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Phase III, Multicenter, Randomized Trial of Maintenance

Chemotherapy Versus Observation in Patients With

Metastatic Breast Cancer After Achieving Disease Control

With Six Cycles of Gemcitabine Plus Paclitaxel

As First-Line Chemotherapy: KCSG-BR07-02

Yeon Hee Park, Kyung Hae Jung, Seock-Ah Im, Joo Hyuk Sohn, Jungsil Ro, Jin-Hee Ahn, Sung-Bae Kim,

Byung-Ho Nam, Do Youn Oh, Sae-Won Han, Soohyeon Lee, In Hae Park, Keun Seok Lee, Jee Hyun Kim,

Seok Yun Kang, Moon Hee Lee, Hee Sook Park, Jin Seok Ahn, and Young-Hyuck Im

See accompanying editorial doi: 10.1200/JCO.2013.48.6894 Yeon Hee Park, Jin Seok Ahn, and Young-

Hyuck Im, Samsung Medical Center, Sungkyunkwan

University School of Medicine;

Kyung Hae Jung, Jin-Hee Ahn, and Sung-

Bae Kim, Asan Medical Center, University

of Ulsan College of Medicine; Seock-Ah

Im, Do Youn Oh, and Sae-Won Han, Seoul

National University Hospital, Cancer

Research Institute, Seoul National University,

College of Medicine; Joo Hyuk Sohn

and Soohyeon Lee, Yonsei University

College of Medicine; Hee Sook Park, Soonchunhyang

University Hospital, Seoul;

Jungsil Ro, Byung-Ho Nam, In Hae Park,

and Keun Seok Lee, National Cancer

Center, Goyang; Jee Hyun Kim, Seoul

National University Bundang Hospital,

Cancer Research Institute, Seoul National

University College of Medicine, Seongnam;

Seok Yun Kang, Ajou University School of

Medicine, Suwon; Moon Hee Lee, Inha

University School of Medicine, Incheon,

Korea.

Published online ahead of print at

www.jco.org on April 8, 2013.

Written on behalf of the Korean Cancer

Study Group.

Support information appears at the end

of this article.

Both Y.H.P. and K.H.J. contributed equally

to this work.

Authors’ disclosures of potential conflicts

of interest and author contributions are

found at the end of this article.

Clinical trial information: NCT00561119.

Corresponding author: Young-Hyuck Im,

MD, PhD, Division of Hematology/Oncology,

Department of Medicine, Samsung

Medical Center, Sungkyunkwan University

School of Medicine, 50 Irwon-dong

Gangnam-gu, Seoul 135-710, Korea; e-mail:

[email protected].

Oncology

0732-183X/13/3199-1/$20.00

DOI: 10.1200/JCO.2012.45.2490

A B S T R A C T

Purpose

The primary purpose of our study was to evaluate whether maintenance chemotherapy with

paclitaxel/gemcitabine (PG) was superior to observation in improving progression-free survival

(PFS) in patients with metastatic breast cancer (MBC) who achieved disease control with an initial

six cycles of PG as their first-line treatment.

Patients and Methods

The study was a prospective, randomized, multicenter, phase III trial. Patients MBC with who

achieved disease control after six cycles of PG chemotherapy were randomly assigned to

maintenance chemotherapy or observation until progression.

Results

Of 324 patients from 10 centers enrolled, 231 patients with MBC exhibited disease control

(complete response partial response stable disease) with first-line PG and were randomly

assigned to maintenance chemotherapy (n 116) or observation (n 115). The median age

was 48 years (range, 28 to 76 years), median follow-up was 33 months, and median number

of chemotherapy cycles in the maintenance group after random assignment was six. The

median PFS time after random assignment was longer in the maintenance group than in the

observation group (7.5 v 3.8 months, respectively; P .026). The median overall survival (OS)

time was longer in the maintenance group than in the observation group (32.3 v 23.5 months,

respectively; P .047). The rate of grade 3 or higher neutropenia after random assignment

was higher in the maintenance group than in the observation group (61% v 0.9%, respectively;

P .001).

Conclusion

In patients with MBC who achieved disease control with an initial six cycles of PG chemotherapy,

maintenance PG chemotherapy resulted in better PFS and OS compared with observation.

INTRODUCTION

Metastatic breast cancer (MBC) is an incurable disease

with a 2- to 3-year median overall survival (OS)

time.1,2 The therapeutic goals are palliative and include

prolongation of survival with good quality of

life (QoL) and symptom control. Therefore, the

management ofMBCis a clinical challenge for medical

oncologists.

Chemotherapy is generally recommended in

patients with hormone receptor (HR) –negative tumors,

endocrine-resistant disease of the luminal

subtype, and rapidly proliferative and/or symptomatic

disease. However, the optimal duration of firstline

chemotherapy in the treatment ofMBCremains

controversial. Several trials have reported that continuous

chemotherapy prolongs the duration of remission,

but its effect on survival and QoL are less

consistent.3-11Arecent meta-analysis of 11 randomized

trials reported that a longer treatment duration

of first-line chemotherapy was associated with a

substantially longer progression-free survival (PFS)

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

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Published Ahead of Print on April 8, 2013 as 10.1200/JCO.2012.45.2490

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and marginally longer OS in patients with MBC.12 However, this

meta-analysis included only three recent studies incorporating

taxane-based chemotherapeutic regimens, which are the current standard

of care. In addition, most of the studies in the meta-analysis did

not address QoL issues. The relative benefits of tumor regression and

improvement in disease-related symptoms provided by chemotherapy

must be balanced with treatment-induced toxicity and its impact

on QoL, even if prolonged chemotherapy has a survival benefit.

Therefore, it is crucial to choose proper first-line chemotherapeutic

agents for maintenance treatment. Recently, two taxanecontaining

chemotherapy regimens have shown significantly

improved responses and PFS and modestly improved OS compared

with single-agent chemotherapy as the first-line treatment.

Capecitabine and docetaxel (CD) were shown to be superior to

docetaxel alone, and paclitaxel and gemcitabine (PG) were found

to have better efficacy than paclitaxel alone without a clinically

meaningful increase in toxicity.13,14

No differences in response rate, PFS, and OS were observed in a

comparison of gemcitabine and docetaxel with CD.15 However, the

nonhematologic toxicity profile favored gemcitabine and docetaxel

over CD, suggesting that gemcitabine may be a better therapeutic

option than capecitabine when combined with a taxane for the treatment

of MBC. This is notable because combination chemotherapy

with PG is the preferred first-line treatment in patients with MBC.

The question remains whether continuation with PG in the

maintenance period after achieving an initial response is feasible when

toxicity and QoL are taken into account. Although single-agent treatment

with gemcitabine or paclitaxel may be superior in terms of

toxicity, the efficacy of single-agent treatment in patients who responded

to initial PG chemotherapy remains unproven. Furthermore,

PG chemotherapy was well tolerated in a previous study and

showed survival benefits in the treatment of MBC.

On the basis of this rationale, we hypothesized that patients with

MBC who achieve disease control with an initial six cycles of PG

chemotherapy would have a longer PFS with maintenance PG chemotherapy

compared with observation. The primary purpose of the

study was to determine whether maintenance PG chemotherapy is

superior to observation in prolonging PFS in patients withMBCwith

disease control after six cycles of PG chemotherapy.

PATIENTS AND METHODS

Eligibility Criteria

Womenwith histologically confirmed metastatic or recurrent breast cancer

wereeligible for the study.Bothpremenopausalandpostmenopausalwomenwith

measurable and/or nonmeasurable lesion(s)whowere candidates for chemotherapy

and who had no prior history of chemotherapy in the metastatic setting were

eligible. Patients were eligible for the study if it had been at least 12 months since

completion of the prior chemotherapy, even if theyhadreceived an anthracyclineor

taxane-containing regimen as neoadjuvant or adjuvant therapy. Patients who

had received hormonal therapy in the adjuvant and/or metastatic setting were

eligible, but hormonal therapy was terminated before random assignment. Patients

who had received radiation to less than 25% of their bone marrow and had

recovered from the acute toxic effects of the treatment were eligible. Additional

requirements included age 18 years or older with an Eastern Cooperative Oncology

Group performance status of 0 to 2; adequate bone marrow, renal, and liver

function; and absence of other concurrent or previous malignant neoplasms, with

the exception of adequately controlled in situ uterine carcinoma and/or cutaneous

basal cell carcinoma.

The exclusion criteria were prior chemotherapy for MBC, clinically detectable

brain parenchymal and/or leptomeningeal metastases, prior treatment with

gemcitabine, other severe medical conditions, and human epidermal growth factor

receptor 2–positive breast cancer treated with trastuzumab.

Study Design

This study is a multicenter, phase III study of the Korean Cancer Study

Group (KCSG; KCSG-BR07-02) with a randomized discontinuation design. Patients

who achieved disease control (complete response [CR], partial response

[PR], or stable disease) after the initial six cycles of PG chemotherapy were randomly

assigned, in a 1:1 ratio, to either the maintenancePGchemotherapyarmor

the observation arm. Patients were accrued from 10 institutes in Korea. Registration

and random assignment were coordinated centrally at theKCSGdata center.

The random permutation method was used for random assignment. The stratification

factors for random assignment were the presence or absence of visceral

disease, prior adjuvant taxane therapy, response (CR/PR v stable disease) to the

initial six cycles of PG chemotherapy, andHRstatus (positive v negative; Fig 1A).

Chemotherapy was started within 14 days after random assignment. Treatment

comprised paclitaxel175mg/m2 intravenousonday1andevery21days thereafter

and gemcitabine 1,250 mg/m2 administered as a 30-minute intravenous infusion

on days 1 and 8 and every 21 days thereafter.

The patients randomly assigned to the maintenance arm continued with

PG chemotherapy until disease progression, development of unacceptable

toxicity, or withdrawal of consent. The patients randomly assigned to observation

were observed without any treatment until disease progression or

withdrawal of consent. Hormonal therapy was not allowed in either group of

patients after random assignment before disease progression.

The study was conducted in full accordance with the guidelines for Good

Clinical Practice and the Declaration of Helsinki and was approved by the

institutional ethics committees of each hospital and the KCSG Institutional

Review Board (ClinicalTrials.gov identifier: NCT00532857). Written informed

consent was obtained from each participant.

Study Evaluation

The prestudy clinical evaluation included a physical examination; vital

signs with performance status; chest x-ray; computed tomography scans of the

chest, abdomen, and pelvis; and a bone scan. Blood chemistry results and

CBCs were obtained for every treatment cycle. Radiographic studies were

performed every 6 weeks. Toxicity was assessed on the first day of each cycle.

OS was measured from the date of random assignment to the date of

death from any cause, with censoring of the last visit date. PFS was calculated

from the date of random assignment to the documented date of disease

progression or the last visit date. Disease response was assessed according to

RECIST (version 1.0).16,17 The duration of the response was measured from

the time of chemotherapy to the date of disease progression. PFS and the

duration of response were assessed by investigators. Toxicity was assessed at

the end of each cycle using National Cancer Institute Common Terminology

Criteria for Adverse Events (version 3.0).

Dose Modifications

On the planned day of therapy, if the absolute neutrophil count (ANC)

was less than 1.5109/L and/or the platelet count was less than 100109/L,

chemotherapy was delayed 1 week. If the ANC and platelet counts were

satisfactory after 1 week, the full intended dose of chemotherapy was given.

However, if after 1 week, the ANC was still less than 1.5 109/L and/or the

platelet count was less than 100 109/L, chemotherapy was given at 75% of

the original intended dose. Treatment was delayed and the dose was reduced in

patients who experienced a second occurrence of a grade 2 nonhematologic

toxicity (except alopecia or nausea/vomiting) or any grade 3 toxicity. In patients

with grade 2 peripheral neuropathy, the dose of paclitaxel was reduced.

In patients with grade 3 neuropathy, paclitaxel was discontinued. Both drugs

were discontinued if one of the drugs was discontinued.

Statistical Methods

Theprimaryendpoint wasPFSafterrandomassignment. Secondaryend

points included OS, QoL, toxicity, and response duration. We hypothesized

that PFS would be longer in the maintenance chemotherapy group compared

with the observation group. A 20% longer 6-month PFS rate was expected in

Park et al

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the maintenance group compared with the observation group. With 90%

power and 5% one-sided type I error, and considering a 10% follow-up loss,

we calculated that 244 patients were needed at the time of random assignment

and a total of 326 patients were needed at the time of enrollment.

All randomly assigned patients were included in the efficacy analysis according

to the intent-to-treat principle, and patients who received at least one dose of

study medication were evaluated for safety. Observations were censored at the last

clinical contact if patientswerelost to follow-up or at the cutoff date for the analysis

(October 31, 2011). PFS and OS were estimated using the Kaplan-Meier method

and were compared using the log-rank test. Analyses of treatment effects were

adjusted for covariates selected before the analysis using a multivariate Cox proportional

hazards model with stratification according to the visceral disease, age,

menopausal status, performance status,numberof metastatic sites, prior adjuvant

taxane therapy, disease response, and HR status. Differences were considered

statistically significant at P.05 with a two-tailed test.

RESULTS

Patient Characteristics

A total of 324 patients were enrolled from 10 centers in Korea

from August 2007 to September 2010. Of these, 231 patients who

achieved disease control with an initial six cycles of PG chemotherapy

were randomly assigned to either maintenance PG chemotherapy

(n116) or observation (n115; Fig 1B). The baseline characteristics

of the patients were similar between the two groups (Table 1). The

median ages of patients were 48 and 47 years in the maintenance and

observation groups, respectively, and about half of the patients were

premenopausal women. The number of HR-positive patients was 85

(73.3%) in the maintenance group and 87 (75.7%) in the observation

group. Forty-two patients (36.2%) in the maintenance group and 38

patients (33.0%) in the observation group had received adjuvant taxane

(P.613). Palliative hormonal therapy because of metastasis had

been administered before enrollment in 20 patients (17.2%) in the

maintenance group and 26 patients (22.4%) in the observation group.

Dose Administration

Atotal of 768 cycles ofPGchemotherapy (median, six additional

cycles) were received in the maintenance group after randomization.

Including the six cycles of chemotherapy administered before random

assignment, the median dose-intensity of gemcitabine was 721.9

mg/m2 per week (86.6% of the expected dose; interquartile range

[IQR], 645.3 to 721.9mg/m2 per week) in the maintenance group and

763.9 mg/m2 per week (91.7% of the expected dose; IQR, 694.5 to

763.9 mg/m2 per week) in the observation group. The median doseintensity

of paclitaxel was 55.2mg/m2 per week (94.7% of the expected

dose; IQR, 49.7 to 55.2 mg/m2 per week) in the maintenance group

and 55.9 mg/m2 per week (95.9% of the expected dose; IQR, 53.5 to

55.9 mg/m2 per week) in the observation group.

Patients with MBC

and no previous

chemotherapy

(N = 324)

PD Withdrawn from study

Observation until PD

••••••• Until PD

6 cycles of PG

Stratification

1. Visceral v nonvisceral

2. Previous adjuvant taxane

3. Response (CR/PR v SD)

4. HR positive v HR negative

CR/PR/SD R

Enrollment

(n = 324)

Randomly assigned

(n = 231)

Reason for discontinuation

Progression (n = 50)

Adverse event (n = 12)

Withdrawal (n = 17)

Death as result of disease (n = 2)

Physician/patient discretion (n = 12)

Reasons for stopping the study drugs

Progression (n = 40)

Adverse event (n = 13)

Withdrawal (n = 14)

Death as result of disease (n = 0)

Physician/patient discretion (n = 33)

Other (n = 9)

Reasons for stopping the study drugs

Progression (n = 80)

Adverse event (n = 0)

Withdrawal (n = 13)

Death as result of disease (n = 0)

Physician/patient discretion (n = 6)

Other (n = 6)

Maintenance*

(n = 116)

Observation*

(n = 115)

Fig 1. (A) Treatment scheme. (B) CONSORT

flow diagram. (*) Patients included

in the final analyses of survival and secondary

efficacy variables with intent-totreat

principle. CR, complete response;

HR, hormone receptor; MBC, metastatic

breast cancer; PD, progressive disease;

PG, paclitaxel and gemcitabine; PR, partial

response; R, random assignment; SD, stable

disease.

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Efficacy Analysis

The overall response rate and disease control rate of the initial six

cycles of PG chemotherapy in 324 patients were 50.0% and 78.6%,

respectively. The median PFS time from random assignment was

prolonged by 3.7 months in the maintenance group, from 3.8 months

in the observation group to 7.5 months in the maintenance group

(hazard ratio, 0.73; 95% CI, 0.55 to 0.97; P .026; Fig 2A). The

6-month PFS rate after random assignment, which was the primary

end point of this study, was 59.7% in the maintenance arm and 36.0%

in the observation arm—a 66% difference (P .001; Fig 2A). In all

patients, the median OS time from random assignment was 26.3

months (95% CI, 19.6 to 32.9 months). The median OS time from

random assignment was longer in the maintenance group than in the

observation group (32.3 v 23.5 months, respectively; hazard ratio,

0.65; 95% CI, 0.42 to 0.99; P.047; Fig 2B).

The PFS benefits of maintenance chemotherapy were observed

in patients younger than 50 years of age (95% CI, 0.33 to 0.74;

P .001), premenopausal women (95% CI, 0.34 to 0.79; P .002),

patients with a response (CR or PR; 95% CI, 0.46 to 0.95; P .024),

patients with visceral disease (95% CI, 0.49 to 0.98; P.041), patients

with HR-negative disease (95% CI, 0.30 to 0.90; P .019), and

patients with two or more metastases (95% CI, 0.47 to 0.93; P.029;

Fig 2C). The response durations were 9.6 and 7.8 months in the

maintenance and observation groups, respectively.

The reasons for nonadherence to randomly assigned treatment

in the absence of progression differed between the two

groups (Table 2). Eighty (69.6%) of 115 patients in the observation

arm and 40 (34.5%) of 116 patients in the maintenance arm

experienced disease progression. In the maintenance group, 33

patients whose disease had not progressed stopped further chemotherapy

at the physician’s discretion. The median number of

chemotherapy cycles for these patients after random assignment

was 12 (range, nine to 26 cycles). Patients who stopped the study

drugs at the physician’s discretion did not receive further anticancer

treatment, including endocrine therapy, until disease progression

was documented.

Table 1. Patient Characteristics in Maintenance Arm and Observation Arm

Characteristic

Maintenance (n 116) Observation (n 115)

No. of Patients % No. of Patients % P

Age, years .768 (t test)

Median 48 47

Range 30-70 29-76

ECOG PS .980

0 58 50.4 57 49.1

1 55 47.8 57 49.1

2 2 1.7 2 1.7

Menopausal status .643

Premenopausal 56 48.3 53 46.1

Postmenopausal 56 48.3 60 52.2

Unknown 4 3.4 2 1.7

IDC v others 107 92.2 112 97.4 .135

HR status

Positive 85 73.3 87 75.7 .679

Negative 31 26.7 28 24.3

HER2 positive 2 1.7 2 1.7 .950

No. of metastatic sites .342

1 32 27.6 38 33.0

2 37 31.9 44 38.3

3 47 40.5 33 28.7

Metastatic sites

Distant lymph nodes 78 67.2 62 53.9 .320

Lung, hematogenous 37 31.9 19 16.5 .029

Lung, lymphangitic 26 22.4 31 27.0 .218

Liver 41 35.3 34 29.6 .776

Bone 53 45.7 50 43.5 .685

Pleura 21 18.1 12 10.4 .192

Others 2 1.7 1 0.9 .503

Visceral metastases 81 69.8 74 64.3 .375

Prior adjuvant chemotherapy

Anthracycline 67 57.8 57 49.6 .212

Taxane 42 36.2 38 33.0 .613

Prior adjuvant endocrine therapy 53 45.7 42 36.5 .182

Palliative endocrine therapy before PG chemotherapy 26 22.4 20 17.4 .339

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IDC,

invasive ductal carcinoma; PG, paclitaxel and gemcitabine.

HR positive status indicates estrogen receptor positive and/or progesterone receptor positive; HR negative status indicates estrogen receptor negative and

progesterone receptor negative.

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Systemic Treatments After Progression

The details of the systemic treatment after progression are listed

in Table 3. A total of 165 patients (71.4%) received additional chemotherapy.

Seven hundred seventy-nine cycles of chemotherapy were

given in the maintenance group, and 708 cycles of chemotherapy were

given in the observation group. PG combination chemotherapy was

not given to any patient in the observation group after progression,

whichmeansthat there wasnocross over.Hormonaltherapy was used

in patients with HR-positive disease. A total of 41% of patients received

hormonal therapy. The types of additional hormonal therapy

were similar in the two groups.

Toxicity Analysis

Table4liststhedrug-relatedtoxicities(accordingtoNationalCancer

InstituteCommonTerminology Criteria for Adverse Events) per patient

observed. Hematologic toxicity of all grades was observed more frequently

in the maintenancegroupthan the observationgroup(neutropenia,

87.1% v 30.4%, respectively; P.001; thrombocytopenia, 25.9% v

Hazard ratio, 0.73 (95% CI, 0.55 to 0.97)

P = .026

6-month PFS rate after random assignment

59.7% v 36.0% (P < .001)

PFS

(probability)

Time (months)

1.0

0.8

0.6

0.4

0.2

No. at risk

Maintenance 116 68 25 11 5 2 0 0 0

Observation 115 41 19 11 6 4 1 0 0

Trial Arm Events Median 95% CI

Maintenance 97 7.5 6.2 to 8.9

Observation 96 3.8 2.4 to 5.3

0 6 12 18 24 30 36 42 48

Hazard ratio, 0.65 (95% CI, 0.42 to 0.99)

P = .047

Overall Survival

(probability)

Time (months)

1.0

0.8

0.6

0.4

0.2

No. at risk

Maintenance 116 112 88 57 26 17 5 0 0

Observation 115 110 71 50 26 13 7 1 0

Trial Arm Events Median 95% CI

Maintenance 37 32.3

Observation 49 23.5 18.9 to 28.1

0 24 30 36 42 48

Favors maintenance Favors observation

6 12 18

n Hazard Ratio 95% Cl

Menopausal status

Premenopausal 109 0.52 0.34 to 0.79

Postmenopausal 116 0.98 0.68 to 1.49

Performance status

0 115 0.69 0.46 to 1.03

1-2 116 0.77 0.52 to 1.15

Age group, years

≤ 50 139 0.50 0.33 to 0.74

> 50 92 1.03 0.69 to 1.56

Response to PG #6

CR+ PR 143 0.66 0.46 to 0.95

SD 88 0.82 0.50 to 1.35

Disease type

Visceral 155 0.70 0.49 to 0.98

Nonvisceral 76 0.82 0.50 to 1.35

Tumor subtype

HR positive 172 0.79 0.56 to 1.10

HR negative 59 0.52 0.30 to 0.90

No. of metastases

1 70 0.86 0.50 to 1.47

≥ 2 161 0.66 0.47 to 0.93

Overall 231 0.73 0.55 to 0.97

0.0 0.5 1.0 1.5 2.0

Fig 2. (A) Progression-free survival (PFS) after random assignment in the maintenance and observation groups. (B) Overall survival after random assignment in the maintenance and

observation groups. (C) Forest plots (PFS analysis). CR, complete response; HR, hormone receptor; PG, paclitaxel and gemcitabine; PR, partial response; SD, stable disease.

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12.2%, respectively; P.008; and anemia, 87.9% v 64.3%, respectively;

P.001). The rate of grade 3 or higher neutropenia was much higher in

the maintenance group than in the observation group (61% v 0.9%,

respectively; P.001). QoL did not differ between the two groups (data

not shown). Additional data will be reported in a separate article.

DISCUSSION

It is important to realize that patients with MBC are a heterogeneous

group, and thus the strategies for treatment differ depending on the

circumstances of the individual patient.18 For patients with human

epidermal growth factor receptor 2–positive MBC, trastuzumab in

combination with cytotoxic chemotherapy has transformed the prognosis,

and this combination therapy is recommended as the first-line

treatment.19 For patients with HR-positive disease, hormonal therapy

is considered initially. It can be assumed that nearly all patients with

MBCwill eventually require chemotherapy, particularly patients with

HR-negative or hormone-resistant disease.

Several clinical trials have attempted to identify the optimal duration

of first-line chemotherapy in the treatment of MBC.3-7,10-12,20

However, one limitation of these results is that in some of the early

studies, the chemotherapeutic regimens were suboptimal compared

with most recent regimens involving modern drugs. In addition, the

extension of full-dose chemotherapy after disease control may be

considered an outdated concept and may not be feasible because of

excessive toxicity and a negative impact on QoL.

Our study has several major strengths. First,PGchemotherapy is

one of two chemotherapeutic regimens that have shown a definite

survival advantage as a first-line treatment of MBC without clinically

relevant toxicity in randomized trials.14 We selected patients who had

already demonstrated at least disease stabilization to this regimen,

thereby enriching for thosewhomight benefit from maintenance. The

improved PFS in the maintenance group translated to a prolongation

of OS irrespective of HR status.

Second, in the Maintenance Paclitaxel 1 (MANTA1) trial, in

which the concurrent use of endocrine therapy with chemotherapy

was allowed, the concurrent use of antiestrogen with chemotherapy

might be regarded as a confounding factor in the interpretation of the

results. Because hormonal therapy would affect PFS, in our study,

patients with HR-positive disease were not allowed to receive hormonal

therapy until disease progression, which is unique compared

with previous studies.11 Third, our trial highlighted subgroups of

patientswhowould have benefited from maintenancePGchemotherapy,

although this was the result of the subset analyses. These subgroups

are patients with MBC who are younger and premenopausal,

who have HR-negative tumors, who demonstrated a response to PG

chemotherapy, and who had rapidly progressive visceral disease and a

high tumor burden. Although a survival benefit was shown in all

patients, including HR-positive patients, the main role of maintenancePGchemotherapymaybe

in patients with HR-negative tumors.

Interestingly, approximately half of the patients were premenopausal

and young. These findings imply an aggressive tumor behavior,

which necessitates cytotoxic chemotherapy. The treatment regimen,

duration, sequence, and order of palliative chemotherapy are major

challenges yet to be defined for patients withMBCwith triple-negative

disease and HR-positive tumors with visceral metastases after failure

of hormonal treatment. In this regard, our study showed promising

results that can be adapted to current practice. Given the observed OS

Table 2. Reasons for Study Discontinuation

Reason

No. of Patients

Maintenance Arm

(n 116)

Observation Arm

(n 115)

Disease progression 40 80

Patient withdrawal 14 13

Adverse events 13 0

Grade 4 neutropenia 2

Grade 2-3 neuropathy 10

Grade 3 hepatotoxicity 1

Physician’s discretion 33 6

Physician/patient’s shared decision 33

Palliative local treatment 4

Switch to other chemotherapy 2

Other 9 6

Endocrine therapy 2 4

Comorbidity 5 2

Second primary malignancy 2

Median, 12 cycles; range, nine to 26 cycles.

Table 3. Systemic Treatment After Progression

Variable

Maintenance

Arm

(n 116)

Observation

Arm

(n 115)

No. % No. % P

No. of subsequent

chemotherapy regimens .933

Total 82 70.6 83 72.1

1 33 28.4 28 24.3

2 23 19.9 27 23.5

3 26 22.6 28 24.3

Median 2.7 2.6 .588 (t test)

No. of total cycles 779 708

Type of chemotherapy

Fluorouracil 16 13.8 18 15.7

Capecitabine 52 44.8 65 56.5

Cisplatin 14 12.1 18 15.7

Cyclophosphamide 40 34.5 32 27.8

Anthracycline 37 31.9 30 26.1

Docetaxel 19 16.4 22 19.1

Vinorelbine 29 25 29 25.2

Methotrexate 5 4.3 11 9.6

Gemcitabine 11 9.5 16 13.9

Trastuzumab 1 0.8 2 1.7

Other 29 25 20 17.4

No. of subsequent endocrine

therapies .268

Total 49 42.2 45 39.1

1 43 37.0 35 30.4

2 6 5.2 8 7.0

3 0 0 2 1.7

Type of endocrine therapy

Tamoxifen 13 11.2 16 13.9

Letrozole 18 15.5 16 13.9

Anastrozole 8 6.9 8 7.0

Exemestane 6 5.2 5 4.3

Fulvestrant 0 0 1 0.9

Goserelin 6 5.2 12 10.4

Park et al

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Table 4. Toxicities

Adverse Event

All Grades Grade 3-4

Before Random Assignment After Random Assignment Before Random Assignment After Random Assignment

Maintenance

(n 116)

Observation

(n 115)

Maintenance

(n 116)

Observation

(n 115)

Maintenance

(n 116)

Observation

(n 115)

Maintenance

(n 116)

Observation

(n 115)

No. % No. % No. % No. % No. % No. % No. % No. % P

Neutropenia 102 87.9 99 86.1 .82 101 87.1 35 30.4 .001 80 69.0 78 67.8 .57 71 61.2 1 0.9 .001

Thrombocytopenia 55 47.4 58 50.4 .55 30 25.9 14 12.2 .008 0 0 1 0.9 .50 1 0.9 0 0 .50

Anemia 106 91.4 109 94.8 .29 102 87.9 74 64.3 .001 3 2.6 6 5.2 .33 1 0.9 0 0 .50

Neuropathy 105 90.5 99 86.1 .31 104 89.7 87 75.7 .005 4 3.4 2 1.7 .68 4 3.4 2 1.7 .68

Azotemia 2 1.7 1 0.9 .62 5 4.3 0 0 .06 0 0 0 0 NA 5 4.3 0 0 .06

AST 69 69.5 68 59.1 .96 45 38.8 36 31.3 .23 0 0 0 0 NA 1 0.9 1 0.9 .10

ALT 72 62.1 71 61.7 .96 50 43.1 28 24.3 .003 4 3.4 2 1.7 .68 0 0 0 0 NA

Nausea 71 61.2 69 60.0 .89 51 44.0 22 19.1 .001 0 0 0 0 NA 0 0 0 0 NA

Vomiting 41 35.3 42 36.5 .89 27 23.3 5 4.3 .001 0 0 0 0 NA 0 0 0 0 NA

Constipation 26 22.4 32 27.8 .34 24 20.7 7 6.1 .001 0 0 0 0 NA 0 0 0 0 NA

Diarrhea 19 16.4 24 20.9 .38 19 16.4 1 0.9 .001 0 0 2 1.7 .25 1 0.9 1 0.9 .10

Abbreviation: NA, not assessable.

Before random assignment, all patients received six cycles of paclitaxel and gemcitabine chemotherapy.

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benefit and improved PFS, the role of first-line chemotherapy and its

total duration may be critical determinants of OS, particularly in

patients with triple-negative tumors, for whom targeted therapeutic

strategies are urgently needed. Maintenance PG chemotherapy may

be a good therapeutic option in this setting.

In the maintenance group, 33 patients stopped the study drugs

without disease progression, and in this group, the median number of

chemotherapy cycles was 12 (range, nine to 26 cycles) in addition to

the initial six cycles of PG chemotherapy. The optimal number of

maintenance chemotherapy cycles should be individualized according

to each patient’s circumstance, although the median number of PG

chemotherapy cycles was six after random assignment in this study. It

seems unrealistic to subject all patients to 18 or more cycles of chemotherapy

in daily practice, although there was no documentation of

serious toxicity or definitive impairment of QoL. Obviously, the QoL

results should be reported in relation to the results from the primary

end point so that a full view of the risks and benefits of the maintenance

chemotherapy can be presented.

In conclusion, our results strengthen the data from a prior metaanalysis

showing the benefits of maintenance chemotherapy.12 This

study showed a clinically meaningful improvement in PFS and OS in

patients receiving maintenance PG chemotherapy for MBC.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS

OF INTEREST

Although all authors completed the disclosure declaration, the following

author(s) and/or an author’s immediate family member(s) indicated a

financial or other interest that is relevant to the subject matter under

consideration in this article. Certain relationships marked with a “U” are

those for which no compensation was received; those relationships marked

with a “C” were compensated. For a detailed description of the disclosure

categories, or for more information about ASCO’s conflict of interest policy,

please refer to the Author Disclosure Declaration and the Disclosures of

Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory

Role: None Stock Ownership: None Honoraria: Seock-Ah Im, Samyang

Corporation Research Funding: None Expert Testimony: None Other

Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Young-Hyuck Im

Administrative support: Young-Hyuck Im

Provision of study materials or patients: Yeon Hee Park, Joo Hyuk

Sohn, Young-Hyuck Im

Collection and assembly of data: Yeon Hee Park, Joo Hyuk Sohn,

Jungsil Ro, Jin-Hee Ahn, Sung-Bae Kim, Do Youn Oh, Sae-Won Han,

Soohyeon Lee, In Hae Park, Keun Seok Lee, Jee Hyun Kim, Seok Yun

Kang, Moon Hee Lee, Hee Sook Park

Data analysis and interpretation: Yeon Hee Park, Kyung Hae Jung,

Seock-Ah Im, Byung-Ho Nam, Jin Seok Ahn, Young-Hyuck Im

Manuscript writing: All authors

Final approval of manuscript: All authors

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Support

Supported by Eli Lilly (Indianapolis, IN) for study drug (gemcitabine) and CJ Korea (Seoul, Korea) for research funding.

■ ■ ■

Park et al

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Acknowledgment

Presented in part at the 48th Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL.

We thank Min Young Son of the Korean Cancer Study Group for data management support and the study coordinators from each institute.

Maintenance Paclitaxel/Gemcitabine for Metastatic Breast Cancer

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