- © 2013 by American Society of Clinical Oncology
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⇑
- 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.
- 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: imyh00{at}skku.edu.
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Both Y.H.P. and K.H.J. contributed equally to this work.
Abstract
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 of MBC is 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 first-line chemotherapy in the treatment of MBC remains controversial. Several trials have reported that continuous chemotherapy prolongs the duration of remission, but its effect on survival and QoL are less consistent.3–11 A recent 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) 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 taxane-containing 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 with MBC with disease control after six cycles of PG chemotherapy.
PATIENTS AND METHODS
Eligibility Criteria
Women with histologically confirmed metastatic or recurrent breast cancer were eligible for the study. Both premenopausal and postmenopausal women with measurable and/or nonmeasurable lesion(s) who were 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 they had received an anthracycline- or 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 maintenance PG chemotherapy arm or the observation arm. Patients were accrued from 10 institutes in Korea. Registration and random assignment were coordinated centrally at the KCSG data 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, and HR status (positive v negative; Fig 1A). Chemotherapy was started within 14 days after random assignment. Treatment comprised paclitaxel 175 mg/m2 intravenous on day 1 and every 21 days thereafter and gemcitabine 1,250 mg/m2 administered as a 30-minute intravenous infusion on days 1 and 8 and every 21 days thereafter.
(A) Treatment scheme. (B) CONSORT flow diagram. (*) Patients included in the final analyses of survival and secondary efficacy variables with intent-to-treat 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.
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 1.5 × 109/L and/or the platelet count was less than 100 × 109/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
The primary end point was PFS after random assignment. Secondary end 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 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 patients were lost 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, number of 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 (n = 116) or observation (n = 115; 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.
Patient Characteristics in Maintenance Arm and Observation Arm
Dose Administration
A total of 768 cycles of PG chemotherapy (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 721.9 mg/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 dose-intensity of paclitaxel was 55.2 mg/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.
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).
(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.
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.
Reasons for Study Discontinuation
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, which means that there was no cross over. Hormonal therapy 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.
Systemic Treatment After Progression
Toxicity Analysis
Table 4 lists the drug-related toxicities (according to National Cancer Institute Common Terminology Criteria for Adverse Events) per patient observed. Hematologic toxicity of all grades was observed more frequently in the maintenance group than the observation group (neutropenia, 87.1% v 30.4%, respectively; P < .001; thrombocytopenia, 25.9% v 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.
Toxicities
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 MBC will 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, PG chemotherapy 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 those who might 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 patients who would have benefited from maintenance PG chemotherapy, 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 maintenance PG chemotherapy may be 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 with MBC with 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 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 meta-analysis 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
Support
Supported by Eli Lilly (Indianapolis, IN) for study drug (gemcitabine) and CJ Korea (Seoul, Korea) for research funding.
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.
Footnotes
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See accompanying editorial on page 1707
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Written on behalf of the Korean Cancer Study Group.
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Support information appears at the end of this article.
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Clinical trial information: NCT00561119.
