cancer invest. 2003;21(1) 87-104
TRANSCRIPT
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 1/20
CLINICAL SCIENCE REVIEW
Taxanes in the Treatment of Advanced (Stage III and IV) Non-small Cell
Lung Cancer (NSCLC): Recent Developments
George R. Simon, M.D.,1,* and Paul A. Bunn Jr., M.D.
2
1Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute,
Tampa, Florida, USA2University of Colorado Health Sciences Center, Denver, Colorado, USA
ABSTRACT
Taxanes, paclitaxel, and docetaxel have become the cornerstone of both first-line and
second-line chemotherapy for advanced non-small cell lung cancer (NSCLC).
Recently, several pivotal phase III randomized trials have been published. These
studies and phase II trials will be discussed. Additionally, studies utilizing a taxane and
radiation therapy for resectable and locally advanced NSCLC will be outlined. The
article will end with a discussion on newer strategies being currently explored to
improve survival in advanced NSCLC.
Key Words: Non-small cell lung cancer; Chemotherapy; Radiaion therapy; Cisplatin;Carboplatin; Paclitaxel; Docetaxel; Gemcitabine; Vinorelbine.
INTRODUCTION
Among cancers, lung cancer continues to be the
most common cause of death for both men and women.
One hundred and fifty-six thousand deaths were
estimated from lung cancer in the year 2001.[1]
Pathologists divide lung cancer into the small cell or
non-small [non-small cell lung cancer (NSCLC)]
histologies. The NSCLCs that include adenocarcinoma,squamous cell carcinoma, and large cell undifferentiated
carcinomas comprise about 80% of all newly diagnosed
cases. After diagnosis is established, lung cancers are
staged by radiographic, biopsy, and other techniques
according to the WHO TNM staging system. Only 20–
25% of cases are stage II or I. Most patients of NSCLC
(75–85%) present in advanced stages of the disease at
which point the disease is largely incurable with a
median survival of 8 –10 months with taxane-based
therapy. In stage IV disease, combination chemotherapy
has important palliative effects and produces measurableresponses in approximately 30 – 40% of patients in phase
II trials and 20–30% in co-operative group trials, with
87
DOI: 10.1081/CNV-120005919 0735-7907 (Print); 1532-4192 (Online)
Copyright q 2003 by Marcel Dekker, Inc. www.dekker.com
*Corresponding author: George R. Simon, M.D., Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute,
12002 Magnolia Drive, Tampa, FL 33612, USA; Fax: (813) 979-3027.
CANCER INVESTIGATIONVol. 21, No. 1, pp. 87–104, 2003
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 2/20
two-thirds of the patients showing symptomatic
improvement. Complete responses are rare and eventual
progression is inevitable. Hence, there is a huge need for
the development of newer agents and innovatively
designed clinical trials to test these newer agents.One of the more exciting and newer class of
anticancer drugs in the treatment of NSCLC are the
taxanes. The first and the prototypic taxane to emerge
was paclitaxel (Taxol, Bristol–Myers Squibb Oncology,
Princeton, NJ). Paclitaxel was first extracted from the
bark of the pacific yew Taxus brevifolia in 1971. The
drug was first approved by the Food and Drug
Administration (FDA) in 1992 for the treatment of
refractory ovarian cancer. Subsequently, phase II and
more recently phase III trials have been published in lung
cancer, breast cancer, head and neck cancer, and bladder
cancer. Docetaxel (Taxotere, Aventis, Antony, France) is
a semisynthetic taxoid produced from the needles of the
European yew Taxus baccata.
The taxanes act primarily by stabilizing micro-
tubules against depolymerization. The binding site for
paclitaxel and docetaxel is identical and is the N-
terminal 31 amino acid residue of the b-tubulin subunit
in tubulin polymers.[2] The binding affinity of
docetaxel is, however, 1.9-fold higher than paclitaxel.
The taxanes induce polymerization of tubulin in the
presence or absence of factors that are usually essential
for this function, such as guanosine triphosphate
(GTP).[2] The assembly of GTP-tubulin induced by
docetaxel proceeds with a critical protein concentrationthat is 2.1-fold lower than that of paclitaxel.[2]
Additionally, docetaxel induces Bcl2 phosphorylation
at concentrations 100-fold less than those required for
paclitaxel. The Bcl2 phosphorylation negatively regu-
lates anti-apoptotic activity of Bcl2. Owing to these
critical differences, the two taxanes may not be
completely cross-resistant.
Primary chemo-resistance to paclitaxel continues to
be common in NSCLC. In a pivotal study by Monzo
et al.,[3] b-tubulin mutations were shown to predict for
paclitaxel resistance. Understanding of these and other
resistance mechanisms needs further study.
Phase I clinical trials with the taxanes began in 1990,with disease-specific clinical trials beginning in 1995.
Both taxanes have shown impressive activity in
previously untreated patients with NSCLC. Additionally,
docetaxel has shown activity in the second-line treatment
of metastatic NSCLC and is currently the only FDA
approved drug for this purpose. The foci of this review
are recently published phase II and phase III trials.
Ongoing trials and future directions will also be
discussed.
TAXANES IN THE TREATMENT OF STAGE IV
(AND IIIB WITH MALIGNANT PLEURAL
EFFUSION) NSCLC
Randomized Trials with Paclitaxel
Several important randomized studies have been
published recently with one of the taxanes as the main
component. These studies have been outlined in Table 1.
In a landmark trial, where paclitaxel plus best
supportive care (BSC) was compared with BSC alone in
advanced NSCLC, Ranson et al.[4] reported their mature
results. A total of 157 patients with stage IIIB or IV
NSCLC who had received no prior chemotherapy were
randomly assigned to receive either BSC alone (78
patients) or paclitaxel plus BSC (79 patients). Paclitaxel
was administered as a 3 hr intravenous infusion at
200 mg/m2 every three weeks. The BSC included
palliative radiotherapy, supportive therapy with corti-
costeriods, antibiotics, analgesics and blood transfusions,
and other symptomatic treatment as and when needed.
The primary end point of the study was survival. Time to
disease progression, response rate, adverse events, and
quality of life (QOL) were secondary end points.
Survival was statistically significantly better in the
paclitaxel arm as compared to the BSC arm (median
survival 6.8 vs. 4.8 months, P ¼ 0:037Þ: The QOL was
similar for both treatment arms except for the functional
activities core, which favored the paclitaxel arm. Hence,
the authors concluded that the addition of paclitaxel toBSC not only prolonged survival, but also improved
certain aspects of QOL. On a relative basis, paclitaxel
reduced the hazard ratio of death by 32%. This is similar
to results in breast cancer and is superior to results
achieved in lung cancer with cisplatin-based regimens.
Two studies that compared the newer paclitaxel-
based regimens to the older cisplatin and epipodophyl-
lotoxin-based regimens are outlined below. Bonomi
et al.[5] reported the updated results of an Eastern Co-
operative Oncology Group (ECOG) trial (ECOG 5592)
conducted in previously untreated stage IIIB/IV NSCLC
patients. Paclitaxel was administered as a 24 hr infusion
in two different dose levels of 135 and 250 mg/m2
[granulocyte-colony stimulating factor (G-CSF) was
administered with the 250 mg/m2 arm]. Etoposide was
given at a dose of 100 mg/m2 days 1–3. Each regimen
was repeated every 21 days and cisplatin in all arms was
given at a dose of 75 mg/m2. The characteristics of 599
patients were well-balanced across the three treatment
groups. Superior survival was observed with the two
paclitaxel regimens. Median survival was 9.9 vs. 7.6
months with etoposide/cisplatin. One-year survival was
Simon and Bunn88
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 3/20
Table 1. Phase III randomized trials with paclitaxel.
Authors Agents/schedule Pts RR (%) MS (mo)
Ranson et al. 3-hr paclitaxel 200 mg/m2 q 21 d þ best supportive care 79 NR 6.8a
Best Supportive Care 78 NA 4.8
Bonomi et al. 24-hr paclitaxel 135 mg/m2, cisplatin 75 mg/m2 d1, q 21 d 599 27 9.6
24-hr paclitaxel 250 mg/m2
, cisplatin 75 mg/m2
d1, q 21 d (þG-CSF) 32 10
Etoposide l00 mg/m2
d1-3, cisplatin 75 mg/m2
d1, q 21 d 12 7.7
Giaccone et al. 3-hr paclitaxel 175 mg/m2, cisplatin 80 mg/m2 d1 q 21 d 152 41 9.7
Teniposide l00 mg/m2, cisplatin 80 mg/m2 d1 q 21 d 162 28 9.9
Schiller et al. Gemcitabine l,000 mg/m2
d 1, 8, 15 cisplatin l00 mg/m2
d1, q 28 d 288 21 8.8
Docetaxel 75 mg/m2 d 1, cisplatin d 1, q 21 d 293 17.3 7.4 24-hr paclitaxel 135 mg/m2, cisplatin 75 mg/m2, q 21 d 292 21.3 7.8
3-hr paclitaxel 225 mg/m2, carboplatin AUC 6, q 21 d 290 15.3 8.2
Kelly et al. 3-hr paclitaxel 225m g/m2
, carboplatin AUC 6. q 21 d 184 27 7.5
Vinorelbine 25 mg/m2 /week, cisplatin l00 mg/m2 q 28 d 181 27 7.5
Gatzemeier et al. 3-hr paclitaxel 200 mg/m2, carboplatin AUC 6, q 21 d 279 25 8.3
3-hr paclitaxel 200 mg/m2, cisplatin 80 mg/m2, q 21 d 284 28 9.1
Kosmidis et al. 3-hr paclitaxel 175/mg/m2, carboplatin AUC 6, q 21 d 90 26 8.9
3-hr paclitaxel 225/mg/m2, carboplatin AUC 6, q 21 d 88 32 10.7
Gatzemeier et al. 3-hr paclitaxel 175 mg/m2, cisplatin 80 mg/m2 d 1, q 21 d b 26 8.1
Ciplatin l00 mg/m2 d 1 q 21 d 17 8.6
Kosmidis et al. 3-hr paclitaxel 200 mg/m2, carboplatin AUC 6, q 21 d 63 21.8 NA
3-hr paclitaxel 200 mg/m2 d 1, gemcitabine l000 mg/m2 d 1 & d 8, q 21 64 37.5 NA
Pts, patients; RR, response rate; MS, median survival; mo, months; NR, not reported; NA, not applicable/available.a Statistically significant difference.b Total number of patients enrolled in all three arms.
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permiss
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permiss
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 4/20
also superior in the two paclitaxel arms with (38 vs. 32%,
P ¼ 0:048Þ: There was no difference in survival between
the two paclitaxel arms. Since paclitaxel at 135 mg/m2
given as a 24 hr infusion plus cisplatin had the best
efficacy with the least toxicity, it was picked to be thereference arm in the ECOG 1594 study detailed below.
Giaccone et al.[6] of the European Organization for
the Research and Treatment of Cancer (EORTC)
reported their phase III randomized study comparing
cisplatin plus teniposide (arm A) vs. cisplatin plus
paclitaxel (arm B). Three hundred thirty-two patients
with advanced NSCLC were randomized to receive
cisplatin 80 mg/m2 on day one either in combination with
teniposide 100 mg/m2 on days one, three, and five, or
with paclitaxel 175 mg/m2 as a 3 hr infusion on day one.
Both regimens were given every three weeks. In arm A,
there were one complete response (CR) and 44 partial
responses (PR), and in arm B, there were two CRs and 61
PRs. There were no significant differences in the median
and one-year survival. (9.8 vs. 9.7 months and 41 vs.
43%, respectively, in arms A and B). The EORTC also
reported the QOL assessment performed by certain
centers. Arm B achieved a better score at week six for
emotional, cognitive, and social functioning, global
health status, fatigue, and appetite loss. Hence, although
survival was not improved, arm B offered better
palliation than arm A. This study used higher doses of
teniposide (100 mg/m2) and there was considerable
hematologic toxicity in both arms.
Several randomized trials compared various newtwo-drug combinations. One of the most important of
these studies reported is the ECOG 1594 study.[7]
Approximately, 290 patients were enrolled in each of the
four arms, consisting of 24 hr paclitaxel with cisplatin,
3 hr paclitaxel plus carboplatin, gemcitabine with
cisplatin, and docetaxel plus cisplatin. The dose and
schedule of administration are outlined in Table 1. There
was no statistically significant difference in response
rates, median survival, or one-year survival in any of the
arms (see Figs. 1 and 2). Time to treatment progression
(TTP) was statistically significantly better with cisplatin
plus gemcitabine arm (4.4 vs. 3.5 months) compared to
the reference arm of cisplatin and paclitaxel. Thecisplatin–gemcitabine arm was the only regimen where
the cycles followed the four-weekly schedule in contrast
to the other three arms where a three-weekly schedule
was followed. Severe toxicity (grade III and grade IV)
was lowest in the carboplatin/paclitaxel arm, especially
in ECOG performance status of two patients.
Another similar study of the Southwest Oncology
Group (SWOG)[8] compared carboplatin plus 3 hr
paclitaxel to vinorelbine plus cisplatin. Approximately
180 patients were enrolled in each arm. The responserates and median survival were similar at 27% and eight
months, respectively. Hematological toxicity and nausea
were higher on the vinorelbine–cisplatin arm, whereas,
peripheral neuropathy was increased in the paclitaxel–
carboplatin arm. More patients on the vinorelbine–
cisplatin arm experienced chemotherapy delays due to
toxicity. Therefore, the authors favored paclitaxel–
carboplatin arm to be the reference arm for future studies
owing to convenience and improved tolerability.
Compared to cisplatin, carboplatin has a more
favorable toxicity profile. Gatzemeier reported the results
of a Pan-European study[9] in which patients were
randomized to receive either carboplatin at an area underthe curve (AUC) of 6 mg/mL min and paclitaxel at
200 mg/m2 over 3 hr or paclitaxel in the same dose with
cisplatin at 80 mg/m2. A total of 618 patients were
randomized with both regimens given every three weeks.
Figure 1. ECOG 1594: Overall survival of stage IIIB
NSCLC.
Figure 2. ECOG 1594: Overall survival of patients with stage
IV NSCLC.
Simon and Bunn90
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 5/20
Response rates, median survival and 1-year survivals for
carboplatin/paclitaxel vs. cisplatin/paclitaxel were 25%
vs. 28% (P=0.45), 8.5 months vs. 9.8 months (P=0.019)
and 33% vs. 38%, respectively; the 2-year survival rates
were 9% and 15%, respectively. Overall quality of life(EORTC Q & Q-C30 and LC-13) were similar in the two
arms with more thrombocytopenia and neutropenia in the
carboplatin arm and more nausea, vomiting and
nephrotoxicity in the cisplatin arm. However, only 76%
of the planned carboplatin dose was delivered compared
to 98% of the cisplatin dose and this may explain the
significant survival difference favoring the cisplatin arm.
The effect of paclitaxel dose intensity was
examined, in the carboplatin – paclitaxel combination
by the Hellenic Co-operative Oncology Group.[10]
Chemotherapy naive patients with inoperable NSCLC
were randomized to receive either carboplatin at AUC of
6 mg/mL min and paclitaxel at 175 mg/m2 (group A) or
the same dose of carboplatin and paclitaxel at 225 mg/m2
(group B). Both drugs in both groups were given on day
one every 21 days. In group A, the response rate was
25.6%, whereas, in group B the response rate was 31.8%.
The difference was not statistically significant. The
median time to progression favored the high-dose
paclitaxel arm with 4.3 vs. 6.4 months ðP ¼ 0:044Þ:
The median survival was 9.5 months for group A vs. 11.4
months for group B ðP ¼ 0:16Þ: The one-year survival
was 37% for group A and 44% for group B with the P-
value being 0.35. In this study, the best prognostic factor
for one-year survival was the response rate. There wereincreased neurotoxicity and leucopenia in the high-dose
paclitaxel group. However, there were no toxic deaths
reported in either arm. The authors concluded that the
higher-dose paclitaxel prolongs the median time to
progression but at the expense of increased neurotoxicity
and leucopenia.
In a study from Germany, Gatzemeier et al.[11]
compared the cisplatin–paclitaxel combination with
single agent cisplatin alone. Four hundred fourteen
previously untreated patients with advanced NSCLC
(stage IIIB/IV) were treated with either single agent
cisplatin (100 mg/m2 day one, every 21 days) or cisplatin
(80mg/m2
day one, every 21 days) plus 3 hr paclitaxel(175 mg/m2 day one, every 21 days). There was
significantly higher response rate (26 vs. 17%, P ¼
0:028Þ and significantly longer time to progression in the
cisplatin/paclitaxel arm but there was no difference in
median survival (8.6 months for platinum alone vs. 8.1
months for cisplatin plus paclitaxel). It is likely that
therapy at the time of progression in the single agent
cisplatin arm accounted for the similar survival despite
the superiority in time to progression seen in the
cisplatin/paclitaxel arm. It is also possible that better
results would have been achieved with a higher
paclitaxel dose of 225 mg/m2. The QOL was similar
overall between the two arms.
Another Hellenic Oncology Group trial published by
Kosmidis et al.[12] compared paclitaxel 200 mg/m2 as a
3 hr infusion and carboplatin AUC of 6 mg/mL min given
on day one with paclitaxel in the same dose with
gemcitabine 1000 mg/m2 given on days one and eight.
Both regimes were repeated every three weeks for a
maximum of six cycles in previously untreated patients
with advanced NSCLC. Sixty-three patients were
randomized to group A (carboplatin/paclitaxel) and 64
to group B (gemcitabine/paclitaxel) with a median
follow up of 4.6 months. Preliminary results showed that
both combinations were well tolerated when adminis-
tered in full doses. Grade III– IV neutropenia wasgenerally mild but was more prominent in group
A. Thrombocytopenia was insignificant in both arms.
There was a trend towards higher response rates in favor
of group B (37.5 vs. 21.8%), although the time to disease
progression did not differ significantly (7.25 vs. 7.1
months). Mature data are awaited.
Summarizing the above data, paclitaxel was found to
be better than BSC, not only in improving survival (with
a 32% reduction in the hazard ratio of death) but also in
improving the QOL. It has become clear that most new
two-drug, platinum-containing regimens are essentially
identical to each other with respect to efficacy. The
paclitaxel–carboplatin combination was found to be aseffective, less toxic, and best tolerated in several of the
studies. The optimal dose of paclitaxel, when used in
combination with a platinum compound, in NSCLC is
still an issue of debate. However, most investigators
would prefer the higher dose of 225 mg/m2, especially in
patients with good performance status. In one Phase III
randomized trial, cisplatin yielded superior median
survival to carboplatin when combined with paclitaxel.
Higher percentage of cisplatin dose delivered in the
cisplatin arm may have accounted for the difference.[9]
Two other randomized trials showed that the cisplatin–
paclitaxel combination was better than either cisplatin–etoposide[5] or cisplatin– teniposide.[6] A nonplatinum-
containing doublet (gemcitabine–paclitaxel) was found
to be similar in survival to a platinum-containing doublet
(carboplatin–paclitaxel) in a recently reported phase III
randomized trial.[12] This trial provided the proof of
principle that a nonplatinum-containing doublet and a
platinum-containing doublet could be comparable in
efficacy and survival in the first-line treatment of
advanced NSCLC.
Taxanes in Treatment of Advanced NSCLC 91
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 6/20
Randomized Trials with Docetaxel in Previously
Untreated Patients
Several phase III studies have been completed using
docetaxel in previously untreated patients. These aresummarized in Table 2.
Roszkowski et al.[13] reported their final results
comparing docetaxel at 100 mg/m2 every three weeks
plus BSC compared to BSC alone in patients with
advanced NSCLC. Two hundred patients were enrolled,
following a 2:1 randomization schema where for every
patient enrolled to the BSC alone arm, two patients were
enrolled to the docetaxel arm. Median survival was 6.0
months for the docetaxel arm vs. 4.6 months for the BSC
arm. One-year survivals were 25 vs. 15% in favor of
docetaxel ðP ¼ 0:012Þ: Importantly, QOL was statisti-
cally significantly better in the docetaxel arm with a
decrease in the need for palliative radiation, pain
medications, and hospitalization. Not surprisingly, the
incidence of neutropenia and the need for antibiotics
were higher in the docetaxel arm. This study corrobo-
rated the result of the paclitaxel vs. BSC study[4] where
the use of a taxane statistically significantly improved
survival and QOL as compared to BSC in advanced
NSCLC patients.
Docetaxel combined with cisplatin, with both drugs
given at 75 mg/m2 every three weeks, was shown to be
equivalent to three other two-drug combinations in the
ECOG 1594 study[7] summarized in Table 1. Two
hundred ninety-three patients were enrolled in thedocetaxel–cisplatin arm with a 17.3% response rate and
a median survival of 7.4 months and a 31% one-year
survival.
Recently, a phase III randomized trial was
completed (TAX 326) that enrolled 1220 advanced
NSCLC. This three-arm study compared docetaxel
(75mg/m2) plus cisplatin (75 mg/m2) given every three
weeks vs. docetaxel (75 mg/m2) and carboplatin (AUC of
6 mg/mL min) vs. the reference arm of vinorelbine
(25mg/m2) weekly and cisplatin 100 mg/m2 given every
four weeks.[14] There were no statistically significant
differences in toxicity in any of the arms. However, alarger percent of the planned chemotherapy was actually
delivered (97 vs. 68%) in both the docetaxel arms
compared to the vinorelbine arm. Cisplatin/taxctere arm
had a statistically significantly superior overall survival
as compared to the cisplatin/vinorelbine arm. Quality of
life parameters were also superior for the taxctere arm.
To determine whether nonplatinum-containing
combinations could replace platinum-containing combi-
nations, Georgoulias et al.[15] conducted a phase II
randomized trial in chemotherapy-naı̈ve advanced
metastatic NSCLC patients comparing docetaxel
(100 mg/m2 given on day one) plus cisplatin (80 mg/m2
given on day two) with G-CSF given on days 3–9 (DC
arm) with gemcitabine (1100 mg/m2 given on days one
and eight) plus docetaxel (100 mg/m2 given on day eight)
with recombinant G-CSF given on days 9 –15 (DG arm).
Cycles in both arms were given every 21 days until
progression. A total of 375 patients were enrolled with
180 evaluable patients in the DC arm and 167 evaluable
patients in the DG arm. There was no statistically
significant difference in response rates (31% for DC vs.
34% for DG), median survival (12 months for DC vs. 11
months for DG), and one-year survival (46% for DC vs.
41% for DG). The similarity of results indicates that both
platinum-containing and nonplatinum-containing com-binations are acceptable for therapy for advanced
NSCLC patients.
Summarizing the randomized studies with the use of
docetaxel in previously untreated patients with advanced
NSCLC, docetaxel plus BSC provided better palliation
and improved survival when compared to BSC alone.[13]
In the ECOG 1594 trial, cisplatin plus docetaxel provided
Table 2. Phase III randomized trials with docetaxel in previously untreated NSCLC patients.
Author Agents/Schedule Pts MS %1-Yr [References]
Roszkowski et al. Docetaxel 100 mg/m2 q 21 d 200a 6.0 25 [13]Best supportive care 4.6 15
Schiller et al. ECOG-1594 (see Table 1) [7]
Belani et al. Docetaxel 75m g/m2, cisplatin 75 mg/m2 q 21 d 1220a NR NR [14]
Docetaxel 75 mg/m2, carboplatin AUC 6 q 21 d NR NR
Vinorelbine 25 mg/m2
q 7 d, cisplatin 100 mg/m2
q 21d NR NR
Georgoulis et al. Docetaxel 100 mg/m2 /d, cisplatin 80 mg/m2 d2 375a 12 46 [15]
Gemcitabine 100 mg/m2 given d2, d8 11 41
Pts, patients; MS, survival in months; NR, not reported.a Total patients enrolled in all arms.
Simon and Bunn92
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 7/20
equivalent response rates and survival as compared with
carboplatin plus paclitaxel and cisplatin plus gemcita-
bine.[7] Docetaxel, when paired with a platinum
compound gave similar survival rates to docetaxel pairedwith gemcitabine, again suggesting the equivalence of
platinum-containing doublet and a nonplatinum-contain-
ing doublet.[15] A large phase III trial comparing cisplatin
plus docetaxel, carboplatin plus docetaxel, and cisplatin
and vinorelbine has been completed. Cisplatin/taxctere
arm had a statistically significantly superior overall
survival as compared to the cisplatin/vinorelbine arm.
Taxctere arms demonstrated benefit in the quality of life
parameters measured.
Randomized Trials with Docetaxel in theSecond-Line Setting
Two important phase III studies have been reported
with docetaxel in the second-line setting and the results
are summarized in Table 3. In the first trial, (TAX
317)[16], docetaxel was compared with BSC. One
hundred patients were randomized to the BSC arm.
Docetaxel at 100 mg/m2 every three weeks was given to
49 patients. Owing to a 22% incidence of febrile
neutropenia, 55 additional patients received docetaxel at
a lower dose of 75 mg/m2 every three weeks. The median
survival in the combined docetaxel arms was 7.0 months
vs. 4.6 months in the BSC arm. This difference wasstatistically significant. There was no significant
difference in survival between the two docetaxel groups.
Additionally, there was a 37% one-year survival in the
docetaxel arm compared to an 11% one-year survival in
the BSC arm (see Fig. 3). In addition to a prolongation of
survival, there was a significant improvement in the QOL
in the docetaxel arm compared to the BSC arm. The need
for palliative radiation therapy, pain medication, and
hospitalization was reduced in the docetaxel arm.
However, the need for antibiotics was increased in the
docetaxel group. In this pivotal trial, the role for second-
line chemotherapy for advanced NSCLC was estab-
lished. In addition to an improvement in survival, animprovement in QOL was also demonstrated. The
docetaxel dose of 75 mg/m2 is preferred to the 100 mg/m2
dose owing to comparable efficacy and reduced toxicity.
In a second phase III randomized study (TAX 320),
docetaxel at 100 mg/m2 was compared to docetaxel at
75 mg/m2, or to vinorelbine or ifosfamide, at the time of a
commonly used second-line chemotherapy for advanced
NSCLC.[17] There was no restriction in the number of
prior cycles. There was a 11% PR rate for docetaxel at
100 mg/m2, 6% PR for docetaxel given at 75 mg/m2, and
1% PR for vinorelbine or ifosfamide. The median
survival in the docetaxel 100 mg/m2 arm was 5.5 months
compared to 5.7 months for the docetaxel 75 mg/m2 arm.
The median survival in the vinorelbine/ifosfamide arm
was 5.6 months. The one-year survival was 32% in the
100 mg/m2 arm, 32% in the 75 mg/m2 arm, and 10% in
the vinorelbine/ifosfamide arm. The survival differences
Table 3. Phase III randomized trials with docetaxel in previously treated patients with NSCLC.
Study/Author Agents/Schedule Pts RR (%) MS 1-Yr (%) [References]
Tax 317/Shepherd et al. Docetaxel 100/75mg/m2 q 21 days 49/55 6 7.0a 37a [16]
Best supportive care 100 NA 4.6 11
Tax 320/Fossela et al. Docetaxel 100 mg/m2 q 21 days 125 11a 5.5 32a [17]
Docetaxel 75 mg/m2 q 21 days 125 6a 5.7 32a
Vinorelbine 30 mg/m2 /Weekly or ifosfamide 2
gm/m2£ 3 days q 3
weeks
123 0.8 5.6 10
Pts, patients, RR, response rate, MS, median survival in months, NA, not applicable.a Statistically significant difference between docetaxel and comparator arm.
Figure 3. TAX 317: Overall survival of taxotere 75 mg/m2
vs. BSC.
Taxanes in Treatment of Advanced NSCLC 93
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 8/20
were statistically significant. Administration of prior
paclitaxel did not affect the probability of response to
docetaxel (see Fig. 4). Thirty-one percent of the patientsin the docetaxel 100 mg/m2 arm and 42% of patients in
the docetaxel 75 mg/m2 received prior paclitaxel. Hence,
docetaxel is still a viable second-line option in patients
who have failed previous paclitaxel containing regimens.
The 75 mg/m2 dose of docetaxel offered better palliation
with an improved therapeutic index.
Phase II Trials with Chemotherapy Doublets
Containing a Taxane
While several of the phase III trials describedabove demonstrate improvement in outcome of post-
1990 drugs over older agents in the treatment of
NSCLC, many questions remain as to how to exploit
their activity. In many instances, the regimen best
suited for treatment has not been clearly identified—
not just in terms of QOL or cost-effectiveness, but also
in terms of dosing and scheduling. To address these
issues, phase I and II studies of newer drugs continue
to be executed. The majority of these trials combine
cisplatin or carboplatin with a taxane. These
nonrandomized studies, while not sufficient to establish
superiority over older treatments can be compared with
historical controls of advanced NSCLC treated with
earlier cisplatin-based regimens, which achieved
median survivals of around 26 weeks, and one-yearsurvival rates of approximately 25%. These trials are
summarized in Tables 4–7.
Phase II Trials with Paclitaxel and a Platinum
Compound
Table 4 summarizes four phase II trials where
paclitaxel was combined with a platinum compound.
Three studies reported results with a combination of
paclitaxel and carboplatin. In one study,[18] paclitaxel
was administered over 1 hr, while in two studies,[19,20]
3 hr infusions were used. The response rates in these
studies ranged from 29 to 55%. The median survivals
ranged from 41 to 55 weeks and the one-year survival
rates ranged from 38 to 55%. A single phase II trial
studied the combination of paclitaxel (135 mg/m2 over
3 hr) and cisplatin (75mg/m2).[21] This study reported a
response rate of 50%, but no survival data were
included.
Phase II Trials with Docetaxel and a Platinum
Compound
Three recent studies with docetaxel and cispla-
tin[22,23] or carboplatin[24] have been published and
outlined in Table 5. The objective response rates ranged
from 33 to 48%. The median survival was reported in
only one of these trials (34 weeks), with a one-year
survival rate of 35%. There are no obvious efficacy
differences between the study results whether the study
used docetaxel or paclitaxel or whether the taxane was
combined with cisplatin or carboplatin. Not surprisingly,
Figure 4. Tax 320: Effect of prior paclitaxel on survival.
Table 4. Phase II trials of platinum– paclitaxel combination in advanced NSCLC.
[References] Agents/Schedule Pts , IV RR (%) MS 1-Yr (%)
[18] 1-hr paclitaxel 200 m g/m2, carboplatin AUC 5, q 21 d 65 29 19 (29%) 41 38
[19] 3-hr paclitaxel 200 m g/m2
, carboplatin AUC 6, q 21 d 53 20 29 (55%) 55 55
[20] 1-hr paclitaxel 130–225m g/m2, carboplatin 230– 375 mg/m2, q 28 d 47 32 18 (38%) 51.8 49
[21] 1-hr paclitaxel 135 m g/m2 d1, cisplatin 75 mg/m2 d2, q 21– 28 d 32 8 16 (50%) NR NR
Pts, patients;,IV, number of evaluable patients with nonmetastatic disease; RR, number of evaluable patients with PR or CR; MS, median survival of
evaluable patients (weeks); %1-Yr, percentage of evaluable patients alive at 1 year; NR, not reported.
Simon and Bunn94
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 9/20
convenience and nonhematological toxicities favored
carboplatin over cisplatin.
Phase II Trials of Docetaxel Plus Vinorelbine
There have been many studies that combined two
nonplatinum compounds with one another to eliminate
the toxicity associated with cisplatin and to determine if
there might be superior results compared to the platinum
combinations. Four phase II trials combining docetaxel
and vinorelbine are summarized in Table 6. The doses
and schedules of the drugs varied considerably. One of
these trials used a very dose-intensive approach, with
vinorelbine (45 mg/m2) and docetaxel (60 mg/m2) being
given every two weeks with G-CSF support.[25] This trial
reported a response rate of 54% and a one-year survival
rate of 86%. These results are clearly superior to the
others described above. Given the small sample size andthe fact that this was a single-institution study, further
studies using this approach will be required before this
aggressive approach can be adopted. The other studies
using more conventional dose schedules showed
response rates of 20– 37%, with median survivals of
20–36 weeks and one-year survival rates of 24–
35%.[26–28] These results more closely resemble those
of other two-drug combinations. When the results of
these four trials are combined, the overall response rate
was 37% among 138 patients.
Phase II Trials of Taxane – Gemcitabine
Combinations
Another combination of two-new drugs is taxane
plus gemcitabine. Four phase II trials are summarized in
Table 7. One of these studies used paclitaxel and
gemcitabine in a four-week schedule,[29] while three
studies[30–32] combined docetaxel and gemcitabine in a
three-week schedule. The results of these studies were
fairly similar, with response rates ranging from 29 to
41% (average 36%). Only one trial[30] reported a median
survival of 52 weeks with a one-year survival rate of
51%. These results are very similar to cisplatin-
containing trials, which suggests that these regimens
could be substituted for regimens containing cisplatin.
Summary of Phase II Trials
With such an array of phase II trials containing a
taxane, it is often difficult to draw any meaningful
conclusions. Table 8 summarizes the results of such
trials. Response rates ranged from 36 to 41%. None of
these combinations stand out as being markedly superior
or inferior, and the 85% confidence limits overlap among
all these combinations. The median survivals reported in
these studies ranged from as low as 20 weeks to as high
as 55 weeks and one study reported a one-year survival
rate of 86%. There is no scientific way to recommend any
Table 5. Phase II trials of platinumdocetaxel combinations in advanced NSCLC.
[References] Agents/Schedule Pts , IV RR (%) MS %1-Yr
[22] Docetaxel 75 mg/m2, cisplatin 75 mg/m2, q 21 d 56 NR 48 NR NR
[23] Docetaxel 75 mg/m2, cisplatin 75 mg/m2, q 21 d 42 8 33 33.6 35
[24] Docetaxel 75 mg/m2, carboplatin AUC 6, q 21 d 41 12 37 34 –55 35 –55
Pts, number of evaluable patients;,IV, number of evaluable patients with nonmetastatic disease; RR, number of evaluable patients with Pr or CR; MS,
median survival of evaluable patients (weeks); %1-Yr, percentage of evaluable patients alive at 1 year; NR, not reported.
Table 6. Phase II trials of docetaxelvinorelbine combinations in advanced NSCLC.
[References] Agents/Schedule Pts ,IV RR (%) MS %1-Yr
[26] Vinorelbine 25 mg/m2 d1, docetaxel 100 mg/m2 d2, q 21 d 41 11 15 (37%) 20 24
[25] Vinorelbine 45 mg/m2
, docetaxel, 60 mg/m2
, q 21 d 35 3 19 (54%) .28 86
[27] Vinorelbine 15 mg/m2 d1, 8, 15, docetaxel, 60 mg/m2 d1, q 21 d 35 6 7 (20%) NR NR
[28] Vinorelbine 15 – 45 m g/m2, docetaxel, 50– 60 mg/m2, q 14 d 27 4 10 (37%) 36 35
Pts, number of evaluable patients; ,IV, number of evaluable patients with nonmetastatic disease; RR, number of evaluable patients with PR or CR;
MS, median survival of evaluable patients (weeks); %1-Yr, percentage of evaluable patients alive at 1 year; NR, not reported.
Taxanes in Treatment of Advanced NSCLC 95
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 10/20
one of these combinations over another. Still, some
conclusions can be drawn. It is likely that many of these
combinations without cisplatin can be substituted for
combinations with cisplatin. Carboplatin can be sub-
stituted for cisplatin with greater convenience and less
toxicity in combination with any of the newer
nonplatinum compounds.
TAXANES AND RADIATION IN THE
TREATMENT OF UNRESECTABLE STAGE III
(WITHOUT MALIGNANT PLEURAL EFFUSION)
NSCLC
Paclitaxel and docetaxel arrest cells in the G2 /M
phase of the cell cycle. Cells are most susceptible to
radiotherapy in this phase, and therefore, it was only
logical to combine a taxane with radiotherapy. Hence,
many studies have attempted to combine a taxane withradiation to achieve synergistic effects. Some of these
studies are outlined below.
Taxanes Given Concurrently with Radiation Therapy
Paclitaxel Given Concurrently with Radiation
Some of the recently published innovative studies
where paclitaxel was combined with radiation are
outlined below and in Table 9. The preliminary results
of a phase I trial using such a combination were reported
by Rathmann et al.[33] In this trial, 29 patients with
inoperable stage II–IIIB NSCLC were treated with two
neoadjuvant cycles of carboplatin and paclitaxel. This
was followed by 68 Gy of radiation given concurrently
with daily paclitaxel. Twenty-six patients were evaluable
for toxicity, and the dose-limiting toxicity was
esophagitis at the 15 mg/m2 dose level. A daily paclitaxel
dose of 10 or 6 mg/m2 in combination with radiotherapy
was recommended for further study.
Oral et al.[34] from Spain enrolled 18 patients to a
weekly paclitaxel schedule at a dose of 16 mg/m2 with
continuous hyperfractionated accelerated radiotherapy
(CHART). They reported 80% response rates to this
concurrent chemo/radiotherapy schema. Survival data
were not available from this preliminary report. The
CHART was given at three daily fractions of 1.5 Gy
each, and was given continuously for 12 days to a total
dose of 54 Gy.Kirkbride et al.[35] used two-weekly paclitaxel with
concurrent radiotherapy in locally advanced stage III
NSCLC. In the phase II segment of their trial, 17 patients
were enrolled and administered 120 mg/m2 of paclitaxel
every two weeks. The overall response rate to this dose of
paclitaxel and concurrent radiation was 78%. The
median survival for all patients was 16 months and the
one-year survival was 64%. The authors concluded that
this combination was active with tolerable toxicity.
Another variation in the use of paclitaxel was tested
by Lau et al.[36] In their phase I/II trial, they used
Table 7. Phase II trials of taxanegemcitabine combinations in advanced NSCLC.
[References] Agents/Schedule Pts , IV RR (%) MS %1-Yr
[29] 3-hr paclitaxel 150 m g/m2, gemcitabine 2000 mg/m2, d1, 15 q 28 d 88 30 31 (35%) NR NR
[30] Docetaxel 100 mg/m2 d8, gemcitabine 900 mg/m2 dl, 8 q 21 d 51 15 19 (37%) 52 50.7
[31] Docetaxel 75 – 80 mg/m2 d1, gemcitabine 800– 900 mg/m2 dl, 8, q 21 d 22 NR 9 (41%) NR NR
[32] Docetaxel 75 mg/m2 d8, gemcitabine 1000 mg/m2 dl, 8 q 21 d 14 0 4 (29%) NR NR
Pts, number of evaluable patients; ,IV, number of evaluable patients with nonmetastatic disease; resp, number of evaluable patients with Pr or CR;
MS, median survival of evaluable patients (weeks); %1-Yr, percentage of evaluable patents alive at 1 year; NR, not reported.
Table 8. Phase II trials of taxane combinations in advanced NSCLC.
Agents Tot Studies Pts Resp MS MS Studies %1-Yr 1-Yr Studies
Taxane þ platinum 7 336 138 (41%) 34– 55 4 35 –55 4
Taxane þ vinorelbine 4 138 51 (37%) 20– 36 3 24 –86 3
Taxane þ gemcitabine 4 175 63 (36%) 52 1 51 1
Tot Studies, number of studies reporting results; Pts, number of evaluable patients; Resp, number of evaluable patients with PR or CR; MS, median
survival of evaluable patients (weeks); MS studies, number of studies with median survival data; %1-Yr, percentage of evaluable patients alive at
1 year; 1-Yr Studies, number of studies with 1-year survival rate.
Simon and Bunn96
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 11/20
bi-weekly paclitaxel with concurrent standard-fraction-
ation radiotherapy given in daily fractions of 1.8 – 2.0 Gyto a total dose of 61 Gy. After encountering esophagitis
and skin desquamation at the 40 mg/m2 dose level, they
selected 35 mg/m2 for the phase II component of the trial.
They reported an overall response rate of 80% to this
combination, with a median survival of 20 months and a
three-year survival of 20%.
Docetaxel Given Concurrently with Radiation Therapy
These phase I/II studies are quite small in size and are
outlined in Table 9. Koukourakis et al.[37] from Greece
reported the largest trial with docetaxel. Thirty-fivepatients with stage IIIA and IIIB NSCLC were treated
concurrently with docetaxel and radiotherapy. Docetaxel
was given in doses of 30 mg/m2 weekly with standard-
fractionation radiotherapy. Complete response of chest
disease was observed in 12 of the 35 patients, giving a CR
rate of 34%. Partial responses were seen in 16 of the 35
patients, giving a PR rate of 46%. The overall response
rate was 80%. The overall survival and local
progression-free survival rates at one-year were 60 and
48%, respectively. The major toxicity was esophagitis:
17% percent of patients had grade III esophagitis requir-
ing a two-week delay in their treatment. The authors
concluded that docetaxel combined with radiotherapywas a promising approach that deserves further testing.
Aamdal et al.[38] from France also used weekly
docetaxel given concurrently with radiotherapy for stage
IIIA and IIIB locally advanced NSCLC patients. In this
trial, 42 patients were initially enrolled, of whom 30 were
evaluable. An overall response rate of 57.7%, including
six CRs was reported. The median survival was 15.9
months, with a 51.2% one-year survival. No major
hematological toxicities were observed. Therefore, the
combination of docetaxel and radiotherapy was shown to
be safe and effective.
Neoadjuvant Chemotherapy Followed by Definitive
Local Therapy
Recently, four studies were reported where neoad-
juvant chemotherapy was given alone for several cycles
followed by definitive local therapy in the form of
surgery, radiotherapy, or concurrent chemo/radiother-
apy. These studies are summarized in Table 10 and
detailed below. Mattson et al. conducted a phase III trial
where definitive local therapy (arm A) in the form of
either surgery or radiotherapy was compared with threecycles of neoadjuvant therapy with docetaxel followed
by definitive local therapy i.e., surgery or radiotherapy
(arm B). In the neoadjuvant therapy arm docetaxel was
administered at 100 mg/m2 every three weeks for three
cycles. A total of 274 patients were accrued in both arms.
There was a trend towards superior median (15 vs. 13
months) and one-year survival (59 vs. 51%) in arm
B. These differences were not statistically significant.
However, this study underscored the feasibility of
administering neoadjuvant chemotherapy prior to defini-
tive local therapy.
The CALGB[39] conducted a randomized phase II
study of two cycles of induction chemotherapy of threedifferent two-drug combinations, followed by two
additional cycles of the same drugs given concomitantly
with radiotherapy. Cisplatin was administered at
100 mg/m2 on days 1, 22, 43, and 64 in all three arms.
In arm 1, gemcitabine was given at 1250 mg/m2 on days
1, 8, 22, and 29, and at 600 mg/m2 on days 43, 50, 64, and
71. In arm 2, paclitaxel was given at 225 mg/m2 over 3 hr
on days one and 22, and at 134 mg/m2 on days 43 and 64.
In arm 3, vinorelbine was given at 25 mg/m2 on days 1, 8,
Table 9. Unresectable stage III NSCLC: phase II and/or nonrandomized trials. Concurrent taxane-radiotherapy for locally
advanced NSCLC.
[References] Stage Therapy Pts RR MS LTS
[33] II – IIIB Daily T with RT 29 NR NR NR
[34] IIIA, IIIB Weekly T with CHART 18 80 NR NR
[35] IIIA, IIIB T with RT 17 78 16 64 (1-yr)
[36] III Biweekly T þ RT NR 80 20 20 (3-yr)
[37] IIIA, IIIB D þ RT 35 80 NR 60 (1-yr)
[38] IIIA, IIIB Weekly D with RT 30 57.7 15.9 51 (1-yr)
Pts, number of patients; RR, response rate (%); MS, median survival (months); LTS, long-term survival rate (%); MVP, mitomycin
C þ vindesine þ cisplatin; VP, vindesine þ cisplatin; alt, alternating; RT, radiotherapy; AHRT, accelerated hyperfractionated RT; PE,
cisplatin þ etoposide; S, surgery; P, cisplatin; C, carboplatin; CCRT, concurrent chemo/radiotherapy; PFE, cisplatin þ 5-flurouracil þ etoposide;
D, docetaxel; T, paclitaxel; CHART, continuous hyperfractionated accelerated RT; CPT-11, irinotecan; NR, not reported; pI/II, phase I/II trial.
Taxanes in Treatment of Advanced NSCLC 97
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 12/20
22, and 29, and at 15 mg/m2 on days 43, 50, 64, and 71.
After two induction cycles, radiotherapy consisting of
200 Gy fractions/day to a total dose of 60 Gy was given
starting with the third cycle. The toxicity was
comparable for the three arms, with the major toxicities
being thrombocytopenia, granulocytopenia, and esopha-
gitis. The CR plus PR rate was 27% for arm 1, 27% for
arm 2, and 45% for arm 3. The median survival for all
patients was 18 months and the one-year survival rate
was 66%. There was no statistically significant survival
difference between the three arms. The authors
concluded that four cycles of gemcitabine, vinorelbine,
or paclitaxel could be used in combination with cisplatin
and safely administered concurrently with radiotherapy.
However, all three arms were comparable in toxicity.
This study was not powered to detect differences in
response rates and survival.Lopez-Picazo et al.[40] enrolled 31 patients with
stage IIIA(N2) and IIIB NSCLC to receive 2–4 cycles of
cisplatin, paclitaxel, and vinorelbine (PTN) induction
chemotherapy, followed by radiotherapy given concur-
rently with two cycles of PTN given at the beginning and
end of radiation. Eight-seven percent of their patients had
either CR or PR. They had a median survival of 16
months and a three-year survival rate of 35%. These
excellent results will need confirmation in larger
randomized trials as with studies of triplet therapy in
stage IV disease; randomized trials will be necessary to
determine if the increased toxicity and expense of three
drugs is justified by improvement in survival.Nyman[41] from Sweden used docetaxel and
cisplatin as induction chemotherapy in 20 patients with
stage IIIA and IIIB NSCLC. Concurrent radiotherapy
(up to 64.6 Gy) was given with one additional cycle of
docetaxel and cisplatin. The response rate after induction
chemotherapy was 65%, increasing to 81% after
radiation. After 21 months of follow-up, the median
survival was not reached. Further follow-up is necessary
before long-term survival data can be generated.
These phase II studies using induction chemotherapy
followed by concurrent chemo/radiotherapy suggest that
this treatment approach is feasible. However, before this
treatment approach can become standard, more detailed
multicentric randomized trials will need to be done. One
such trial has completed accrual and is known as the
locally advanced multimodality protocol (LAMP) ran-
domized study, which compares carboplatin plus
paclitaxel followed by radiotherapy (arm 1), vs.
carboplatin plus paclitaxel followed by radiotherapy
given concurrently with carboplatin plus paclitaxel (arm
2), vs. carboplatin plus paclitaxel given concurrently with
radiotherapy followed by carboplatin and paclitaxel (arm
3). All arms are to be compared to the sequential chemo-
radiationregime in RTOG-8808with a median survival of
13.7 months. Two hundred forty-three patients were
randomized to this study. An initial report of 80 patientsenrolled in arm 2 was published in abstract form. [42] For
the 56 patients in whom survival data are available the
median survival is 12.5 months. Accrual to this arm has
been terminated since no survival improvement was noted
when compared to sequential chemo-radiation historical
data (RTOG 8808). The preliminary report of the trial was
recently updated. Arm 3 emerged as the superior arm with
a 16.1 month median survival compared to an 11-month
median survival for arm 2 and a 12.5 month median
survival for arm 1.
More recently Choy et al.[43] reported phase II
results of concurrent use of RSR13 (a synthetic allosteric
modifier of hemoglobin, which decreases the hemo-globin – oxygen binding affinity) and radiation therapy
after induction therapy with carboplatin and paclitaxel.
Fifty-two patients with unresectable stage IIIA and IIIB
NSCLC care enrolled on the study overall response ratio
was 87%. Estimated one-year survival was 68%. Median
survival has not been reached at the time of this report.
Summarizing the results from phase II randomized
trials, it appears that the median survival for patients
treated with concurrent chemo/radiotherapy appears to
Table 10. Unresectable stage III NSCLC: phase II and/or nonrandomized trials (neoadjuvant chemotherapy followed by concurrent
taxaneradiotherapy for locally advanced NSCLC).
[References] Stage Therapy Pts RR MS LTS
[39] IIIA, IIIB CT £ 2 þ CT £ 2 with CCRT 181 54 18 66 (1-yr)
[40] IIIA (N2), IIIB PTN £ 2, CCRT PTN þ 69.9 Gy (1.2 cGy b.i.d.) 31 87 16 35 (3-yr)
[41] IIIA, IIIB DP £ 2 þ CCRT (64.6 Gy) l DP £ 1 20 81 a NR
[43] IIIA, IIIB TC £ 2 þ RT with RSR13 52 87 NR 68 (1-yr)
Pts, number of patients; RR, response rate (%); MS, median survival (months); LTS, long-term survival rate (%);CT, chemotherapy; CCRT, concurrent
chemo/radiotherapy; RT, radiotherapy; C, carboplatin; PTN, cisplatin þ paclitaxel þ vinorelbine; AHRT, accelerated hyperfractionated RT; DP,
docetaxel þ cisplatin; NR, not reported.a Median survival not reached after 21 months of follow-up.
Simon and Bunn98
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 13/20
be around 16 months. However, toxicity is higher in
patients who receive concurrent chemo/radiotherapy as
compared to when chemotherapy and radiotherapy are
administered sequentially. In a recently published phase
III randomized trial comparing sequential chemotherapywith concurrent chemotherapy, the concurrent approach
yielded superior survival that was statistically significant.
However, this study used nontaxane chemotherapy using
mitomycin, vindesine, and cisplatin.[44] These findings
were also corroborated by the recently reported RTOG
9410 trial.[45]
The need forsurgery forpatients whoare downstaged
after combined-modality treatment is under evaluation. A
SWOG trial is currently underway to address this issue.
Many of the concurrent trials are done with the newer
agents, and thelogical reason fordoing concurrent trials is
to take advantage of the radiation-potentiating effects of
chemotherapy. There are multiple studies using pacli-
taxel, docetaxel, and gemcitabine currently underway.
The largest clinical experience has been reported with
paclitaxel. In these studies, paclitaxel has been given both
weekly and three-weekly schedules. The weekly sche-
dules use short infusions, whereas both long- and short-
infusion schemas were used in the three-weekly
programs. These studies underscore the feasibility of
using full-dose paclitaxel concurrently with radiotherapy.
Excessive toxicity was generally not noted in the weekly
regimens where paclitaxel was given either alone or with
weekly carboplatin. In regimens given every three weeks,
a 3 hr infusion of paclitaxel at a dose of 225 mg/m
2
with orwithout carboplatin appeared to be safe.
Concurrent Chemo/Radiotherapy Followed by
Consolidative Therapy with a Taxane
The efficacy of concurrent cisplatin/etoposide (PE)
and radiotherapy followed by two cycles of consolidative
PE in unresectable stage III NSCLC has been previously
reported by Albain et al. for the SWOG (S9019).[46] To
further extend this benefit, in a follow-up phase II study
performed by SWOG (9504),[47] radiation therapy (total
dose of 61Gy in 1.8– 2.0 Gy fractions) was givenconcurrently with cisplatin 50 mg/m2 administered on
days 1, 8, 29, and 36 and etoposide infused on days 1–5
and 29–33. Consolidative therapy was then given with
docetaxel in three-week cycles. In the first-cycle,
docetaxel was given at 75 mg/m2 and if this was
tolerated well then for the second and third cycles
docetaxel was given at 100 mg/m2. There were 83
evaluable patients with response rate of 63%, median
survival of 20 months and one-year survival of 73% and
two-year survival of 47%. This compared favorably with
the SWOG 9019 study where the median survival was 15
months, one-year survival was 58%, and two-year
survival 34% (see Table 11). To further improve these
results, SWOG is planning a study where patients withunresectable stage III disease will be treated in a fashion
similar to the SWOG 9504 trial following, which they
will be randomized to observation alone or to
maintenance therapy with an oral anti-epidermal growth
factor receptor tyrosine kinase inhibitor (SWOG 0023)
(Iressa, Astra-Zeneca, London, UK).
TAXANES IN STAGE I–IIIA NSCLC
Pisters et al.[48] reporting for the bimodality lung
oncology team (BLOT) recently published their phase IItrial where induction chemotherapy was administered
prior to surgery in early-stage NSCLC patients.
Chemotherapy consisted of paclitaxel 225 mg/m2 over
3 hr and carboplatin at AUC of 6 mg/mL min every 21
days. In the first phase of the study, 94 patients were
scheduled to receive for two cycles preoperatively and
three cycles postoperatively. In the second phase of the
study, 40 patients were scheduled to receive three
preoperative cycles and two postoperative cycles. In the
first phase there were 56 objective responses. Ninety-four
patients were enrolled in the study. Fifty-six major
objective responses were seen. Complete resection was
accomplished in 82 patients (86%). Two postoperativedeaths occurred. Five patients had pathologic CRs.
Ninety-six percent of patients received the planned
preoperative chemotherapy and 45% received the
planned postoperative chemotherapy. Estimated one-
year survival is 85% and four-year survival is 58%.
Median survival has not been reached. Results in the
second phase were similar with high rates of delivery of
all three preoperative cycles and a two-year survival rate
Table 11. Phase III randomized study between cisplatin
(P) þ gemcitabine (G) þ vinorelbine vs. cisplatin þgemcitabine vs. cisplatin þ gemcitabine þ paclitaxel.
Response rates and survival figures.[49]
Regimen
Response Rate
(%) MS
1-Year S
(%)
2-Year S
(%)
PGV 44 51 47 15
PG 28 38 39 9
PGT 48 51 46 12
MS, median survival in weeks; S, survival in percentages.
Taxanes in Treatment of Advanced NSCLC 99
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 14/20
of 75%. A prospective randomized trial comparing three
cycles of induction chemotherapy and surgery with
surgery alone is currently underway. If the above-
mentioned phase II results are confirmed, then neoadju-
vant chemotherapy followed by surgery could becomethestandard of care for early-stage NSCLC patients.
TRIPLE DRUG COMBINATIONS CONTAINING
A TAXANE
Several phase II trials and randomized phase III
trials have been published using various drugs in triple
drug combinations. One phase III randomized study
(containing a taxane) has been completed recently where
the combination of cisplatin, gemcitabine, and vinor-
elbine was compared with cisplatin and gemcitabine,which in turn was compared with cisplatin, gemcitabine,
and paclitaxel.[49] The response rates, median survival,
one- and two-year survivals are outlined in Table 12,
showed a suggestion for benefit for the three-drug
combination. However, there were study design flaws
and additional, randomized trials are needed.
The SWOG is initiating a randomized trial (SWOG
200X) where the standard arm, paclitaxel at 225 mg/m2,
and carboplatin at an AUC of 6 mg/mLmin, every three
weeks is being compared with the same drugs in the same
doses but with tirapazamine added.
Until this and other phase III randomized trials are
completed a two-drug combination continues to be thestandard of care.
TRIALS WITH A TAXANE-CONTAINING
DOUBLET IN COMBINATION WITH A
BIOLOGICAL AGENT
Recently, a phase II randomized trial was reported
where an antivascular endothelial growth factor (Anti-
VEGF) humanized monoclonal antibody (rhumab VEGF,
Genentech, South San Francisco, CA), was combined in
two different dose levels of 7.5 mg/m2 and 15 mg/m2
every 21 days with paclitaxel and carboplatin or
chemotherapy alone followed by the higher dose rhumab
VEGF at progression.[50] There was no statistically
significant difference in response rates or survival in any
of the three arms although the best results were obtainedwith the high dose rhumab VEGF arm. Time to treatment
progression was improved ðP ¼ 0:02Þ in the 15 mg/m2
rhumab VEGF arm as compared to carboplatin and
paclitaxel arm. Unfortunately, there were six unexpected
severe pulmonary hemorrhages in the rhumab VEGF
arms of which four were fatal. These occurred in patients
with central tumors and/or squamous histology. There-
fore, the ECOG has proposed a randomized phase III
study in advanced NSCLC patients with a nonsquamous
histology comparing carboplatin/paclitaxel alone to
carboplatin/paclitaxel plus rhumab VEGF at 15 mg/m2.
Nationally, phase III randomized trials are currently
underway where carboplatin and paclitaxel is being
compared with the same combination in addition to a
biological compound. Compounds being studied in this
way are Iressa (ZD1839), AG3340, OSI-774,
BMS275291, TNP 470, ISIS 3521, and others. Recently,
the results of INTACT-I trial were reported which
compared carboplatin and paclitaxel plus placebo to
carboplatin and paclitaxel plus Iressa. There were no
statistically significant differences in response rates,
median survival and 1-year survival. Thus, Iressa failed
to add benefit to carboplatin and paclitaxel in the first-
line treatment of advanced NSCLC. Results of the
INTACT-II trial comparing cisplatin and gemcitabineplus placebo to cisplatin and gemcitabine plus Iressa also
showed no statistically significant differences in response
rate, median survival and overall survival. Studies
similar in design are underway with other targeted agents
and the results of these studies are awaited.
NEWER MICROTUBULE STABILIZATION
AGENTS
The clinical success of paclitaxel and docetaxel
stimulated the search for compounds with a similar mode
Table 12. Comparison of SWOG 9504 with SWOG 9019.[57]
Study
Number of
Patients
Median Survival
(months)
1-Yr Survival
(%)
2-Yr Survival
(%)
3-Yr Survival
(%)
SWOG 9504 83 26 76 53 40
SWOG 9019 50 15 58 34 18
Simon and Bunn100
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 15/20
of action and has resulted in the identification of these
nontaxane chemical classes of natural products: the soil
bacteria-derived epothilones A and B (Epo A and Epo
B),[51] the marine sponge-derived discodermolide,[52]
and the coral-derived Eleutherobins/Sarcodictyins.[53,54]
All three classes stabilize microtubules and competi-
tively inhibit the binding of paclitaxel to tubulin
polymers, indicating overlap of binding sites.[51] The
epothilones, however, display some superior qualities;
they are water soluble, can be produced in large
quantities through bacterial fermentation, and retain
activity against multidrug-resistant cell lines and
tumors.[55,56] The epothilones are farthest along in
clinical development and are in phase I and II trials in
various disease sites.
CONCLUSIONS AND FUTURE DIRECTIONS
Taxane therapy has improved the outlook for
patients with NSCLC; both paclitaxel and docetaxel
reduce the hazard rate of death by 32% compared with
BSC. This reduction is greater than that achieved with
cisplatin or older cisplatin combinations. Combinations
of paclitaxel with cisplatin or carboplatin have been
shown to improve survival compared to etoposide and
cisplatin. Combinations of paclitaxel or docetaxel plus
cisplatin or carboplatin yielded survival results that were
equivalent to the very best two-drug combinations. In
large, multicenter phase III trials, the two-drugtaxane/platinum combinations consistently gave median
survival times of eight-months, one-year survival rates of
35–38% and two-year survival rates of 15%. These
results compare to median survival of four months, one-
year rates of 10–15% and two-year rates , 5% for BSC
and median survival of 6 months, one-year rates of 25%
and two-year rates of 5– 10% for older cisplatin
combinations. While the absolute increase (median 4–
8 months) is relatively modest, this represents a 50%
reduction in the hazard rate of death. If these results can
be reproduced in earlier stages, there will be a marked
improvement in the cure rate in NSCLC.
Carboplatin is more convenient, better tolerated, andless toxic than cisplatin. When combined with paclitaxel,
carboplatin/paclitaxel combination provides efficacy
results as good as those achieved with any combination
and with superior convenience, tolerability, and toxicity.
Both docetaxel and paclitaxel can be combined
safely with other new agents including vinorelbine and
gemcitabine. These two-drug combinations have similar
activity to taxane/platinum combinations and similar
toxicity profiles to taxane/carboplatin.
Triplet therapy with paclitaxel, gemcitabine, and
carboplatin or cisplatin can be delivered safely. Small
underpowered studies show higher response rates, and
longer survival and increased toxicity rates. Because of
the increased cost and toxicity, triplet therapy will
remain experimental unless large randomized trials show
a survival advantage.
Taxane/platinum combinations can be combined
readily with newly targeted therapies using full doses of
all agents. In many instances, phase II studies have
yielded provocative results. Several randomized trials
that are in progress hold the promise to provide another
small increment in prolongation of survival.
Data in earlier stages of NSCLC suggest that taxanes
may provide an equivalent reduction in hazard ratio of
death that will markedly improve survival. For example,
the SWOG found that the addition of docetaxel to theirstandard chemo-radiation therapy for stage III B patients
increases three-year survival from 18 to 40%. In stage
IB–IIIA disease the BLOT study reported that
preoperative paclitaxe/carboplatin was well-tolerated
and did not increase operative mortality. The three- and
four-year survival rates were much higher than reported
in any historical series. Thus, taxanes have a major role
in the therapy of NSCLC patients of all stages and
histologies. They are likely to be a major part of lung
cancer therapy for many years to come.
REFERENCES
1. Greenlee, R.T.; Murray, T.; Bolden, S.; et al. Cancer
Statistics, 2000. CA Cancer J. Clin. 2000, 50, 7–33.
2. Diaz, J.F.; Andreu, J.M. Assembly of purified GDP-
tubulin into microtubules induced by taxol and taxotere:
reversibility, ligand stoichiometry, and competition.
Biochemistry 1993, 32 (11), 2747–2755.
3. Monzo, M.; Rosell, R.; Sanchez, J.J.; et al. Paclitaxel
resistance in non-small cell lung cancer associated with
beta-tubulin gene mutations. J. Clin. Oncol. 1999, 17 (6),
1786–1793.
4. Ranson, M.; Davidson, N.; Nicolson, M.; et al. Random-
ized trial of paclitaxel plus supportive care versus
supportive care for patients with advanced non-small
cell lung cancer. J. Natl Cancer Inst. 2000, 92 (13),
1074–1080.
5. Bonomi, P.; Kim, K.; Fairclough, D.; et al. Comparison of
survival and quality of life in advanced non-small cell
lung cancer patients treated with two dose levels of
paclitaxel combined with cisplatin versus etoposide with
cisplatin: results of an Eastern Cooperative Oncology
Group Trial. J. Clin. Oncol. Feb. 2000, 18 (3), 623–631.
Taxanes in Treatment of Advanced NSCLC 101
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 16/20
6. Giaccone, G.; Splinter, T.A.; Debruyne, C.; et al.
Randomized study of paclitaxel–cisplatin versus cispla-
tinn-teniposide in patients with advanced non-small cell
lung cancer. The European Organization for Research and
Treatment of Cancer Lung Cancer Cooperative Group.J. Clin. Oncol. 1998, 16 (6), 2133–2141.
7. Schiller, J.H.; Harrinton, D.; Sandler, A.; et al. A
randomized phase III trial of four chemotherapy regimens
in advanced non-small cell lung cancer(NSCLC). Proc.
ASCO 2000, 19, 1a.
8. Kelly, K.; Crowley, J.; Bunn, P.A.; Livingston, R.B.;
D.R.G. A randomized phase III trial of paclitaxel plus
carboplatin (PC) versus vinorelbine plus cisplatin (VC) in
untreated advanced Non-small Cell Lung Cancer
(NSCLC): A South West Oncology Group (SWOG)
Trial. Proc. ASCO 1999, 18, 461a.
9. Gatzemeier, U.; Rossell, R.; Betticher, D.; et al.
Randomized paneuropean trial comparing paclitaxel
(Tax/Carboplatin(CAR) versus paclitaxel cisplatin(CIS)in advanced Non-small Cell Lung Cancer (NSCLC). Eur.
J. Cancer 1999, 35 (suppl. 4), s246.
10. Kosmidis, P.; Mylonakis, N.; Skarlos, D.; et al. Paclitaxel
(175 mg/m2) plus carboplatin (6 AUC) versus paclitaxel
(225 mg/m2) plus carboplatin (6 AUC) in advanced Non-
Small Cell Lung Cancer (NSCLC): a multicenter
randomized trial. Hellenic Cooperative Oncology Group
(HeCOG). Ann. Oncol. 2000, 11 (7), 799– 805.
11. Gatzemeier, U.; von Pawel, J.; Gottfried, M.; et al. Phase
III comparative study of highdose cisplatin versus a
combination of paclitaxel and cisplatin in patients with
advanced non-small cell lung cancer. J. Clin. Oncol. 2000,
18 (19), 3390–3399.
12. Kosmidis, P. Interim Results of a phase III trial.
Paclitaxel/Carboplatin vs Paclitaxel/Gemcitabine in
advanced non-small cell lung cancer. Oncology (Hun-
tingt) 2000, 14 (7 suppl. 4), 41 –48.
13. Roszkowski, K.; Pluzanska, A.; Krzakowski, M.; et al. A
multicenter, randomized, phase III study of docetaxel plus
best supportive care versus best supportive care in
chemotherapynaive patients with metastatic or nonresect-
able localized Non-small Cell Lung Cancer (NSCLC).
Lung Cancer 2000, 27 (3), 145–157.
14. Belani, C.; Rodriguez, J.; von Pawel, J.; et al. A
multicenter randomized phase III study of Docetaxel þ
Cisplatin (DC) vs Docetaxel þ Carboplatin (DCB) vs
Vinorelbineþ
Cisplatin (VC) in chemotherapy-naivepatients (Pts) with advanced and metastatic Non-small
Cell Lung Cancer (NSCLC). Lung Cancer 2000, 29, 60.
15. Georgoulias, V.; Papadakis, E.; Alexopoulos, A.; et al.
Docetaxel plus cisplatin versus docetaxel plus gemcita-
bine chemotherapy in advanced non-small cell lung
cancer: priliminary analysis of a multicenter randomized
phase II trial. Proc. ASCO 1999, 18, 461a.
16. Shepherd, F.A.; Dancey, J.; Ramlau, R.; et al. Prospective
randomized trial of docetaxel versus best supportive care
in patients with non-small cell lung cancer previously
treated with platinumbased chemotherapy. J. Clin. Oncol.
2000, 18 (10), 2095–2103.
17. Fossella, F.V.; DeVore, R.; Kerr, R.N.; et al. Randomized
phase III trial of docetaxel versus vinorelbine or
ifosfamide in patients with advanced non-small celllung cancer previously treated with platinumcontaining
chemotherapy regimens. The TAX 320 Non-small Cell
Lung Cancer Study Group. J. Clin. Oncol. 2000, 18 (12),
2354–2362.
18. Helsing, M.; Thaning, L.; Sederholm, C.; et al. Treatment
with paclitaxel 1-h infusion and carboplatin of patients
with advanced non-small cell lung cancer: a phase II
multicentre trial. Joint Lung Cancer Study Group. Lung
Cancer 1999, 24 (2), 107–113.
19. Laohavinij, S.; Maoleekoonpairoj, S.; Cheirsilpa, A.; et al.
Phase II study of paclitaxel and carboplatin for advanced
non-small cell lung cancer. Lung Cancer 1999, 26 (3),
175–185.
20. Scagliotti, G.V.; Crino, L.; Pozzi, E.; et al. Phase I/II dosefinding study of paclitaxel and carboplatin in advanced
non-small cell lung cancer. Lung Cancer 1999, 25 (1),
39–46.
21. Hsu, J.W.; Hsu, J.Y.; Chiang, C.D. Preliminary result
of pha se i i study of pac li ta xe l a nd c ispl at in
chemotherapy for advanced non-small cell lung cancer
in chinese patients. Am. J. Clin. Oncol. 1998, 21 (5),
487–490.
22. Faderl, B.; von Pawel, J.; Wagner, H.; et al. Phase II study
of docetaxel and cisplatin in a circadian timong a first line
chemotherapy (CT) in advanced Non-small Cell Lung
Cancer (NSCLC). Eur. J. Cancer 1999, 35 (suppl. 4),
s256.
23. Le Chevalier, T.; Monnier, A.; Douliard,, J.; et al.
Docetaxel (Taxotere) plus cisplatin: an active and
welltolerated combination in patients with advanced
non-small cell lung cancer. Eur. J. Cancer 1998, 34,
2032–2036.
24. Millward, M.; Bishop, J.; Lehnert, M.; et al. Phase II
trial of docetaxel taxotere and carboplatin in advanced
Non-small Cell Lung Cancer (NSCLC). Proc. ASCO
1999, 18.
25. Krug, L.; M.G.K.; Grant, S.; et al. Phase II trial of dose
dense docetaxel plus vinorelbine with prophylactic
filgastrim (G-CSF) in advanced Non-small Cell Lung
Cancer (NSCLC). Proc. ASCO 1999, 18.
26. Kourousis, C.; Androulakis, N.; Kakolyris, S.; et al. First-line treatment of advanced non-small cell lung carcinoma
with doctaxel and vinorelbine. Cancer 1998, 83,
2083–2090.
27. O’Rourke, M.; Garfield, D.; Ellis, P.; et al. Phase II trial of
Taxotere (T) and Navelbine (N) as first-line therapy in
patients with Advanced Non-small Cell Lung Cancer
(ANSCLC). Proc. ASCO 1999, 18.
28. Miller, V. Docetaxel (Taxotere) in combination with
vinorelbine in non-small cell lung cancer. Semin. Oncol.
1999, 26 (3 suppl. 10), 12–14.
Simon and Bunn102
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 17/20
29. Martin, C.; Isla, D.; Gonzalez-Larriba, J.; et al. A phase II
study of bi-weekly gemcitabine/paclitaxel in advanced
Non-small Cell Lung Cancer (NSCLC). Proc. ASCO
1999, 18, 462a.
30. Georgoulias, V.; Kouroussis, C.; Androulakis, N.; et al.Front-line treatment of advanced non-small cell lung
cancer with docetaxel and gemcitabine: a multicenter
phase II Trial. J. Clin. Oncol. 1999, 17 (3), 914–920.
31. Jensen, N.; Hansen, O.; Rose, C. Combination of
docetaxel and gemcitabine in the trament of advanced
Non-small Cell Lung Cancer (NSCLC). Eur. J. Cancer
1999, 35 (suppl. 4), s258.
32. Rubio, G.; Blajman, C.; Capo, A.; et al. Docetaxel and
gemcitabine in meztastatic Non-small Cell Lung Cancer
(NSCLC). A Phase II Study. Preliminary Feasibility
Report. Proc. ASCO 1999, 18, 522a.
33. Rathmann, J.; Leopold, K.A.; Rigas, J.R. Daily paclitaxel
and thoracic radiation therapy for Non-small cell lung
cancer: preliminary results. Semin. Radiat. Oncol. 1999, 9(2 suppl. 1), 130–135.
34. Oral, E.N.; Bavbek, S.; Kizir, A.; et al. Preliminary
analysis of a phase II study of paclitaxel and CHART in
locally advanced non-small cell lung cancer. Lung Cancer
1999, 25 (3), 191–198.
35. Kirkbride, P.; Gelmon, K.; Eisenhauer, E. Paclitaxel
and concurrent radiotherapy in locally advanced non-
small cell lung cancer: the canadian experience. Semin.
Radiat. Oncol. 1999, 9 (2 suppl. 1), 102–107.
36. Lau, D.; Ryu, J.; Gandara, D.; et al. Concurrent twice-
weekly paclitaxel and thoracic irradiation for stage III
non-small cell lung cancer. Semin. Radiat. Oncol. 1999, 9
(2 suppl. 1), 117–120.
37. Koukourakis, M.I.; Bahlitzanakis, N.; Froudarakis, M.;
et al. Concurrent conventionally factionated radio-
therapy and weekly docetaxel in the treatment of stage
III non-small cell lung carcinoma. Br. J. Cancer 1999,
80 (11), 1792– 1796.
38. Aamdal, S.; Hagen, I.; Avril, I.; et al. Docetaxel (D,
Taxotere) with concurrent radiation in locally advanced
Non-small Cell Lung Cancer (NSCLC). Proc. ESMO
1999, S260.
39. Vokes, E.; Leopold, K.A.; Herndon, J.E.; et al. A
randomized phase II study of gemcitabine and paclitaxel
or vinorelbine with cisplatin as induction chemotherapy
(Ind Ct) and concomitant chemoradiotherapy (XRT) for
unresectable stage III Non-small Cell Lung Cancer(NSCLC) (CALGB Study 9431). Proc. ASCO 1999, 18,
459a.
40. Lopez-Picazo, J.M.; Azinovic, I.; Aristu, J.J.; et al.
Induction platinum-based chemotherapy followed by
radical hyperfractionated radiotherapy with concurrent
chemotherapy in the treatment of locally advanced non-
small cell carcinoma of the lung. Am. J. Clin. Oncol.
1999, 22 (2), 203–208.
41. Nyman, J. Docetaxel and cisplatin as induction and
concomitant chemotherapy combined with accelerated
radiotherapy for stage III Non-small Cell Lung Cancer
(NSCLC)—A Phase II Study. Proc. ASCO 1999, 18,
518a.
42. Curran, W.; Scott, C.; P.B.; et al. Initial Report of Locally
Advanced Multimodality Protocol (LAMP): Acr 427: ARandomized 3-arm phase II study of paclitaxel (T),
carboplatin (C) and thoracic radiation (TRT) for patients
with stage III Non-small Cell Lung Cancer (NSCLC).
Proc. ASCO 2001, 20, 312a.
43. H.C; A.N.; B.S.; et al. Positive phase II results of RSR13
and concurrent radiation therapy after induction che-
motherapy with paclitaxel and carboplatin for locally
advanced inoperable non-small cell lung cancer. Proc.
ASCO 2001, 20, 313a.
44. Furuse, K.; Fukuoka, M.; Kawahara, M.; et al. Phase III
study of concurrent versus sequential thoracic radio-
therapy in combination with mitomycin, vindesine, and
cisplatin in unresectable stage III non-small cell lung
cancer. J. Clin. Oncol. 1999, 17 (9), 2692–2699.45. Curran, W.; Scott, C.; Langer, C.; et al. Phase III
comparison of sequential vs. concurrent chemoradiation
for pts with unresected stage III Non-small Cell Lung
Cancer (NSCLC): Initial Report of Radiation Therapy
Oncology Group (RTOG) 9410. Proc. ASCO 2000, 19,
484a.
46. Albain, K.S.; Rusch, V.W.; Crowley, J.J.; et al.
Concurrent cisplatinetoposide plus chest radiotherapy
followed by surgery for stages IIIA (N2) and IIIB non-
small cell lung cancer: mature results of Southwest
Oncology Group Phase II Study 8805. J. Clin. Oncol.
1995, 13 (8), 1880–1892.
47. Gandara, D.R.; Lovato, L.C.; Albain, K.S.; et al.
Prolonged survival in patholgic stage IIIB Non-small
Cell Lung Cancer (NSCLC) with concurrent chemor-
adiotherapy followed by consolidation docetaxel: a phase
II study (S9504) of the Southwest Oncology Group
(SWOG). Proc. ASCO 2000, 19, 490a.
48. Pisters, K.M.; Ginsberg, R.J.; Giroux, D.J.; et al.
Induction chemotherapy before surgery for early-stage
lung cancer: a novel approach. bimodality lung oncology
team. J. Thorac. Cardiovasc. Surg. 2000, 119 (3),
429–439.
49. Comella, G.; Comella, P.; Frasci, G.; et al. Cisplatin–
gemcitabine, vs. cisplatin– gemcitabine– vinorelbine, vs.
cisplatin– gemcitabine– paclitaxel in advanced non-small
cell lung cancer. First Stage Analysis of a Southern ItalyCooperative Oncology Group (SICOG) Phase III Trial.
Proc. ASCO 2000, 19, 494a.
50. Devore, R.F.; Herbst, R.S.; Langer, C.J.; et al. A
randomized phase II trial comparing rhumab VEGF
(recombinant humanized monoclonal antibody to vascu-
lar endothelial cell growth factor) plus Carboplatin/
Paclitaxel(CP) to CP alone in patients with stage IIIB/IV
NSCLC. Proc. ASCO 2000, 19, 485a.
51. Bollag, D.M.; McQueney, P.A.; Zhu, J.; et al. Epothi-
lones, a new class of microtubule-stabilizing agents with
Taxanes in Treatment of Advanced NSCLC 103
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 18/20
a Taxol-like Mechanism of Action. Cancer Res. 1995, 55
(11), 2325–2333.
52. Kowalski, R.J.; Giannakakou, P.; Gunasekera, S.P.;
Longley, R.E.; Day, B.W.; Hamel, E. The micro-
tubulestabilizing agent discodermolide competitivelyinhibits the binding of paclitaxel (Taxol) to tubulin
polymers, enhances tubulin nucleation reactions more
potently than paclitaxel, and inhibits the growth of
paclitaxel-resistant cells. Mol. Pharmacol. 1997, 52 (4),
613–622.
53. Long, B.H.; Carboni, J.M.; Wasserman, A.J.; et al.
Eleutherobin, a novel cytotoxic agent that induces tubulin
polymerization, is similar to paclitaxel (Taxol). Cancer
Res. 1998, 58 (6), 1111–1115.
54. Nicolaou, K.C.; Finlay, M.R.; Ninkovic, S.; et al.
Synthesis and biological properties of C12,13-Cyclopro-
pyl-epothilone a and related epothilones. Chem. Biol.
1998, 5 (7), 365– 372.
55. Cowden, C.J.; Paterson, I. Synthetic chemistry. Cancerdrugs better than taxol? Nature 1997, 387 (6630),
238–239.
56. Service, R.F. Tumor-Killer Made; How does it work?
Science 1996, 274 (5295), 2009.
57. G aspa r, L .; G anda ra , D .; Cha nsky, K .; e t a l.
Consolidation docetaxel following concurrent chemor-
adiotherapy in pathologic stage IIIB Non-small Cell
Lung Cancer(NSCLC) (SWOG9504). Patterns of Fail-
ure and Updated Survival. Proc. ASCO 2001, 20, 315a.
Simon and Bunn104
MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK , NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
8/4/2019 Cancer Invest. 2003;21(1) 87-104
http://slidepdf.com/reader/full/cancer-invest-2003211-87-104 19/20