Cancer Invest. 2003;21(1) 87-104

8/4/2019 Cancer Invest. 2003;21(1) 87-104

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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

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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

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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.

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8/4/2019 Cancer Invest. 2003;21(1) 87-104


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.

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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.

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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.

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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.




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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.

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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.




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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.

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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.




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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.

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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.




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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

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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.

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