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Taxanes in Combined- Modality Therapy for Solid Tumors

Taxanes in Combined- Modality Therapy for Solid Tumors

ABSTRACT: The taxanes, paclitaxel and docetaxel, are novel antimitotic agents that are under extensive investigation in clinical trials in patients with various solid tumors. The taxanes have demonstrated significant activity against many solid tumors as single agents and in combination with other chemotherapeutic agents. In addition, paclitaxel and docetaxel arrest cells at the G2/M phase of the cell cycle, which is the most radiosensitive phase. Numerous clinical trials have assessed paclitaxel-based chemoradiation therapy in a variety of tumor types, including non–small-cell lung cancer, small-cell lung cancer, head and neck cancers, esophageal cancer, brain tumors, pancreatic and gastric tumors, and locally advanced breast cancer. Fewer clinical trials have assessed docetaxel plus radiation therapy in these tumor types. This review highlights recent clinical trials of the taxanes in combination with radiation therapy for solid tumors. [ONCOLOGY 13(Suppl 5):23-38, 1999]

Introduction

Solid tumors present a significant treatment
challenge due to poor overall cure rate. However, increasing use of
chemotherapy and radiation may lead to improved local control as well
as overall survival of patients with many locally advanced tumors
treated traditionally with radiation alone, surgery alone, or
chemotherapy alone. Radiation therapy alone may fail due to the
inability to deliver higher than standard doses without unacceptable
toxicities and the presence of a subpopulation of tumor cells that
are relatively insensitive to radiation therapy.[1] Surgery alone may
fail due to the presence of disease outside of the surgical bed. In
addition, chemotherapy alone has limited activity against many common
solid tumors.[2]

The taxanes have several properties that are favorable for
combined-modality therapy. Both paclitaxel (Taxol) and docetaxel
(Taxotere) are generally well tolerated, with significant activity in
the treatment of many tumor types and a high potential for
radiosensitization.[3-22] Extensive clinical experience has been
gained with paclitaxel in combined-modality therapy. Recent and
ongoing clinical trials are beginning to explore the
radiosensitization properties of docetaxel. Both taxanes, paclitaxel
and docetaxel, can be administered on an outpatient basis, and
extensive clinical experience has enabled the circumvention of
anaphylactic reactions. Furthermore, combinations of taxane and
radiation therapy may result in less toxicity than other concurrent
chemotherapy/radiotherapy regimens (eg, cisplatin [Platinol],
etoposide, and irradiation). Major advances in the use of the taxanes
in combined-modality therapy for different tumor types are discussed here.

Taxanes as Radiosensitizers

Taxanes are mitotic inhibitors that stabilize microtubules by
promoting their assembly and retarding their depolymerization.[23,24]
After exposure to the taxanes, cells are arrested in the G2/M
phase of the cell cycle, which is the most radiosensitive
phase.[7,25] In addition to enhanced response to radiation, other
effects have been observed that depend on factors that are only
partially understood at present. For example, stimulation of
apoptosis with paclitaxel has been observed in cell cultures[26] and
in vivo.[16] Recently, the effects of paclitaxel were evaluated with
16 different murine tumors.[16] With a single dose of paclitaxel at
40 mg/kg, mitotic arrest was induced to some degree in all tumor
types, and apoptosis was observed in 50% of the tumors. The kinetics
of mitotic arrest and apoptosis were studied in these tumors to
determine the possible mechanism of taxane effects. Apoptosis, rather
than mitotic arrest, appeared to predict antitumor efficacy (as
determined by the delay in tumor growth).[16] Tumor reoxygenation and
repopulation occurring with taxanes also may be important in
radiation enhancement.[15]

The increased cell radiosensitivity with exposure to the taxanes is
evident at very low levels of the agents, below the levels required
for cytotoxic effects. Numerous studies have demonstrated the
radiosensitizing properties of paclitaxel in various cell
lines.[3,5,12,17,20,21] Docetaxel also has been shown to enhance
response to radiation and induce mitotic arrest and apoptosis in
murine tumor cells.[15,27] The effects of taxane exposure have been
studied with numerous human cell lines derived from lung
tumors,[12,13,22,28,29] head and neck tumors,[6,9,11,30] brain
tumors,[8,20,21] breast tumors,[12,13,19,28] colon tumors,[19]
pancreatic tumors,[12] ovarian tumors,[12,13,18] cervical tumors,
[5,9,17,31] vulvar tumors,[10] prostate tumors,[14,19] and from
melanoma[22] and leukemia[3] cells. A supra-additive effect was
observed most frequently, but additive or subadditive effects also
were demonstrated under some experimental conditions. The extent of
enhancement of the taxane-radiation interaction is dependent on the
specific cell line, growth status, and intensity and duration of drug exposure.

Most in vivo studies analyzing taxane-induced radiopotentiation
focused on paclitaxel and characterized both paclitaxel-sensitive and
paclitaxel-resistant tumor types.[16] Radiation-induced inhibition of
tumor growth is possible even in tumors that are resistant to
single-agent paclitaxel, and the effects of the taxanes on the
radioresponse of normal tissues are clearly less significant. The
results of preclinical studies also suggest that the timing of
exposure to paclitaxel relative to radiation may be critical and that
the optimal timing may vary depending on the sensitivity of tumor
type to the taxane. Preclinical evidence also indicates possible
applications of docetaxel in combined modality therapy. Collectively,
these observations form a compelling basis for the continued design
of clinical trials including the taxanes in chemoradiation treatment.

Combined-modality therapy including paclitaxel or docetaxel results
in substantial responses in several tumor types. Extensive experience
has been gained with non–small-cell lung cancer, head and neck
tumors, and esophageal tumors. Additional information will be
required to determine the optimal dose and schedule of taxanes for
different tumor types, the exact mechanism of action of
taxane-induced radiosensitization, and the most effective use of
radiation therapy in combined-modality therapy.

Non–Small-Cell Lung Cancer

No single modality of therapy has emerged as clearly most beneficial
for stage III non–small-cell lung cancer.[32] Long-term survival
is rare (5% to 15% of patients), regardless of whether patients
undergo surgical resection or standard radiation therapy.[33]
Although chemotherapy results in improved quality of life and modest
survival benefits in patients with advanced, recurrent, and
metastatic non–small-cell lung cancer, it is rarely effective
for cure.[34-36] Several new agents with substantial activity in
advanced and metastatic non–small-cell lung cancer are now
available.[37] Combined chemotherapy and radiation therapy have been
evaluated extensively in patients with locally advanced, unresectable
non–small-cell lung cancer.[38-42]

The use of chemotherapy with radiation therapy potentially may
improve control of local disease and distant micrometastases in
patients with stage III non–small-cell lung cancer.[43] Early
trials of chemoradiation therapy included radiation-sensitizing
agents, such as hydroxyurea, bleomycin (Blenoxane), 5-fluorouracil
(5-FU), and cisplatin,[42,44-47] and did not improve patient survival
appreciably. A pivotal Cancer and Leukemia Group B (CALGB) trial,
CALGB 8433, determined that sequential chemotherapy (cisplatin and
vinblastine) followed by radiation therapy conferred a significant
survival advantage over radiation alone in patients with inoperable
stage III non–small-cell lung cancer.[38,39] Both taxanes have
substantial activity as observed in phase II studies of previously
untreated patients with metastatic non–small-cell lung
cancer.[48-57] Their radiosensitizing properties stimulate continued
interest in combined chemoradiation therapy using these agents.[3]

Paclitaxel

Paclitaxel, as a single agent and combined with other
chemotherapeutic agents, has been investigated in several phase I and
II studies in combination with radiation therapy in patients with
unresectable, stage III non–small-cell lung cancer (Table 1). In
a series of studies at Brown University and at Vanderbilt
University,[43,58,61,70] paclitaxel and concurrent radiation therapy
were assessed. The maximum tolerated dose (MTD) and dose-limiting
toxicities (DLTs) of paclitaxel with concurrent thoracic radiation
were determined in a phase I study in which paclitaxel was
administered weekly as a 3-hour infusion, starting at 10 mg/m²
per week.[54] Over a period of 6 weeks, 27 patients were treated with
paclitaxel at seven different dose levels, ranging from 10 to 70
mg/m² per week, with concomitant chest irradiation (60 Gy
total). The MTD of paclitaxel was 60 mg/m² per week, and
reversible esophagitis was the principal DLT.

In another phase I trial, Lau et al evaluated paclitaxel administered
twice weekly plus concurrent radiation therapy in 26 patients with
locally advanced, unresectable non–small-cell lung cancer (Table
1).[59] In 25 evaluable patients, three (12%) achieved a complete
response, and 17 (68%) achieved a partial response, for an overall
response rate of 80%. The most common toxicity was esophagitis, which
occurred in approximately 50% of patients who received paclitaxel
doses > 30 mg/m² twice weekly.

In a phase II trial (LUN-27), the response rate, toxicity, and 2-year
survival rate were assessed in 33 patients who received weekly
paclitaxel and concurrent radiation therapy (Table 1).[43] Previously
untreated patients with histologically documented unresectable stage
IIIA or stage IIIB non–small-cell lung cancer received
paclitaxel 60 mg/m² administered weekly as a 3-hour infusion
with concurrent radiation therapy (60 Gy total) for 6 weeks. Of 27
evaluable patients, three patients (10%) achieved a complete response
and 22 patients (76%) achieved a partial response, for an overall
response rate of 86% (95% confidence interval, 68% to 96%). The
median follow-up duration was ³ 20
months. The 1-, 2-, and 3-year survival rates for all patients were
determined to be 61%, 33%, and 18%, respectively, and the median
overall survival was 20 months. Esophagitis was the most significant
toxicity noted, but this adverse effect was manageable and reversible.

Paclitaxel in combination with platinum agents also has been
investigated in the context of combined-modality therapy. A recent
phase II trial (LUN-56) of paclitaxel/radiation therapy added two
adjuvant cycles of chemotherapy to a regimen of induction
chemoradiotherapy and was designed to enhance both systemic and local
disease control.[70] This trial added carboplatin (Paraplatin), an
agent with radiation-sensitizing potential and systemic activity when
used in combination with paclitaxel. Forty previously untreated
patients (25 male, 15 female) with stages IIIA and IIIB
non–small-cell lung cancer entered the trial. On an outpatient
basis for 7 weeks, patients received paclitaxel 50 mg/m² per
week as a 1-hour infusion and carboplatin at an area under the plasma
concentration-time curve of 2 (AUC in mg/mL • min) weekly as a
30-minute infusion, with radiation to the tumor and regional lymph
nodes (44 Gy) followed by a boost to the tumor (22 Gy). Following
chemoradiation therapy, patients received an additional two cycles of
paclitaxel (200 mg/m² as a 3-hour infusion) and carboplatin (AUC
of 6) every 3 weeks.

In 39 eligible patients, 12- and 24-month survival rates were 55.7%
and 40.6%, respectively, with a median overall survival of 20.5
months. The 12- and 24-month progression-free survival rates in 39
eligible patients were 48.3% and 38.6%, respectively, with a median
progression-free survival of 8.8 months. The overall response rate
(partial plus complete response) of 37 evaluable patients was 75.7%.
The major nonhematologic toxicity was esophagitis. Seventeen patients
(46%) developed grade 3 or 4 esophagitis at the end of the concurrent
phase. However, only two patients developed late esophageal toxicity,
with stricture at 3 and 6 months posttreatment. This study
demonstrated that combined-modality therapy with paclitaxel,
carboplatin, and radiation is a promising treatment for locally
advanced non–small-cell lung cancer, by virtue of a high
response rate, acceptable toxicity, and survival rates that compare
favorably with those in other multimodality studies.[70]

In a Vanderbilt Cancer Center Affiliate Network (VCCAN) phase II
study (LUN-63), chemotherapy with concurrent hyperfractionated
radiation therapy was investigated.[61] Forty-three patients with
unresectable stage IIIA/IIIB non–small-cell lung cancer received
weekly treatment with paclitaxel/carboplatin plus hyperfractionated
radiation therapy, followed by two cycles of consolidation
paclitaxel/carboplatin administered 3 weeks apart. Of the 42 patients
evaluable for response, three patients (7%) experienced a complete
response and 30 patients (71%) experienced a partial response for an
overall response rate of 79%. The 1-year overall survival rate was
63% for all patients. As in previous studies, esophagitis was the
principal toxicity; grade 3 or 4 esophagitis occurred in 11 patients
(26%). Although a randomized trial is necessary to fully evaluate
this regimen, these results with concurrent weekly
paclitaxel/carboplatin and hyperfractionated radiation therapy are promising.

Another phase II trial[65] evaluated twice-weekly paclitaxel/weekly
carboplatin plus concurrent radiation therapy followed by
consolidation paclitaxel/carboplatin in patients with locally
advanced, unresectable non–small-cell lung cancer. In 17
evaluable patients, complete responses were achieved in two patients
(12%) and partial responses in eight patients (47%), for an overall
response rate of 59%. Grade 3/4 toxicities included esophagitis,
myelosuppression, and nausea/vomiting; these occurred primarily
during the concurrent chemoradiation therapy phase of treatment.

Other trials of chemoradiotherapy with paclitaxel/platinum compounds
involved various paclitaxel doses and administration schedules (Table
1).[62,66-68,71-73] Induction chemotherapy was used in some studies,
in which concurrent chemoradiation therapy with paclitaxel and
platinum combinations was initiated following induction.[54,67,68]
Results of these trials also are encouraging, with overall response
rates of 59% to 82%, and 1-year survival rates of 60% to 74%.[54,67,68]

Results of recent trials of paclitaxel/carboplatin and radiation
therapy demonstrated manageable toxicity and highlight the importance
of chemoradiation therapy for locally advanced non–small-cell
lung cancer.[63] Several current and proposed trials are being
conducted by the large cooperative oncology groups in the United
States.[74] Ongoing phase II and III trials are evaluating the
utility of continuous infusion of paclitaxel,[75] amifostine mucosal
protection,[76,77] as well as induction chemotherapy with paclitaxel
plus concurrent chemoradiotherapy.[78-80] In the CALGB 9431
trial,[81] induction chemotherapy with subsequent concomitant
chemoradiotherapy is being investigated. Patients with stage IIIB
non–small-cell lung cancer are receiving four cycles of
cisplatin 80 mg/m², with two cycles being administered
concurrently with gemcitabine (Gemzar) 1,250 mg/m² (arm 1),
paclitaxel 225 mg/m² (arm 2), or vinorelbine (Navelbine) 25
mg/m² (arm 3), and a total of 60 Gy of radiation. In an early
analysis of the results of this trial, the treatments in all three
study arms generally were tolerable.

In the CALGB 9531 trial, patients with stage IIIB non–small-cell
lung cancer receive two cycles of induction chemotherapy with
paclitaxel 200 mg/m² and carboplatin (AUC of 6), followed by
paclitaxel 50 mg/m² per week and carboplatin (AUC of 2) weekly
with concurrent radiation therapy. The results of this trial will
determine the protocol for a randomized phase III CALGB trial in
which patients will receive either concurrent chemoradiotherapy with
paclitaxel/carboplatin or two cycles of induction chemotherapy with
paclitaxel/carboplatin followed by concurrent chemoradiotherapy with paclitaxel/carboplatin.[74]

Paclitaxel/carboplatin was evaluated in a recent phase III Eastern
Cooperative Oncology Group (ECOG) 1594 study of patients with stage
IV (and selected stage IIIB) non–small-cell lung cancer. The
ECOG is planning to use

a similar regimen of paclitaxel/carboplatin in patients with stage
III non–small-cell lung cancer in a trial evaluating two cycles
of induction paclitaxel/carboplatin followed by randomization to
conventional daily radiotherapy (64 Gy/7 weeks) or hyperfractionated
accelerated radiation therapy (57.8 Gy/36 fractions/15 treatment days).[74]

The Southwestern Oncology Group (SWOG) is conducting a trial of
induction paclitaxel/carboplatin followed by weekly
paclitaxel/carboplatin plus concurrent radiation therapy and
consolidation paclitaxel/carboplatin in patients with unresectable
stage III non–small-cell lung cancer.[74] The Radiation Therapy
and Oncology Group (RTOG) is conducting a phase II trial (RTOG 9801)
of induction paclitaxel/carboplatin followed by
paclitaxel/carboplatin plus concurrent radiation therapy, with or
without amifostine for mucosal protection.[77] Results of these
ongoing trials should further define the role of paclitaxel-based
chemoradiation therapy in patients with unresectable stage III
non–small-cell lung cancer.

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