A three-drug induction chemotherapy with gemcitabine, carboplatin, and paclitaxel for stage III...

ORIGINAL PAPER

A three-drug induction chemotherapy with gemcitabine,carboplatin, and paclitaxel for stage III non-small cell lung cancer

Giuseppe Luigi Banna • Helga Lipari • Maurizio Nicolosi • Antonio Basile •

Filippo Fraggetta • Marina Vaglica • Francesco Marletta • Orazio Ezio Urso •

Massimo Ippolito • Alberto Terminella • Salvatore Saita

Received: 9 February 2013 / Accepted: 2 March 2013 / Published online: 20 March 2013

� Springer Science+Business Media New York 2013

Abstract The aim of the study is to evaluate the efficacy

and safety of a three-drug chemotherapy regimen including

gemcitabine, carboplatin, and paclitaxel as induction ther-

apy in clinical stage III non-small cell lung cancer

(NSCLC). Patients aged 18–75 years, ECOG PS 0–1, with

unresectable clinical stage IIIA or IIIB NSCLC suitable for

definitive radiation treatment, were treated in a phase II

study with i.v. carboplatin AUC 5 and i.v., paclitaxel

175 mg/m2 on day 1, and i.v. gemcitabine 800 mg/m2 on

days 1 and 8, every 3 weeks for 3 cycles, as previously

assessed in a dose-finding study. Primary end point was

overall response rate (ORR). Secondary end points inclu-

ded: toxicity, progression-free survival (PFS), resection

rate, and overall survival (OS). Out of the 60 enrolled

patients, 49 were males and 11 females, 31 patients had

stage IIIA and 29 stage IIIB NSCLC. Forty-four partial

responses and one complete response were observed, for an

ORR of 75 %. The most frequent G3–G4 toxicity included:

neutropenia (in 23 % of cases), hypertransaminasemia

(12 %), and diarrhea (5 %). With a median follow-up of

15 months (range 2–72), median PFS was 10.5 months

(95 % CI 9.9–11.4) and median OS was 21.1 months

(95 % CI 19.7–22.8). Fourteen stage IIIA patients under-

went surgery, for a resection rate of 45 %. A median PFS

of 17.8 months (95 % CI 16.2–19.7) and a median OS of

25.5 months (95 % CI 23.0–28.4) were observed in stage

IIIA patients. The three-drug chemotherapy regimen, at the

employed dose, demonstrated a considerable disease

response and resection rate, with acceptable toxicity.

Keywords Triplet chemotherapy � Radiotherapy �Surgery � Unresectable � Locally advanced non-small cell

lung cancer

Introduction

The prognosis of locally advanced stages IIIA and IIIB

NSCLC is poor, with a 5-year OS rate of 23 and 3 %,

respectively [1]. Local relapse and distant metastases

occurring in a large number of patients are highly indica-

tive of suboptimal treatment [2].

Thoracic radiotherapy has traditionally been considered

the cornerstone therapy in locally advanced and inoperable

NSCLC, and consists of the administration of a total dose

G. L. Banna (&) � H. Lipari � M. Vaglica � O. E. Urso

Division of Medical Oncology, Cannizzaro Hospital, Via

Messina 829, 95126 Catania, Italy

e-mail: [email protected]

M. Nicolosi

Division of Thoracic Surgery, Cannizzaro Hospital, Via Messina

829, 95126 Catania, Italy

A. Basile

Department of Diagnostic and Interventional Radiology,

Ospedale Garibaldi Centro, Piazza Santa Maria del Gesu,

Via Trieste 14, 95127 Catania, Italy

F. Fraggetta

Department of Pathology, Cannizzaro Hospital, Via Messina


F. Marletta

Division of Radiotherapy, Cannizzaro Hospital, Via Messina


M. Ippolito

Division of Nuclear Medicine, Cannizzaro Hospital,

Via Messina 829, 95126 Catania, Italy

A. Terminella � S. Saita

Division of Thoracic Surgery, A.O.U. Policlinico Vittorio

Emanuele Hospital, Via Plebiscito 629, 95128 Catania, Italy

123

Med Oncol (2013) 30:533

DOI 10.1007/s12032-013-0533-8

of 60 Gray delivered in daily fractions for 6 weeks [2]. The

optimal treatment strategy for these patients remains to be

determined and depends not only on the disease stage (IIIA

or IIIB) and the extent of the disease, but also on some

clinical factors, such as age, performance status, and

comorbidities.

The American Society for Clinical Oncology (ASCO)

guidelines recommend combined platinum-based chemo-

therapy and definitive thoracic radiotherapy, particularly

for patients with good performance status [2]. By ran-

domized trials [3–6] and a meta-analysis [7], concomitant

chemoradiotherapy produces superior outcome compared

to the sequential treatment, though associated with an

increased treatment-related local toxicity.

A two-drug platinum-based chemotherapy regimen is

considered the standard. In a meta-analysis [8], a platinum-

based regimen containing gemcitabine resulted signifi-

cantly superior compared to the one including another

first- or second-generation drug, in stage IV NSCLC [8]. A

three-drug platinum-based regimen, with the addition of

gemcitabine to carboplatin and paclitaxel, has demon-

strated superior outcome results compared to a two-drug

one with carboplatin and paclitaxel, in a phase II–III study

on advanced NSCLC [9]. The addition of gemcitabine to

carboplatin and paclitaxel was also effective as induction

chemotherapy in operable (clinical stage IB, II, or IIIA)

NSCLC, with an ORR of 76 % and a resection rate of 81 %

[10], and in locally advanced unresectable (stages IIIA and

IIIB) NSCLC, with an ORR of 62.5 %, although none of

responding patients has become eligible for surgery [11].

However, this triplet resulted in significantly more fre-

quent and severe hematological toxicity requiring transfu-

sions of red blood cells and platelets, an increased use of

granulocyte colony-stimulating factors (G-CSFs) and

hematopoietic growth factors (HGFs) and frequent therapy

withdrawals, at the employed dose of: gemcitabine at

1,000 mg/m2, on days 1, 8, every 21 [9–11]; carboplatin

at AUC 5 [10, 11] to 6 [9], every 21 days; and paclitaxel at

175 [10, 11] to 200 mg/m2 [9], every 21 days [9–11].

Given the significant hematological toxicity observed in

these series, in a previous dose-finding study we performed

in patients with stages IIIA and IIIB NSCLC, we reported as

the safest level dose of the three-drug regimen the following:

gemcitabine (at the dose of 800 mg/m2, on days 1, 8, every

21); carboplatin (at AUC 5, every 21 days); and paclitaxel

(175 mg/m2, every 21 days). The highest level dose of

gemcitabine (1,000 mg/m2, on days 1, 8, every 21) resulted

in a significant rate of dose-limiting toxicities [12]. In the

present study, we explored this three-drug regimen, at the

dose levels established in the previous dose-finding study, as

induction chemotherapy in stage IIIA and IIIB NSCLC.

Patients and methods

Study population

The eligibility criteria for the study included: histological

or cytological diagnosis of NSCLC; unresectable clinical

stage IIIA NSCLC or stage IIIB (according to TNM ver-

sion 6.0) [13] NSCLC suitable for definitive radiation

treatment; age between 18 and 75 years; ECOG (Eastern

Cooperative Oncology Group) performance status of 0 or

1; adequate hematological, renal, and hepatic function; no

significant cardiovascular, pulmonary, hepatic, or renal

comorbidity; no previous treatment with radiation or che-

motherapy; written informed consent. Pre-treatment eval-

uation and baseline clinical staging included: anamnesis;

physical examination; computed tomography (CT) scan of

brain, chest, abdomen, and pelvis; bone scan when not

performed a 18Fluoro-deoxy-glucose (18FDG)-positron

emission tomography (PET); 18FDG-PET, only in patients

with stage IIIA disease; laboratory tests for the evaluation

of hematological, liver, and kidney function; magnetic

resonance imaging (MRI) of the brain with gadolinium

when clinically indicated.

As part of an interdisciplinary evaluation for each case

in the presence of a medical oncologist, a surgeon, and a

radiation oncologist, the following criteria have been fol-

lowed for the definition of initial non-resectability, N2

lymph node involvement, and surgical indication to

pneumonectomy.

Induction chemotherapy

Chemotherapy included three cycles delivered every

21 days with the following drugs: gemcitabine (at the

dose of 800 mg/m2 i.v., on days 1 and 8) in 250 cc saline

solution over 30 min; paclitaxel (175 mg/m2 i.v., on day

1) in 500 cc saline solution over 3 h; carboplatin (AUC 5

i.v., on day 1) in 500 cc saline solution over 1 h. As

chemotherapy premedication, the following drugs were

used: ranitidine 100 mg i.v., methylprednisolone 250 mg

i.v., chlorphenamine 10 mg i.v, ondansetron 8 mg i.v.

15 min before chemotherapy of day 1, and prednisolone

25 mg p.o. on the evening of the day before day 1;

ranitidine 100 mg i.v., dexamethasone 8 mg i.v., and

ondansetron 8 mg i.v. 15 min before the chemotherapy of

day 8.

On the day 8 of each cycle, a complete blood count and

the determination of AST and ALT were performed. On

day 22, complete blood count and laboratory tests for the

assessment of hematological, hepatic, and renal function

were requested.

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Assessment of toxicity and response

Toxicity registration by clinical evaluation was performed

according to the CTC version 3.0 on days 8 and 22 of each

cycle. The assessment of response was performed using CT

(and/or 18FDG-PET only for stage IIIA NSCLC) within

3 weeks after the third cycle.

Locoregional treatment

Patients with stage IIIA disease, with respondent disease,

were re-evaluated for surgery; in case of non-resectability

or patient refusal, patients were sent for definitive radio-

therapy. Patients with stage IIIB disease, with respondent

or stable disease, were initiated with definitive radiother-

apy. Patients with disease progression (PD) dropped out of

the study and were treated with a further line of chemo-

therapy. Surgery or radiotherapy should be started within

6 weeks of the response assessment.

Postoperative radiotherapy was allowed in case of

operated stage IIIA for pN2 NSCLC and should be started

between the fourth and tenth week after surgery.

Follow-up visits were performed every 3 months for the

first 2 years and every 6 months thereafter, and included

clinical evaluation, a CT scan of brain, thorax, abdomen,

and pelvis, further investigations when clinically indicated.

Chemotherapy dose reduction

In the case of G3 non-hematological toxicity, the following

dose reductions were carried out: gemcitabine 650 mg/m2

i.v., days 1,8; paclitaxel 150 mg/m2 i.v., day 1; carboplatin

AUC 4 i.v., day 1. In the case of G4 non-hematological

toxicity, chemotherapy was permanently discontinued. In

the case of G3 hematological toxicity, G-CSFs and HGFs

have been used; when clinically indicated transfusions of

red blood cells or platelets were administered. If indicated,

antibiotics and other supportive care were used.

Statistical analysis

The primary objective of the study was to evaluate the

efficacy of the three-drug induction chemotherapy in a

phase II study. The primary end point was overall response

rate, including complete responses and partial responses

according to the RECIST criteria [14]. Secondary end

points were PFS, resection rate (for stage IIIA disease),

toxicities (according to the CTC version 3.0), and OS. The

disease responses were reported as relative proportions to

the total number of patients. Percentages were approximate

to the nearest unit. The PFS was calculated from the date of

diagnosis until the date of PD, or death from any cause.

The OS was calculated from the date of diagnosis until

death, or last date of follow-up. Patients who had not died

or progressed at the time of the final analysis were censored

at the date of last contact. The PFS and OS were estimated

using the Kaplan–Meier method [15]. The study was

designed as a phase II study. In order to reject an overall

response rate of disease B45 %, 31 eligible patients were

to be enrolled in the study [16]. After the demonstration of

an overall response rate of [45 % in the first cohort of

patients, a further unspecified additional number of patients

could be included in the study. All analyses were per-

formed according to the intention to treat (ITT). The con-

fidence limits (95 % CI) response rates were estimated

according to Simon [17].

In order to study the possible influence of the main

baseline characteristics (stage of disease, age, sex, histol-

ogy, and performance status) on the OS, uni- and multi-

variate logistic regression models of Cox were used [18].

Results

Characteristics of patients

From May 2006 to December 2011, 60 patients were

consecutively enrolled to the study, 49 males and 11

females, with a median age of 63 years (range 39–77) and

median ECOG performance status of 0. The characteristics

of patients are shown in Table 1. Thirty-one patients

(52 %) had clinical stage IIIA and 29 (48 %) clinical stage

IIIB disease. In three patients, the clinical stage IIIB was

Table 1 Patient characteristics

Characteristic No. %

Age

Median 63

Range (39–77)

Sex

Male 49 82

Female 11 18

Histology

Adenocarcinoma 31 52

Squamous cell 20 33

NSCLC-NOS 9 15

Stage

IIIA 31 52

IIIB 29 48

ECOG PS

0 48 80

1 12 20

NOS not otherwise specified

Med Oncol (2013) 30:533 of 7

123

defined by the presence of ipsilateral pulmonary nodules,

even in the presence of a N0 lymph node status.

Treatment and outcome

The data related to the treatment and disease outcome are

shown in Tables 2 and 3.

Six patients (10 %) did not complete chemotherapy: one

patient had an acute myocardial infarction after adminis-

tration of the first day of the third cycle of chemotherapy;

one patient discontinued treatment after the first cycle for

G4 hematologic toxicity; two patients have not received

the eighth day of gemcitabine and the third cycle, for

G3 hypertransaminasemia and G3 hematological toxicity,

respectively; one patient has not completed the eighth day

of gemcitabine of the first and second cycle for G2

hematological toxicity; one patient has not received the

eighth day of gemcitabine of the first, second, and third

cycle for G3 hematological toxicity at recycling.

Following chemotherapy, a disease partial response in

44 patients (73 %) and one pathologic complete response

(2 %) were observed among the 58 assessable patients, for

an overall response rate of 75 %; two patients (3 %) had a

PD.

Seventeen patients (28 %) were submitted to surgery

after chemotherapy: 10 of them (59 %) underwent lobec-

tomy/bilobectomy and 7 (41 %) pneumonectomy. Fourteen

patients (45 %) who underwent surgery had initial stage

IIIA disease; three patients had stage IIIB disease due to

ipsilateral pulmonary nodules (T4).

Thirty-six patients received radiotherapy after chemo-

therapy: 21 of them (72 %) had initial stage IIIB disease

and 15 (48 %) had stage IIIA disease. Radiotherapy was

not performed in 8 patients with stage IIIB due to: surgery

(in 3 patients), early disease progression (in 2 patients),

early death (in 3 patients).

Surgery or radiotherapy after chemotherapy was not

performed in 2 patients with stage IIIA due to: cardiac

toxicity (in one patient) and early disease progression (in

one patient). Therefore, radiotherapy or surgery following

chemotherapy was not feasible in 7 out of 60 patients

(12 %) due to disease progression and/or early death (6

patients) and cardiac toxicity (one patient).

Toxicity

The toxicity data are reported in Table 4. Twenty patients

(33 %) reported grade 3 or 4 toxicity. G3/G4 toxicities

occurring in C5 % of patients were neutropenia in 16/7 %

of cases, hypertransaminasemia in 10/2 % of cases, and G3

diarrhea in 5/0 % of cases. Although G3–G4 neutropenia

was reported in 23 % of cases, in none of them, it has been

complicated by fever. As previously described, one patient

had an acute myocardial infarction after administration of

the first day of the third cycle of chemotherapy.

Survival

With a median follow-up of 15 months (range 2–72), 30

patients were alive (50 %) and 25 (42 %) were alive and

Table 2 Treatment and disease response


No. of cycles of chemotherapy

Median 3

Range (1–4)

Dose reduction/withdrawal 6 10

Response

CRa 1 2

PR 44 73

SD 11 18

PD 2 3

NVb 2 3

Progression-free survival

Median, months 10.5

95 % CI 9.9–11.4

Overall survival

Median, months 21.1

95 % CI 19.7–22.8

CI confidence intervala Pathological complete remissionb Not evaluable because of early death

Table 3 Treatment and disease response according to clinical stage


Surgerya

Total 14 45

(Bi-)lobectomy 8 57

Pneumonectomy 6 43

Radiotherapy

Total 36 60

Stage IIIB 21b 81c

Stage IIIA 15d 48

a Only stage IIIA (n = 31); not included 3 pts with stage IIIB (T4 for

other ipsilateral lung nodules) treated with lobectomy (n = 2) or

pneumonectomy (n = 1)b Radiotherapy was not performed in 8 stage IIIB pts (n = 29) for:

surgery (3 pts), early PD (2 pts), and death (3 pts)c The proportion excluded 3 pts with stage IIIB who underwent

surgery (see above)d Radiotherapy or surgery was not performed in 2 stage IIIA pts for:

cardiac toxicity (1 pts) and early PD (1 pt)

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disease-free. The median PFS was 10.5 months (95 % CI

9.9–11.4). The median OS was 21.1 months (95 % CI

19.7–22.8) (Table 2; Fig. 1).

Prognostic factors

The clinical stage (IIIA versus IIIB) resulted the only

significant prognostic factor by multivariate analysis for

both PFS (P = 0.001) and OS (P = 0.010). The median

PFS was 17.8 months (95 % CI 16.2–19.7) in clinical stage

IIIA versus 9.4 months (95 % CI 8.6–10.6) in clinical stage

IIIB. The median OS was 25.5 months (95 % CI

23.0–28.4) in clinical stage IIIA versus 14.4 months (95 %

CI 7.9–23.1) in clinical stage IIIB (Fig. 2). None of the

other potential prognostic factors were significantly asso-

ciated with progression-free survival or overall survival by

multivariate analysis, such as sex (male versus female,

P = 0.317 for PFS and P = 0.650 for OS), histology

(adenocarcinoma versus squamous cell, P = 0.210 for PFS

and P = 0.775 for OS), performance status (0 versus 1,

P = 0.476 for PFS and P = 0.965 for OS), disease

response (complete or partial response versus stable dis-

ease, P = 0.077 for PFS and P = 0.921 for OS).

The prognostic role of surgery following chemotherapy

in clinical stage IIIA was also evaluated (Fig. 2). Although

a trend in PFS and OS has been observed in patients

operated compared to those non-operated, this did not

reach a statistical significance (P = 0.06 and P = 0.59,

respectively). The median PFS and OS have not yet been

reached in operated patients versus 14.9 months (95 % CI

13.2–17.1) and 16.6 months (95 % CI 14.7–19.0), respec-

tively, in non-operated patients.

Discussion

The present study shows a three-drug induction chemo-

therapy for three cycles including carboplatin, paclitaxel,

and gemcitabine, administered before a definitive locore-

gional treatment is effective and safe in clinical stage III

NSCLC. These results are consistent with data previously

reported with a similar therapeutic combination in different

NSCLC stages [9–11, 19].

An high ORR, of 75 %, was observed. In the studies of

Abratt et al. [10] and Schallier et al. [19], using a similar

three-drug induction chemotherapy in stage IB-II-III and

IIIA-IIIB NSCLC, the reported ORR was of 76 and

62.5 %, respectively [10, 11]. By the final results of the

study of Schallier et al. [19], on 64 patients with stage

IIIA–IIIB NSCLC, the reported ORR of 55 % was slightly

lower than previous data.

Similarly to the study of Schallier et al. [19], the ORR in

the present study was higher in stage IIIA (81 %) compared

Table 4 Treatment toxicity

Toxicity G1–G2

No.

G1–G2

%

G3–G4

No.

G3–G4

%

Neutropenia 3–18 5–30 10–4 16–7

Hypertransaminasemia 15–3 25–5 6–1 10–2

Diarrhea 16–8 26–13 3–0 5–0

Thrombocytopenia 2–2 3–3 1–1 2–2

Anemia 4–0 7–0 1–1 2–2

Stomatitis 1–2 2–3 1–0 2–0

Myalgias/Arthralgias 16–7 26–11 2–0 3–0

Peripheral neuropathy 21–8 34–13 2–0 3–0

Pulmonary hemorrhage 0–0 – 0–1 0–2

Acute pulmonary edema 0–0 – 0–1 0–2

Nausea/vomiting 21–5 34–8 – –

Asthenia 13–15 21–25 – –

Constipation 5–4 8–7 – –

Fever 4–0 7–0 – –

Headache 1–0 2–0 – –

Fig. 1 Progression-free and overall survival

Med Oncol (2013) 30:533 of 7

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to stage IIIB (74 %) disease, probably due to the increased

activity of chemotherapy in the presence of a lowest tumor

burden. However, the ORR was not significantly associated

with survival on multivariate analysis (P = 0.077 for PFS

and P = 0.921 for OS).

Only 6 patients (10 %) did not complete the planned

chemotherapy, mainly due to hematological (4 patients)

and non-hematological (2 patients) toxicity; one patient

died during treatment for an acute myocardial infarction.

This, together with the good toxicity profile observed,

confirms on a larger series the feasibility of the optimal

dose used for the three drugs that we have previously

identified in a dose-finding study [12]. This differed from

the study of Schallier et al. in the dose of gemcitabine, of

800 mg/m2 (on days 1, 8, every 21 days) versus 1,000 mg/

m2 (on days 1, 8, every 21 days).

A surgical resection rate of 45 % was observed in stage

IIIA disease following chemotherapy. As expected, these

data were lower than that reported in the study of Abratt

et al. [10] (of 81 %) that included the stages IB and II,

beyond the stage IIIA disease. Of note, in patients with

stage IIIA disease who underwent surgery, the median PFS

and OS were not yet reached, with a median follow-up of

15 months, and a nonsignificant trend in PFS and OS

comparing with non-operated stage IIIA disease patients

(Fig. 2); the nonsignificance of this trend could be related

to the small number of the subgroup and to the short

median of follow-up time.

In most cases (86 %), it was possible to administer a

definitive treatment, surgery, or radiotherapy, following

induction chemotherapy. In particular, radiotherapy in stage

IIIB was not performed in 5 patients (19 % of cases) for

death or early PD. But then, it should be taken into account

that patients in this study, while having a good performance

status (ECOG 0 or 1), had frequently cardiorespiratory

comorbidity that often would represent a contraindication to

concomitant chemoradiotherapy. In this regard, the toxicity

profile would seem to favor a sequential approach [7].

The median OS observed in this study was 21.1 months

that is higher than that reported in four randomized trials of

Fig. 2 Progression-free survival and overall survival according to clinical stage and to surgery in clinical stage IIIA patients

of 7 Med Oncol (2013) 30:533

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concurrent versus sequential chemoradiotherapy in stage

III NSCLC (16.5 months, range 16.3–17.0 months) [3–6]

and that of 17.2 months reported in the similar study of

Schallier et al. [19]. Instead, the median PFS of

10.5 months was similar to that reported of 10.9 months in

the study of Schallier et al. [19].

As reported in the study of Schallier et al. [19], we

observed a particularly high median OS in patients with

stage IIIA, of 25.5 months; this was higher than expected for

clinical and pathological stage IIIA (of 14 and 22 months,

respectively) based on the new version 7.0 of TNM classi-

fication [20]. However, it is not possible to exclude that these

particularly favorable results observed in stage IIIA NSCLC

patients were due to a selection bias of patients with low

tumor burden. An equivalent striking benefit from the three-

drug chemotherapy has not been observed in patients with

stage IIIB, for which the median OS was of 14.4 months,

though higher than that expected for clinical and patholog-

ical stage IIIB (of 10 and 13 months, respectively) [20], as

well as than that reported by Schallier et al. of 10.5 months

[19]. One possible explanation for these favorable results

may lie in a reduced toxicity and possible more efficacy of

radiotherapy on a reduced volume of disease.

Conclusion

The present study confirms the efficacy of a sequential

treatment with a three-drug induction chemotherapy

including carboplatin, paclitaxel, and gemcitabine given at

adequate safe doses in clinical stage IIIA NSCLC. In

clinical stage IIIB disease, this sequential approach may

not be lower in terms of efficacy than a concomitant che-

moradiotherapy. These observations should be confirmed

in a phase III trial. Moreover, implementation of such

treatment should include: a more accurate staging of dis-

ease (for example by 18FDG-PET and brain MRI brain), in

order to avoid overtreatment for patients with more

advanced stage at the disease onset; identification of indi-

cators and early predictive markers of tumor response, with

the aim of limiting the number of cycles of chemotherapy

and unnecessary drugs; the use of conformational radio-

therapy based on 18FDG-PET residual disease volume.

Conflict of interest All authors have no conflicts of interest.

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A three-drug induction chemotherapy with gemcitabine, carboplatin, and paclitaxel for stage III...

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