxel/cisplatinum combination in a large, phase III randomized trial, the combination of docetaxel and cisplatin resulted in similar response, median survival, and 1-year survival rates. Another randomized phase III trial compared docetaxel/platinum combinations to the US Food and Drug Administration (FDA)-approved vinorelbine (Navelbine)/cisplatin regimen. The docetaxel/cisplatin combination produced a superior overall survival, 2-year survival, and overall response rates compared to vinorelbine/cisplatin. The combination of docetaxel and carboplatin (Paraplatin) demonstrated similar survival and response, and was associated with quality-of-life benefits over the vinorelbine/cisplatin arm. Docetaxel has been successfully combined with gemcitabine in multiple trials with impressive response and survival rates, and an acceptable toxicity profile. A large phase IIb trial demonstrated therapeutic equivalence and lesser toxicities for the docetaxel/gemcitabine combination compared to the combination of docetaxel and cisplatin. The docetaxel/gemcitabine combination therefore represents a viable nonplatinum regimen for first-line treatment of NSCLC. Other combinations that have been tested include docetaxel with vinorelbine, and docetaxel with irinotecan (CPT-11, Camptosar). Docetaxel is active in NSCLC and should be investigated further in combination with novel molecularly targeted drugs such as tyrosine kinase inhibitors, and farnesyl transferase inhibitors. [ONCOLOGY 16(Suppl 6):53-62, 2002]

Lung cancer is by far the leading cause of
cancer-related death. In 2002, an estimated 183,200 patients will be diagnosed
with lung cancer, and an estimated 161,400 deaths will occur.[1] Much work
remains to be done in this disease, which is associated with a 5-year survival
of only 15.8%, and a median survival for stage IV disease (even with enhanced
cytotoxic therapies used in combination) ranging from 7.4 to 9.2 months.[1-6]
However, it should be noted that over the past 15 years, combination
platinum-based cytotoxic chemotherapy has resulted in a doubling of the median
survival rate among stage IV NSCLC patients, from approximately 4 to
8 months. Furthermore, an almost threefold increase in the 1-year survival
rate (from 11% to 14% up to 30% to 35%) and meaningful 2-year survival rates
have been demonstrated in several randomized trials.[7]

Docetaxel (Taxotere) has demonstrated modest but very real survival and
quality-of-life advantages when used in the second-line NSCLC setting; it could
ultimately produce a more meaningful survival advantage in early- to
intermediate-stage disease.[8,9] This theory was evaluated in a phase II trial
conducted by the Southwestern Oncology Group (SWOG) in which patients received
docetaxel after completing concurrent chemoradiation therapy with cisplatin and
etoposide. The patients, all of whom had stage IIIB NSCLC without a malignant
pleural effusion, demonstrated a median overall survival of 27 months and a
3-year survival of 37%.[10] The results of this phase II
multi-institutional, cooperative group study highlight the fact that agents that
have activity in advanced, refractory cancers often show significantly more
activity in earlier stages of disease. Therefore, docetaxel should be
investigated as a single agent and in combination with other cytotoxic agents,
as a building block to improve upon the results now possible in the treatment of
patients with NSCLC.

Front-Line Therapy of NSCLC: Single-Agent Docetaxel

Every-3-Week Regimen

Numerous phase I and II trials have shown that single-agent docetaxel is
active in the treatment of incurable or metastatic NSCLC in chemotherapy-naive
patients. A combined overall response rate of 27% was documented in six phase II
trials of docetaxel, 100 mg/m² every 3 weeks, in this patient population, with a
median response duration of 6 months, a median overall survival of 9.2 months,
and a 1-year survival of 39%.[11] Lower doses of docetaxel have also been
investigated in phase II trials in the front-line therapy of NSCLC. Docetaxel at
75 mg/m² and 60 mg/m² every 3 weeks resulted in overall response rates of 25%
and 19%, respectively, and median survivals of 10 and 9.2 months.[12,13]

Based on these findings, Roszkowski et al conducted a randomized, open-label
phase III trial in 207 patients with either unresectable or metastatic NSCLC who
were treated with docetaxel plus best supportive care (BSC) or BSC alone.[14]
Patients in the chemotherapy arm received docetaxel at 100 mg/m² as a 1-hour
intravenous infusion every 21 days until evidence of disease progression,
the estimated maximal benefits from treatment were obtained, or unacceptable
toxicity. The study was conducted with 2-to-1 randomization; 137 patients
received docetaxel and 73 received BSC.

Overall survival was significantly longer for the docetaxel plus BSC arm as
compared to the BSC alone arm (P = .026). The 2-year survival in the docetaxel
plus BSC arm was 12%, whereas none of the patients in the BSC arm survived
longer than 20 months. The overall response rate in the patients who
received a minimum of two cycles of docetaxel was 19.7%. Time to disease
progression was significantly better in the docetaxel plus BSC arm vs the BSC
alone arm at 12.6 weeks vs 8.9 weeks, respectively (P < .001).
Quality-of-life tests revealed the superiority of the docetaxel arm (P = .0401).
Additionally, requirements for narcotic analgesics and palliative radiation
therapy were significantly lower in the docetaxel plus BSC arm vs the BSC alone
arm, in spite of the fact that 16% of the BSC arm went on to receive
chemotherapy.

Weekly Docetaxel Regimen

A trial of single-agent docetaxel as a weekly regimen in the treatment of
patients with NSCLC has been reported by Hainsworth et al.[15] Docetaxel was
administered at 36 mg/m²/wk for 6 consecutive weeks of an 8-week cycle to
39 elderly or poor performance status patients with chemotherapy-naive NSCLC. An
overall response rate of 18% was demonstrated, with one complete response and
six partial responses. The median survival was 5 months, with an estimated 1
year survival rate of 27% in this group of elderly patients. Similar to findings
from other studies of weekly docetaxel administration, hematologic toxicities
were greatly reduced. Grade 3 leukopenia was noted in only three patients, with
none developing grade 4 myelosuppression.

As a result of these findings, and in particular in light of the absence of
grade 3/4 neutropenia or neuropathy, many community physicians favor using a
weekly schedule of docetaxel administration. Further testing remains to be
completed to determine whether response rates and survival are equivalent to the
every-3-week regimen. As will be discussed below, the use of docetaxel on a
weekly schedule also offers attractive options for the development of
combination regimens.

Combination Regimens of Docetaxel With the Platinum Agents

Docetaxel and Cisplatin

Based on docetaxel’s single-agent activity as first- and second-line
therapy of NSCLC, and because the platinum compounds have long been a staple of
front-line therapy for NSCLC, the next logical step was to combine docetaxel
with cisplatin or carboplatin (Paraplatin). The lack of cross-resistance and the
largely nonoverlapping toxicity profile of docetaxel and the platinum agents
provided additional rationale to investigate the combinations.

Several phase I trials of docetaxel and cisplatin have established the
toxicity profile and activity of the combination in advanced NSCLC.[16-18] The
two maximum tolerated doses achieved were either docetaxel at 100 mg/m²
administered as a 1-hour infusion followed by cisplatin at 75 mg/m² 3-hour
infusion or docetaxel at 75 mg/m² as a 1-hour infusion followed by cisplatin at
100 mg/m² as a 3-hour infusion with cycles repeated every 3 weeks. Many
phase II trials have used doses of 75 mg/m² of each of the two compounds
administered at 3-week intervals; however, other regimens have also been
explored, as discussed below.

The Zalcberg et al Trial—Zalcberg treated a total of 47 chemo-naive
patients with the combination of docetaxel at 75 mg/m² followed by cisplatin at
75 mg/m².[19] Premedications included ondansetron (Zofran), dexamethasone,
promethazine, and standard hyperhydration with magnesium supplementation. Of the
47 patients (72% male) enrolled, two-thirds had metastatic disease and 85% had a
good performance status (World Health Organization [WHO] 0 or 1). All 47
patients were assessable for toxicity and 37 were evaluable for response, with 3
patients ineligible for enrollment and 8 discontinuing treatment due to
significant toxicity.

Among assessable patients, the overall response rate was 38.9% (95%
confidence interval [CI]: 23.1% to 56.5%). An additional 36.1% had stable
disease and 25% had disease progression. Based on an intent-to-treat analysis,
the objective response rate was 29.8%, with a median survival of 9.6 months and
an estimated 1-year survival of 33%. The most significant toxicities seen
included grade 3/4 nausea (26%), hypertension (15%), diarrhea (15%), and
dyspnea (13%). However, only one patient (1.2%) experienced grade 3 neurosensory
toxicity after completing eight cycles of therapy. Other grade 3/4 toxicities
included hypomagnesemia (24%), febrile neutropenia (13%), and neutropenic
infections (11%), leading to two treatment-related deaths. The authors concluded
that docetaxel/cisplatin is active and feasible as a front-line therapy for
NSCLC, with a favorable response rate, an acceptable toxicity profile, and good
median and 1-year survivals.

The Le Chevalier et al Trial

Le Chevalier et al evaluated docetaxel, 75 mg/m², plus cisplatin, 100 mg/m², administered every 3 weeks for three
cycles and then every 6 weeks in 51 chemotherapy-naive patients with locally
advanced or metastatic (80%) NSCLC, including 37% with bone involvement.[20] The
patient population was largely male (92%), with a median age of 54 years, and a
median WHO performance status of 1. Patients received a median of four treatment
cycles (range: 1 to 9), with more than 90% receiving full doses of both drugs as
planned per protocol.

An overall response rate of 33% (95% CI: 19.6%-49.6%), was demonstrated
among the 42 evaluable patients, 14 of whom responded. The median response
duration was 7.3 months, with a median survival of 8.4 months and a 1-year
survival of 35%. Neutropenia was the predominant toxicity, occurring in
approximately two-thirds of patients, with febrile neutropenia reported in seven
patients (14%) and sepsis in one. Nonhematologic toxicities included grade 3
vomiting (14%), although neuromotor and neurosensory deficits were infrequent,
with grade 3 neuromotor and neurosensory toxicities occurring in one
patient each (2%).

The authors concluded that the results were encouraging, given the poor
prognostic factors of the patient population, but questioned whether cisplatin
added to the efficacy of single-agent docetaxel, given its impressive cumulative
phase II response rate of 27% in a similar patient population.

The Belani et al Trial

The third multicenter trial was conducted by
Belani et al, who tested a combination of docetaxel at 75 mg/m² and cisplatin at
75 mg/m² every 3 weeks in 47 patients with stage IIIB or IV NSCLC.[21] Among the
40 patients evaluable for response, 1 achieved a complete response and 14
achieved a partial response, for an overall response rate of 37.5%
(intent-to-treat response rate: 32%). The median duration of response was 34.6
weeks. The median duration of survival was 11.3 months, and the median time to
progression was 18.9 weeks. As demonstrated previously, grade 3/4 neutropenia
was predominant, reported in 74.4% of patients and in 55.4% of cycles. The
incidence of febrile neutropenia was 12.8%. Nonhematologic toxicities included
asthenia in 14.9% of patients. Other grade 3/4 toxicities included nausea (20%),
vomiting (12.5%), neurosensory effects (15%), neuromotor effects (12.5%),
diarrhea (10%), and infection (7.5%). The Belani trial was the third phase II
trial to demonstrate the substantial activity of the docetaxel/cisplatin
combination.

The Georgoulias et al Trial

The fourth phase II trial of the
docetaxel/cisplatin combination was conducted by Georgoulias et al, who
performed a multicenter investigation of the regimen in 53 chemotherapy-naive
patients with stage IIIB/IV NSCLC. Eligible patients received docetaxel at 100 mg/m²
on day 1 and cisplatin at 80 mg/m² on day 2 every 21 days. Prophylactic
granulocyte colony-stimulating factor (G-CSF, Neupogen), 150 µg/m², was
administered on days 3 to 13.[22] An overall response rate of 45% was
documented, with 1 complete response and 23 partial responses. The median time
to progression was 36 weeks, and the median survival was 48 weeks. The 1-year
survival rate of 48% was notable.

Despite the use of prophylactic G-CSF, grade 3/4 neutropenia developed in 43%
of patients and resulted in febrile neutropenia in 28%. There were two septic
deaths reported in this study. Nonhematologic toxicities included grade 3
fatigue (13%), grade 3/4 diarrhea (11%), grade 3 neurotoxicity (9%), and grade
3/4 mucositis (7.5%). The authors concluded that although the
docetaxel/cisplatin combination was highly active at the doses used in this
study, the incidence of hematologic toxicity was high despite the prophylactic
use of G-CSF.

Several other trials of the docetaxel/cisplatin combination have been
reported in abstract form, with overall response rates ranging from 47% to
52%.[23-25] As a result of the encouraging response rates, time to progression,
and median survival rates consistently demonstrated in phase II studies, the
docetaxel/cisplatin combination has been investigated in large, phase III
randomized trials, the results of which will be discussed below.

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