Shinshu M ed J, 59 ⑹ :411〜418, 2011

Phase II Trial of Biweekly Paclitaxel and Gemcitabine as
Second‑Line Chemotherapy for Non‑Small Cell Lung Cancer
Previously Treated with Platinum‑Based Chemotherapy
Takashi KOBAYASHI, Tomonobu KOIZUMI＊, M asanori YASUO
Kenji TSUSHIMA, Hiroshi YAMAMOTO and Keishi KUBOFirst Department of Internal Medicine, Shinshu University School of Medicine

A phase II study was conducted to evaluate the feasibility and eﬃcacy of biweekly administration of
paclitaxel and gemcitabine in patients with non‑small cell lung cancer (NSCLC) who had been treatedpreviously with platinum‑based chemotherapy. Paclitaxel (150 mg/m ) and gemcitabine (1,000 mg/m ) wereadministered biweekly for at least 4 cycles. Thirty‑one patients with a median age of 64 years (39 ‑75 years)
were enrolled in this study(stage IIIB/IV :11/20,PS 0/1/2:13/16/2).Partial response was observed in 7 cases(23%), and stable disease was seen in 18 cases (58%).Median survival time was 8.8 months with a one‑year
survival rate of 41.9 %.Hematological toxicities were mild and neutropenia of grade 3 or above was observedin one patient (3%). Non‑hematological toxicities were also mild, including neurotoxicity (3%). Biweekly
paclitaxel and gemcitabine combination chemotherapy was eﬀective and tolerated well as second‑line therapy
against NSCLC. Shinshu Med J 59 : 411―418, 2011
(Received for publication May 2, 2011;accepted in revised form August 8, 2011)
Key words:second‑line chemotherapy, biweekly, platinum‑resistant,non‑small cell lung cancer, neurotoxicity

Among the agents useful for NSCLC,paclitaxel is

Introduction

the ﬁrst clinically available taxane the cytotoxicity

In recent years,the eﬃcacy of second‑line chemo-of which is derived from suppression of the func-

therapy has been established in phase III clinical‑tions of mitotic microtubules . Gemcitabine (2ʼ,2ʼtrials for patients with advanced non‑small cell lung‑deoxycytidine)is also a novel pyrimidine
diﬂuoro‑2ʼ

cancer (NSCLC) . Two chemotherapeutic agents,

nucleoside analog . Both agents have yielded

docetaxel and pemetrexed,and the biological agent

response rates of 21%‑26% in advanced NSCLC

erlotinib are currently approved for clinical use inwith only mild toxicities when used in single‑agent

patients with advanced NSCLC. However, theregimens .Platinum in combination with paclitaxel

improvements in survival after these therapies areor gemcitabine has been studied extensively andmodest and other novel agents have become avail-shown response rates in the 21%‑62% rangein ﬁrst‑

able for patients with NSCLC over the past decade.

line chemotherapy for NSCLC

Therefore, it is still important to conduct clinicalinformation is available regarding the activity andtrials to evaluate the activity of other agents as

feasibility of paclitaxel plus gemcitabine when usedsecond‑line treatment for NSCLC.

as second‑line chemotherapy for NSCLC. These. However, little

agents appear promising due to their speciﬁc mechaCorresponding author:Tomonobu Koizumi
First Department of Internal M edicine, Shinshu University School of M edicine, 3‑1‑1 Asahi, M atsumoto‑city,
Nagano‑prefecture 390‑8621, Japan

No. 6, 2011

nism of action and favorable toxicity proﬁles.

Previously, we conducted a phase I study of abiweekly combination of paclitaxel and gem411

Kobayashi.Koizumi.Yasuo et al.

citabine and the results indicated recommended

mance status, diﬀerential blood cell counts,routine

doses of 150 mg/m for paclitaxel and 1,000 mg/m

laboratory tests, and urinalysis results werefor gemcitabine . The present study was perfor-

obtained before the study. Electrocardiography,

med to further evaluate the eﬀectiveness and safety

chest radiography, chest computed tomographyof biweekly administration of paclitaxel and gem-

(CT), abdominal ultrasound and/or CT scan, andcitabine as second‑line therapy for patients withwhole‑brain CT scan or magnetic resonance imag-

advanced NSCLC who had been unsuccessfullying (M RI) and isotope bone scan were also perfor-

treated with platinum‑based chemotherapy.

med in all cases.

Method and Subjects
Patient eligibility

Toxicity and response evaluation
During the study period, complete diﬀerential
blood cell counts were obtained weekly. Routine

Patients with histologically or cytologicallychemistry measurements were performed biweekly

conﬁrmed stage IIIB or IV NSCLC in whom ﬁrst‑

before chemotherapy. If necessary, additionalline chemotherapy with a platinum‑containing regi-

examinations of blood samples were performed.

men had failed or who had relapsed were eligible for

Examination of chest CT was performed after four

this study. Other criteria were as follows:1)age≧

cycles of chemotherapy for detailed tumor measure-

20 and≦75 years; 2) Eastern Clinical Oncology

ments. Toxicity was evaluated according to theGroup (ECOG) performance status 0 to 2; 3) ade-

National Cancer Institute Common Toxicity Criter-

quate bone marrow function (neutrophil count≧2×

ia Version 2 .Tumor assessment by chest CT was

10 /μL,hemoglobin≧10 g/dL,platelet count≧100×

performed after four cycles of chemotherapy.

10 /μL), normal hepatic function (total bilirubin

Response Evaluation Criteria in Solid Tumors

level≦1.5× and AST≦2× the upper normal limits),(RECIST) was used for evaluation of tumor(creatinine≦ 1.5 mg/dL,

response . All responses were evaluated carefully

creatinine clearance≧60 mL/min). Individuals withand conﬁrmed by independent veriﬁcation. Tox-

peripheral neuropathy were excluded.Patients with

icities were expressed at the highest grade during

a history of partial response after prior paclitaxel

chemotherapy and the delivery and compliance ofchemotherapy were permitted to participate in thethe treatment were evaluated for the ﬁrst four

present study. In addition, patients were excluded

cycles of paclitaxel/gemcitabine administration.

from the trial for any of the following reasons:1)

Treatment delivery and dose reduction

and renal function

active infection ; 2) severe heart disease; 3) past

On day 1 of each chemotherapy cycle, paclitaxel

history of hypersensitivity to drugs; 4) pleural or(150 mg/m ) was administered ﬁrst as an intra-

pericardial eﬀusion requiring drainage; 5) active

venous infusion over 1 h followed by gemcitabinebrain metastasis; or 6) pregnancy. Patients with

(1,000 mg/m )intravenously over 30 min.Paclitaxelother concurrent active malignancy were also ex-(Taxol) and gemcitabine (Gemzar) were diluted included.No other concomitant anticancer therapyor

250 mL and 100 mL of normal saline, respectively.

experimental drug administration of any type was

To avoid hypersensitivity reactions, the following

permitted. Written informed consent was obtained

standard premedication was administered : dex-

from each enrolled patient. The study was under-amethasone 20 mg intravenously (IV), diphenhy-

taken in accordance with the Declaration of Helsin-

dramine 50 mg IV,and cimetidine 150 mg IV.Theseki.

drugs were administered 30 min prior to paclitaxel
Pretreatment evaluation

administration.Chemotherapy cycles were repeated

Before enrollment in the present study, allevery 2 weeks.Recombinant human G‑CSF was notpatients underwent clinical and physical examina-

given prophylactically. Administration of subse-

tion. General condition, medical history, perfor-

quent chemotherapy was allowed when absolute

412

Shinshu Med J Vol.59

Biweekly paclitaxel and gemcitabine as second‑line chemotherapy for NSCLC

neutrophil and platelet counts were more than 1.5×

cycle occurred because of neutropenia (3cases),non‑

10 /μL and 75×10 /μL, respectively. If these vari-

neutropenic infection or fever (3 cases), and otherables did not return to adequate levels by a maxi-

reasons unrelated to treatment (2 cases).Pulmonary

mum of 2 weeks,doses of both agents were reduced

toxicity developed after only one cycle in one

by 20%.Similarly,the dose reduction was adjusted

patient and disease progression was observed afterin cases showing chemotherapy‑induced febrile

two cycles in one patient, and chemotherapy was

neutropenia or grade 4 hematological toxicity last-

subsequently discontinued. Dose modiﬁcation of

ing for 4 days.Patients with disease progression atthese agents was not performed.Thus,111 cycles ofany cycle of chemotherapy or presenting with grade

chemotherapy received the intended ﬁrst four

3 or 4 nonhematological toxicity and requiring

cycles,resulting in a completion rate of 89.5% (111/hospitalization were withdrawn from the study.

124 cycles).

Statistics

Toxicity

The main endpoint of this study was the response

Toxicities were assessed in all patients.

rate.Secondary endpoints were toxicities and over-Hematological toxicities were generally mild, as

all survival. Response and survival rates were bothshown in Table 2. Grade 3 neutropenia occurred in

calculated on an intent‑to‑treat basis. Overall sur-

only one patient (3%) and none developed

vival was calculated from the date of initiation ofneutropenic fever during the present chemotherapy

this regimen to death or date of last follow‑up

regimen. Interestingly, there were no cases of(cutoﬀ date: 31 March 2008). The Kaplan‑Meiersevere thrombocytopenia or anemia during therapy.

method was used to determine the medians of theNonhematological toxicities are summarized intime‑related parameters.

Table 3.Grade 2 and 3 peripheral sensory neurotox-

Results
Patient characteristics
A total of 31 patients were enrolled in the study
between August 2000 and January 2006.The clinical

Table 1 Patient characteristics
Characteristic

characteristics of the patients are summarized inTable 1. The study population consisted of 23 men

Age (years)

and 8 women,with a median age of 67 years (range

M edianRange

1, and 2 had a PS of 2. Adenocarcinoma histology
was noted in 26 patients. Eleven patients had stage
IIIB disease and the remaining 20 had stage IV
disease. All patients had been previously treatedwith platinum‑containing regimens as ﬁrst‑line
chemotherapy;26 received platinum compound plus
docetaxel, and the remaining 5 patients had beentreated with platinum compound plus paclitaxel.
Treatment delivery
A total of 161 cycles of biweekly administrationof paclitaxel and gemcitabine were performed witha median of 4 cycles (range 1‑20).Treatment delivery was evaluated during the ﬁrst four cycles ofchemotherapy. A delay of one week until the next
No. 6, 2011

%

23
8

74
26

Sex
M ale
Female39 ‑75 years).Of the 31 patients,29 had a PS of 0 orNo.

67
39 ‑75

Performance status
PS0
PS1
PS2
Histology
Adenoca.
Squamous cell ca.
Large cell ca.
Stage
Ⅲb
Ⅳ
First line chemotherapy
cisplatin＋docetaxel
carboplatin＋paclitaxel
nedaplatin＋paclitaxel
carboplatin＋docetaxel

13
16
2

42
52
6

26

84

2
3

6
10

11
20

35
65

25
3
2

81
10
6

1

3
413

Kobayashi.Koizumi.Yasuo et al.
Table 2 Hematological toxicities
Grade (No.)

Toxicity

Grade≧3 (%)

0

1

2

3

4

Leukopenia

21

7

3

0

0

0

Neutropenia
Thrombocytopenia
Anemia

19
30
24

5
1
4

6
0
3

1
0
0

0
0
0

3
0
0

Table 3 Non‑hematological toxicities
Toxicity

Grade (No.)

Grade≧3 (%)

0

1

2

3

4

NauseaDiarrhea
Constipation
Neuropathy

19
27
28
15

10
3
3
7

2
1
0
8

0
0
0
1

0
0
0
0

0
0
0
3

Myalgia
Eruption

19
27

11
2

1
2

0
0

0
0

0
0

Alopecia
Edema
Infection without neutropenia
Liver dysfunction

11
31
28
28

10
0
1
3

10
0
1
0

0
0
1
0

0
0
0
0

0
0
3
0

Renal dysfunction
Pneumonitis

31
30

0
0

0
0

0
0

0
1

0
3

Table 4 Response rateicities were observed in 8 cases (28%)and one case(3%), respectively. One patient developed severe

Overall response

30

pulmonary toxicity after only one cycle of chemotherapy, which resulted in a fatal outcome. No

Partial response (PR)patients showed an allergic reaction to therapy or

Stable disease (SD)
Progressive disease (PD)developed edema during chemotherapy.
EﬃcacyNot evaluatedNo. (%)
7 (23%)(95%CI 9.6‑41.1%)
18 (58%)5 (16%)

1(only 1 cycle)

All 31 patients were included in the analyses oftumor response and survival. Partial response was

responses to docetaxel.

observed in 7 patients (23% ;95% conﬁdence inter-

The overall survival curve is shown in Fig. 1.

val (CI)9.6%‑41.1%), and stable disease was seen

M edian survival time was 8.8 months (95%CI 4.9 ‑in 18 patients (58%)(Table 4).Among the 7 patients

15.0 months), and 1‑year survival rate was 41.9 %who responded to prior docetaxel plus platinum(95%CI 24.6%‑59.3%).

compound chemotherapy, one patient achieved apartial response (14%) to the gemcitabine andDiscussion

paclitaxel regimen. On the other hand, among 19

The results of the present study indicated thatpatients who failed to response to the docetaxel‑

paclitaxel plus gemcitabine administered biweekly

containing chemotherapy regimen, 5 patients

could be combined safely for treatment of patients

showed a partial response(26%)to the gemcitabinewith NSCLC who had relapsed after or were resis-

and paclitaxel regimen. There were no signiﬁcanttant to platinum ‑based chemotherapy. The

diﬀerences in response rate related to previous

response rate was 23% and median survival time414

Shinshu Med J Vol.59

Biweekly paclitaxel and gemcitabine as second‑line chemotherapy for NSCLC

Fig. 1

Overall survival when treated with paclitaxel and gemcitabine as second‑line
chemotherapy in patients with non‑small cell lung cancer (n＝31).
The median survival time was estimated as 8.8 months (95%CI 4.9 ‑15.0 months),
and 1‑year survival rate was 41.9 % (95%CI 24.6%‑59.3%).

was 8.8 months with a 1‑year survival rate oftion with docetaxel failed to show a survival beneﬁt

41.9 %,which were promising results as second‑line

compared with docetaxel alone in patients withchemotherapy. Furthermore, the toxicity proﬁlespreviously treated NSCLC. Several studies, includ-

were also acceptable.

ing the present study, demonstrated that combined

Several studies using a combination of paclitaxel

gemcitabine and paclitaxel in second‑line chemo-

and gemcitabine as second‑line therapy in patients

therapy provided a relatively high response ratewith NSCLC have been reported. Mori et al.

compared with studies using docetaxel. Thus, pa-

conducted weekly administration of paclitaxel (100clitaxel plus gemcitabine is a potentially useful

mg/m on days 1 and 8)and gemcitabine (1,000 mg/

novel regimen, which should be examined in phasem on days 1 and 8) in patients with NSCLC andIII clinical trials as second‑line chemotherapy forreported a response rate of 32.5% and MST of 41.7

patients with NSCLC.

weeks. Androulakis

also reported an overall

In the initial planning stages of this study, there

response rate of 18% and M ST of 47 weeks. The

was no patient selection for previous agents indose settings were: paclitaxel, 175 mg/m day 8;

combination with platinum. However, all patientsand gemcitabine, 900 mg/m days 1 and 8. These

enrolled in the present study were treated withﬁndings were almost identical to our results

chemotherapy regimens that included taxanes. Lit-

obtained by biweekly administration of paclitaxel

tle information is available regarding the inﬂuence(150 mg/m ) and gemcitabine (1,000 mg/m ),of previous administration of docetaxel on subse-

although survival beneﬁt was slightly lower in thequent paclitaxel activity in patients with NSCLC.

present study. To our knowledge, no clinicalThe superior activity of docetaxel in second‑line

studies have shown the superiority of a doublet

therapy is comparable to those of vinorelbine andregimen over single‑agent chemotherapy in second‑

ifosfamide . However, the response and survival

line treatment of NSCLC.Gemcitabine in combina-

beneﬁt of subsequent docetaxel therapy were in-No. 6, 2011

415

Kobayashi.Koizumi.Yasuo et al.

dependent of the previous use of paclitaxel . The

dose‑limiting toxicity of paclitaxel. The neurotox-

current paclitaxel and gemcitabine therapyregimen

icity observed in the present study may have been

showed a response rate of 23% in patients treated

due to paclitaxel or the previous use of docetaxel orpreviously with a docetaxel‑containing regimen.In

paclitaxel.Although patients with preexisting neur-

addition, the 26% response rate of paclitaxel plus

opathy were excluded from the present study, thegemcitabine in patients who failed to response toincidences of neurotoxicity exceeding grade 3 (3%)

docetaxel‑including chemotherapy regimens sug-were low and were similar to those in othergested partial non ‑cross ‑resistance between

reports

docetaxel and paclitaxel,gemcitabine,or the combi-

gemcitabine combined with paclitaxel did not leadnation therapy. The present study suggested thatto worse neurotoxicity than that observed withpaclitaxel is also promising as second‑line therapy

paclitaxel as single therapy

in patients with NSCLC previously treated withdata support this.

docetaxel.

. As it has been demonstrated that

,we believe that our

One patient in the present study showed severe

In the present study, hematological toxicities

pulmonary toxicity. It has been reported that gem-

were mild. In particular, thrombocytopenia wascitabine combined with docetaxel increases the risk

infrequent.Grade 3‑4 thrombocytopenia was obser-of pulmonary toxicity compared to docetaxel

ved in 30%‑50.4% of cases treated with a combina-

alone .Based on reports in the literature,the rates

tion of platinum plus gemcitabineof pulmonary toxicity in paclitaxel plus gem-

.Isla et al.

performed a Phase II study of biweekly paclitaxel

citabine combination are low compared with those(150 mg/m )and gemcitabine (2,000 mg/m )as ﬁrst‑

associated with docetaxel plus gemcitabine.Thus,itline chemotherapy against NSCLC and reported

is unlikely that the combination of paclitaxel andthat no thrombocytopenia exceeding grade 3 was

gemcitabine could be associated with increased

observed. Similar ﬁndings at a lower frequency of

pulmonary toxicity. However, pulmonary adverse

thrombocytopenia were observed in other studies

events should be noteworthy toxicities in any

using gemcitabine and paclitaxel

chemotherapy regimen.

. However,weekly administration of paclitaxel and gem-

In summary, a biweekly regimen of a combina-

citabine showed an incidence rate of throm-tion of paclitaxel (150 mg/m ) and gemcitabine

bocytopenia exceeding grade 3 of 12.5%.Therefore,(1,000 mg/m ) was well tolerated and showed good

the administration of combined paclitaxel and gem-

activity as second‑line therapy in patients withcitabine every two weeks appeared to show a

NSCLC who had relapsed after or developed resis-

reduced rate of thrombocytopenia.

tance to platinum‑based chemotherapy.The results

Neurotoxicity was seen frequently in cases treat-of our trial suggest that this is a candidate regimen

ed with paclitaxel‑containing regimens. In particu-

for second‑line treatment in NSCLC with a well‑lar, cumulative peripheral neuropathy could be thetolerated schedule of administration.

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